Pharm Assessment 2 (add’l/background info on slides: 82-86, 88-89, 100-102, 106, 119-123, 130-131, 165)

DRUGS ACTING ON AMINE SYNTHESIS, UPTAKE, OR METABOLISM

• Metyrosine (Demser) – blocks tyrosine hydroxylase • Carbidopa (Lodosyn) – blocks DOPA decarboxylase in periphery; used w/ L-DOPA to treat Parkinson’s

o DOPA decarboxylase is also in the periphery (does NOT cross BBB), so this decreases metab of L-DOPA in peripheral tissues (and GI tract), so more can get to the brain.

o Allows decreased dosage of L-DOPA – good b/c high dose can cause nausea & vomiting o Does not block completely; still making sufficient amount of NE * You canNOT just give pt DA b/c it does not cross the BBB; so give L-DOPA, which enters brain, in to

dopaminergic neurons, and then DA.

• Disulfiram (Antabuse) – blocks DA hydroxylase and acetaldehyde dehydrogenase (in the metabolism of alcohol) – because it chelates the Cu that these enzymes need! Used to treat alcoholism.

o so this drug decreases NE, but… o the MAIN POINT: causes a buildup of acetaldehyde (intermed in metab of alcohol) vasodilation

hypotension feel very sick. • Entacapone (COMTan) – blocks COMT (liver & kidney); used w/ L-DOPA to treat Parkinson’s

o Similarly to Carbidopa, this decreases metab of L-DOPA in the periphery and allows decreased dosage of L-DOPA, avoiding nausea and vomiting.

• Reserpine (Serpasil) – inhibits DA & NE into synaptic vesicles; Tx hyperT and psychosis.

o After ~12 hrs, damages vesicles and they cannot be released, so get “depletion” of NE from noradrenergic n terminals – fx like a sympathectomy (like cutting the nn). block symp fx (and therefore increase parasymp fx).

o Takes ~48 hrs to reform vesicles. o BUT… w/ exogenous NE administration, Reserpine will potentiate fx. o CONTRAINDICATIONS: depression and peptic ulcers

In brain, blocks DA, NE, and Serotonin uptake, which can lead to depression. • Cocaine – inhibits amine pump in nerve endings; uses: Tx depression, local anesthetic

o inhibits reuptake by the amine pump of NE, DA, GABA, Serotonin, and Epi!! o Tx of depression and as a local anesthetic o DA buildup increased libido, NE buildup increased symp fx, Serotonin buildup euphoria. o recall that 70% or more of NE is usually taken back up, so this increases NE in cleft a LOT; can MI.

Tyrosine (tyr hydroxylase) DOPA (DOPA decarboxylase) DA (DA hydroxylase) NE

in periphery: L-DOPA (DOPA decarboxylase) DA liver/kidney: L-DOPA (COMT) 3-0-MD

• TCA’s (e.g. Desipramine or Amitriptyline) – also block the amine pump; Tx depression o Mech not fully understood, but increases NE in brain. Takes a few weeks. o Also increase NE overall and increased basal BP. If give NE w/ TCA, will see potentiated response.

• α-Methyldopa (Aldomet) – false nt w/ NE; Tx hypertension

o

o α-Methyl-NE is the active agent here, on α2 receptors in RVLM. It is a false neurotransmitter, i.e. it is taken up in nn, then stored w/, released w/, and acts like NE

* acts like NE, but treats hypertension?? An injection in the periphery would increase BP by acting on vessel α2 receptors, but… It is given so that it acts centrally, on the RVLM (rostral ventrolateral medulla), reducing

impulses from the brain that signal NE release, to decrease BP. o [compare to Clonidine and Guanabenz below, w/ direct axn on α2 in RVLM]

Enzymatic Degradation of Catecholamines:

− Enzymes: o MAO-A (GI tract and liver) – metabolizes Epi, NE, serotonin, and Tyramine (see below) o MAO-B (esp. brain, and platelets) – metabolizes DA o COMT (liver and kidney) – metabolizes L-DOPA, Epi, and NE

blocked by Entacapone (see above) − Urinary metabolites:

o Epi and NE VMA, MHPG, MOPEG o NE normetanephrine; Epi metanephrine (Dx pheochromocytoma) o DA HVA and DOPAC (homovanillic acid and dihydroxyphenylacetic acid)

• Tranylcypromine (Parnate) and Phenelzine (Nardil) – inhibit MAO-A & MAO-B

o Tx: depression and panic disorders • Selegiline (Eldepryl) – inhibits MAO-B

o Tx Parkinson’s, +/- L-DOPA _______________________________________________________________________

Pre-Junctional Adrenergic Receptor Actions (*slide 102 pic)

α2 Β2 On adrenergic n: inhibits release of NE On adrenergic n: increases release of NE

On parasymp n: inhibits Ach release On serotoninergic n: inhibits serotonin

α-Methyldopa (Dopa decarboxylase) α-Methyldopamine(DA β-hydroxylase) α-Methyl-NE

Post-Junctional Adrenergic Receptor Actions, Agonists, & Antagonists α1 α2 β1 Β2

(NE does not bind!!) Vessels: constrict Vessels: constrict

* Hypotension in RVLM Heart: Increase HR

(also contractility and conduction velocity)

Vessels: dilate

Decrease GI motility & tone;

* cntrxn of sphincter mm in GI and bladder

Decrease GI motility & tone

Decrease GI motility & tone Decrease GI motility & tone; * relax bladder detrussor‡

Pancreas: inhibit Insulin secretion

Pancreas: increase Insulin secretion

Also: increase Glucagon secretion

Liver: increase glycogenolysis

Liver & Muscle: increase glycogenolysis

and gluconeogenesis Fat cell:

decrease lipolysis Adipose tissue: FA mobilization

Bronchial smooth m: relax

Contract Radial m in eye (dilation, “mydriasis”)

Platelets: aggregation Kidney: increase renin release†

Pregnant uterus: relax (prevent premies)

(Ritodrine) Specific: Phenylephrine, Methoxamine Metaraminol (mixed action,

so also get fx of NE!)

Specific: Clonidine (Catapress)

Specific: Dobutamine (Dobutrex)

Short-acting: (all Tx asthma) Metaproterenol (Alupent) Terbutaline (Brethin) Albuterol (Proventil) Bitolterol (Tornalate) Pirbuterol (Maxidair) Long-acting: Salmeterol (Serevent) Formoterol (Foradil)

Epi (α1 α2 β1 β 2) NE (α1 α2 β1) Ephedrine (α1 β2) –(mixed action!)

Epi (α1 α2 β1 β2) NE (α1 α2 β1)

Epi (α1 α2 β1 β2) NE (α1 α2 β1) Isoproterenol (β1 β2) Ephedrine (mixed action!)

Short-acting: Epi (α1 α2 β1 β2) Isoproterenol (β1 β2)

Prazosin (Minipress) Terazosin Doxazosin

Rauwolscine (not on list; not used clinic.)

Acebutolol, Atenolol (low¥) Metoprolol (Lopressor)

(moderate)

Butoxamine (not approved, not on list)

Phenoxybenzamine (α1 α2) Phentolamine (α1 α2) Carvediolol (α1 α2 β1 β2) Labetalol (α1 α2 β1 β2)

Phenoxybenzamine (α1 α2) Phentolamine (α1 α2) Carvediolol (α1α2β1β2) Labetalol (α1 α2 β1 β2)

Pindolol£€ , Nadolol (low) Timolol (low-moderate) Propranolol€ (High) Penbutolol (High) (all β1 β2)

Pindolol, Nadolol (low) Timolol (low-moderate) Propranolol, Penbutolol (High)

(all β1 β2)

† β-blockers used to treat hypertension b/c they decrease renin release decrease Angio II decrease BP. ‡ Detrussor m does not have adrenergic innerv, but does have β2 receptors. ¥ Low/moderate/high indicates lipid solubility. Low - slow into CNS and slow out; High – fast into CNS and fast out. £ Pindolol also a partial agonist – good for very senstive pt’s that may get bradycardia w/ B1 blocked. € Pindolol and Propranolol stabilize membranes w/ direct effect on membrane Na conductors – prevent arrhythmias. Note: also have β3 receptors, which are involved in lipolysis in brown adipose tissue.

DIRECT SYMPATHOMIMETICS

Note: There are α receptor subtypes (slide 113), but we don’t have drugs (yet) that are subtype-specific. • Epinephrine (Propine) – acts on α1 α2 β1 β2

[Note: Propine is a prodrug and is converted to Epi in the body.] o Relative effect on α receptors: Epi > NE o Small dose Epi vasodilation via β2 (decreased peripheral resistance) o Normal doses vasoconstriction via α1 α2 o Fx on HR unpredictable – may see increase, decrease, or no change – depending on whether the Epi or

reflex predominates. o Increase systolic, decrease diastolic BP no change in MAP. o Used in dentistry w/ local anesthetic – given locally in high dose to vasocnstrxn (α effects

predominate) reduce systemic absorption of anesthetic and reduce bleeding. o Tx A-V heart block. o Tx open-angle Glaucoma, along w/ β-blocker Timolol (see Timolol below) – Epi reduces prdxn of aq humor

by ciliary processes and increases outflow. • Norepinephrine (Levarterenol) – acts on α1 α2 β1 (NOT β2)

o REFLEX decrease in HR due to marked increase in BP; most prominent w/ α1 agonists i.e. symp outflow is decreased; parasymp is increased, and Ach overpowers NE fx on heart

− if give Atropine, fx of Ach blocked, so NE increases BP and HR also have vasodilation of coronary vessels due to local mediators (lactic acid, PGI2, NO, etc.)

o Increase systolic and diastolic BP. β-blocker does not change its BP fx b/c does not act on β2 and no β1 in vessels.

o Increase peripheral resistance. o Would NOT give to decrease HR in tachycardia b/c combo of no cholinergic innerv to ventricles (no

parasymp), plus NE acting directly on ventricles induce 2o pacemakers in ventricles ventricular tachycardia and arrhythmias.

• Phenylephrine (Neo-synephrine) - α1 selective agonist vasocnstrxn and increased BP.

o Will REFLEX decrease in HR with increased BP. But here, if you give Atropine and then Phenylephrine, will see increased BP but no change in HR!

b/c no direct fx on HR (no β1). o Tx paroxysmal atrial tachycardia (if pt NOT hypertensive) – b/c increases parasymp activity

Will also cause increased BP though. o DIRECT, i.e. not taken up by nn to exert its fx... * therefore, fx will NOT be altered by cocaine/TCAs or reserpine. o Decongestant (any α1 agonist) – b/c nasal mucosa is highly vascularized. o Blocked by Prazosin

• Methoxamine (Vasoxyl) - α1

o Like NE and Phenylephrine, will see increased BP and REFLEX decreased HR. o Decongestant (any α1 agonist) – b/c nasal mucosa is highly vascularized. o Blocked by Prazosin

• Clonidine (Catapress) and Guanabenz (Wytensin) – α2 o Clonidine crosses the BBB, so can give injection. It will cause an initial increase in BP by acting on

vessels, then once it crosses the BBB, will act on RVLM and decrease BP by reducing flow of impulses from brain that signal release of NE. (Symp’s account for 40-60 mm Hg of total BP.)

o Used as preanesthetic drug (sedative, antianxiety, pain). o Used for Heroin and Nicotine w/drawal – b/c pt’s in w/drawal have increased symp activity, want to

decrease it. o Relative effect on α2: Clonidine = Guanabenz > NE o Both blocked by Rauwolscine (not on drug list & not used clinically)

• Isoproterenol (Isuprel) – acts on β1 and β2

o Decrease peripheral resistance; increase systolic and decrease diastolic decrease MAP o Large increase in HR b/c direct and reflex mechanisms o Tx A-V heart block. o Increased HR fx blocked by Propanolol (β1) * Relative effect on β receptors: Isoproterenol >> Epi > NE

• Dobutamine (Dobutrex) – acts on β1 increases HR; @ high doses, β2 and α1 also o Tx cardiac decompensation after surgery or in CHF o Blocked by Metoprolol

• Albuterol (Proventil), Bitolterol (Tornadate), Metaproterenol (Alupent), Terbutaline

(Brethin), Pirbuterol (Maxidair) - act on β2; Tx asthma o Blocked by Butoxamine (NOT on list)

• Salmeterol (Serevent), Formoterol (Foradil)- acts on β2; long-acting • Ritodrine (Yutopar) - β2; prevents premature labor

Side effects and Toxicity: • Throbbing headache

• Precordial pain

• Cerebral hemmorhage (due to excessive increase in BP)

• Palpitations

• Cardiac arrhythmias

• Restlessness

• Panic, Anxiety, Tremor, Respiratory difficulties (due to CNS stimulation)

• Pulmonary edema (after prolonged drug use)

Contraindications: • Hyperthyroidism

− b/c have increased β1 receptor density in heart.

• Heart disease

• Severe hypertension – − could use e.g. Clonidine or

α-Methyldopa, but nothing that increases BP.

• Inhalation anesthesia -

(arrhythmias) – b/c sensitizes heart to the effects of NE and Epi.

INDIRECT SYMPATHOMIMETICS Indirect – i.e. they do not act on adrenergic receptors, but act presynaptically to release nt’s that can then act

on their respective receptors postsynaptically. • Amphetamine – taken up by amine pump at nerve terminal; then pushes the nt’s out…

o Primary: increases NE alertness o Then: increases DA euphoria o Then: increases Serotonin hallucination o Passes BBB! (*except for amphetamine and ephedrine, sympathomimetics have little CNS fx) o Tx psychogenic disorders o Tx narcolepsy – (NE fx) – b/c NE is low in these pts’ brains; can also counteract barbiturates.

• Tyramine – taken up by amine pump at nerve terminal; releases NE

o Found in many foods (cheese, wine, fish), * normally metabolized by MAO-A * (GI tract and liver) o If blocking MAO-A w/ drug (e.g. Tranylcypromine or Phenelzine) tyramine absorbed in intestine, into n

via amine pump, releases NE hypertensive crisis.

* If give Amphetamine/Tyramine after cocaine/TCA, will NOT be taken up b/c amine pump blocked. * Amphetamine and Tyramine do NOT promote the influx of Ca2+ in the nerve terminal and do NOT need an AP

to “push out” or release the other nt’s. * If give Amphetamine/Tyramine after Reserpine, no effects of NE seen b/c Reserpine blocks the storage of

NE (and DA) in the vesicles.

MIXED-ACTION SYMPATHOMIMETICS • Ephedrine (Pretz-D) – mixed action: direct on α1 and β2, indirect by increasing release of NE.

o so indirectly has axn on α1 α2 β1 via NE release * Given w/ Reserpine, will see decreased fx b/c Reserpine depletes NE in n terminals. o Passes BBB! (*except for amphetamine and ephedrine, sympathomimetics have little CNS fx) o Tx narcolepsy – (NE fx) – b/c NE is low in these pts’ brains

• Metaraminol (Aramine) – mixed action: direct on α1, indirect by increasing NE (α1 α2 β1) * Is a false nt – i.e. it is taken up, stored in vesicles, and released w/ NE. o Tx when want to temporarily increase BP, e.g for drug-induced hypoT, excision of pheochromocytoma,

orthostatic hypotension. (NOTE: can use any α1 agonist to increase BP!) Comparison of Directly & Indirectly Acting Sympathomimetics:

Direct Axn: Post-Synaptic Indirect Axn: Pre-Synaptic BP response after sympathectomy,

Cocaine, or Reserpine

(NE >> E) or none

COMT Effect Inactivated (shorter duration) Resistant (Amphetamine or Ephedrine) MAO Effect Inactivated (shorter duration) Resistant (Amphetamine or Ephedrine)

Effect Duration Shorter Longer Oral Activity No Yes (Amphetamine or Ephedrine)

Receptor Blockade Response Response

α-ADRENERGIC ANTAGONISTS • See Chart above! • Pharmacological Effects:

o Heart & Vasculature (pic slide 149): Do NOT block the chronotropic fx of catecholamines/symp stimulation (β1). BP:

− Orthostatic hypotension – (normally have reflex symp activity upon standing, but if α blocked, vessels do not constrict) – esp do NOT give to pt’s on vasodilators!! (e.g. NO)

o Note: Clonidine and Aldomet cause symp output, do NOT cause this b/c they don’t block the receptors.

− Venous pooling preload CO − REFLEX tachycardia − Na+ and H2O retention b/c increased symp to β1 receptors in JG renal cells.

* This is called “pseduo-tolerance” b/c eventually you will have plasma expansion, and the BP will not be lowered anymore.

* α blockers are given with β blockers to block the reflex tachycardia and pseudo-tolerance!! o Other:

Eye: radial muscle – miosis w/o loss of accomodation. (accomodation is ciliary m, parasymp) * Urinary: α1 blockage relaxes sphincter; can help in benign prostatic hypertrophy (BPH).

[The “zosin” drugs.] • Therapeutic Uses:

o Hypertension – only if given w/ β blockers o Pheochromocytoma – use w/ metyrosine (blocks syn of catecholamines); may also add β blockers.

Used pre-op to make sure pt has endogenously high levels of catecholamines Used post-op to prevent severe symp fx of circulating catecholamines still present.

o Peripheral Vascular Disease: Raynaud’s and Buerger’s syndrome – intense vasocnstrxn in fingers and toes, commonly seen in teens exposed to cold.

o Shock: NOT a primary Tx! First choice is to replace fluid and give DA (see below). Given as a last resort if vasocnstrxn persists after other Tx.

o BPH, hyperreflexia, incomplete urinary voiding: α2 blockers used to relax sphincters. o Pulmonary Congestion (CHF): b/c decreases BP – (indirect effect, and only a temporary soln).

Side effects: • Postural hypotension • Tachycardia (REFLEX) • Arrhythmia • Abdominal Pain • Nausea and vomiting • Diarrhea

Contraindications: • Hypotension – e.g. on NO, nitroglycerin,

Cialis, Viagra… will pass out if standing up! • Heart disease (b/c will tachycardia) • Peptic ulcer

Β-ADRENERGIC ANTAGONISTS “-olol” • See chart above! • Pindolol – β1

β2 and special: o Membrane stabilizer – DIRECT effect on Na+ channels – in heart, has a depressant effect and

prevents arrhythmias. o Also has partial agonist activity – advantage b/c some pt’s very sensitive to blocking β1

• Propranolol (Inderal) – β1

β2 and special o Membrane stabilizer – DIRECT effect on Na+ channels – in heart, has a depressant effect and

prevents arrhythmias. • Timolol (Blocadren) – blocks β; used w/ Epi to treat open-angle Glaucoma

o Open-angle glaucoma is the most common form of glaucoma; gradual, painless, but inevitably leads to vision loss due to optic n damage if not treated.

o Timolol primarily reduces the prdxn of aq humor (Epi does this but also increases outflow). o Also: Tx migraines

* Carvediolol, Labetalol - α AND β!

o Tx hypertension – recall α blockers used w/ β blockers to treat hyperT, and this already has both! • Pharmacological Effects:

o Heart & Vasculature (slide 155): Decrease HR, contractility, CO, cndxn velocity, and O2 consumption: all primarily due to

blockade of catecholamine fx on β1. [neg chrono-, dromo-, and iono-tropic fx] May direct myocardial depressant w/ membrane stabilizing (Pindolol, Propranolol) Anti-arrhythmic Decreased periph vasc resistance decrease BP, esp in pt’s w/ high renin and CO.

o Other: Resp System: may bronchocnstrxn and block β2 relaxation fx. Metab:

− Inhibit glycogenolysis in heart and skel m (β2) − Increase insulin secretion (β2) − Block FFA release (β1)

CNS: decrease in BP partly due to CNS fx. Kidney: decreases renin release from JG (β1).

• Therapeutic Uses: o Cardiac arrhythmias – catecholamine OD; during anesthesia; digitalis toxicity (narrow Tx winodow). o Angina pectoris – combine w/ NO to decrease workload of heart. o Hypertrophic obstructive cardiomyopathies – large heart with increased O2 demand o MI – to decrease risk of 2nd MI o Marfan’s – use to decrease incidence of acute dissecting aortic aneurysm o in CHF – (*use in low doses and NOT in severe cases*) – b/c upreg of β1 receptors and then remove

the antagonist to get a rebound effect. o Fallot’s tetralogy – (pulmonary stenosis, IV septal defect, ventric hypertrophy, aortal juxtaposition) –

to decrease workload on heart. o Tx tachycardia: reflex, stress- or fear-induced. o Hypertension o Hyperthyroidism – pt’s have increased β1 receptors in heart via hormonal stimulation of synthesis o Pheochromocytoma o Glaucoma:

Timolol – decreases formation of aq humor by ciliary processes. o Migraine headache – Propanolol, Timolol

Only effective as a prophylactive before headache starts; mech unknown

Side fx and Toxicity: • Decrease cardiac cndxn (β1),

Bradycardia, Hypotension • Exacerbation of periph vasc

disease • Bronchospasm (β2) • Hypoglycemia (β2) • Nightmares – common • Depression, Fatigue

Contraindications: • Severe CHF • A-V heart block • Diabetics on Insulin – does not allow

tachycardic sensing of max insulin injxns; can lead to seizure and convulsions

• Periph Vasc Disease • Renal Insufficiency – do NOT give to

pt with renal a. stenosis; prevents monitoring of BP via JG cells and inhibits release of renin and restoration of BP renal failure.

• Bronchial asthma – avoid β blockers in

general, but if necessary use β1

specific blockers. (e.g. Metoprolol)

DOPAMINERGICS

D1 Post. (~D5) D2 Post. (~D3, D4) D2 Pre. Renal and Mesenteric vessels:

relaxation Pituitary gland:

inhibit PL release Adrenergic nn:

inhibit NE release

Kidney: natriuresis and diuresis

(i.e. Na+ and overall urine output)

DA-ergic nn (CNS): Inhibit DA release

Parathyroid gland: PTH release

(D1): Fenoldopam

(D2): Bromocriptine Pramipexole

(D1 D2): Dopamine Apomorphine Pergolide

(D1 D2): Dopamine Apomorphine Pergolide

(D2): Domperidone

(D1 D2): Haloperidol (D1 D2): Haloperidol

• NON-SELECTIVE AGONISTS (D1 and D2):

o Dopamine (Inotropin) – * Tx for SHOCK: b/c low doses also stimulate β1 receptors in heart to increase HR and CO;

also good b/c increases coronary and renal perfusion – a major advantage over Epi! High doses – acts much like Epi.

o Apomorphine (Apokyn) – Tx Parkinson’s Acts on DA receptors in hypothalamus

o Pergolide (Peremax)

• SELECTIVE AGONISTS:

o Fenoldopam (Corlopam) – D1 – promotes diuresis and natriuresis in renal failure and shock lowers BP

o Bromocriptine (Parlodel) – D2 – Tx Parkinson’s and impotency

o Pramipexole (Mirapex) – D2

• ANTAGONISTS: o Haloperidol (Haldol) – D1 and D2 - Tx psychogenic disorders (e.g. schizophrenia) o Domperidone (Moltilium) – D2 – Antiemetic (i.e. alleviates nausea/vomiting)

Think: need it after Dom Perignon

Which of the following statements regarding efficacy (intrinsic activity) of a drug is CORRECT?

A. The efficacy of a drug is the dose that is required to produce 50 percent of the maximal response

B. The efficacy of a drug is the minimal dose of a drug that produces a quantal response

C. The efficacy of a drug is directly related to its potency and affinity

D. The efficacy of a drug can be accurately estimated from the slope of a dose-response curve

E. The efficacy of a drug is the intrinsic activity by which an agonist produces the maximal effect

Quantal dose-response curves describes:

A. the relationship between the concentration of the drug and the progressive increment in the magnitude of the response

B. the relationship between the concentration of the drug and the number of receptors occupied by the drug

D. the relationship between the concentration of the drug and the number of receptors activated by the drug

F. the relationship between the concentration of the drug and the frequency of the individuals responding in a given population

E. the relationship between the concentration of the drug and the rate at which drug activates the receptor

Which statement describing a drug receptor interaction studied by radioligand binding is CORRECT?

A. The ED50 represents the dose of a drug that produces the maximal biological response

B. The lower the IC50 of the drug, the lower the drugs affinity for its receptor will be

C. The IC50 denotes the concentration of a nonradio- labeled ligand required to displace a radioligand by

50% from its receptor

D. The Bmax determined from radioligand binding studies denote the lowest number of receptors involved in the biological response to an agonist

Which of the following drugs inhibits the activity of dopamine-beta-hydroxylase and acetaldehyde dehydrogenase?

A) Carbidopa [Lodosyn]

B) Disulfiram [Antabuse]

C) Tyramine

D) alpha-methyl-para-tyrosine [Demser]

E) alpha-methyldopa [Aldomet]

Reserpine:

A) inhibits the activity of dopamine beta-hydroxylase

C) inhibits the transport of norepinephrine and dopamine into synaptic vesicles in adrenergic nerves

E) depletes norepinephrine from adrenergic nerves by inhibiting the activity of tyrosine hydroxylase

D) does not deplete epinephrine from the adrenal gland

E) prevents the re-uptake of norephinephrine and dopamine into varicosities through amine pump in adrenergic nerves

B.P.Mm, Hg

Drug “X”

ISO PHE TYRNE E

ISO PHE TYRNE E

Mean arterial

B.P.

100

0

H.R.

200

504

0

Intestinalcontraction

Drug “X”

Which of the following drugs is useful in the treatment of paroxysmal tachycardia?

A. Isoproterenol (Isuprel)

B. Epinephrine

C. Propranolol (Inderal)

D. Methoxamine (Vasoxyl)

E. Metaproterenol (Alupent ®)

A 67-year-old woman is admitted to the ICU with sepsis secondary to a urinary tract infection. She is tachycardic, BP is 80/40, and renal output is low. Antibiotic therapy is instituted, together with iv fluids and a low-dose infusion of dopamine. Which of the following drugs would directly antagonize the action of this agent at D1 and D2 receptors?

A) alpha-methyl-para-tyrosine [Metyrosine]

B) entacapone [Comtan]

C) carbidopa [Lodosyn]

D) Pindolol (Visken)

E) haloperidol [Haldol]

Cholinergic Drugs Organ Muscarinic Agonist

Muscarinic Antagonist

Ganglionic Agonist

N1 Ganglionic Antagonist

Block N1 Eye * iris Contraction (Miosis) Mydriasis Mydriasis * ciliary muscle

Accommodation Cycloplegia cycloplegia

Heart ↓ HR, ↓ BP Initial ↓HR ↑ HR Initial ↑ HR ↓ HR Moderate ↑ HR, ↓ CO Blood Vessels

Dilation Block of agonist Ax. Constriction (NE & EPI adrenal

release)

Orthostatic hypotension, Dilation,

↑ peripheral blood flow Veins Dilation ↓ venous return Lung * Muscles Bronchoconstriction Bronchodilation * Glands ↑ secretion & motility ↓ secretion GI Tract ↑ motility ↓ motility & tone * Sphincters ↓ tone=Relaxation * Secretion ↑ ↓

↑ motility & tone= nausea,

Vomiting, diarrhea

↓ motility=constipation

Bladder ↑ urination Relaxation=retention ↓ contraction=retention * Detrussor ↑ tone=Contraction * Sphincters ↓ tone =Relaxation Glands ↑ secretion ↓ secretion

Xerostomia, anhidrosis Skeletal Muscle

+ Neuro end plates ---- Stimulationparalysis Relaxation

CNS --- Sedation, antiparkinsons, Prevention of motion sickness,

Hallucinations

+ vomiting center + ADH release

analgesia

Ach, Carbachol, Methacholine,

Bethacholine, Cevimeline, Pilocarpine

Atropine, Scopoline, Glycopyrrolate, Ipratropium, Oxybutynin,

Trihexphenidyl HCL, Benztropine, Tropicamide

Acetylcholine, Nicotine

Hexamethonium, Mecamylamine

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Pharm Assessment 3

INHIBITORS OF Ach (synthesis, storage, and release)

• Hemicholinium - inhibits choline transport into neuron inhibits Ach synthesis. o Active uptake of choline is RLS in Ach synthesis, NOT activity of ChAT. Uptake

mediated by [Na], so normally increases with depolarization.

• Vesamicol – inhibits storage of Ach in vesicles; NOT used clinically. • Botulinum Toxin – inhibits fusion of Ach vesicles at presynaptic membrane.

o Contains proteases that degrade VAMP’s and SNAP’s, which are necessary for fusion.

o Clinical uses: Facial wrinkles Strabismus (eyes not properly aligned) Blepharospasm (abnl tic/twitch of mm around eye) Meige’s syndrome (unilat spasm due to facial n. inflammation) Spasmodic torticollis (invol cntrxn of neck mm)

*[slides 174-178: effects on BP with combo’s of Ach, Nicotine, NE, Atropine, Hexamethonium, and Phentolamine]

Small dose Ach IV decrease BP, unless blocked by Atropine Large dose Ach IV decrease BP

− w/ Atropine, then will increase BP (relase of Epi and NE) − w/ Atropine and Hexamethonium no effect on BP (block M and N1) − w/ Atropine and Phentolamine no effect on BP − w/ Hexamethonium only decrease BP (direct axn on M)

Nicotine increase in BP (release Epi and NE), − w/ Hexamethonium (N1) no effect on BP − w/ Phentolamine no effect on BP

NE increase in BP − w/ Phentolamine no effect on BP

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MUSCARINIC AGONISTS (aka parasympathomimetics)

[Beth Cevim Carries Methylated Pillows.]

• Acetylcholine (Miochol-E) – binds to M and N receptors. (*slide 172 diagram) o No Tx uses o Does NOT cross BBB o Muscarinic

Actions: Think parasympathetics: axns similar to those seen w/ postgang parasymp’s (for all, see slides 185, 187, 194) ; vessel dilation via NO. − Accomodation (close-up vision), myosis (pupil cntrxn) − Atrium: can atrial flutter/fibrillation b/c decrease refractory

periods and duration of each AP, increase conduction velocity. * opposite of axns in AV node

− Glands (sweat, salivary, lacrimal, nasopharyng, bronch) – increase secretion.

Receptors = GPCR’s, M1-M5 − M1: Nerves, Gq − M2: Heart (and nerves, smooth muscle), Gi − M3: Endothelium (and glands, smooth muscle), Gq

Locations: − Postgang parasymp’s − Blood vessel smooth muscle –(NOT innervated, but have M3

receptors: Ach release NO relaxation). − Sweat glands (except soles, palms, and axillae, which are NE).

Blocked by Atropine o Nicotinic

Actions: many, see below. Receptors = Na ion channels, classified by sensitivity to α-bungarotoxin. N1 Locations:

− Autonomic ganglia of symp AND parasymp (see below) − Adrenal medulla release Epi − Adrenergic nerve terminals NE − Blocked by Hexamethonium

N2 Location: − NMJ (skeletal mm.) − Blocked by Curare (and others, see below)

o Small dose Ach IV NO release in endothelium decrease BP. Will not see other effects. If give atropine first, will see no effect!

o Large dose Ach… Direct effect on M2 and effect on parasymp ganglia decrease HR Symp ganglia (N1) release NE Adrenal Medulla (N1) release Epi NMJ (N2) cntrxn of skel m * have BOTH vasodilators and –constrictors released, but Ach effects

predominate decrease BP!!

Note: Subtypes of GPCRs not covered in class but for boards

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• Carbachol (Carbacol) – urinary retention and post-op atonic bowel

o Also has some N action… give w/ atropine increase BP. o NOT hydrolyzed by cholinesterase.

• Methacholine (Mecholyl) – Dx asthma

o Also has some N action… give w/ atropine increase BP.

• Bethanechol (Urecholine) – urinary retention and post-op atonic bowel o no N action!! ONLY Muscarinic… so if give w/ atropine, no effects. o NOT hydrolyzed by cholinesterase.

• Cevimeline (Evoxac) – Tx: Sjogren’s syndrome, Mikulicz’s syndrome, and Sicca syndrome

Sjogren’s = dry mouth, dry eyes, AND arthritis Sicca = dry mouth, dry eyes (xerostomia, xerophthalmia) Mikulicz’s = bilat enlargement of lacrimal and salivary glands, no arthritis

o no N action!! ONLY Muscarinic… so if give w/ atropine, no effects.

• Pilocarpine (Salagen) – (an alkaloid) – Tx closed-angle glaucoma, applied topically increase outflow of aqueous humor. o Common cause is dilation of pupil due to an emotional crisis, w/ symp discharge;

drugs like NE, E, and atropine can also cause if pt is very susceptible to mydriasis. o Rapid onset accompanied by pain (oppo. of open-angle glaucoma). o also increases saliva o no N action!! ONLY Muscarinic… so if give w/ atropine, no effects.

RECALL:

- Only M axn: Bethanechol, Cevimeline, Pilocarpine - M and N axns: Ach, Carbachol, Methacholine - Not hydrolyzed by cholinesterase: Bethanechol, Carbachol (note these have the same

uses, too) ALSO:

- All w/ “chol” in the name (i.e. the choline esters) – do NOT give IV b/c hypotension coronary insufficiency; give oral or subQ.

- SIDE EFFECTS are ~same as the axn’s (slide 199). *effects on heart! - Atropine is an antidote for the side effects.

CONTRAINDICATIONS (200): asthma, hyperthyroid (atrial fib), coronary insufficiency (hypoT),

peptic ulcer disease

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MUSCARINIC ANTAGONISTS – compete w/ Ach and M agonists for M receptors [After Trying a hex (Trihex.), Ben and Ipra Glistened on the pier (Glycopyrrolate), Scooping up the Oxygen of the Tropics.]

• Atropine – blocks M receptors, naturally occurring o Selected Effects (for all, see 204-205):

Cycloplegia (lack of accommodation due to paralysis of ciliary m.), mydriasis “Atropine flush” – vasodilation in cutaneous vessels, esp. of the face and

neck, as a rxn to hyperthermia. – NO cholinergic innerv to blood vessels! Bronchodilation, but not as effective as �2-blockers b/c density of M

decreases from trachea to bronchioles, while density of �2 increases. CNS – atropine and scopolamine can cause hallucinations and euphoria;

stimulates medullary centers/ depression in larger doses. o Tx:

exposure to anticholinesterases or organophosphates (decrease Ach fx) Decrease salivation and resp secretion for endotrach tubing *acute MI when bradycardia is associated w/ hypotension w/o arrhythmias –

b/c increased HR. Digitalis toxicity (digitalis stimulates the vagus n.)

o Contraindications: Glaucoma - b/c dilate pupil. - *can cause acute glaucoma in sensitive pt’s. Hypertension Alzheimer’s – b/c cholinergic NS is imp for cognition, and these pt’s already

have some loss of cholinergic fnxn.

• Scopolamine – Tx motion sickness; naturally-occurring o Lipid soluble – crosses BBB, patches avail.

• Glycopyrrolate (Robinul) – decrease gastric hypermotility.

• Ipratropium (Atrovent) – Tx asthma/ COPD; inhaled o NOT absorbed from GI; does NOT cross BBB.

• Oxybutynin (Ditropan) – inhibit hyperactive bladder

• Trihexphenidyl HCl (Artane) and Benztropine (Cogentin) – Tx Parkinson’s • Tropicamide (Mydriacyl) – examination of fundus

o Shorter duration than atropine. o Reverse fx with pilocarpine.

RECAP: - note that the naturally-occurring agents (Atropine & Scopolamine) are well absorbed and

widely distributed (i.e. go to CNS). - Quaternary cpd’s not well-absorbed, limited distribution (i.e. Ipratropium)

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GANGLIONIC AGONISTS – (acting on N1)

• Acetylcholine – (recall no Tx uses, does NOT cross BBB) • Nicotine – binds N1 (and N2 at NMJ); crosses BBB.

o FX: CV: - Small dose: increase HR

− Large dose: first increase HR, then decrease HR (via modulation of medullary center).

− Vessels: constriction (release NE and Epi)

Skel m.: − Stimulation, followed by paralysis

when R’s are desensitized CNS:

− Stim then inhib of medullary centers − Vomitting (chemoreceptors) − Release ADH – antidiuretic − ~analgesia

o NICOTINE TOXICITY: acute, w/ rapid onset Nausea, vomitting, diarrhea, hypotension,

mental confusion * death from respiratory paralysis Tx: gastric lavage w/ KMNO4 soln; ventilation and anticonvulsant Chronic tobacco toxicity: many S&S not due to nicotine, but some are.

(slide 211)

GANGLIONIC ANTAGONISTS

• Hexamethonium – blocks N1 receptors, NOT used clinically. o (i.e. autonomic ganglia – including parasymp (Ach) and symp: NE, adrenal medulla (Epi)

and sweat glands(Ach)). o Does NOT cross BBB – (a quaternary ammonium cpd) o “Hexamethonium Man” –(slide 216)

• Mecamylamine (Inversine) – blocks N1 receptors, used clinically.

o Crosses BBB! o Tx severe hypertension and hypertensive crisis: Tourette’s Syndrome – only

Mecamylamine b/c hexamethonium does not cross BBB. o ACTIONS & SIDE EFFECTS – see 214-215.

* Parasymps dominate (& therefore will see opposite fx w/ this drug) everywhere except vessels and sweat glands.

Also impotence, CNS effects (Meca only), and Tolerance. o CONTRAINDICATIONS: Renal, cerebrovascular, and coronary insufficiency

(b/c marked hypotension; blood will pool away from these organs).

Therapeutic: • Analgesia • Cognitive

Enhancement (release of Ach)

• Neuroprotection • Anxiolytic (release

of GABA) • Antipsychotic

Harmful • GI distress • Hypothermia • Emesis • Hypertension • Seizures (release

of Glu in brain) • Resp distress

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NON-DEPOLARIZING NEUROMUSCULAR BLOCKERS a.k.a. “competitive” “-cur-“ All non-depolarizing:

- Locally-acting, @ the NMJ (bind N2); prevent binding of Ach no AP’s. - Produce a competitive, reversible block - can reverse with anticholinesterases, b/c

increase amt of Ach to compete. *** NONE of the NM blockers cross the BBB; NONE analgesia.

• D-Tubocurarine (Curare) – Short onset (min), long duration (1-1.5hrs) o Releases histamine – may cause hypoT, decreased CO, bronchospasm, and urticaria. o Muscle paralysis: face/neck limbs trunk intercostal mm diaphragm!

(Recover in reverse order.) o Treat O.D. w/ assisted ventilation, and anticholinesterases (e.g. neostigmine,

pyridostigmine) o Some X-rxn w/ autonomic ganglia some blockade in Tx doses. o Tx use:

w/ general anesthesia; can then decrease dose of anesthestics. Treat convulsions – tetanus, epilepsy, *electroshock therapy* * Assisted ventilation should be avail. immediately as a precaution.

o CV effects due to: histamine, auto gang N1

• Pancuronium (Pavulon) – short onset, long duration

o does NOT release histamine – so does NOT hypoT; is M-specific!! o M. relaxant for endotrach intubation – (as are many of the others!) o Renal/hepatic degradation

• Vecuronium (Norcuron) – short onset, intermed duration

o congener of Pancuronium o Hepatic/Renal degradation o No CV fx (does not release histamine)

• Atracurium (Tracrium) – short onset, intermed duration

o Undergoes Hoffman degradation (spontaneous!) o CV effects due to: (minimal) histamine release in Tx doses

• Rocuronium (Zemuron) – short onset, intermed duration

o Hepatic/renal degradation o No CV fx (does not release histamine)

• Mivacurium (Mivacron) – short onset, short duration

* degraded by pseudocholinesterase, so if pt doesn’t have that enzyme, drug will have increased action – BAD.

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DEPOLARIZING NEUROMUSCULAR BLOCKERS Locally-acting, @ the NMJ (bind N2).

• Succinylcholine (Anectine) – rapid onset, ultra-short dur.

o CV effects due to: Histamine, SA node M receptors, and Autonomic Ganglia fx

o When combine w/ N2, two phases: PHASE 1: Depolarizing block muscle activation

(fasciculations) − Action would be like super-potent Ach − Antagonized by curare − Intensified by anticholinesterases

PHASE 2: Desensitized block (acting like the competitive NM blockers) − Antagonized by anticholinesterases − Intensified by curare.

RECALL: - S.T.A.M. – release hiSTAMine! - V.A.R. – intermediate duration - V.R. – no CV fx

�������������

NOTE: not on list, but in slides and some in review session…

• Benzoquinonium – BOTH competitive and depolarizing NM blocker. o A synthetic, quaternary ammonium cpd. o Also has considerable anticholinesterase activity.

• Drug-drug Interaxns that Enhanced NM Blockade

o Inhalational Anesthetics: Ether, Halothane, Isoflurane

Have curare-like axn – i.e. act on CNS and cause relaxation (must decrease amt curare if given w/ these).

Synergize w/ competitive NM blockers.

o Antibiotics: Streptomycin, neomycin, Polymyxin Cause competitive NM blockade – decrease release of Ach; can have

synergistic fx w/ competitive NM blockers. Similar effects w/ colistin and kanamycin

Advantages: • Rapid onset • Ultra-short duration • IM injxn

Disadvantages:

• Hyperkalemia (due to depolarizations)

• Cardiac dysrhythmias (due to hyperkalemia)

• Masseter spasm * Malignant Hyperthermia:

some have big release of Ca and activate a lot of enzymes, e.g. patients w/o pseudocholin-esterase.

• Increased ICP, IOP, IGP

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ANTICHOLINESTERASES • They inhibit cholinesterase increase Ach *enhance activity of cholinergic NS* • Potential sites of axn:

- postgang parasymp neuroeffector jnxns (M) - postgang symp cholinergic sites, (i.e. sweat glands EXCEPT palms, soles, and axillae) (M) - symp and parasymp ganglia (N1) - skeletal NMJ (N2) - adrenal medulla (N1) - CNS – many cross BBB

• REVERSIBLE:

o Edrophonium (Tensilon) – Dx myasthenia gravis (pt has decreased Ach R’s) Rapid onset, short duration – so NOT used for Tx Stimulates skel mm by a direct axn (But primary effect is block of Ach-ase) [example pt shows improvement of ptosis and weak smile]

o Physostigmine (Eserine) – for certain types of glaucoma and atropine O.D. Readily absorbed from GI, subQ, and mucous memb’s Crosses BBB CNS stim then depression * M and N axns (INdirectly by inhib. of Ach-ase, NOT directly on N or M)

o Neostigmine (Prostigmin) –

Clinical Uses: − Dx and Tx of myasthenia gravis − post-op bladder and bowel atony − to reverse non-depolarizing NM blockers (-cur-)

No CNS fx * M and N axns, w/ DIRECT axn on skeletal m via stim of N2

o Pyridostigmine (Mestinon) – Tx of myasthenia gravis

same axn’s as neostigmine (w/ direct axn on N2) lasts longer, fewer side fx

• IRREVERSIBLE

o Echothiophate (Phospholine) [and DFP, not on list] – Tx Glaucoma • An organophosphorous cpd • Long duration of axn • not preferred but used when other Rx not helping * can cause CATARACTS in older pt’s

o Toxicity M, N, and CNS fx o Pyridostigmine given as prophylaxis to block irreversible binding. o Tx of Intoxication:

− Atropine (blocks M axn), Assisted ventilation, Remove source − Tremethadone or thiopental − CHOLINESTERASE REACTIVATORS (Pralidoxime (2-PAM) and

DAM)

Not on drug list: - Nerve gases (Sarin, Tabun, Soman) - Insecticides

1

Pharmacology – Assessment 4 (start of Block 2)

AUTOCOIDS Local hormones produced by various tissues that act on same or nearby tissues. 5 Categories: Eicosanoids, Kinins, Natriuritic peptides, Endothelins, and Other

Eicosanoids • Some specific eicosanoids and their actions System PGE2 PGI2 PGH2 PGF2α TxA2 Cardio ↓ BP,

dilate ♥ vessel ↓ BP, ↓platelet aggregation, dilate ♥ vessel

↑ platelet aggregation

-- ↑BP, ↑ platelet aggregation, constrict ♥ v’s

Renal Vasodilation ∴ ↑ blood flow ↑ natriuresis, kaluresis, ↓ Cl- ↑ renin; ↓ ADH

-- -- --

Respiratory dilate bronchioles -- bronchoconstriction Gastro ↓ acid secretn,

↑ peristalsis ↓ acid secretn (esp in fundus)

-- ↑ peristalsis --

Reproductive relax empty uterus, contract gravid uterus, induce abortion

-- -- contracts every uterus; Corpus Leut regression; induce abort.

--

CNS ↑hyperthermia -- -- -- -- Autonomics ↓ NE release ∴↓BV constriction

that was caused by NE,ADH,A2. -- -- --

Metabolism ↓ lipolysis (in adipose + heart) -- -- -- Other hyperalgesic;

PGE1 (synth) ↑ erection

hyperalgesic -- -- --

Associated DRUGS

Dinoprostone Epoprostenol (other analogs)

Dinoprost Carbaprost

• Major Synthetic Steps: (see slide 250)

o Phospholipids → arachidonic acid o COX I and COX II convert arachidonic acid to PGG2

inhibited by aspirin and ibuprofen COX I – constituitively present COX II – induced in most tissues by two things (??)

• Selective COX II inhibitors: Celecoxib (Celebrex) & Rofecoxib (Vioxx) o PGG2 is a precursor for:

• prostaglandins • prostacyclin (PGI2) – ↓ platelet aggregation • thromboxane - ↑ platelet aggregation

o Synthesized as needed (not stored in tissues)

2

Eicosanoids and their Analogs • PGI2 = Epoprostenol (Flolan) – very unstable

o Tx: severe Pulmonary Arterial HTN; congenital heart defects. Can be substituted for heparin during dialysis in renal disease (why?).

o PGI2 analogs: Carbacyclin & Iloprost - more stable; used for tx gastric ulcers Trepostinil and Beraprost – same uses as Epoprostenol

o Side efx: jaw and muscle pain; very expensive

• PGE1 = Alprostadil o Used to tx congenital heart defects & erectile dysfunction o Misoprostol, Rioprostil – PGE1 analogs for tx gastric ulcers o Gemeprost – PGE1 analog dilation of cervix for uterine exam

• PGE2 Dinoprostone (Cervidil) – dilation of cervix for uterine exam; induce abortion in

gravid uterus; decrease postpartum hemorrhage • PGF2α (Dinoprost) and 15-methyl-PGF2α (Carbaprost) – induce labor and abortion • Latanoprost (Xalatan) – preferred tx for glaucoma

o PGF2α prodrug that ↑ outflow of aqueous humor via uvulosclera output o side efx: permanent change of eye color (brown) o Combo: Latanoprost + Timolol = Xalacom.

• Niacin o tx: atherosclerosis by ↑ HDL levels o Side efx: skin flushing

• Cordaptive - PGD2-1 receptor antagonist combo (Niacin + Laropiprant) o Tx atherosclerosis without flushing.

Let’s Review:

− Drugs to tx gastric ulcers: Carbacyclin, Iloprost, Misoprostol, Rioprostil − Drugs with Gynecological uses: Dinoprostone (PGE2), Gemeprost, Dinoprost & Carbaprost − Good tx for glaucoma: Latanoprost − Drugs to tx atherosclerosis: Niacin, Cordaptive − Drugs to tx ductus arteriosis: Epoprostenol, Alprostadil

Other Notes: − NEVER prescribe anti-inflamm’s or COX inhibitors to CHF patients!!! (but baby aspirin is OK

b/c it blocks TxA2 without blocking those protective prostaglandins). − hyperalgesic – this is why antiinflamm like COX inhib’s pain. − in Cirrhosis with ascites, have PG syn.

3

The Other Autacoids Kinins Major Synthetic Steps (see slide 263)

− Kininogen gets metabolized by Kalikrein (enzyme) into Bradykinin (or Kallidin) − Bradykinin actions: venoconstriction, pain, ↑catecholamines, bronchoconstriction, dieuresis,

natriuresis − ACE (Angiotensin Converting Enzyme) has 2 functions:

o ↑ Angiotensin II o ↓ Bradykinin

• ACE Inhibitors (slide 263)

o Preferred HTN Rx for pts with diabetes mellitus (with good renal fxn). o Side efx: cough

• Aprotinin (Trasylol) - Inhibits kallikrein o (not common use) reduce blood loss in patients undergoing coronary bypass surgery o side efx: anaphylactic shock

Natriuretic Peptides • Endogenous Types:

o ANP (atriopeptin) – synthesized 1° in atrium o BNP (brain natriuretic peptide) – synth. in ventricles & brain o CNP (C-type) – synth. in brain and endothelial cells.

• Stimuli that release them (slide 269): ↑BP, ↑AngioII, endothelin, sympathetic stimulation • Effects (slide 270): diuresis, natriuresis, vasodilation, ↓aldosterone • Inactivated by neutral endopeptidase (so inhibiting endopeptidase would prolong NP actions)

• Nesiritide (Natrecor) – recombinant BNP; tx dyspnea due to CHF (compare to

nitroglycerine); side efx: hypotension

Endothelins – most potent vasoconstrictors in the body – whoa Endopeptidases are needed for cleavage/activation. Different isoforms are pharmalogicly distinct. Actions are mediated through endothelin receptor sub-types (ETA, ETB1, ETB2). Endothelin Receptor Antagonists: Tx pulmonary HTN (but all have bad side efx) • Bosentan (Tracleer) – blocks ET1 A+B receptors (hepatotoxic, peripheral edema) • Sitaxentan (Thelin) – selective ET1A blocker (hepatotoxic; flushing; Warfarin interaction) • Ambrisentan (Letairis) – selective AT1 receptor blocker (flushing, but less hepatotoxic) Other Substances • Substance P & Calcitonin – vasodilator; neurotransmitter (pain signals) • VIP (Vasoactive Intestinal Peptide) – vasodilator, NTM • Histamine, Angiotensin II, and Serotonin – to be covered later in the course

4

DIURETICS Drugs that affect the Kidney so that you excrete more fluid. Many are used as Anti-Hypertensives Review: pathway through the kidney and key facts about each

− Glomerulus: things that influence GFR: o Capillary permeability o Filtration pressure – regulated by afferent

arterioles o Renal blood flow o Plasma oncotic pressure

− Proximal convoluted tubule: bicarbonate reabsorption − Loop of Henle: in the medulla − Thick Ascending Limb: Na-K-2Cl symport; water

impermeable − Distal convoluted tubule: macula densa; aquaporin-2

(regulated by ADH); 3 more segments o Na-K-aldosterone independent (has Na-Cl symport) o Aldosterone sensitive segment o Sodium load segment

− Collecting Duct: one last chance for water reabsorption Proximal Convoluted Tubule Diuretics: • Acetazolamide (Diamox) - Carbonic Anhydrase Inhibitor

o Action: inhibit C.A → HCO3- loss in urine (alkaline)

Cl- is reabsorbed instead Also ↑ excretion of NaCl & H2O

o Tx is limited, but may be used for: glaucoma; cysteinurea (alkaline urine ↑cysteine excretion); seizures (↓pH helps), and occasionally liver sirrhosis & renal failure

o Side Efx: metabolic acidosis, hyperchloremia, drowsiness, ↑ sensitivity to thiazides

• Mannitol - Osmotic Diuretic (10-fold ↑ urine flow) o Tx: prophylaxis of acute renal failure when there is low GFR (ex: trauma, shock) o Inert; ↑ osmolarity of plasma & tubular fluid so more water flows into PCT. o side efx: volume overload may →heart failure

Loop Diuretics:

o inhibit Na-K-2Cl symporter; ↑renin; maintain GFR o causes ↑↑diuresis w/ significant NaCl losses; venodilator o General Tx: edema, hypercalcemia, washout toxins, prophylaxis for renal failure,

dieuretic for HTN used w/ other drugs. o Side efx:↑BUN, hypokalemia, alkalosis, ototoxicity, drug interactions

• Furosemide (Lasix) - inhibits NaCl resorption; high safety margin; interacts with Warfarin

5

• Bumetanide (Bumex) - 40x more potent than furosemide (and doesn’t interact with warfarin)

• Torsemide (Demadex) - longer half-life (dose once daily) Distal Convoluted Tubule Diuretics: • Thiazide Diuretics

o Tx: HTN (but not with diabetes mellitus), edema from CHF, liver cirrhosis, renal failure, nephrogenic diabetes insipidus (b/c ↓receptors mean Desmopressin no help).

o Action: inhibit Na/Cl symporter in the Na-K-Aldo independent segment, causing natriuresis and dieuresis (and many other side efx).

Short Term Effects: dieuresis, hypokalemia, ↓CO and ↓BP Long Term Effects: ↓ hypervolemia & direct vasodilation (unknown mech.)

o Side efx: (a lot, see slide 38) Hypokalemia, hypo-Mg, hyper-Ca, hyperuricemia, hypercholesterolemia

o Class 1 – used when GFR is high (>40 ml/min) HYDROCHLOROTHIAZIDE (Esidrex) – short-acting; tx HTN,

nephrogenic diabetes insipidus CHLORTHALIDONE (Hygroton) – long-acting, tx HTN Quinethazone -

o Class 2 – used when GFR is lower (20<40) Metolazone - ↑ potency, tx HTN even if renal insufficiency is present Indapamide - ↑↑ potency, tx HTN; also has direct vasodilatory effects

• K-sparing Diuretics – inhibit Na resorption in DCT. Often used with HCTZ to normalize K+. o SPIRONOLACTONE (Aldactone) – aldosterone antagonist (competitive

inhibitor) o Eplenerone (Inspra) – aldosterone antagonist o AMILORIDE (Midamor) and TRIAMTERENE (Dyrenium)

inhibit Na reabsorption in late distal tubule used with other diuretics like HCTZ side efx: hyperkalemia, anemia

ANTI-DIURETICS -Act on Collecting Ducts • ADH = 8-Argenine Vasopressin - acts on 2 receptors

o V1 receptor: vasopressor (via IP3 and Ca++ release) o V2 receptor: activates aquaporin for ↑ water reabsorption

• Desmopressin (DDAVP) – V2 receptor agonist; tx central diabetes insipidus and bleeding • Demeclocycline (Declocyclin) – pro-diuretic, anti-ADH

o use with OPC-31260 o action: antagonizes ADH at V2 receptors o tx Syndrome of Inappropriate Secretion of ADH

6

HYPERTENSION

Defined as:

Contraction of Vascular Smooth Muscle: Calcium and Important Receptors

• An ↑ in intracellular Ca++ is required for contraction o Ca++ can be released from the Golgi o Ca++ can enter the cell via L-Type Ca Channel

• Now, Ca++ can bind calmodulin→ move troponin→ free myosin head to grab actin filament→ contraction of muscle fiber→ vasoconstriction.

• Important Receptors: o Gq coupled receptors → IP3 → ↑ Ca++ release

α1 adrenergics, Angiotensin II receptors, and endothelin-1 receptors o Gs and Gi coupled receptors regulate cAMP

β-adrenergic receptors ↑ cAMP → ↑PKA → ↑Ca++ M2 muscarinic receptors ↓ cAMP → ↓PKA → ↓Ca++

Control of Blood Pressure

• Baroreflexes – rapid adjustment of BP o Baroreceptors in carotid sinus signal the… o Solitary Nucleus in the brainstem, which signals the... o Vasomotor Center in the medulla, which is tonically active and will ↑or↓ tone.

• Kidney – slow but long-term adjustment of BP o Juxtaglomerular cells are stretch sensors in afferent arteriole: lack of

stretch → signal Renal Nerves (β1-adrenergics) → ↑ Renin. o Macula Densa senses osmolarity in distal tubules: low osmolarity → ↑ Renin.

BP Classification SBP mmHg DBP mmHg Normal <120 and <80 Pre-HTN 120-139 or 80-89 Stage 1 HTN (drug tx advised) 140-159 or 90-99 Stage 2 HTN >160 or >100

7

ANTI-HYPERTENSIVES that interfere with the Sympathetics Centrally Acting Agents General: They stimulate central postsynaptic α2 receptors in the RVLM, which causes ↓symp output → ↓HR, ↓perif vascular resistance • α-Methyldopa (Aldomet) – false NTM, mimics NE.

o Only used for severe HTN in preeclampsia during pregnancy b/c severe side efx. (but not teratogenic)

o Side Efx: sedation, sleep disturbance, Na + H2O retention; immunological dysfxn. • Clonidine (Catapres), Guanfacine (Tenex), and Guanabenz (Wytensin)

o α2 agonists in RVLM o Side efx: sedation, drowsiness, fatigue, anxiety, Na + H2O retention, xerostomia o Clonidine is also analgesic. o Guanabenz also lowers plasma cholesterol (and doesn’t retain H2O).

Peripheral Sympatholytics • Reserpine

o Tx: inhibits NE uptake into vesicles ∴ endogenous NE is “depleted” o Side Efx: do NOT use in pts with peptic ulcers or hx of depression/suicide!!! o Note: it may be cheap, but it’s a generic drug from India, so there’s no drug company

buffer if tx goes bad and the patient wants to sue somebody. Hmm….

• Guanadrel – not discussed in lecture. α-adrenergic Antagonists General: cause ↓arterial pressure & small reflex ↑HR • Prazocin (Minipress) – α1 specific antag.; tx HTN

o short acting, so ↑dose gradually to prevent postural hypotension o Other benefits: ↑HDL & improves insulin resistance

• Doxazocin (Cardura) and Terazocin (Hytrin) - α1 specific antag. o Tx: HTN + BPH (enlarged prostate) o Side efx: orthostatic hypotension

• Phenoxybenzamine and Phentolamine – non-selective α-antagonists o Obsolete for tx HTN. Used for Pheochromocytoma.

8

Beta-Blockers (slide 50) General Tx: HTN, esp associated with CHF or previous MI (prophylactic b/c protects against CAD).

(Can be used to treat CHF, but dose must start LOW and titrate upward b/c of initial ↓CO) General Action: ↓ CO by ↓HR + ↓contractility; inhibits reflex tachycardia General Side Efx: Raynaud’s, bradycardia, bronchospasm, depression/CNS efx, drug interaction w/

conduction blockers, fatigue, ↓GFR Non-Selective β-blockers: (slide 48) • Propanolol (Inderol) – also anti-arrhytmia • Carvedilol (Coreg) – blocks α+β receptors non-selectively

o 1° drug for CHF o Also ↓ROS production.

• Pindolol (Visken) and Acebutol (Sectral) – partial agonists o ISA (increased sympathetic activity) → less drastic ↓CO and HR

• Timolol (Blocadren) – very slight ISA • Labetalol (Normodyne) - Selective β1 Blockers • Metoprolol (Lopressor) and Atenolol (Tenormin) – cardioselective (β1) ∴ OK for

asthmatics • Betaxolol (Kerlone) and Bisoprolol (Zebeta) – long-acting • Esmolol (Brevibloc) – very short half-life; used to tx tachycardia • Nebivolol (Bystolic) – newest; claims to exhibit vasodilation b/c ↑ NO Direct Vasodilators (mnemonic? MSNDFH) Usually Rx’d only after 2 or 3 other drugs have been tried without success. • Minoxidil (Loniten) – a pro-drug (liver sulfation) that opens K+/ATP channels in smooth muscle

o dilates arterioles (not veins) o Side efx: reflex tachycardia; hirsutism → topical cream sold as Rogaine

• Sodium Nitroprusside (Nitropress) – prodrug for NO o Dilates both arteries and veins via ↑cGMP → ↓TPR → ↓afterload o Tx: great for HTN crisis and Left-sided HF. o Side efx: hypotension, tachycardia, palpitations, metabolism into cyanide, nausea

• Diazoxide (Hyperstat IV) – opens K+ channels in smooth muscle o Tx HTN crisis o Effect augmented in combo with β-Blocker (b/c BB prevents reflex tachycardia) o Side efx: tachycardian, fluid retention, hyperglycemia (inhibits insulin release)

• Fenoldopam (Corlopram) – D1 receptor agonist; short half-life o tx HTN crisis; contraindicated for glaucoma.

• Hydralazine (generic) – tx CHF

9

Interfere with Renin/Angiotensin ACE Inhibitors = (-pril) Improves prognosis for CHF by reducing afterload!!! First choice anti-HTN for diabetics. Mechanism of Action: block ACE enzyme that 1) converts Angio1→Angio2 & 2) degrades bradykinin Side Efx: orthostatic hypotention (first dose), hyperkalemia, dry cough, angioedema, fetotoxicity • Captopril (Capoten) – short half-life; ↑synthesis of prostaglandins → ↑vasodilation • Enalapril (Vasotec) – prodrug → (de-esterification) → elanaprilat (active) • Lisinopril (Zestril) – lysine derivative of elanaprilat • Ramipril (Altace) – prodrug with long half-life • Fosinopril (Monopril) – ideal for CHF pts with renal disease (b/c 100% hepatic metabolism) Angiotensin II Receptor Blockers = (-sartan) Advantages over ACE-I: no cough, ↓angioedema Disadvantages compared to ACE-I: don’t affect (↑) bradykinin (∴ no vasodilaton) Mechanism of Action: blocks Angio2-1 Receptor (AT1)

- more effective angio stopper than ACE-I ∴ better ↑ vasodilation and duresis. Side Efx: orthostatic hypotension, hyperkalemia, fetotoxicity, hepatic dysfunction • Losartan (Cozaar) – prodrug → active metabolite is non-competitive inhibitor of receptor

o Also ↑ uric acid excretion & inhibits CYP450 • Irbesartan (Avapro) and Valsartan (Diovan) • Telmisartan (Micardis) – longest half-life; not excreted by kidneys Renin Inibitor • Aliskiren (Tekturna) – nonpeptide inhibitor of renin → no Angio1

o NEVER used alone; usually used with A2RB (like Valsartan)

L-type Calcium Channel Blockers (CCB’s) • Verapamil – a phenylalkylamine; tx angina and arrhythmias; ↓↓ contractility + AV conduction

o Good Tx for healthy patients with HTN + arrhythmias or angina.

• Diltiazem – benzothiazepine; good intermediate (can ↓P without ↑↑ reflex tachychardia) • Dihydropyridines: Amlodipine (long acting), Nifedipine (short acting), Nicardipine, etc

o Tx HTN (may use with diuretic to ↓ edema) o ↑ selectivity for L-type vascular smooth muscle (not cardiac)

10

Congestive Heart Failure (CHF) The Death Spiral:

1) something causes activation of sympathetics and renin/aldo system - may be ↓CO, MI, HTN, or other problem with volume or pressure overload 2) ↑NE, Angio2, Aldo, Vasopressin, Endothelin - ↑ contractility and HR via vasoconstriction (↑preload + afterload) and fluid

retention (note that this also ↑O2 demand). 3) Initially helpful, but prolonged presence causes problems = Maladaptive responses: - myocyte hypertrophy prevents effective contractility AND ↑O2 demand. - peripheral and pulmonary edema (from vasoconstriction) → orthopnea + PND - interstitial fibrosis, apoptosis, and arrhythmias. Many of the above drugs are used for Tx!!!

Which one do you use???

ACE Inhibitors are #1 o clinically proven to reduce

morbidity/mortality in CHF!!! o They “balance” vasodilation (via Bradykinin) and ↓ myocyte hypertrophy.

Use AT2-Blockers instead of ACE-I (maybe equally effective) if cough develops • Digoxin (Lanoxin) – a digitalis glycoside that ↑Ca++ intracellularly for ↑contractility.

o Mechanism of Action: blocks Na+/K+-ATPase causing ↑Na intracellularly, which allows ↑ activity of Na+/Ca++ exchanger, which ↑Ca++ intracellularly → ↑ contractility.

o 1° Tx: severe CHF w/ low EjFr. o Side efx: many drug interactions, including diuretics (↑arrythmias), warfarin;

Individual response to digoxin is highly variable.

• Milrinone (Primacor) – phosphodiesterase inhibitor → ↑cAMP; short-term IV use only • Bosentan (Tracleer) – competitive Endothelin-1 Receptor antagonist → vasodilation

o Tx: CHF, pulmonary arterial HTN (fatal w/ no great tx) o Side efx: teratogenic, hepatotoxicity, hole in wallet (very expensive!)

• Bepridil (Vasocor) – a miscellaneous anti-HTN that inhibits both L-type Ca++ & Na+ channels o Side efx: arrhythmias, agranulocyosis

• Vasopeptidase Inhibitors: Omapatrilat & Sampatrilat

1

A 73A 73--yearyear--old woman with congestive heart old woman with congestive heart failure requires treatment with failure requires treatment with digoxindigoxin[[LanoxinLanoxin] to improve cardiac muscle ] to improve cardiac muscle contractility and reduce her SOB. contractility and reduce her SOB. DigoxinDigoxinworks by:works by:A.A. Activating betaActivating beta--adrenergic receptor in the adrenergic receptor in the heartheartB.B. Increasing the synthesis of Increasing the synthesis of cAMPcAMPC.C. Directly activating G proteinsDirectly activating G proteinsD.D. Releasing mitochondrial calcium from Releasing mitochondrial calcium from storagestorageE.E. Inhibiting the sodium/potassium Inhibiting the sodium/potassium ATPaseATPase

A 50 yearA 50 year--old man with wellold man with well--controlled type II controlled type II diabetes and normal renal function requires an diabetes and normal renal function requires an oral agent to treat his hypertension. Select the oral agent to treat his hypertension. Select the best agent from this group of drugs.best agent from this group of drugs.A. A. AtenololAtenololB. B. NifedipineNifedipineC. HydrochlorothiazideC. HydrochlorothiazideD. D. CaptoprilCaptoprilE. E. VerapamilVerapamil

Which of the following drugs would be most Which of the following drugs would be most likely to trigger an attack of gout in an likely to trigger an attack of gout in an individual who is individual who is hyperuricemichyperuricemic??A. A. AtenololAtenololB. B. NifedipineNifedipineC. C. HydrochlorothiazideHydrochlorothiazideD. D. CaptoprilCaptoprilE. E. VerapamilVerapamil

Which of the following is representative of a class of agents that is contraindicated in pregnancy by virtue of teratogenicity?A. A. AtenololAtenololB. B. NifedipineNifedipineC. HydrochlorothiazideC. HydrochlorothiazideD. D. CaptoprilCaptoprilE. E. VerapamilVerapamil

Which of the following would be a poor choice Which of the following would be a poor choice as an antihypertensive in an individual with as an antihypertensive in an individual with insulininsulin--dependent diabetes because it masks the dependent diabetes because it masks the symptoms of hypoglycemia and may delay symptoms of hypoglycemia and may delay recovery from a hypoglycemic episode?recovery from a hypoglycemic episode?A. A. AtenololAtenololB. B. NifedipineNifedipineC. HydrochlorothiazideC. HydrochlorothiazideD. D. CaptoprilCaptoprilE. E. VerapamilVerapamil

An asthmatic requires antihypertensive An asthmatic requires antihypertensive therapy. Which of the following potential drug therapy. Which of the following potential drug choices would be most likely to exacerbate the choices would be most likely to exacerbate the pulmonary condition?pulmonary condition?A. A. AtenololAtenololB. B. NifedipineNifedipineC. HydrochlorothiazideC. HydrochlorothiazideD. D. CaptoprilCaptoprilE. E. VerapamilVerapamil

2

Which of the following Which of the following antihypertensivesantihypertensives would would exacerbate COPD or asthma by thickening the exacerbate COPD or asthma by thickening the airway mucous, thereby obstructing the airway mucous, thereby obstructing the airways?airways?A. A. AtenololAtenololB. B. NifedipineNifedipineC. C. HydrochlorothiazideHydrochlorothiazideD. D. CaptoprilCaptoprilE. E. VerapamilVerapamil

Compared with Compared with nifedipinenifedipine, , diltiazemdiltiazem and and verapamilverapamil::A. are suitable for use in conjunction with a A. are suitable for use in conjunction with a betabeta--blocker or blocker or digoxindigoxinB. cause more reflex tachycardiaB. cause more reflex tachycardiaC. C. produce a greater slowing of AV nodal produce a greater slowing of AV nodal conductionconductionD. cause significant D. cause significant venodilationvenodilation leading to leading to profound orthostatic hypotensionprofound orthostatic hypotensionE. produce more significant positive E. produce more significant positive ionotropicionotropiceffectseffects

Compared to Compared to captoprilcaptopril, , losartanlosartan::A. Has a higher incidence of A. Has a higher incidence of bronchospasmbronchospasm and and hyperuriciemiahyperuriciemiaB. is B. is preferedprefered for managing hypertension during for managing hypertension during pregnancypregnancyC. C. doesndoesn’’t inhibit synthesis of t inhibit synthesis of angiotensinangiotensin IIIID. blocks catecholamineD. blocks catecholamine--mediated mediated vasoconstrictionvasoconstrictionE. should only be used after other drug classes E. should only be used after other drug classes like calcium channel blockers and betalike calcium channel blockers and beta--blockers blockers have been tried and found to be ineffectivehave been tried and found to be ineffective

A 57 yearA 57 year--old man with CHF being treated with old man with CHF being treated with digoxindigoxin, , furosemidefurosemide and and captoprilcaptopril now presents now presents with awith a--fib. Serum electrolytes are normal and fib. Serum electrolytes are normal and the the digoxindigoxin level is at the upper end of the level is at the upper end of the normal range. After electrical conversion, he is normal range. After electrical conversion, he is started on anticoagulant therapy, together with started on anticoagulant therapy, together with an antian anti--arrhythmic agent, arrhythmic agent, quinidinequinidine. What is the . What is the most likely outcome of the last addition?most likely outcome of the last addition?A. development of A. development of quinidinequinidine toxicitytoxicityB. B. development of development of digoxindigoxin toxicitytoxicityC. inhibition of C. inhibition of furosemidefurosemide renal activityrenal activityD. increased D. increased angiotensinangiotensin levelslevels

AngiotensinAngiotensin--converting enzyme inhibitors are converting enzyme inhibitors are associated with a relatively high incidence of:associated with a relatively high incidence of:A. hepatitisA. hepatitisB. B. hypokalemiahypokalemiaC. C. agranulocytosisagranulocytosisD. D. proteinuriaproteinuriaE. E. hirsutismhirsutism

““Do not administer this drug to patients with Do not administer this drug to patients with secondsecond--degree or greater heart block or degree or greater heart block or administer with other drugs that produce heart administer with other drugs that produce heart block.block.”” To which of the following would such a To which of the following would such a warning justifiably apply?warning justifiably apply?A. A. CaptroprilCaptroprilB. B. LosartanLosartanC. C. NifedipineNifedipineD. NitroglycerinD. NitroglycerinE. E. VerapamilVerapamil

3

A 43A 43--yearyear--old man asks his physician for a old man asks his physician for a prescription for prescription for sildenafilsildenafil [Viagra] to enhance [Viagra] to enhance his sexual performance. Due to lifehis sexual performance. Due to life--threatening threatening hypotension, this drug should not be used in hypotension, this drug should not be used in patients receiving which of the following drugs?patients receiving which of the following drugs?A. ACE inhibitorA. ACE inhibitorB. BetaB. Beta--blockerblockerC. C. NitrosovasodilatorNitrosovasodilatorD. D. ThiazideThiazide diureticdiureticE. ATE. AT--1 blocker1 blocker

DiureticDiuretic--induced induced hypokalemiahypokalemia can have can have significant clinical consequences. Which of the significant clinical consequences. Which of the following is least likely to produce this following is least likely to produce this condition?condition?A. A. AmilorideAmilorideB. B. BumetanideBumetanideC. HydrochlorothiazideC. HydrochlorothiazideD. D. MetolazoneMetolazoneE. E. TorsemideTorsemide

AmilorideAmiloride and and triamterenetriamterene produce their produce their potassiumpotassium--sparing effects by:sparing effects by:

A. A. blocking tubular Na+ channels and therefore blocking tubular Na+ channels and therefore Na+/K+ exchangeNa+/K+ exchange

B. enhancing the binding of B. enhancing the binding of aldosteronealdosterone to its to its receptorsreceptors

C. Hastening metabolic inactivation of C. Hastening metabolic inactivation of aldosteronealdosterone

D. Inhibiting proximal tubular Na+/K+D. Inhibiting proximal tubular Na+/K+--ATPaseATPaseE. E. supressingsupressing cortisolcortisol and and aldosteronealdosterone release release

from the adrenal cortexfrom the adrenal cortex

Most diuretics (not osmotic diuretics) can Most diuretics (not osmotic diuretics) can significantly increase the toxicity of:significantly increase the toxicity of:A. A. cholestyraminecholestyramineB. B. lithiumlithiumC. C. nifedipinenifedipineD. D. phenylephrinephenylephrineE. E. statinstatin--type antitype anti--lipemiclipemic agentsagents

A patient who is being treated with A patient who is being treated with furosemidefurosemideand and digoxindigoxin develops signs and symptoms of develops signs and symptoms of digoxindigoxin toxicity, although a check of levels toxicity, although a check of levels reveals that they are reveals that they are ““within normal limits.within normal limits.””Which of the following likely accounts for the Which of the following likely accounts for the development of toxicity?development of toxicity?A. A. DigoxinDigoxin displacement from plasma protein displacement from plasma protein binding sitesbinding sitesB. B. HypocalcemiaHypocalcemiaC. C. HypokalemiaHypokalemiaD. D. HyponaremiaHyponaremiaE. Reduction in E. Reduction in digoxindigoxin metabolism metabolism

A patient with CHF has a 3A patient with CHF has a 3--year history of year history of successful treatment with successful treatment with digoxindigoxin and and furosemidefurosemide. . Following the development of Following the development of osteoosteo--arthritis, he arthritis, he begins highbegins high--dose therapy with a nondose therapy with a non--specific (COXspecific (COX--1 & 2) non1 & 2) non--steroidal steroidal antiinflammatoryantiinflammatory agent. Which agent. Which of the following is the most likely outcome?of the following is the most likely outcome?A. A. HyperchloremicHyperchloremic acidosis, indicative of acute acidosis, indicative of acute diuretic toxicitydiuretic toxicityB. Dramatic increase in B. Dramatic increase in furosemidefurosemide’’ss potassiumpotassium--sparing effectsparing effectC. C. Edema, weight gain and other signs/symptoms of Edema, weight gain and other signs/symptoms of reduced reduced diuresisdiuresisD. Rapid onset of D. Rapid onset of digoxindigoxin toxicity due to reduce toxicity due to reduce drug eliminationdrug eliminationE. Reduced E. Reduced digoxindigoxin activity because of competition activity because of competition with the NSAID at the with the NSAID at the myocytemyocyte receptorreceptor

4

A patient on which of the following drugs is A patient on which of the following drugs is most likely to develop most likely to develop hyponatremiahyponatremia??A. A. BumetanideBumetanideB. B. FurosemideFurosemideC. C. HydrochlorothiazideHydrochlorothiazideD. D. TorsemideTorsemideE. E. MannitolMannitol

↑↑↓↓0000↑↑↑↑D.D.↑↑↑↑0000↓↓↑↑C.C.00↑↑↑↑↑↑↑↑↑↑B.B.

0/0/↑↑↑↑↑↑↓↓↑↑↑↑A.A.HCOHCO33

--ClCl--MgMg2+2+CaCa2+2+KK++NaNa++DRUGDRUG

Which of the following drugs produces the qualitative change in urinary electrolyte profileshown in line B?shown in line B?A. A. TriamtereneTriamtereneB. B. FurosemideFurosemideC. HydrochlorothiazideC. HydrochlorothiazideD. D. AcetazolamideAcetazolamideE. E. AmilorideAmiloride

Rx for Angina

1. Nitrates: Nitroglycerin − NO cGMP PKG relaxation of VSMC − FX:

• Venodilation preload – (do NOT affect afterload!) − *higher doses (e.g. IV) can arterial vasodilation*

• Coronary Vasodilation • Pulm Vasc R • slight CO • BP ~same • HR ~same

− Side Fx: • Hypotension

− Reflex symp stim: tachycardia, contractility − coronary perfusion

• paradoxical worsening of angina pectoris − *** do NOT take w/ Sildenafil (Viagra) or HYPOtension − Preparations (to help w/ rapid absorp & 1st pass metab): see slide 14 & 15! − Tolerance – avoid by having 8-12 hrs w/o Rx each day. − Anginal Rebound – do NOT stop IV suddenly or coronary vasospasm.

2. B-blockers: *slide 31 chart • Propranolol, Timolol – cardioprotective • Naldolol – water soluble • Pindolol, Labetolol – ISA • Acebutolol –ISA; B1 selective • Esmolol – B1 selective • Metoprolol – B1 selective; cardioprotective • Atenolol – B1 selective; cardioprotective; water soluble • FX:

− *Tx exertional angina – HR & inotropy response to stress; myocard O2 demand − Tx post-MI − CNS fx afterload (NOT preload) − Do NOT prevent coronary vasospasm – ineffective in vasospastic angina!

• Side Fx: (mostly non-cardiac fx, B2) − Bronchospasm, hypoglycemia, CNS fx, alopecia − * Contraindications:

• Asthma, labile type II diabetes, depression • COPD, PVD – may use B1-selective • Sinus bradycardia, SA/AV block, decompensated CHF

− Do NOT suddenly w/draw rebound tachycardia unstable angina or MI!

3. Ca2+-Channel Blockers: L-type Ca2+ channels only. *Slide 24 • ALL PREGNANCY CATEGORY C • * B-blockers considered 1st choice for angina! Use CCB when pt can’t tolerate BB, or BB +

nitrate does not work. • Non-DHP: use-dependent, i.e. access in the open state of the channel – target CARDIAC

− Verapamil • Reduces clearance of Digoxin • Constipation

− Diltiazem − FX of Both: (Verapamil > Diltiazem)

• HR; slow AV cndxn; contractility – do NOT use w/ CHF pt’s! − myocardial O2 demand

• arteriolar vasodilation afterload (NOT preload – do not relax vv) • Coronary vasodilation prevent or reverse vasospasm

− Side FX of Both: • * Bradycardia, asystole, SA/AV block – do NOT use w/ B-blockers! • CHF • * CYP3A4 – metabolized by and inhibit CYP3A4! – see slide 27 for drug interaxn.

• Dihydropyridines: voltage-dependent, i.e. access @ certain membrane potential – target VSMC − Nifedipine, Amlodipine, Nicardipine − Felodipine – longer t1/2 than others. − Isradipine - *use in pt’s w/ CHF (no negative inotropy); also longer t1/2 than others! − FX:

[More potent vasodilators more indirect fx. overall fx more subtle than non-DHP] • * Afterload & coronary vasodilation main antianginal fx

− use w/ angina + left-sided valvular insufficiency • HR & contractility: overall no change.

[b/c reflex symps contractility, tachycardia] • All DHP better in pt’s w/ CHF than non-DHP (esp. Isradipine)

− Side Fx: • excessive vasodilation hypotension • periph edema (b/c precap aa dilation) • paradox. exacerbation of angina – b/c less blood to heart

4. Combo’s:

• *BB + Nitrate* − BB prevents reflex tachycardia & contractility from Nitrate hypoT − Nitrates prevent coronary vasospasms & increased LV EDV (preload) from BB − Both: myocardial O2 consumption & subendocardial blood flow

(diff mech’s)

• *BB + DHP* - (slow-release or long-acting DHPs) − DHPs prevent coronary vasospasm & systemic vasc R (afterload) − BB prevents reflex tachycardia of DHPs

• BB + non-DHP – don’t do it! – marked fatigue; extreme bradycardia; AV block!

1

Anti-Arrhythmic Drugs – Assessment 5

Clinical approach to tx arrhythmias: 1. Assess the Rhythm and Symptoms 2. Identify and Treat underlying cause of arrhythmia (caffeine, CHF, hypokalemia, drugs…) 3. Then assess need for drugs/AICD. 1.) Class 1: Na+ Channel Blockers

• Action: decrease membrane responsiveness by binding to “open” & “inactivated” channels o ↓ rate of rise of phase 0 depolarization (“tilted”) → ↓ conduction velocity o fewer Na+ Channels → delayed recovery → ↑ ERP (effective refractory period)

• Side Efx: Torsades de Pointes, reports of ↑mortality post-MI • Those with (T) < 1sec. (super fast!) ∴no interference with normal fxns, but will interfere

with tachycardia by interrupting re-entry.

o Lidocaine (Xylocaine) – ↓ automaticity in ventricles only • lipid soluble ∴toxicity usu. manifests w/ CNS problems • IV only (short half-life and very high 1st pass metabolism)

o Mexilitine (Mexitil) – same, except orally effective w/ GI distress ∴↓ use

• Those with (T) > 1sec. (fast) – prolong AP – overall bad side efx ∴↓ use o Quinidine (Quinidex) – tx chronic/outpatient arrhythmias.

o Procaineamide (Procan-SR) – IV only, use limited to acute control of

arrhythmias b/c bad side efx long term (SLE, GI intolerance, hyperkalemia).

o Disopyramide (Norpace) –

• Those with (T) > 10 sec. (eh, not so fast) - ↓conduction velocity ∴ prolong QRS

o Flecainide (Tambocor) – cardiac depressant ∴many bad side efx. • Clinical use limited to: WPW, supraventricular arrhythmias w/out any

structural heart disease.

o Propafenone (Rhythmol) – limited use in atrial arrhythmias.

2

2.) Class 2: β-Blockers • Reduce mortality post-MI (by tx sx like ischemia + Vfib)

o Adrenergic blocking → ↓conduction velocity and ↑ERP of AV node o ↓ automaticity in all conducting heart tissues (if caused by Ach or ischemia)

• specific for anti-arrhythmias b/c they are cardio-protective. o Used to tx DAD (delayed after-depolarizations, ie, intracellular Ca++ overload) o Can tx Torsades de Pointes

• Metoprolol - β1 selective; use for arrhythmias is “off-label” use, but common. • Propanolol - • Timolol -

3.) Class 3: K+ Channel Blockers – prolong repolarization → ↑ERP + suppress reentry

o Pacemaker rhythm of SA + AV nodes is mediated by special K+ channels undergoing automaticity.

o Hierarchy of Pacemakers (backup plan): SA > Atrial > AV > Purkinje > Ventricular o Common bad side efx: Torsades de Pointes

• Amiodarone (Cordorone) – has class 1 and 3 actions!!!!!! And some class 2 actions. o Tx: acute life-threatening (ex: Vtach) or chronic Afib, Vfib o drug of choice in cardiac rescuscitation. Most effective in maintaining rhythm

after Afib, BUT pts still have 80% recurrence within 1 yr. o Half-life is 20-200 DAYS (accumulates in tissues) o Side efx: Inhibits CYP3A4, pulmonary fibrosis, hypo- & hyper-thyroidism,

blindness, ↓liver o Good: Torsades de Pointes is rarer b/c of BB + Na+B effects.

• Sotolol (Betapace) – mostly class 3, but has some non-selective β-Blocker effects.

o Overall, a good drug choice. Tx A + V arrhythmias. o Contraindicated in: COPD, renal insufficiency, overt CHF, AV block, bradycardia o Side efx: BB (bradycardia, bronchospasm). Can be used with other BB’s but

watch HR carefully.

• Bretylium (Bretylol) – emergency IV; inhibits NE release → profound orthostatic HTN (last resort drug).

• Ibutilide (Convert) – IV for acute Vfib

• Dofetilide (Tikosyn) –

3

4.) Class 4: Calcium Channel Blockers (CCB’s)

• Verapamil and Diltiazem

• Actions: SA + AV depolarization is Ca++ dependent, so CCB’s slow conduction velocity specifically in the AV node → ↑ ERP

o Good for preventing re-entry. o Wouldn’t this also cause bradycardia b/c slowing of SA node, too?? No, b/c the

drug is AV node specific. Handy. • Side Efx:

o SA, AV block o Impaired contractility o Hypotension o No significant protection post-MI o Contraindicated in WPW pts

• When would you use them? o Tx atrial arrhythmias in Pts with normal LV function, or who can’t tolerate BB’s

5.) Digoxin

• Vagal stimulation → ↓conduction velocity and ↑ERP of AV node only o Also ↓SA node automaticity o Mechanism of Action: blocks Na/K ATPase

• Side Efx: atrial fibrillation (paradoxical effect) o Paradoxical Effect: vagal stimulation in atrium → shorter AP, ↑ conduction

velocity, and ↓ERP in the atrial cells. That’s why AFib is a common side efx. o Contraindicated in WPW pts b/c ↑ conduction through 3rd pathway.

6.) Adenosine

• Tx: acute PSVT by blocking AV node • Short half-life (10 seconds) • Side Efx: tight chest, flushing, recurrence of fib. • Interactions

o Methylxanthines (like caffeine) blocks adenosine receptors o Dypyridamole prevents uptake so effect potentiated. o Contraindicated in WPW pts.

7.) Implantable Defibrillators: AICD. Effective chronic tx of arrhythmias.

• Studies show 50% reduction in mortality. • Drug therapy may accompany AICD to reduce frequency of discharge.

4

Review: - Good drug class for tx automaticity (DAD): β-Blockers - Good drugs classes for tx re-entry: Class 1 (Na+ Blockers) and Class 3 (K+ blockers) - Good drugs to tx paroxysmal supraventricular tachycardia (re-entry @AV node):

Ca++ Blockers, Digoxin, β-Blockers, and Adenosine. - Good drug for stopping Torres des Pointes? First MgSO4 (then maybe BB.)

Treatment of Choice: the final chart from the Anti-Arrhythmia lectures. Arrhythmia Drug/Device of Choice Alternatives Atrial Fibrillation (Afib) (Rate Control)

CCB, BB, Digoxin None

Atrial Fibrillation (conversion to SR)

DC Cardioversion IV procaineamide or ibutilide,

Oral propafenone or flecainide.

Atrial Fibrillation (Maintinence of SR)

Amiodarone, Sotolol, Flecainide, Propafenone, Dofetilide

Quinidine, procaineamide, disopyramide

Supraventricular Tachy. (SVT, acute termination)

IV adenosine or CCB IV esmolol, some other BB, or digoxin

SVT (long-term suppression)

BB, CCB, flecainide, propafenone, amiodarone, sotolol, or digoxin

Quinidine, procainamide or disopyramide

Ventricular Premature Contractions (VPC)

If asymptomatic, no drugs. BB for pts with symptoms

Ventricular Tachycardia (SCD or post-MI with ↓ EjF)

AICD Amiodarone, sotolol, procainamide, mexilitine

Cardiac Glycoside-induced Ventricular Arrhythmias

Dogoxin – immune Fab Lidocaine, Phenytoin

Torsades de Pointes (Drug-Induced)

IV magnesium sulfate (and remove offending drug!)

Cardiac Pacing, isoproterenol

Hyperuricemia and Gout

1. Hyperuricemia = >7mg/dL uric acid in plasma

• Causes: − 1. Metabolic (10%)

• Primary: specific enzyme abnl’s • Secondary: synth too much purine

− certain blood disorders − chemo- or radiation Tx

− 2. Renal (90%) • Primary: kidney Dz (renal failure) • Secondary:

− long-term diuretic Tx − toxemia of pregnancy

2. Purine Metabolism:

3. Tx Goals & Rx:

• Acute attack – terminate − Colchicine, Indomethacine

• Acute gouty arthritis – prevent recurrence − Colchicine

• Ureate crystal deposition – reverse/ prevent complications − Allopurinol; Probenecid, Sulfinpyrizone

• Kidney stones – prevent formation − Allopurinol

• Other assoc’d factors – prevent 4. Colchicine

Hypoxanthine guanine phosphoribosyl transferase (HGPRT)

Xanthine Oxidase (X.O.)

Xanthine Oxidase (X.O.)

PRPP synthase

• MECH: depolymerizes m-i-c-r-o-t-u-b-u-l-e-s • TX: only against gouty arthritis

− Terminate acute attacks of gout − Prevent recurrence of gouty arthritis − Familial Mediterranean fever

• SIDE FX: − GI – acute − Blood dyscrasias – chronic

• note: dyscrasia = a morbid general state resulting from the presence of abnl material in the blood, usu applied to diseases affecting blood cells or platelets.

5. Indomethacine • PHARM:

− COX inhibitor − Analgesic, antipyretic − Inhibit leukocyte motility

• TX: acute attack • PK: 50mg, 3x/day • SIDE FX(toxic):

− GI: N/V, ulcers (b/c COX inhibitor!) − CNS: severe frontal headache − Hematopoietic disorders − Antagonizes Furosemide & HCTZ

6. Allopurinol • MECH:

− Competitively inhibits X.O. − Oxypurinol – non-competitively inhibits X.O.

• FX: − UA in plasma and urine − xanthine & hypoxanthine in plasma and urine – i.e. oxypurine precursors − dissolve UA crystals in joints and kidneys − prevent UA kidney stone formation

• * TX: − 1o Hyperuricemia:

• gout due to enzyme abnl’s • children w/ familial juvenile hyeruricemic nephropathy

− 2o Hyperuricemia: • hematologic disorders (e.g. multiple myeloma) • chemo-Tx

• SIDE FX: − acute gout incidence − Hypersensitivity rxns: Dermatitis (2%), Exfoliative dermatitis

• Desensitize w/ Low dose of allopurinol OR substitute Oxypurinol − Liver fnxn fx − 6-mercaptopurine interaxn dose to 25% − Ampicillin (& related antibiotics) – contraindicated!!

7. Uricosuric Agents – (Probenecid & Sulfinpyrizone)

• Renal Handling of UA (pic below) − 1. Filtered in glomerulus

− 2. Reabsorbed in PT (= pre-secretory reabsorption) − 3. Secreted − 4. Partially reabsorbed (= post-secretory reabsorption)

• Probenecid − MECH:

• Inhibits transport of organic anions across epith barriers • Interferes w/ UA reabsorp by organic acid transporter (brush border of PT)

− FX: • UA excretion if pt excretes <1g/day • Dissolve UA crystals in joints

− [Note: given w/ adequate hydration to pt w/ good renal fnxn] − SIDE FX:

• Salicylates inhibit uricosuric action – e.g. aspirin! • Sulfinpyrizone

− MECH: (same as Probenecid) − FX:

• More potent than Probenecid in mobilizing UA crystals • (otherwise same)

− SIDE FX: • GI fx • Blood dyscracias • Inhibits metab of oral hypoglycemics hypoglycemia • platelet lifespan

Antihistamines (not included: slides 1-18) I. First Generation

A. Drugs: --- * see slide 24 for comparison

1. Ether or ethanolamine derivatives:

a) Diphenhydramine (Benadryl)

b) Deminhydrinate (Dramamine)

c) Clemastine (Tavist)

2. Alkylamine derivatives:

a) Chlorpheniramine (Chlor-Trimeton)

b) Brompheniramine (Dimetane)

c) Triprolidine (Actidil)

3. Phenothiazine derivatives: *the most sedative & antiemetic

a) Promethazine (Phenagren)

4. Piperazine derivatives:

a) Cyclizine (Marezine)

b) Meclizine (Antivert)

c) Hydroxyzine (Atarax)

5. Ethylenediamine derivatives:

a) Tripelennamine (Pyrabenzamine Citrate)

B. Properties:

1. based on histamine structure

2. often short-lived -- multiple dosing -- piperazines can last longer (4-24hrs)

3. highly sedative – lots of rings, not very polar cross BBB inhib H1 in hypothalamus

4. anti-cholinergic side fx – (bind to muscarinic R potent antiemetic)

5. GI cramps (+ /++)

6. NOT anti-asthmatic (*asthmatics should not use these drugs)

7. do NOT inhibit Histamine release

C. Tx:

1. s/s - allergy & hayfever (rhinits & urticaria)

2. s/s - insect bites/ stings; contact flora

3. * motion sickness & vertigo – specific to 1st gen.

a) CN VIII (Musc R) vomit center chemoreceptor trigger zone emesis

D. Side FX:

1. *sedation, decreased alertness, slowed rxn time; insomnia (? – slide 41)

2. impaired cognition, confusion, dizziness

3. dystonia

4. potentiation of nasal congestion

II. Second Generation A. Drugs --- *slide 31 compares

1. Piperidine derivatives

a) Loratadine (Claritin)

b) Terfenadine (Seldane)

(1) Taken off the market due to cardiotoxicity: when combo’d w/ macrolide antibiotics or imidazole antifungals (hepatic metabolism) increase serum Seldane bind heart K+ channels severe arrhythmias

(2) Developed Fexofenadine (Allegra) – active metabolite of Seldane.

(a) Excreted by kidney w/o hepatic metabolism avoid Rx interaxns

(b) all of the newer 2nd generation antiH also have much lower affinity for K+ channels!

c) Astemizole (Hismanal)

(1) same problems as Seldane!

2. Alkylamine derivatives

a) Acrivastine (Semprex)

b) Telemastine

3. Piperazine derivatives

a) Cetirizine (Zyrtec) [ appetite stimulation]

B. Properties:

1. Structures divergent, diff from Histamine

2. Longer duration of axn -- single/ multiple dosing; better compliance

3. limited or non-sedating – structures more polar, limited ability to cross BBB

4. limited or no anti-cholinergic fx – NOT antiemetic

5. Anti-asthmatic (++) – not prescribed as antiasthmatics, but safe for asthmatics to use

6. NOT sedative; NOT anti-cholinergic; do NOT cause GI cramps; do NOT inhib H release

C. Tx:

1. s/s - allergy & hayfever (rhinits & urticaria)

2. s/s - insect bites/ stings; contact flora

D. Side FX:

1. mild cognitive disturbance

2. appetite stimulation – Zyrtec

III. Other – may consider in 2nd gen, but different… A. Desloratadine (Clarinex)

1. more specific

a) H1: 14-17x greater binding than Loratadine (Claritin)

b) Muscarinic: 15-50x lower affinity than for H1

2. rel long t1/2 = 27 hrs

B. Olopatadine (Patanol)

1. *inhibits release of Histamine from mast cells – the ONLY H1 blocker that does this.

2. more selective for H1 than other ocular anti-H: ketotifen, levocabastine, antazoline, pheniramine

3. Tx: ocular rhinitis

C. Levocabastine (Livostin)

1. *more specific for H1 than anything else!

a) 1250x more potent than 1st gen (chlorpheniramine)

2. low side fx – even w/ 40,000x effective dose; ocular application does not bother eyes; nasal application fast release of s/s (minutes)

3. Tx: ocular rhinitis

D. Azelastine (Astelin)

1. inhibits histamine, leukotriene, and PAF activity

2. long t1/2

3. Tx: rhinitis & hay fever

a) Can use in asthma pt’s!

b) * not used to treat asthma directly

4. Side FX:

a) Somnolence, bitter taste, nasal burning, sore throat, dry mouth

b) Teratogenic w/ high doses – avoid in Pg

* Slide 41 – good review of 1st gen vs. 2nd/3rd Names: 1st gen: -amine -zine… except Cetirizine (Zyrtec) which is 2nd gen Also: Deminhydrinate (Dramamine), Clemastine (Tavist), & Triprolidine (Actidil) 2nd gen & “other”: -adine -astine… except Clemastine (Tavist) which is 1st gen Remember Cetirizine (Zyrtec) is 2nd gen Astemizole (Hismanal) too – which is no good anyway b/c of cardiotoxicity w/ Rx interaxns

Asthma and COPD Note: slides 5-9, 18, 33, 38 not included here

I. Adrenergic Agonists: Bronchodilators A. Non-Specific: all have hyperT & cardiac fx

1. Epinephrine – B1B2α1α2 – lasts 30-90min

2. Ephedrine - B1B2, some α

3. Isoproterenol - B1B2

B. B2 specific – fast: Metaproterenol, Albuterol, Terbutaline

1. “relievers”

2. quick onset + intermed dur (3-6hr)

C. B2 specific – slow: Salmeterol, Formoterol 1. “preventers” – commonly for nighttime or exercise-induced asthma

2. slower onset + long dur (12+ hr)

D. FX:

1. B-agonists stim Adenylyl Cyclase cAMP bronch dilation (pic slide 11)

2. Other:

a) some inhib of release of mediators from mast cells

b) some inhib of microvasc perm

c) slight promotion of mucociliary transport

E. FX:

1. nausea, vomiting, headache

2. BP, HR, cardiac arrhythmias

3. PaO2 CNS toxic fx: agitation, convulsions, coma, respiratory & vasomotor collapse

II. Cholinergic Antagonists: Bronchodilators –

A. Atropine B. Ipratropium

1. quarternary cpd – poorly absorbed – no systemic fx

C. FX of BOTH:

1. (cause competitive Ach-muscarinic blockade)

2. airway smooth m constrxn

3. mucous secretion

4. B2-mediated bronchodilation

D. SIDE Fx:

1. on contact: pupillary dilation & cycloplegia (loss of fnxn of ciliary m)

NOTE: Combivent = Albuterol + Ipratropium –(combined B2 agonist + Muscarinic antag) greater improvement in lung fnxn than either alone. --- Tx: COPD

III. Methylxanthines: Bronchodilators and Anti-Inflammatory – Aminophylline, Theophylline

A. Mech and 1o FX: - (pic slide 16)

1. inhibit PDE cAMP bronchodilation

2. block muscle adenosine receptors bronchodilation

3. release of mediators anti-inflamm

B. Other FX:

1. + chronotropic, + ionotropic

2. CNS activity, gastric acid secretion, diaphragm m strength

3. weak diuretic effect

C. SIDE Fx:

1. 10-20ug/mL serum nausea, vomiting, nervousness, headache, insomnia

2. >20ug/mL serum vomiting, hypoK, hyperglycemia, tachycardia, arrhythmias, tremor, neuromuscular irritability, seizures

IV. Cromolyns: Anti-Inflammatory – Cromolyn, Nedocromil

A. FX:

1. alter Cl- channel activity

2. mast cells in lung – inhib degranulation

3. eosinophils – inhib inflamm response

4. airway nn – inhibit cough

5. bronchial hyperactivity assoc’d w/ exercise- and inhaled Agn-induced asthma

B. SIDE Fx:

1. (No systemic toxicity)

2. bad taste (inhaled Nedocromil)

3. irritation of trachea cough, bronchospasm after inhalation

4. Rarely: chest pain, restlessness, hypoT, arrhythmias, nausea, vomiting, CNS depression, seizures, anorexia

V. Corticosteroids: Anti-Inflammatory

A. Inhaled – Beclomethasone, Budesonide, Triamcinolone, Fluticasone

1. Side Fx:

a) Oropharyngeal candidiasis, hoarseness, dry mouth

b) bone density in premenopausal women

c) growth rate in children

B. Oral – Prednisone, Prednisolone

1. Side Fx: (prolonged use)

a) Glc intolerance

b) BP and weight

c) Bone demineralization

d) Cataracts

e) Immunosuppression

f) growth in children

C. FX of BOTH:

1. DNA binding/activation anti-inflamm proteins (this also side fx!)

2. Inhib transcription prdxn of inflamm proteins (cytokines, enzymes, adhesion molecules, etc)

3. mucus secretion

4. bronch hyperactivity

5. fx of B2 agonists

D. Cushingoid Syndrome:

1. weight gain: abdomen, moon face, buffalo hump

2. leg/arm muscle weakness and thinning

3. thin skin – easily bruised, stretch marks

4. women: acne, facial hair, scalp hair

5. ruddy complexion, neck skin darkening (acanthosis)

6. child obesity, poor growth

7. high BP

NOTE: Advair = Fluticasone + Salmeterol – (combined glucocorticoid + B2 agonist)

…BG on Luekotrienes (LT)… - (*slide 25 diagram) - Memb Phospholipids (PLA2) AA (5-LO) LTA4 LTB4 & LTC4, LTD4,

LTE4 receptors - LTB4 = neutrophil chemoattractant - LTC4 & LTD4 – mimic asthma symptoms – bronch hyperreactivity, bronchocnstrxn,

mucosal edema, mucus secretion VI. Leukotriene Receptor Blockers: Anti-Inflammatory –

A. Monteleukast – side fx:

1. GI disorders, laryngitis, pharyngitis, nausea, otitis, sinusitis (2% freq of viral infxn; more in pediatric pt’s)

2. NOT tumorigenic in rodents

B. Zafirleukast

1. GI disturbances, mild headache, liver enzymes in some pt’s

2. cancer risk: high doses in rodents hepatic & bladder cancer, hisocytic carcinoma

C. Mech of BOTH:

1. block LTD4 receptors

D. FX of BOTH (oppo. of axns of LTD4):

1. bronch reactivity and bronchocnstrxn

2. mucosal edema and hypersecretion

3. airway inflamm

E. Tx: aspirin-induced asthma (do not give COX inhibitors to asthma pt’s) VII. Leukotriene Syn Inhibitors: Anti-Inflammatory – Zileuton

A. Mech: inhibits 5-lipoxygenase inhibits LT formation (LT-B,C,D,E-4)

B. FX:

1. smooth m cntrxn

2. blood vessel perm, leukocyte migration to damaged area

C. SIDE Fx: 1. hepatic enzymes – req’s LFTs (liver fnxn tests)

2. metab’d by and inhibits CYP1A2 – interaxn w/ theophylline (& others)

VIII. Anti-IgE Monoclonal Aby: Anti-Inflammatory – Omalizumab A. Mech: binds IgE prevents IgE-mediated release of inflamm mediators decreases

allergic response.

B. FX:

1. severity & freq of asthma attacks

2. req of inhaled corticosteroids; improves long-term asthma control

C. SIDE Fx:

1. ***Anaphylaxis: difficulty breathing, closing of throat, swelling of face, lips, or tongue, hives – *do not give unless pt is under medical supervision*

2. Other: bruising, warmth, burning, stinging, itching, pain or inflamm @ injxn site; sore throat, cold symptoms

3. Tumors reported in some pt's

D. Contraindications – no known drug interaxns, but… avoid concurrent agents w/o consulting physician (like Rx, OTC, vitamins, herbal supplemements)

Stepwise Approach to Treatment:

Asthma vs. COPD

Contraindicated in Airway Dz: - sedatives - BBs - COX inhib’s (aspirin) - ACE inhib’s - Local anesthetics

COPD Tx Options: - Smoking cessation w/ nicotine

replacement (Bupropion +/- patch) - Bronchodilators: incl. Terbutaline,

Ipratropium, Formoterol, Salmeterol - Combo of Bronchodilators

- Theophylline, Aminophylline - Corticosteroids (poor response) - O2 Tx; mucolytics, KI, Guaifenesin,

N-acetylcysteine - Surgery, lung vol rdxn, lung

transplant

Immunosuppressants BG info slides 1-18, 40 not included. NOTE: Slides 19, 48, 51 = muy útiles. *trend to reduce exposure to calcineurin inhibitors & limit steroids, to use more specific Rx.

1. Polyclonal Aby’s (ATG = anti-thymocyte globulin) • Horse – ATGAM –adverse rxns in many pts • Rabbit – rATG – used much more than horse • BOTH:

− FX: NONSPECIFIC binding to T-cells lose 80-90% of T-cells; recover in 2 mos. − Uses:

• Bone marrow transplant • Organ transplant • Aplastic anemia

− * ~ TOLERANCE – i.e. w/ repeated use develop neutralizing Abys to these Abys! … so used to initially T-cells in induction.

− Side Fx: • Fever • Chills • hypoT • thrombocytopenia (platelets)

2. Anti-CD52 Aby: Alemtuzumab

• (humanized, mono-clonal) • CD52: esp on B & T (also on NK, monocytes, macro’s, platelets, male repro.) • FX:

− B & T most sensitive to lysis; cellular- or complement-mediated − Affect esp. blood & bone marrow; less in spleen & lymph nodes − Profound, long-term lymphopenia - *antibiotic prophylaxis necessary

• Side Fx: Infusion rxns common (chills, rigors, nausea/vomiting)

3. Co-stimulatory Molecules: Muromonab –CD3 • = IV mouse anti-CD3 Aby • FX:

− On CD3+,4+,8+ T-cells in peripheral blood & tissues − Reversible; normalize w/in 1 week

• *~TOLERANCE – pts can develop human-mouse Abys; no good if titer> 1:1000 • Side Fx:

− Acute hypersensitivity w/in minutes – b/c can activate immune system – do NOT use this Rx again.

− @ 30-60 min, symptoms cytokine-mediated (a lot of symptoms – slide 22) − * minimize w/ high-dose steroid pretreatment

4. Calcineurin Inhibitors: • Cyclosporine

− Hirsutism/hypertrichosis − Gingival hyperplasia

• Tacrolimus – 100x potency of Cyclosporine! − Neurotoxicity − CYP3A5 SNPs

• Pimecrolimus • FX for all:

− Inhibit 1st phase of T-cell activation by blocking NFAT-P NFAT by calcineurin • Inhibit activation of T (IL-2, IFγ) and B (IL-4)

• Side Fx for all: Calcineurin is widely expressed affect many other tissues. − *Renal toxicity – even though it may be given for renal transplant!

• due to renal vasocnstrxn • serum creatinine, BUN, K+, MAP • difficult to distinguish from graft rejection (20% have both) • stop drug – see cont’d deterioration in renal fnxn.– specific fx slide 24.

− Mild-moderate hyperT: symp tone; renal vasocnstrxn − Various infxns − 2o malignancies – lymphomas & skin cancers

5. Corticosteroids: Methylprednisolone

• Recall these have cytoplasmic receptor, then to nucleus for fx – takes hours. • FX:

− Low Dose: inflamm cytokine transcrip − High Dose: anti-inflamm gene transcrip − T & B inhibited; monocytes, eosinophils, neutrophils

• Side Fx: − CNS – confusion; psychosis – can happen in 2 wks, may be b/c of w/drawal − HPA suppression (hypothalamic pituitary adrenal axis) – in 5 days w/ high dose; long

Rx use 1 year recovery. − Steroid withdrawal sydrome – mood swings, arthralgias, etc

• Must TAPER off dosing to prevent all of these! − w/ prolonged dosing above physio levels: protein metab dysfnxn (myopathy,

osteoporosis, fractures, stunted growth), infxn, Cushing’s, hyperglycemia, DM aggravation, menstrual irreg, hypercholesterol, atherosclerosis, fat embolism, thrombosis, thromboembolism, phlebitis, neuro fx (insomnia, depression, anxiety), skin fx (atrophy, impaired healing) – wow.

6. CD25 Inhibitors:

• Daclizumab and Basiliximab • FX: Block IL-2Rα (CD25) on activated T-cell surface

− Impairs immune response to Agn challenge − * does NOT change lymphocyte # or phenotype – just prevents upreg

• Long elimination t1/2 – weeks • Side Fx: severe acute hypersensitivity; no increase in 2o malignancies

7. mTOR Inhibitors: Sirolimus • binds same thing as Tacrolimus (hence the name) BUT presents in different location…

• FX: inhibits mTOR (mammalian target of rapamycin) − Inhibits 2nd phase of T-cell activation (signal transduction & clonal prolif) G1 arrest − Prevents B-cell differentiation into Aby-producing cells

• IgM, IgG, IgA − Synergistic w/ Cyclosporine – but Sirolimus itself does not affect calcineurin! − Affects prolif of non-immune cells too, but no signif fx.

• Side Fx: − Hyperlipidemia – monitor − azotemia (=uremia), serum creatinine, GFR – monitor kidney fnxn. − Tumors − [Others slide 31]

• CYP3A4 & P-glycoprotein fx

8. Cell Cycle Disruptors:

• Mycophenolate mofetil − FX: inhibits IMPDH (inosine monoP deHase)

• IMPDH: IMP GMP; necessary in all tissues in S phase, BUT lymphocytes’ IMPDH is much more sucsceptible to MM.

• Affects mostly T & B cells – inhibits prolif b/c cannot make enough GMP • Advantages:

− Blocks 2o Aby responses of memory B cells − Selective on lymphocyte prolif – unlike Azathioprine, Methotrexate − no chrom breaks

− Side Fx: typical (GI fx, infxns, tumors) − Enterohepatic recirculation − [also: has been shown to reduce anti-A, anti-B RBC Aby’s in ABO incompatible pt’s]

• Azathioprine − FX: an S phase-specific purine antagonist

• Lymphocytes must rely on de-novo purine synthesis • Principal fx mediated by 6-thioguanine triphosphate – inhibits RAC1 – blocks

CD28 costimulation – promotes apoptosis, esp of memory T cells − Side Fx:

• Pregnancy category D; also avoid in lactation • risk skin cancer, esp w/ UV

− Other: • *many other side-paths that toxic/radical products

− pt w/ low TPMT increased toxic products, must decrease dose · e.g. on 5-aminosalicylates, which inhibit TPMT activity

− high TPMT, must increase dose • Allopurinol Aza toxicity • Decreased Warfarin levels

− * Before/during use: TPMT test, Pg test, skin exams

• Cyclophosphamide − prodrug − FX: lymphopenia, B > T ( greatest effect is suppression of humoral immunity) − Side Fx:

• Hematologic pancytopenia (leuko-, neutro-, thrombocyto-, anemia) is dose-limiting. • Acrolein (metabolite of cyclophosphamide) hemorrhagic cystitis –

Tx w/ hydration & MESNA • Menstrual irreg/ amenorrhea; *infertility • infxns

• Methotrexate

− FX: S-phase specific inhibition of cell cycle; inhibits tetrahydrofolate reductase • Cofactor depletion inhibits thymidylate & purine synth • Also undergoes polyglutamation MTX-PGs & DHFA-PGs inhibit thymidylate

synth & enzymes in purine synth − Side Fx:

• Rapidly dividing cells most sensitive serious toxicity & increased cytotoxicity • * GI: severe nausea & vomiting

− pretreat w/ 5HT3-antagonist & corticosteroid • Hematologic toxicity – pancytopenia • Hepatotoxicity • Infxns; neurologic syndrome • * Teratogen

9. Co-stimulator Blockers:

• Recall full T-cell activation req’s MHC-TCR stim & co-stim signal. − lack of 2o signal apoptosis

• Abatacept, Belatacept – fusion protein − FX: blocks engagement of CD28

• T-cell prolif and prdxn of cytokines (e.g. TNFα, IFγ, IL-2). − Side Fx:

• R.A. • Headache, dizziness, hyperT, GI • infxns

• Efalizumab – monoclonal Aby − FX: binds T-cell LFA-1 α-subunit (CD11α) - prevents binding to ICAM-1

• inflamm & rejection • Prevent binding of T-cell to endoth – prevent T migration to inflamm sites

− CD11α also on B-cells, monocytes, neutro’s, NK, other… may affect their activation, adhesion & migration

• Tx Psoriasis − Side Fx:

• Mild-moderate 1st dose rxn • Pain, flu-like S/S, arthralgia, asthenia, periph edema • URT infxns • 2o malignancies skin, solid tumors

• Alefacept – fusion protein

− FX: binds to T-cell CD2 & simult to Ig receptors on cytotoxic T-cells. • * CD2 mostly on memory effector T-cells; naïve T-cells largely unaffected! • Simult binding granzyme-mediated apoptosis • Tx Psoriasis

− Side Fx: • Lymphopenia 6-8 wks after start • 2o malignancy skin • Serious infxns • Hypersensitivity rxns – urticaria & angioedema

− (the most signif problem w/ these more specific protein drugs)

NSAIDS and DMARDS NSAIDS Salicylates Para-aminophenol derivatives COX-2 inhib Acetylslicyclic acid (Aspirin) acetaminophen (Tylenol) celecoxib (Celebrex) Indomethacin Heteroaryl acetic-acid der. Propionic acid derivatives Enolic acid der Ketorolac Ibuprofen (Advil, Motrin, Nuprin) piroxicam Diclofenac Naproxen (Aleve, Naprosyn) meloxicam Anthrotec Oxaprozin Pathophys: Osteoarthritis

• Damage to cartilage w/ increased amts of ECM components of cartilage (PG and collagen) • Bone tissue under cartilage stiffens can cause osteocytes (outgrowths) • Cartilage debri and osteocytes in jt space cause pain and inflamm response

Rheumatoid Arthritis • Immune mediated

o Intense lymphocytic inflamm infiltrate in synovium o Synovial macrophages and fibroblasts proliferate and secrete proteolytic enzyes o Macro and lympho secrete cytok (IL-1 and TNF) cause array of cell responses

like cell death and release of lysosomal enzymes o Later in disease, irrev cartilage damage, bony erosion

• Symptoms (can last for many years) o Redness of affected joint, some fever, tender, warm, swollen joints o Symmetrical pattern, affected jts not nec weight bearing o Fatigue, maybe fever, malaise o Pain stiffness >30 mintes in morning/after long rest

• Tx needs: decrease pain, maintain mobility, minimize disability, decrease inflamm, preserve fxn

• Use of NSAIDS: inflammation (anti-inflamm), pain (analgesic), fever (anti-pyretic) PG synthesis

• not stored in cells/tissues • COX-1 – constitutively expressed; COX-2 inducible by cytokines, serum factors, GFs • **NSAIDS – not inhibit lipoxygenase (Leukotrienes-chemotactic)

o Overproduction of Leukotrienes may be involved w/ aspirin hypersensitivity • PGI2 &PGE2 -

o potent vasodilation, potentiate vasc perm due to bradykinin, o bronchodilation, o stomach- protect GI mucosa from acid by decreasing gastric acid secretion,

increasing mucosal blood flow • PGE2

o Produce bone reabsorption possible contribution to bone/jt damage assoc w/ RA o Produce fever (leukocytes release polypeptide that acts on hypothal to release PGE) o Produce pain potentiates effects of agents like bradykinin and histamine

• PGF2a o Stim uterine contractions (too much dysmenorrheal)

o Role in parturition NSAIDS may delay onset of labor o PGI2 – maintain patent DA NSAIDS may lead premature closure in late pregs

• TXA2 o Rapidly converted to inactive thromboxane B2 o Vasoconstriction o Inducer of platelet aggregation

Leukotrienes- LT C4, D4, E4 o Bronchoconstriction o Increase vasc perm and chemotactic o Imp in inflamm and allergic rxns blocking cyclooxygenase path will reduce by

NOT eliminate inflamm NSAIDS

Common Properties -Mechanism of Action

• NSAIDS inhibit enzymatic production of PGs via inhibition of COX-1 AND COX-2 • Don’t inhibit formation of Leukotrienes (diff enzyme- lipoxygenase) • Synth of LT from arachidonic acid may be accelerated by COX inh

-Therapeutic Activities of NSAIDS: • Analgesic – effective against low-to-moderate pain, pain due inflamm well controlled • Antipyretic – NSAIDS decrease body temp in febrile states • Antiinflammatory – used to treat minor injuries, RA, OA, ankylosing spondylitis

Other Uses: • Closing of ductus arteriosus in neonates (PG maintain patency)

o Indomethacin and related agents will close DA in neonates when remained patent • Treat headache, muscle aches, dysmenorrheal • Protection from CV disease aspirin • Prevent colon cancer – frequent use of aspirin/NSAIDS assoc w/ decrease risk colon cancer

Shared Side FX: • Most common: gastric or intestinal ulceration

o Caused by local irritation by orally administered drugs allows back diffusion of acid into the gastric mucosa inducing tissue damage

o Inhibition of biosynthesis of protective PGs (esp PGI2 and PGE2) o All NSAIDS except acetaminophen tend cause GI Fx

Coadminister PGE1 analog misoprostol to help prevent gastric ulceration • increase bleeding time due disturbances decreased formation in the platelets of TXA2 • Prolongation of gestation or spontaneous labor • Changes in renal fxn: decrease renal BF and glomerular filtration in CHF, retain Na and H20 • Intolerance of aspirin and most NSAIDS

Contraidications for NSAIDS • History of GI ulcers • Bleeding disorders or on anticoags • Pregnant patients - NSAIDS delay onset of labor o cause premature closing of DA in fetus • Hypersensitivity to aspirin - may also demonstrate hypers to other NSAIDS • Renal disorders

Salicylates and Aspirin Mechanism of action

• Aspirin covently modifies both COX-1 and COX-2, irreversibly inhibiting cyclooxygenase activity ( a unique property to aspirin)

• Aspirin acetylates COX enzymes (ALL other NSAIDS are reversible inhibitors) • Inhibits platelet aggregation for the life of the platelet • Platelets have no capacity for protein biosynthesis and can’t regenerate the COX enzyme

Therapeutic Uses • Treat inflammation – in rheumatoid and other arthritis, musculoskeletal injury, acute

rheum fev • Alleviate fever, pain and other signs of inflamm • Relieve types of pain like headache, arthritis, dysmenorrheal, neuralgia, myalgia • Large doses (3-6 g/day) can treat RA

Metabolism • Administered orally and absorbed rapidly in stomach and upper GI • Rapidly converted to salicyclic acid in liver

o Salicyclic acid a reversible inhibitor of COX enzymes o Salicyclic acid reduces PG synthesis in vivo

• Half life- 15 minutes, salicylate 2-3 hours @ low doses w/ 12 hours at anti-inflamm doses • Salicylates are subject to hepatic metab and renal excretion

Routes of admin: • Oral • Topical – Asper Cream (15% trolamine salicylate), ICY hot (2% menthol, 29% methyl

salicyte) patches and sleeves Side Fx:

• GI Ulceration- misoprostol use in conjuction • Tinnitus (ringing) and hearing loss w/ higher doses • Hepatic injury over time, not acute • Reyes Syndrome in children infected w/ chicken pox or form of influenza virus • Asprin Induced asthma • Prolonged bleeding time – single dose aspirin inhibit platetel COX for life of plately (8-11

days) in as little as 40 mg to produce this effect o Decreased platelet agg useful in patients who have had their first MI

Contraindication • Bleeding disorders (hemophiliacs) or taking oral anti-coag

Para-aminophenol derivatives Acetominophen (Tylenol) Mechanism of Action

• Weak inhibitor of COX 1 and 2 • Also a strong inhibitor of COX-3 (expressed in the brain)- not sure of therapeutic actions

Therapeutic Actions • Analgesic and antipyretic effects similar to aspirin (acetaminophen present in over 200

generic and prescribed meds)

• NOT!! A useful agent to treat inflammatory conditions o Only WEAK antiinflamm FX – (NOT an NSAID), not useful in RA

• Useful for patients in whom aspirin is contraindicated Metabolism

• Oral admin, peak blood levels 30-60 min, half life 2 hours • Hepatic metabolism:

o Hepatotoxicity may occur after ingestion of single dose of 10-15 g w/ doses of 20-25 g potentially fatal

o Acetaminophen normally converted in liver to acetaminophen-glucuronide or –sulfate o Also formed is highly reactive intermediate N-acetyl-para-benzoquinonimine which is

conjugated w/ glutathione (GSH) o In overdose, hepatocellular levels of GSH are depleted and hepatic protein

modification occurs o Hepatocytes susceptible to oxidant injury

• Tx: o Gastric lavage (has own risks) o Measure serum drug levels > 4 hours after ingestion o If >150 mcg/mL @ 4 hr OR 75 mcg/mL @ 8 hr give sulfhydryl compounds which

replenish hepatic stores of glutathione N-actelycysteine o Most effective treatment begin <8-10 hours following ingestion (efficacy decrease)

Side Fx: • DO NOT produce GI irritation or bleeding at therapeutic doses • NO effects on platelets or excretion of uric acid • Hepatic toxicity (excess acetaminophen leading cause of hepatotoxicity whether accident

or intentional) OTC Drugs: anacin, Excedrin (slides 41- 42) Combo of NSAIDS and opioids for pain relief (also marketed w/ ibuprofen)

• Propoxyphene/Acetominophen o Propoxyphene (Darvon)- opioid analgesis o Used for relief moderate pain o Combo more effective than either alone o 2 mechs of pain relief- central and peripheral o Reduce opiate exposure o Sedation, respiratory depression, habit forming

• Oxycodone/acetaminophen (Percocet) o Oxycodone (Oxycontin) – opioid analgesis

• Hydrocodone/acetaminophen (Vicodin) • Butalbital/aceta/caffeine (Fioricet) • Butalbital/aspirin/caffeine (Fiorinal)

Indomethacin Mech of action: one of the more potent inhitors of COX enzymes Therapeutic actions:

• Antiiflammatory, analgesic, antipyretic • Useful to treat gout, arthritis

Side Fx:

• GI irritation common • CNS effects: headache, dizziness, depression, esp w/ elderly patients • Renal dysfxn • CA in pregnancy

Heteroaryl Acetic Acid derivatives Ketorolac

• Potent analgesic but only moderately effective anti-inflam o Use for short term (5 days or less) for severe pain o Approved for parenteral admin (IM or orally)

Therapeutic uses: • Postoperative pain and inflamm following surgery (IM or oral) • Topical use for inflamm conditions of the eye (allergies)

Side Fx: similar other NSAIDS Diclofenac

• Inhibitor of COX, potency greater than inodmethacin, naproxen Therapeutic uses: RA, OA Side Fx:

• GI effects • Not recommended pregs • Elevation of hepatic aminotransferase activies in 15% of patients (do liver tests)

Anthrotec (diclofenac and misoprotol)

• Will provide gastric protection • Misoprostol PGE1 analog

Propionic Acid derivates Ibuprofen, naproxen, oxaprozin, ketoprofen, flurbiprofen, fenoprofen Pharm properties of all:

• All COX inhibitors (reversible) • All alter platelet fxn and prolong bleeding time • All anti-inflamm, antipyretic, analgesic • All cause GI irritation, usually less severe than with aspirin

Ibuprofen (advil, motrin, nuprin) Uses:

• For RA, w/ daily dose – 3200 mg/day • For mild/moderate pain (400 mg, 4-6 hours as needed)

Pharmacokinetics: oral admin, w/ half life 2 hours Side fx:

• GI intolerance, although less than other NSAIDS

• Not to be used in pregnant women Naproxen

• half life 14 hours (2 x daily dosing) Oxaprozin

• antiinfalmm, analgesic, antipyretic • long half life – 40 hours (single day dose)

Side Fx: GI

Enolic Acids Piroxicam

• anti-inflamm, analgesic, anit-pyretic • equiv aspirin, indomethacin, or naproxen • long t1/2 50 hours (allow singe dosing)

Side Fx: GI and renal adverse rxns (high risk) Drug: may reduce renal excretion of lithium Meloxicam

• more selective COX -2 (will also inhibit COX-1) • single dose day • Treat OA, RA • Side Fx:

o sim other NSAIDS (lower GI adverse rxns) DRUG Interactions: Slide 59 – PASTE

Selective COX-2 inhibitors Celecoxib (Celebrex) Mechanism of Action: selective COX-2 inhibitor/not affect COX-1 Therapeutic uses:

• anti-inflamm, antipyretic, analgesic • OA, RA, acute pain, dysmenorrheal

Side Fx: • Potential CV probles • Less GI ulceration, but still possible • Dyspepsia, diarrhea, GI discomfort • Fewer antiplatelet effects • Fewer CV effects than Vioxx or Bextra • Inhibition induction of labor • Alterations renal function • Hypersensitivity rxns

Drug Interactions: • Sulfonamide (Bactrim, Septra D.S) Celebrex has sulfonamide side chain can cause

allergic symptoms • Coumadin potential for increased bleeding time • Interactions when administered w. drugs that inhibit P450 2C9 (that is the main way it is

metabolized in the liver) so would cause increased levels of celecoxib • Interactions w/ fluconazole and lithium

DMARDS DMARDS Methotrexate (Rheumatrex), Leflunomide, Sulfasalazine, Hydroxychloroquine, Gold Etanercept, Infliximab, Adalimumab, Anakinra Abatacept, Rituximab Methotrexate Mech of action: inhibitor of dihydrofolate reeducates (DHFR) and interferes w/ de novo purine biosynth Uses:

• Very common for RA o Low doses improve o Therapeutic effects seen 4-6 wks o Admin orally w/ folic acid o Can be co-admin w/ glucocorticoids

• High doses used in leukemias • Psoriasis • Immune suppressor (can be used in organ transplant)

o Decrease serum levels Igs (IgA, G, M) o Inhibits activity pro-inflam cyto: (TNF, IL-1, IL-6)

CA/Side Fx: • Liver disease or alcohol use (signif) • Certain infections more common with immunosuppression • Renal excretion, so toxicity more likely in poor renal fxn • NSAIDS will decrease methotrexate clearance • Teratogenic • Co-admin w/ leflunomide can cause liver toxicity

Combo therapy:

• Patients w/ refractory RA to methotrexate alone may be treated w/ methotrexate, sulfalazine, and hydroxycholorquine

• Addn of etanercept, infliximab, or anakinra may provide relief Leflunomide Mech: oral pyrimidine synthesis inhibitor Tx: slow progression of mild RA Side Fx:

• Diarrhea, skin rash, hepatic toxicity • Teratogenic (not use pregs)

o Use cholestyramine (questram) to bind and eliminate leflunomide (can take 1-2 yrs to clear)

Hydroxychloroquine

• Anitmalarial • 2nd line agent for mild RA • 3-6 months onset of effects, well tolerated

Side FX: • Nausea, epigastric pain • Hemolysis w/ glucose -6- P DHG def • Retinal damage/vision monitored

Sulfasalazine

• Prodrug; colonic bacteria release (5ASA therapeutic benefit) Uses:

• RA, mild to moderative ulcerative colitis, Crohn’s Side Fx: GI disturbances, drop WBC (rare) Gold (myochrysine)

• Primary for RA • Produces gradual reduction of symptoms of inflamm in RA (suppresses, not cure) • Unknown mech of action • Administer IM (injectable more effective than oral)

SIDE FX: • Toxic effects involve skin, mucous membranes, usually mouth (15%) • Kidney fxn may be affected • Blood dyscrasias (severe) • High incidence of side effects

TNF Inhibitors TNF

• Role in pathology of RA stimulates macrophages which produce TNF IL-1, IL-6 • TNF, Il-1, IL-6 induce chondrocytes, osteoclasts, and fibroblasts • Elevated TNF levels found in synovial fluid in RA patients

Goals of inhibitors: • Reduce circulating levels of TNF-a and block interaction of TNF-a with its receptor

Etanercept Mech of action: dimeric fusion protein of ligand-binding portion of the human 75 TNF receptor

• Produced in CHO cells • Action: to decrease TNF-a levels

Administration • Once (50 mg) or twice (25 mg) a week by Subcutaneous injection • Half life – 3-4 days • Onset of actions 2-4 weeks

Therapeutic Uses: • For active RA in patients who have had inadequate response to other DMARDS • Can be used in comob w/ methotrexate, NSAIDS, or other agents

Infliximab MEch of action: inhibits binding of TNF-a w/ its receptor Administration:

• IV infusion • Administerd 0 and 2 weeks (every other month)

Uses: RA and Crohn’s disease Tables 82? Adalimumab Mech of action:

• human monoclonal TNF-a antibody, • clears soluble and membrane bound TNF

Administration: • SC injection, every other week • Can be admin w/ other DMARDS or NSAIDS

Side Effects of TNF Inhibitors (etanercept, infliximab, adalimumab)

• Injection site reactions common (usually mild w/ redness, itching, pain, swell) • Infections • Auto-Ab • Expensive compared to NSAIDS

Interleukin-1 Receptor Antagonists

Anakinra • Recombo, nonglycosylated form of human IL-1 receptor antag (one aa diff than IL-1

Mecho of action: blocks biologic activity of IL-1 by competitively inhibiting IL-1 binding to IL-1 type I receptor Uses:

• Moderately to severely active RA, in patients who have failed 1 or more DMARDS Admin:

• Used alone or in combo w/ DMARDS • Not used with TNF blocking agents • Admin SC daily

• Combo therapy: Side Fx: most commonly injection site reactions Abatacept Mech of action:

• T-cell costim blocker • Has extracellular domain of CTLA4 conjugated w/ human IgG • CTLA4 binds CD28 on T cell and diminishes T cell response and inflamm cytokine secretion

(TNF) Administration:

• IV at 0,2,4 weeks and once a month • Onset of action 3 months

Rituximab MEch of action: deplete B cells

• Monoclonal Ab against CD20 on B cells leads decrease cytokines and B/T interact Administration:

• 2 IV infusions 2 weeks apart • Onset action 3 months for RA

Uses: in US for RA patients who fail resond to TNF antags

Corticosteroids/Glucocorticoids Predinisolone or Triamcinolone MEch of action:

• Decreased numer circ lymphocytes, eosinophils, monocytes, basophils • Inhibit production of cytokines • Inhibit cytokines (IL 1,2,3,6) and TNF-a

Uses: • Anti-inflammm and immunosuppression • Provide relief until other, slower acting anti RA durgs (methotrexate) take effect

Side Fx: • Osteoporosis, Mood changes, Fragile skin, bruising, Fluid retention, Weight gain, muscle

weakness, worsening of diabetes, cataracts, increased risk of infection

1

Opioids Assessment 6

1) Foundation

• Mechanism of Action o Stimulate endogenous opioid receptors → analgesia

Types of opioid receptors: a. Mu (MOR) - ↓respiration, ↓GI activity b. Delta – GI regulation, autonomics c. Kappa (KOR)- hallucinations

Activated receptors… a. block ascending pain pathways (ie, spinothalamic tract) b. activate descending pain inhibitory pathways (from peri-aqueductal

gray in midbrain

o o o o o o o o o o o o o o CNS Actions of Opioids

↓ Respiration respiratory acidosis a. eventual tolerance develops BUT narrow therap. window initially

↓ cough miosis – no tolerance develops nausea/vomiting euphoria sedation/drowsiness seizures/myoclonus – high doses

Endogenous Peptides: large precursor protein cleaved to form:

‐ Enkephalins ‐ Endorphins ‐ Dynorphin

2

o Peripheral Axns of Opioids Constipation – no tolerance develops ↑ histamine

a. cardiovascular vasodilatioin b. skin urticaria

contracts sphincter of bladder (acute) urgency + retention ↓ uterine muscle excitability impair labor (unless intraspinal dose)

o Drug Interactions w/ opioids:

Sedatives, Hypnotics, Alcohol, Barbiturates ↓↓ respiration Sympathomimetics ↑↑analgesia

a. Opioids + Sympathomimetic = good combo for enhancd pain relief Anti-histamines ↑↑analgesia MAO-inhibitors LETHAL with Meperidine

a. Toxic metabolite of Meperidine accumulates seizures + death b. Morphine and Fentanyl safe

o Pharmacokinetics

Extensive 1st pass metabolism parenteral dosing preferred Some are inactive pro-drugs and must be activated

a. Codeine, Heroin, LAAM

o Tolerance Inevitably develops with repeated dosing

a. Cellular changes at first dose b. ↓ analgesia after several days

Cross-tolerance if acting on same receptor (may be incomplete)

o Dependence and Addiction Withdrawal Symptoms

a. 6-12hr restless, sweating, lacrimiation b. 12-24hr irritable, tremor, dilated pupils c. 24-72hr weak, depressed, nausea, vomiting, cramps, chills, flushes,

aches, pains, ↑HR, ↑BP, dehydration can be fatal! d. 7-10 days physical recovery but behavioral cravings persist

Physical Dependence ≠ Addiction! a. Addiction has a lot to do with brain re-wiring cravings b. Physical Dependence is a pain but most patients recover without

developing an addiction. Never undermedicate out of fear of causing abuse!

3

2) Opioid Receptor Agonists • Morphine*

o Axn: MOR agonist Active and has active metabolite: M-6-glucaronide = 100x potency

o Tx: dull, diffuse, continuous pain Half-life = 4hr Dosing: parenteral best; intrathecal, epidural; oral but 70% 1st pass metab.

o Side efx: tolerance, constipation, renally cleared Contraindicated in asthmatics b/c can ↑ histamine use Fentanyl instead

• Codeine

o Axn: low affinity for MOR but 1st pass metab. 10% converted to Morphine Oral or parenteral Renal clearance

o Tx: mild analgesia cough suppressant (use only if not responsive to dextromethorphan)

• Meperidine

o Active and has toxic metabolite: normeperidine = long ½ life + seizure risk Thus Meperidine is bad for chronic usage.

o Benefits: no miosis, less seizures, ↓ constipation, only 50% 1st pass metab. o Side Efx:

Renal clearance watch out for toxic metabolite accumulation! Lethal if combined with MAO-inhibitors Contraindicated in children (toxicity)

• Fentanyl - 80x potency than Morphine

o Transdermal patch for chronic pain o Initial anesthesia IV b/c rapid onset + short duration

• Methadone - Tx withdrawal

o slower onset, lower peak o treats craving; may be used indefinitely

• Propoxyphene

o 4hr duration o renally cleared toxic metabolite norproproxyphene cardiac tocicity

• Heroin - Equal efficacy as morphine; illegal • Others Briefly Mentioned

o MS Contin - Morphine with a longer half-life (8-12 hr) o Hydromorphone – oral and parenteral o LAAM – very long half-life o Pemifentanil o Oxycodone

4

3) Mixed Agonist/Antagonist • Pentazocine and Butorphanol

o Axn: Bind but do not activate MOR Bind and activate KOR

o Efx (compared to Morphine) Slight ↓ analgesic affect (still OK for moderate pain) No constipation ↓↓ respiratory depression ↓ abuse potential

4) Partial Agonist

• Buprenorphine o Axn: low MOR ativation o Tx: addiction

Suboxone = Buprenorphine + Naloxone a. Supposed to take sublingual (naloxone ineffective) b. If bad pt tries to inject, Naloxone will kill effects of Buprenorphine

o Side Efx: abstinence syndrome 5) Opioid Receptor Antagonist – “say No to opioids”

• Naloxone o Axn: Bind but do not activate OR’s (non-selective)

IV only: rapid onset (1-2 min), short duration (1-2hr) o Tx: opioid OD respiratory depression

Beware withdrawal syndrome start with low dose!

• Nalmefene – tx opioid OD longer duration (4hr)

• Naltrexone o Longer-er duration (24hr) o Oral efficacy o Tx Alcohol abuse: ↓ craving and relapse

6) Other agents derived from Opiates

• Loperamide o No CNS axn b/c does not penetrate BBB o Tx: diarrhea

peripherally ↓ GI motility, peristalsis, & secretion ↑ absorption time

• Dextromethorphan o Tx: cough suppressant o Axn: non-opioid receptors o Does NOT cause GI, respiratory ↓, or analgesia

5

7) Adjuvant agents for pain = drugs that ↑ analgegsic effect of the opioid o Ideal for ↑ relief without ↑ opioid side efx

• Mild/Moderate Pain – with milder opioids o Acetaminophen + codeine o Acetaminophen + propoxyphene (Darvocet) o Aspirin + codeine

• Moderate Pain o Acetaminophen + hydrocodone (Lortab) o Acetaminophen + oxycodone (Percocet) o Aspirin + oxycodone

• Other Adjuvants o Clonidine o Hydroxyzine o Desipramine

• If you want to treat… Combine opioid with… o Bone Metastasis Pain NSAIDS or Calcitonin o Neuropathic Pain tricyclic anti-depressants or anticonvulsants

(finicky dosing) o Nerve Compression Corticosteroids

8) When do you use what? Mild Pain Moderate Pain Severe Pain Addiction NSAIDs Propoxyphene

Opioid + NSAID + Adjv Codeine Hydrocodone Oxycodone Dihydrocodeine Tramadol

Morphine MS Contin Fentanyl Hydromorphone Oxymorphone Meperidine

Methadone (clinics) Buprenorphine Buprenorph + Naloxone LAAM

1) Cyclosporine is effective in organ transplantation. The actions of this drug are to:

A) Activate natural killer (NK) cells

B) Block the tissue response to inflammatory mediators

C) Increase catabolism of Increase catabolism of IgG antibodies

*) Inhibit gene transcription of interleukins

E) Interfere with antigen recognition by T cells

1) Azathioprine

A) Binds to cytoplasmic immunophilin

B) Blocks formation of tetrahydrofolic acid

C) Is a precursor of cytarabine

*) Produces hematotoxicity and causes skin neoplasms

E) Is a metabolite of mercaptopurine

3) Your previously diagnosed asthma patient complains of feeling fatigued and unable to

always obtain a good night’s sleep owing to awakening with breathlessness. The drug of

choice for this medical condition is:

A) terbutaline [Brethine]

B) epinephrine

C) albuterol [Proventil]

*) formoterol [Foradil]

E) metaproterenol [Alupe

4) Which of the following drugs is a nonselective parenteral bronchodilator that is

effective in treating bronchospasm?

A) Cromolyn [Intal]

B) Terbutaline

C) Zileuton [Zyflo]

*) Epinephrine

E) Prednisone

5) Which of the following is effective only as a prophylactic treatment by mast cell

stabilization?

A) Albuterol [Proventil]

B) Zafirlukast [Accolate]

*) Nedocromil [Tilade]

D) Prednisone

E) Terbutaline

6) The major clinical use of second-generation antihistamines is:

A) coughs and colds

B) insomnia

*) hay fever

D) motion sickness

7) A long distance truck driver complains of serious allergic rhinitis. Which of the

following would be the best antihistamine to prescribe for him?

A) Diphenhydramine [Benadryl]

*) Fexofenadine [Allegra]

C) Meclizine [Antivert]

D) Promethazine

E) Chlorpheniramine [Chlor-Trimeton]

8) Which of the following statements correctly describes H1 antihistamines and their

clinical utility?

A) Agents that are useful for allergic rhinitis also inhibit gastric acid secretion

B) Antihistamines are generally useful for the control of asthma

C) Antihistamines are the drugs of choice in treating anaphylaxis

*) Second-generation drugs have fewer anticholinergic effects than first-generation

agents

9) In the ER, the administration of large doses of terbutaline s.c. have failed to dilate the

airways of an asthmatic but instead caused tachycardia. In addition to the provision of

oxygen, what else should be done to manage the bronchoconstriction and restore the

activity of the beta-adrenergic drug?

A) Give inhaled cromolyn [Intal]

*) Give a parenteral corticosteroid

C) Give parenteral diphenhydramine

D) Switch to epinephrine

E) Switch to isoproterenol

10) Which of the following is NOT an effect of first generation antihistamines?

A) Reduction in urinary bladder tone

B) Local anesthetic effects if injected

C) Reduction in motion sickness

*) Increase in total peripheral resistance

E) Sedation

11) A 9 year-old boy suffers from severe asthma. The wheezing and other symptoms

have been inadequately controlled by the present treatment regimen. Combination

therapy with drugs chosen to target different mechanisms of action is indicated. Which of

the following would inhibit the increased parasympathetic bronchoconstrictor tone?

A) Cromolyn [Intal]

*) Ipratropium [Atrovent]

C) Nedocromil [Tilade]

D) Theophylline [Theo-Dur]

E) Zafirlukast [Accolate]

13) Olopatadine [Patanol] is unique among the second generation H1-antagonists in its

ability to:

A) block H1 and H3 histamine receptors with potency

*) block histamine release from mast cells

C) block H1 receptors only in the peripheral vasculature

D) be effective in blocking H1 receptors without causing sedation

E) effectively blunt acute asthmatic attacks

14) Through which of the following actions does morphine produce analgesia?

A) Activation of neuronal adenylyl cyclase

B) Increase pre-junctional neurotransmitter release

C) Reduction of post-junctional neuronal potassium conductance

*) Reduction in pre-junctional neuronal calcium conduction

15) Which of the following adverse effects of opiate therapy is least likely to become

tolerized upon chronic therapy?

A) Respiratory depression

B) Nausea and vomiting

C) Analgesia

D) Sedation

*) Constipation

16) Which of the following agents would produce salivation, lacrimation, urination,

defecation, depression and autonomic hyper-activity in an opioid “addict”?

A) Morphine

B) Oxycodone

C) Alfentanyl

*) Naloxone

E) Methadone

17) Meperidine and morphine are alike in many way, but meperidine does possess one

effect that is not observed with morphine or indeed the other opiates. That unique effect

is:

A) Constipation and paralytic ileus

B) Heightened pain perception (hyperalgesia)

C) Intense biliary tract spasm

*) Psychoses and possible seizures

E) Respiratory depression, apnea and ventilatory arrest

18) Which of the following opioid agonists is metabolized to a more potent analgesic?

A) Clonidine

*) Codeine

A) Meperidine

B) Naloxone

C Oxycodone

19) Which of the following agents possesses antipyretic and analgesic properties, BUT

NOT anti-inflammatory or anti-thrombotic effects?

*) Acetaminophen

B) Aspirin

C) Ibuprofen

D) Ketoprofen

E) Naproxen

20) Which of the following agents is contraindicated in infants suffering from chicken

pox or influenza virus?

A) Acetaminophen

*) Aspirin

C) Ibuprofen

D) Ketoprofen

E) Naproxen

21) Which of the following drugs produces its pharmacologic effects through the specific

inhibition of cyclooxygenase-2?

A) Amitryptyline

*) Celecoxib

C) Caffeine

D) Phenytoin

E) Ketoprofen

22) Ibuprofen, Naproxen and Indomethacin all reduce the production of:

A) cyclooxygenase (COX)

*) prostaglandins

C) arachidonic acid

D) phopholipase A2

23) With regard to inflammatory conditions, which of the following is specifically

inhibited by pharmacologic doses of glucocorticoids?

A) Cyclooxygenase-1 & 2

B) Histidine decarboxylase

C) 5’-lipoxygenase

*) Phospholipase A2

E) Xanthine oxidase

24) Which of the following drugs would be administered to close the ductus arteriosus in

a premature infant suffering from blood gas and hemodynamic problems?

A) Histamine

B) Cimetidine

C) Diphenhydramine

*) Indomethacin

E) Prostaglandin E1 [alprostadil]

25) A 67 year-old woman with rheumatoid arthritis has been placed on high dose

indomethacin treatment by her physician. Which of the following additional drugs would

be most likely used to prevent drugs would be most likely used to prevent

gastroesophageal ulceration?

A) Celecoxib

B) Cimetidine

C) Diphenhydramine

*) Misoprostol

E) Sumatriptan

26) Aspirin’s inhibition of platelet aggregation arises from:

A) inhibiting thrombin and activating antithrombin III

B) blocking platelet aggregation by preventing bridging between glycoprotein between

glycoprotein IIb IIb/IIIa IIIa receptors on neighboring platelets

C) blocking platelet ADP receptors

*) inhibiting thromboxane A2 synthesis

E) stimulating fibrinogen synthesis and enhancing thrombolysis

27) Which of the following is a classical early sign of aspirin toxicity?

A) Constipation

B) Cough

C) Hypertension

D) Myopia

*) Tinnitus

28) Which of the following signs/symptoms would you expect to observe in a patient

suffering from a massive aspirin overdose?

A) Hypothermia

B) Metabolic alkalosis

C) Respiratory acidosis

*) Metabolic acidosis

E) Ventilatory depression

29) Concerning rheumatoid arthritis, which of the following correctly describes the

significant difference between methotrexate, gold salt and penicillamine versus aspirin or

indomethacin?

A) Activate immune/inflammatory responses

B) Are primary therapies for gout, gouty arthritis and hyperuricemia hyperuricemia

C) Are remarkably free of serious toxicities

D) Provide much quicker relief of arthritis signs and symptoms symptoms

*) Slow, stop and possibly reverse joint pathology in rheumatoid arthritis

Ancillary Drugs in Anesthesia *note: all of these are covered elsewhere w/ other fnxns!

I. Pre-anesthetic medication:

A. psych & pharm prep; relieve anxiety, sedation, amnesia

B. dry secretions (bad w/ intubation), autonomic responses (esp in kids); gastric fluid, gastric pH

C. antiemesis

D. anesthetic req’s; facilitate indxn

E. prophylaxis against allergic rxn

F. there is no “best” drug or combo – use tradition & experience

G. Timing is everything! – as important as drug selection –(b/c these are mostly oral/i.m)

1. oral 60-90min before OR

2. i.m. >20min, pref. 30-60min before OR

H. Children vs. Adults:

1. psych prep

2. more easily induced vagal reflex to airway manipulation

3. greater use of rectal route of admin in kids

4. intranasal drip, fentanyl lollipop, etc.

II. “Typical” Drug sequence

A. pre-op visit + interview

B. night before surgery:

1. BZ p.o.

C. 1-2 hr before surgery – [this lecture tells us what these are all for]

1. BZ p.o., 150mL water

2. opioid i.m. for analgesia

3. Scopolamine for amnesia & sedation

4. Cimetidine &/or Metoclopramide p.o.

5. Glycopyrrolate or atropine i.m.

D. transfer to surgery:

1. 8-10 add’l drugs; idea of balanced anesthesia

III. Sedation, amnesia, anxiolysis A. Benzodiazepines: sedative effects, amnesic, calming; NO analgesia –

1. act on GABA receptors in CNS to prolong binding of GABA

2. notice diff. durations of fx

B. Barbiturates: sedative effects, NO analgesia

1. act on GABA receptor in CNS to its activity

2. pre-op use b/c:

a) lower Tx index than BZ’s

b) tolerance & substance abuse

C. Butyrophenones: inhibit dopamine in CNS; NO analgesia alone

1. for anxiety that accomp’s psychoses; less effective against “situational” anxiety

2. Uses:

a) Innovar (Droperidol + Fentanyl) to “neurolept-analgesia”

b) antiemesis

D. Phenothiazines: anti-dopamine/cholinergic/histamine fx; sedative; antiemetic

1. act on Dopamine, Cholinergic, and Histamine receptors in the CNS

2. side effect: threshold for seizures – do not use in pt w/ epilepsy

E. Antihistamine: bronchodilator, sedative, anxiolytic, AND analgesic

F. H1 vs. H2 Antagonists:

Notice only H1 antagonists have: - sedative effect - cholinergic antag useful to dry airways useful for anti-tussive (also to Tx extra-pyramidal s/s in Parkinsonism) - anti-emesis usu. to Tx motion sickness, not w/ anesth N/V

IV. Analgesia A. Opioids: act on ORs in CNS & spinal cord

1. Problems:

a) orthostatic hypoT, epigastric distress, constipation (anti-diarrheal), sphincter tone

b) N/V via chemoreceptor trigger (Dopamine antag.) + delay of GI transit + GI secretions

c) * morphine esp N/V!

B. NSAIDs: COXII inhibitors; a large class – some examples:

1. [alternatives to opioids for analgesia; avoid opioid side fx]

2. post-op may use PCA + opioid; progress to NSAID

3. inhibit PG syn, may inhibition of platelet aggregation, inhibited ossification

a) Post-surgical bleeding outside GI tract: esp. surgery of GU, cardiac, oral cavity

(1) most other surgery NOT signif’ly impacted by NSAID-reduced hemostasis

b) Fracture healing: COXII inhibitors inhibit ossification

(1) clinical impact on bone healing unclear

(2) other risk factors: smoking, DM, periph aa occlusive dz

V. Aspiration pneumonitis A. recall protective reflexes may be lost w/ anesthetic agents – one of those reflexes protects the lungs from

aspiration of stomach contents, which can Aspiration pneumonitis

B. factors that can influence risk: (DNTM!) abdominal tumor, drugs/EtOH, anesthesia, anxiety, cardiac arrest, unconsciousness, diabetes, emergency abdominal surgery, very young age, hiatal hernia, intracranial P, nasogastric tube, ascites, day surgery, seizures, trauma

C. Gastric pH

1. nl values: pH<2.5; >25mL

2. pH & volume reduce incidence of aspiration pneumonitis if aspiration does occur

3. secretion of gastric acid impacted by many different receptors (gastrin, M3, H2, somatostatin, PG)

4. anticholinergic agents

5. H2 receptor antagonists: more signif effect; no CNS sedation!

a) no consistent effect on volume that already exists

b) no effect on existing content pH – only on prdxn of more acid

6. Side fx: headache; confusion, seizures, agitation in elderly(?)

7. Antacids: neutralize existing contents (no lag time waiting to change acid secretion)

a) particulate: [not on list!] – may not be good to introduce particulates into stomach…

b) non-particulate: (liquid)

D. Gastric Volume

1. Gastrokinetic agent: accel emptying

a) Fx:

(1) sensitizes upper GIT to Ach fx gastric emptying/peristalsis

(a) * only provided that Ach receptor system is working!

(b) Anticholinergics /narcotics will antag axn of Metoclopramide!

(2) central fx: Dopamine antag fx sedation, lowers seizure threshold*

b) alters bioavail of oral drugs +/–

2. Water: 150mL?? this stimulates stretch receptors to stim natural emptying

VI. N/V – Anti-emetics A. myltiple stimuli of emesis:

[CTZ = chemo trigger zone]

B. w/ N2O or opiates in regimen, N/V!

C. N/V esp troubling w/ day surgery – b/c need to get rid of pt.

D. need for routine prophylaxis? – no consensus

1. wide choice of agents

2. costs vary: cost-effectiveness?

E. Mech: Antagonists of: dopamine, histamine, Ach-muscarinic, serotonin receptors – all acting on CTZ on CNS

1. serotonin (5-HT) receptor antagonists – $$$ - reserved for extreme emesis e.g. w/ chemoTx

2. Dopamine antagonists - $$

(1) recall Metoclopramide also stim’s gastric emptying

b) Cholinergic antagonist:

(1) blocks pathways from inner ear

(2) recall very commonly for motion sickness prophylaxis

VII. Prophylaxis of Allergic Rxn A. many drugs & additives

B. often preTx w/ Cimetidine & Diphenhydramine (H2 + H1 blocker) – to “prevent” the consequences of the rxn, not to prevent Histamine release

C. *not always effective

VIII. Prophylaxis of Infection

- avoid vancomycin resistance, not routine

A. antimicrobials risk infection, esp @ surgical site – weigh against risk of rxn & producing resistant bac

1. esp in surgery of GU and GI

B. prophylaxis aimed @ most likely infxs agent, not every potential pathogen

C. Long pre-op hospitalization risk infxn for any pt; trend to day surgery

IX. Anticholinergics

(antisialogogue effect = dry secretions)

A. pre-op use

B. lack specificity, use “as needed”

C. Uses:

1. Tx reflex bradycardia

2. block muscarinic fx of anticholinesterases (e.g. Neostigmine), which is used to reverse NMB, and can cholinergic stim @ M & N receptors

a) typical side fx of Neostigmine = N/V, diarrhea, miosis, hypersalivation, sinus bradycardia, bronchospasm, & bronch secretions

b) very common to give w/ Atropine when NMB reversal is done

3. drying of secretions – recall some inhaled anesth’s can secretions

4. only Scopolamine sedation & amnesia

D. Why might drugs be needed here to Tx reflex bradycardia?

Rapid Sequence Intubation: immed before surgery, initial O2 to pt so O2 stays high while intubating. O2 stays high several min. (graph) Also pretreat highrisk pt’s before intubation with other drugs (chart). High risk pt’s:

- those who can’t tolerate increased ICP - reactive airway dz - CV dz - children – respond to intubation w/ profound bradycardia.

PreTx drugs are given & then wait 3 min to let drugs take effect before proceeding w/ Succinylcholine.

IV push of sedative, then NMB (usu. Succinylcholine)

X. Post-anesthetic Period A. ~25% pt’s have complications (%)

1. N/V (10)

2. resp depression - i.e. need airway support (7)

3. hypoT (3)

4. disrhythmia (2)

5. hyperT (1)

6. altered mental status (<1)

B. ~Risk factors:

1. ASA class II

2. 2-4 hr procedure

3. type of surgery: abdominal, orthopedic

4. hypothermia

5. smoking

C. Airway Support:

1. central resp depression seen w/ ANY anesthetic, but esp narcotics & NMB’s

2. narcotic antag’s reverse resp depression of narcotics (e.g. Naloxone, Nalmefene)

a) small doses

b) t1/2 problems if diff bet agonist & antag

c) in high doses, pain returns symp stim HR & BP

3. NMB’s failure to reverse inadequate resp mm. fnxn; seen in…

a) renal failure inadeq excretion

b) use w/ gentamycin, neomycin, clindamycin or furosemide

c) hyperMg2+ or hypothermia

D. Cardiac Support:

1. HypoT:

a) fluids

b) i.v. Dopamine 1-3ug/kg/min (β effect on heart + renal perfusion preservation)

c) Phenylephrine (α1 agonist) or ephedrine (indirect – causes presyn NE release)

(1) hypoT often seen w/ spinal or epidural anesthesia

2. HyperT:

a) often due to pain, hypercapnia, hypoxemia, hypervolemia

b) most resolved <4 hrs – can use short-term drugs

(1) long-acting drugs are unnecessary

c) rapid-acting drugs – e.g. Nitroprusside

(1) vasodilator, arterioles & venules

d) Trimethaphan (ganglion blocker) symp tone and vasodilation

(1) prevents reflex effects on heart

E. Wake up!!

1. most common reason pt won’t wake up = residual anesthetics & ancillary drugs

2. Reversal aimed @ most likely agent:

a) Narcotic or BZ antag likely – give respective antagonist

b) Physostigmine can reverse fx of some other sedatives & inhaled anesth’s

c) discount NM agents if no signif resp depression

d) rarely Lidocaine OD can unconsciousness

e) old age in itself does not delayed awakening

F. Post-op N/V

1. no strong evidence implicates one anesth technique more, except:

a) Propofol anesthesia has lower incidence of NV even compared w/ others

b) N2O is assoc’d w/ N/V: evaluate its use if want low chance of N/V

G. Delerium & Cognitive Decline: (slides 31-32) – DNTM

1. drugs & other factors – very complex. Just know it may happen.

H. Drug-related Complications

1. more drugs are administered for a surgery than at any other time

a) 8-10 pre-op + 8-10 during surgery + any other meds pt is on

2. Admin errors

a) wrong drug!

b) inadvertent soln!

(1) most anesth’s relatively aq insoluble

(2) rely on pH (e.g. Thiopental pH 10) or formulation as salt of acid or base

(3) may req surfactant for solubility

(4) problems w/ extravasational or i.a. precipitation

3. incorrect site choice – e.g. some irritation if injected

4. incorrect admin rate

a) e.g. Histamine release w/ opioids when give too much too rapidly

5. allergic/immune rxns

6. drug-drug interaxn:

a) chance w/ drugs taken

b) other anesthetics, ancillary meds, longstanding meds unrel’d to surgery

7. genetic predisposition to unusual rxn

8. Peri-operative Drug Withdrawal (slide 36) - DNTM – but know that it is often more imp to continue w/ regular drug Tx and manage that w/in the combo than it is to suspend it for surgery.

9. Anaphylaxis in Anesthesia

a) 1/5000 – 1/25,000 incidence; mortality 3.4%

b) many anesth’s are known to assoc’d w/ Anaphylactic rxns:

(1) anesthetic indxn agents

(a) cremophor solubilized drugs, barbiturates, etomidate

(2) para-amino benzoic ester type local anesthetics

(3) muscle relaxants

(a) succinylcholine, gallamine, pancuronium, d-tubocurarine, metocurine, atracurium

(4) Narcotics

(a) meperidine, morphine, fentanyl

(5) Others:

(a) antibiotics, bone cement, drug additives, radiocontrast dye

(b) protamine, blood products, colloid volume expanders

c) the problem is release of inflamm mediators, primarily Histamine, which resp, CV, & cut. fx

d) Respiratory:

(1) cyanosis, wheezing, peak airway P

(2) acute pulm edema, bronchospasm (23%)

e) CV:

(1) tachycardia, dysrhythmias, pulm hyperT

(2) SVR, CV collapse (>68%)

(3) cardiac arrest (11%)

f) Cutaneous:

(1) urticaria, flushing

(2) perioral/ periorbital edema

g) Anaphylaxis Mgmt:

(1) Initial:

(a) stop drug admin, discont. anesthesia if possible – difficult to det what is the cause w/ so many drugs

(b) give O2

(c) give Epi – stim CV, vasoconstrict against hypoT

(d) i.v. volume expansion (e.g. isotonic crystalloid)

(2) Secondary:

(a) antihistamine – e.g. diphenhydramine – does not prevent H release, but blocks H1 receptors

(b) catecholamines – e.g. Epi, norepi, isoproterenol

(c) aminophylline – use w/ persistent bronchospasm bronchodilation

(d) corticosteroids – e.g. hydrocortisone, methylprednisolone – antag inflamm fx of LTs, PGs, kinins released by mast cells

(e) NaHCO3 – w/ acidosis of anaphylaxis

DERMATOLOGIC AGENTS1) Pharmacokinetics 

a) Threeeffectiveroutes:topical,systemic,orintralesionalroutesi) Topicaldrugpenetrationisdeterminedbydrugionization,hydrophilicityandmolecularweight.

(1) Water‐solubleions/polarmoleculesdonotpenetratewell.(2) Druguptakeisdependona[]gradientacrossskin

b) Theintact(normal)skinblocksextensivedrugabsorptionbutismorepermeablei) Invariousbodyareas(scrotum,face,axilla,scalp)ii) Attheextremesofage(preterminfantsandelderly)

c) Percutaneousabsorption:i) ↑ineczema(brokensurface);↓inpsoriasis(thickenedepidermalplaques)

d) Drugmayresideinthedermallayersandactasanatural“sustainedrelease”mechanism.e) Drugvehicleimpin:drugdelivery;skinhealth(moisturizing);providingstableyeteasilyreleasable

environmentforactiveingredients;easeofapplication/removalnonirritating;cosmeticallypleasingi) ImprovedpenetrationisachievedwithDMSO,propyleneglycol&ureaformulations

2) Topical Antibiotics a) Packagedasmultipleantibioticsatwellabovethresholddoseintopicalpreparationstoprovidebroad

coverageanddelaytheemergenceofdrugresistance.b) Tx:

i) Preventcleanwoundinfection;earlyTxofinfectedermatoses/wounds;preventStaphcolonizationofnares;TxAcnevulgaris;axillarydeodorization

ii) 2oinfecteddermatoses,diaperermatitis,otitisexternaandimpetiginizedeczemaiii) Usedincombinationw/corticosteroid

c) Polymyxin i) Side Fx:Ifsystemicallyabsorbedneurotoxicandnephrotoxic

(1) Avoidinopenwoundsordenudedskind) Gentamicin 

i) Side Fx:Ifsystemicallyabsorbedneurotoxic,nephrotoxic,andototoxicii) Limitedintopicalusageto↓emergenceofresistance

e) Tetracyclines i) Rarelyphototoxicii) Contraindicatedinpregnancy,renalandhepaticdz.

3)  Topical Antifungal Agents—welltoleratedwithfewproblems:eg.Contactdermatitis a) Azole derivatives (‐azole)

i) Mech: Inh14α‐demethylase↓convertlanosteroltoergosterol↓fungalcellwallintegrityii) Clotrimazole—CYP3A4interaction iii) Econazole iv) Ketoconazole v) Miconazole—ifusedintravaginally,↓efficacyofspermicidaldrugs vi) Oxiconazole vii) Sulconazole 

b) Allylamines (‐fine) i) Mech: Inhsqualenemonooxygenase(keyenzinsterolsynth)↑squalene↓structuralintegrityii) Naftifine iii) Terbinafine iv) Butenafine 

c) Thiocarbamates  i) Tolnaftate [Tinactin]  

d) Polyenes i) Mech: bindtoergosterol ii) Nystatin [Mycostatin]  iii) Amphotericin B [Fungizone]  

e) Addingazolew/polyenedoesnotaddeffectb/cthetwomechworkagainsteachother

4) Oral Antifungal agents—↑drug‐druginteractiondueto↑systemiclevels a) Griseofulvin [Fulvicin]

i) Mech: disruptsfungalmitoticspindlestructuremetaphasearrest(1) mayalsoproducedefectiveDNAinhreplication

ii) “Ultramicronized”drugformulationshavegreatlyimprovedbioavailability.iii) Side Fx:

(1) Leukopeniaandproteinuria(a) Routinehepatic,renal,hematopoieticmonitoringadvised).

(2) Signifinteraxnsduetochangesinmetabolism(a) ↓anticoagulanteffectofCoumarin&Warfarin;maymanifestlate(12weeks)(b) ↓contraceptiveeffectwithoralagents(c) ↓Cyclosporineserumlevels↓immunosuppression↑organrejection(d) ↑Ethanoleffects:tachycardia,diaphoresis,flushing

b) The “Azoles”i) Mech: seetopicalazoleii) Ketoconazole[Nizoral]—Oral/topical/shampoo

(1) Inhtestosteronesynthinhigh[](2) InhCYP2C19&3A4,5,7

iii) Fluconazole [Diflucan]—Oral(1) NOtestosteroneeffectattherapeutic[](2) InhCYP2C9

iv) Itraconazole [Sporanox]—Oral/parenteral(1) Morepotentthanketoconazole(2) InhCYP3A4,5,7

v) Voriconazole [VFEND]—Oral/parenteral(1) Enhancedpotencyandspectrumofactivity(2) InhCYP2B6,2C9,2C19,3A4

vi) ContraindicationsduetoCYP450inhibitions(1) STATINS:atorvastatin, cerivastatin, lovastatin, simvastatin

(a) Substantially↑riskofmyopathy,rhabdomyolysis,andacuterenalfailure.(i) Interaxnunlikelywithfluvastatin,pravastatin,rosuvastatinb/cnotCYP3A4

metabolized?(2) BENZODIAZEPINES:midazolam,triazolam,alprazolamandestazolam

c)  Terbinafine (Lamisil)i) Side Fx:inhCYP2D6

(1) ↓conversionofcodeinetomorphine(2) ↑[theophylline](CYP1A2metabolized)—mechforinteraxnunknown

5) Corticosteroids a) Immunomodulatory,anti‐inflammatory,antipruritic(anti‐itch),vasoconstrictiveb) Mech: Inducelipocortin↓phospholipaseA2activity↓breakdownofleukocytelysosomal

membranesandreleasearachidonicacid↓formationandreleaseofendogenousinflammatorymediators:prostaglandins,kinins,histamine,liposomalenzymes,thecomplementsystem.

c) Topical glucocorticoids i) If↑cutaneousblanching,then↑potencyii) Potent/verypotentdrugsforacutecontrol;lesserpotencydrugformaintenanceiii) HighpotencydrugsshouldNEVERusedonfaceorintertrigenousareas(neck,groin)andonlyfor

shortperiodsontrunkorextremitiesiv) Side Fx: 

(1) Worseningandspreadoftheinfection(2) Striae&skinatrophylocallywithglaucoma&cataractsifthedrugisusedoneyelids(3) Long‐termuseHirsutismacneanddepigmentation(4) Potentglucocorticosteroidsonface‘perioraldermatitis’(5) Long‐termsystemicexposureCushingoidfeatures

(6) Amplifiedby:(a) occlusivedressings(b) wideareaofapplication(c) longdurationofexposure(d) highpotencydrugs(e) skindamage,inflammation,occlusion,orthinstratumcorneum(f) mostcommonlyininfants&youngchildren

v) Hydrocortisone0.1,0.5,1,2.5%—mildvi) Betamethasone valerate0.025%—moderatevii) Budesonide0.025%—potentviii) Clobetasol propionate0.05%—verypotent

d) IM glucocorticoids—acuteTxoftransientillnessesorlife‐threateningdermatoses.i) Methylprednisolone [Solu‐Medrol]—LargeIVdailydoses

(1) Tx:resistantpyodermagangrenosum,organ‐threateningSLE&dermatomyositise) IVmayhypo‐/hyperT,hyperglycemia,hypo‐/hyperkalemia,anaphylaxis,acutepsychosisandCHF

i) TaperedwithdrawalpsoriasisPtmaysufferpustularflareii) WithdrawalofhighdoseTxmayarthralgias,myalgias&jointeffusions

6) Immunosuppressantsa) Calcineurin blockers

i) Tx:atopicdermatitisii) Mech: 

(1) InhcalcineurindePhosofNF‐AT—nuclearfactorofactivatedtranscriptionpreventNF‐ATfromtranslocatingtothenucleus(a) ↓regulateinterleukin(IL)‐4andCD40ligandinhB‐cellactivation(b) ↓regulateIL‐2andIFN‐γinhT‐cellactivation

(2) Maybindtocellsurfacesteroidreceptors↓regulateentireinflammatorycascadeiii) Donotinhcollagensynthorcauseskinatrophyiv) Notaseffectiveashigh‐potencysteroidsv) Tacrolimus [Protopic]—topical/oral

(1) Mech: bindtoFK‐bindingproteininhcalcineurin(2) Side Fx: metabbyCYP3A4multipledrug‐druginteractions

vi) Pimecrolimus [Elidel]—topicalonly(1) Side Fx:Disulfiram‐likerxnw/alcoholhasbeenreported.

vii) Cyclosporine [Neoral]—oral(1) Tx:severe,plaque‐typepsoriasisinimmuno‐competentpatientswhofailedatleastone

systemictherapy(e.g.,PUVA,retinoids,methotrexate)(a) OrinPtforwhomothersystemictherapiesarecontraindicatedorcannotbetolerated

(2) Mech:bindstocyclophilininhcalcineurin(a) DoesnotaffectsuppressorT‐cellsorT‐cellindependent,Ab‐mediatedimmunity

(3) Side Fx:(a) Dose‐andduration‐dependentnephrotoxicity(↑serumcreatinineandK+,↑arterialBP)

(i) duetorenalvasoconstrxn(ii) ↑ScreatinineandBUN(azotemia)mayprogresstoirreversiblerenaldysfnxn(iii) UncommoninTxforskindzb/clowdoses(max5mg/kg)used

(b) Skincancer—inallimmunosuppressants;Avoidsun,UVBorPUVAtherapyviii) Imiquimod [Aldara]—topical

(1) Tx:temporarysymptomaticreliefofexternalgenitalorperianalwartscausedbyHPV(a) DoesnoteliminateHPVandwartsmayreappear

(2) Mech: unknown(a) LocallyinducesmRNAencodingcytokineslikeIFN‐α(b) Signif↓HPVL1,mRNAandHPVDNA

ix) Alefacept [Amevive]—IV/IMfusionprotein(1) Tx:mod‐severechronicplaquepsoriasis(2) Mech:modulatesCD2receptormediatedimmuneresponseandinducescellular‐mediated

apoptosisofCD2+cells.(3) Side Fx:

(a) Lymphopenia(b) 2°basalorsquamouscellmalignancies(duetoimmunosuppression)(c) Anti‐alefaceptAbformationreported(3%)butnotcorrelatedw/FxorsideFx

x) Efalizumab[Raptiva]—monoclonalAb(1) Tx:psoriasis

7) Scabies and Pediculosis Treatmentsa) Lindane [Scabene]—γ‐hexachlorocyclohexane;Rxonlyliquidagent

i) Tx:Pediculosishumaniscapitis(headlice),Pthiruspubis(crablice),Sarcoptesscabiei(scabies)(1) Onlyusedifcannottolerateorfailed1stlineTx

ii) Mech:absorbedintotheparasitesandtheirovaiii) Side Fx:

(1) Seizuresanddeathsw/prolongedapplication(2) CNSstimulantifabsorbedsystemicallyadverseeffectssimilartoDDT(blockGABAaxn)

b) Crotamiton [Croton]—creamorlotion(10%)i) Mech:unknownii) Avoidinflamedskinorraworweepingskinsurfaces

c) Permethrin [Acticin;OTCasNix]i) Txofchoiceforpediculosiscapitis(headlice)

(1) [Elimite]—5%topicalcream:Txofscabiesii) Mech:Na+channeldisruptorparalysisanddeathoftheparasites(lice,ticks,fleas,mites)iii) Residualovicidalactivitypersistsafterrinsingiv) ResistancetoPermethrinhasbeendocumentedv) Side Fx: none

(1) Minpercutaneousabsorption(2) Inactivatedbyesterhydrolysisifdrugabsorbedintosystem

d) Malathion [Ovide]i) Tx: LiceresistanttoPermethrinorPyrethrinsii) Mech:Inhinsectacetylcholinesterase(AChE)iii) Side Fx:

(1) Notassocw/signiftopicalcholinergicactivity(2) Oral/pulmonaryingestionproducescholinergicFx

(a) Txw/atropineandpralidoxime8) Retinoids—derivativesofvitaminA

a) Intracrineandparacrinemediatorsofcelldifferentiationandproliferation,apoptosis,reproductionb) Bindtoallretinoidreceptors:retinoidXreceptors(RXRs)vs.retinoicacidreceptors(RARs)

i) Bothtypeshaveα,β,γsubtypes,eachhasmanyisoforms(1) RAR‐αacutepromyelocyticleukemia(2) RAR‐βsquamouscellcancers(1) RAR‐γretinoideffectsonmucocutaneoustissuesandbone

c) Tx: inflammatorydisorders,hyperproliferativedisorders,skinmalignancies,photo‐agingetc.i) Topicalapplicationcannormalizedisorderedskinkeratinizationinsebaceousfolliclesandcan

enhancethepenetrationofothertopicalagentsii) Espeffectiveifusedw/benzoyl peroxide/topicalantibiotics

d) Mechfordermi) Bindtoskinretinoicacidreceptors(RAR)β&γand↑regulateskinproliferation(↑RNA

polymeraseactivity,↑PGE2,↑DNAthymidineincorporation)↓epidermalcellcohesion,↑epidermalcellturnover

e) Side Fx: i) SimilartoVitAtoxicity:dryskin,nosebleeds,conjunctivitisandhairlossii) ↑tumorigenicityofUVlightiii) ↑effectsofphotosensitizingagents(allRetinoids)Quinolones(particularlySparfloxacin),

Phenothiazines,Sulfonamides,Sulfonylureas,Tetracyclines,andThiazidediureticsiv) ORALRETINOIDSAREPOTENTTERATOGENS

(1) Fxmaypersistforseveralyearsbeyondcessationoftherapyf) Drugexamples

i) 1stgen:Tretinoinretinoic acid [Retin‐A]—oral/topical;Isotretinoin [Accutane]—oralii) 2ndgen:Acitretin [Soriatane]—oraliii) 3rdgen:Adapalene [Differin], Tazarotene [Tazorac]—topical

g) LatergenhavemorerigidchemicalstructuresmorespecificandlesspronetoproduceadverseFx9) Benzoyl peroxide–topical

a) Tx:P. acnesinsebaceousfolliclesandcomedones(blackheads)b) Mech: 

i) Releasefree‐radicalO2speciesoxidizebacterialproteinsii) Dryinganddesquamative(keratolytic)effect↓P. acneslevels,lipids,andfreefattyacidsinthe

skinfollicleacneresolutionc) Side Fx: 

i) Xerosis,erythema,skinirritation,mildstingingii) Physicalincompatibilitieswithtopicalretinoids&antibiotics↑riskofskinirritationiii) TopicalHydroquinoneandBenzoyl peroxideonthesameskintransientdarkstainingdueto

oxidationofHydroquinone10) Keratolytics 

a) Salicylic Acid—topical(3‐6%=keratolytic;>6%=destructive)i) Mech:solubilizationofcellsurfaceproteins.ii) Side Fx: 

(1) Salicylism:ringinginears,nausea/vomiting (a) Tx:hemodialysis

(2) Allergicrxn:urticaria,anaphylaxis,erythemamultiforme(3) Death

iii) Propylene Glycol—topical;maybeformulatedw/6%Salicylic acid(1) Effectivekeratolyticagentaloneat40‐70%(2) Side Fx:allergiccontactdermatitis

11) Trichogenic & Antitrichogenic Agents (drugs affecting hair growth)a) Minoxidil [Rogaine]—topical;relatedtoLoniten—potentoralvasodilator

i) Tx:hairlossii) Mech forhairregrowth:unknown

(1) InhPDE[cAMP]Smmcontrxn(2) Mayactivatethehairfollicledirectlyorstimulatefollicularmicrocirculation(3) Mayalsoalterlocalandrogenmetabolism

iii) Side Fx:SystemicabsorptionhypoT(1) Minpercutaneousabsorption(2) Skinabrasionorirritations,eg.excoriations,psoriasis,sunburn,↑systemicabsorption

b) Finasteride [Propecia]—orali) Tx:hairloss@1mg/day;BPH@5mg/dayii) Mech: Block5‐alpha‐dihydrotestosterone(DHT)production↓scalpandserum[DHT]

(1) NoFxoncortisol,estradiol,prolactin,TSH,thyroxine,cholesterolorPTH‐axisiii) Side Fx:Lowincidence,mainlysexualdysfuncxn

(1) Saw palmetto (Serenoa repens)andfinasteridehaveasimilarpharmacologicmech(a) Concurrentuseisnotrecommended

c) Eflornithine [Vaniqua]—topicali) Tx:unwantedfacialhairinwomenby↓hairgrowth

(1) usedinfacialandchinareasonly;donotapplyaroundeyesortomucousmembranes(2) Notadepilatory(abilitytoremovehair)(3) ParenteraldrugusedbyWHOtotreatprotozoalinfections

ii) Mechofreductionofunwantedhair: unknownbutrelatedtoskinODClevels(1) Specificirreversibleinhibitorofornithinedecarboxylase(ODC)↓polyamines,↓nucleic

acidsynth,↓celldivision&differentiationiii) Limitedpercutaneousabsorption

12) Pigmentation Agentsa) Tri‐Luma—combinationofFluocinolone,Hydroquinone,andTretinoin

i) Tx:Tempreliefoffacialskindarkeningbyhormonalchanges,pregnancy,oralcontraceptiveorhormonereplacementtherapy

ii) Fluocinolone:Anti‐inflammatoryactionsofcorticosteroidsiii) Hydroquinone:Inhmelanocyteenzymaticoxidationoftyrosineto3,4‐dihydroxyphenylalanine

(DOPA)↓melaninformation(1) Othermelanocyteprocessesarealsoinhibited

iv) Tretinoin:Modulateskingrowthandpigmentation(1) ↑keratinocytesheddingfromtheretinoid‐treatedepidermis↓epidermalmelanincontent

b) Methoxsalen [8‐methoxypsoralen;UVADEX]—oral/topicali) Tx:

(1) Vitiligo(smoothwhitespotsonskin)(2) w/UVAforsymptomaticreliefofpsoriasis(3) w/photopheresisforcutaneousT‐celllymphoma(mycosisfungoides),alopeciaareata,

inflammatorydermatoses,eczema,andlichenplanus.ii) Mechforvitiligo:stimmelanocytesinhairfollicleiii) Side Fx:

(1) WhenactivatedbyUVradiation(320‐400nm),itisapotenterythemogenic,melanogenic,andcytotoxictherapy(a) Conjugateandcross‐linkw/DNA

(2) ExposuretoUVA+methoxsalencellinjuryandinflammation(3) Delayederythemafollowedoverseveralweeksby↑epidermalmelanizationandthickening

ofthestratumcorneum(4) Peakphotosensitivitywithin1‐2hours;canpersistfordays

13) Topical Antiviral Agents a) Acyclovir [Zovirax], Valacyclovir [Valtrex], Penciclovir [Denavir], Famciclovir [Famvir]  

i) Tx:minorherpessimplexvirusinfections;herpeslabialisorherpesfibrilisii) Minpercutaneousabsorptioniii) Side Fx:

(1) Irritation(mildpain,stinging)(2) Alopecia(3) Erythemamultiforme(4) Photosensitivityrash(5) Pruritus

14) Topical Antihistaminesa) Tx:acuteandchronicurticaria,localallergicrxn,likeinsectbites.b) Cetirizine [Zyrtec], Desloratidine [Clarinex], Loratadine [Alavert]

i) Non‐sedatingagentsii) Mech: blockeffectsofhistamineonH1receptors,butdon’taffecthistaminerelease

15) Alkylating Agents and Antimetabolites  a) Coveredinanti‐cancerlectures

Inhalation Anesthesia

Definitions: 1. analgesia = relief of pain without intentional production of altered mental state 2. anxiolysis = decreased apprehension with no change in the level of awareness 3. conscious sedation = dose-dep; protective reflexes are maintained; have

independent maintenance of airway, oxygen sat., and ventilation; response to physical or verbal stimuli

4. deep or unconscious sedation = profound effects with loss of 1 or more components above

5. general anesthesia = sensory, mental, reflex, and motor blockade; concurrent loss of all protective reflexes

Drug List: Currently Approved Agents GASES: Nitrous Oxide

LIQUIDS: Halothane Enflurane Isoflurane Desflurane Sevoflurane *Methoxyflurane * now withdrawn due to the fact that 50% of the drug undergoes sig. metabolism liberating F ions and transforming into a reactive metabolic intermediate that causes cumulative impairment of RENAL FXN.

General Anesthetics:

• Agents that can produce REVERSIBLE depression of neuronal fxn , loss of ability to perceive pain, etc.

• Depression of spontaneous ventilation or a drug-induced NM Blockade often requires maintaining a patent airway and + pressure ventilation

• DOSING = INHALATION and INTRAVENOUS preferred. WHY?? They offer a more immediate control over dose and t/f DOA. Oral drugs offer no such control over depth of consciousness of pt.

*Father of Anesthesia = Crawford Long Indicated use of chloroform in childbirth. MECHANISM OF ACTION:

• UNKNOWN!!! We still don’t completely understand how they work….but we do know a lot about what affects their onset of action, etc.

Myer-Overton Hypothesis: (see graph of MAC vs. Oil:Gas partition coefficient) • MAC = minimum alveolar concentration = the concentration of the drug

needed to produce immobilization to stimulus in 50% of patients; defines the potency of inhaled agents – lower the MAC, more potent the drug (ie – less [] needed to see effect in 50% of pts.)

• Oil:Gas Partition Coefficient = measure of a drug’s lipid solubility; higher the PC, the more lipid soluble the rx

• Activity of agent/pharmacological potency is linked to LIPID SOLUBILITY!!!

• The more lipid soluble, the more easily it passes to the CNS and a lower dose is t/f needed to produce unconsciousness.

• LS is NOT the only component important because we can chemically alter Rxs to make them more lipid soluble, but they have LESS pharmacological act.

Dose-Response Curves of Inhalation Anesthetics:

• Normal Curve for a Rx and receptor system is SIGMOID, meaning as you increase the dose, you increase the effect over a range of [].

• Anesthetics drugs receptor interaction is still unknown. • IA curve is much steeper – ie a slight increase in [] of the rx you go from no effect

to 100% effect quickly. Not a classical rx:r interaction. *These agents dissolve within the lipid bilayer of membranes, affecting the lipid components and the transmembrane ion channels. These ion channels are responsible for neuronal activity and can be INHIBITED to get CNS depression. *Agents can also dissolve in more specific areas of TM proteins, affecting the flexibility of the protein and inhibiting it from carrying out its intended fxn. Spinal Cord as Mediator of Immobility:

• Immobility DOES NOT correlate to EEG act, rather to suppression of motor neuron activity.

• 2 Distinct Pharmacological Effects of IA: 1. ENHANCE = inhibitory effectors in CNS

GABA Glycine 2. INHIBIT = excitatory agents that arouse neuronal activity

Ach Serotonin Glutamate

• How do both above conflicting actions occur in a single rxn??? 1. Inhibitory Synapse: Normally, GABA release opens Cl channels to change

neuronal polarity and activity. Anesthetic agents bind to a site on a 5 transmembrane protein to cause changes with how GABA interacts with its receptor system = ENHANCES GABA act.

2. Excitatory Synapse: Ach release opens Na channels on post-synaptic neuron to stimulate it and increase neuronal act. In this rxn., the agent does not bind

to the TM protein itself, but IN the ion channel to prevent the easy passage of Na = INHIBITING ACH POST-SYN NEURONAL ACT.

• Recent Hypothesis = agents use a wide range of receptors, and they don’t

necessarily act directly on the receptor system but also accessory proteins – ie PDZ that is responsible for internal signaling of receptor act. These proteins are common to many post-synaptic receptor systems.

• So, anesthetics have a DIRECT EFFECT on the anesthetic site of action, and an INDIRECT EFFECT at sites where the agents can modulate anesthetic effect.

Guedel Stages of Anesthesia:

1. Delerium – no surgery - ↑ RR, ↑ BP, irritation of tracheo-bronchial, mydriasis, ↑ muscle tone

2. Plane 1 – dental/thoracic surgery 3. Plane 2 – abdominal surgery 4. Plane 3 – deep abd. Surgery 5. Plane 4 – no surgery 6. Medullary Paralysis/Death • As ↑ depth and uptake of agent into CNS, there is a progressive ↓ RR and

breathing fxn, ↓BP, loss of protective reflexes, papillary constriction then dilation, and prolonged ↓ muscle tone.

• There is also different responsiveness of parameters in CNS to the agent being used. Low [] of agents elicit no response in explicit memory and perceptive awareness first. It then takes higher []s to inhibit movement and then even higher to blunt autonomic axns. (See graph slide 23)

Structure of Volatile Agents:

• Simple, diverse, containing HALOGENS!!! • Halogens contribute to organ toxicity so why include them in the Rx?? To ↓

flammability that is inherent in many of these agents. • Have an asymmetric C atom so exist in RACEMIC MIXTURES. It is thought that

one isomer has a higher potency than the other. Absorption of Inhalation Agents:

• In mixture of gases, the partial pressure or tension of a gas is proportional to its [] in the overall mixture.

• ADMIXTURE = 70% nitrous oxide, 25% O2, 5% halothane • All partial pressures add up to atm. P = 760 mmHg.

Blood/Gas Partition of Halothane:

• The inhaled agent must pass the alveolar wall once inhaled to get from the gas into the blood, and from there then distributed into organ systems.

• EX: of Halothane – [] of 2 Vol. % in gas corresponding to a PP of 15.2 mmHg. It must reach equilibrium between the alveolar and blood and for the PP to be the

same, the vol % has to be 4.6%. Need this level to get the PP equilibriated. Halothane in the blood dissolves in the lipid components and is not free to be a gas to pass biological membranes into the next system. Is sort of analogous to the protein binding of other Rxs in blood. FREE Rx is only one that passes membranes and exerts effects.

Comparison of Inhalation Agents: See slide 27 for actual #s and 33 for chart.

• HALOTHANE = older Rx side fxn: arrhythmias and hepatoxicity – “halothane hepatitis” most often occurs in obese females with previous exposure to the Rx. It is converted into a reactive metabolic intermediate that binds to liver proteins eliciting and immune response

• ISOFLURANE = irritant, muscle relaxation

• ENFLURANE = irritant, muscle relaxation, seizures only in susceptible ind.

• SEVOFLURANE = newer Rx

• DESFLURANE = newer Rx; irritant

• NITROUS OXIDE = “incomplete anesthetic” – given alone it cannot render the

pt. unconscious [note MAC value of 105!!!] – VERY low potency but does add to the overall admixture.

-low [] produce analgesia - give alone, you have maintenance of protective reflexes - TOXICITY??? – teratogen in animals, ↑ risk spontaneous abortion?, myelin sheath degeneration in infants due to chronic exposure, inhibit vitamin B12 synthase; med facilities have expensive N2O scavenging air systems to ↓ ambient air levels of N2O. - SECOND GAS EFFECT = high vol. of N2O and relative insolubility = leads to rapid uptake of gas from alveoli including any accompanying anesthetic agent or O2 (ie. ↑ rate of uptake of volatile agent with coadminstration of N2O.) - DIFFUSIONAL HYPOXIA = administer O2 to maintain oxygenation in immediate post-anesthetic phase because large quantities exiting via exhalation can ↓ O2 tension in lungs - SOLUBILITY – 34xs that of nitrogen so in some spaces in the body can displace it. Not a problem in places that have adequate compliance to accommodate such as the bowels, etc. But an ↑in P in middle ear can rupture the eardrum. - WHY DO WE USE N2O??? cheaper! 1. Vapor sparing effect – reduced requirement for expensive volatile agent

2. Reduced inspired volatile concentration - ↓ repiratory depression and CV effects, smoothens anestheic procedure (↓ consequences of other agents to spare protective reflexes) 3. Mild analgesic properties - USE of N2O Alone: produces drowsiness, dizziness, vertigo, dysphoria, panic, amnesia, inappropriate laughing (“laughing gas”), parasthesias - IMPORTANT – 70-75% of overall admixture is N2O – high volume, that is relatively insoluble in blood and rapidly taken up across alveolar walls. BUT this also ↓ component of O2, and low levels of O2 have been shown to have adverse effects on the patient on surgical wound infections and post-op recovery.

• XENON = inert gas thought to be used eventually in anesthesia due to its

extremely low PC of blood:gas and rapid equilibration [Isoflurane, Desflurane, and Sevoflurane are current agents of choice.] Regardless of muscle relaxation or pain relieving qualitites, it is customary to administer a neuromuscular blocking drug and an analgesic such as nitrous oxide or an opiod. *Lower MAC = more potent the drug ( #s for this value are not imp. Just recognize that they are all very potent Rxs – a low % in the admixture can elicit vast effects. EXCEPTION – Nitrous Oxide – see above) *Partition Coefficient = low PC signifies that the Rx equilibrates rapidly between compartments. Low blood:gas PC means that you after administer it, it renders the pt. unconscious faster because it equilibriates faster. Halothane was once the prime inhaled agent with a relatively low blood:gas PC, however, the newer, sevoflurane and desflurane were created and have an even lower PC and are currently used. Newer drugs are taken up faster into brain too and t/f have a more rapid onset of action. *LIPOPHILICITY – These agents are very lipophilic and would very much like to distribute into fat but they are not delivered there very readily because fat has a ↓ blood supply. T/f no sig. accumulation here in short term administation. *Most common route of exit from the body = EXHALATION. Give mask – inhaled – blood – brain – leave via exhalation after anesthesia stopped. Some % of drugs are metabolically coverted to metabolites and extreted. OLD DRUGS = higher conversion NEW DRUGS = lower conversion due to less time in the body OVERALL TREND = New drugs (Sevo and Des) accumulate and equilibrate faster than halothane. In addition, they are exhaled more rapidly than halothane allowing the patient to recover consciousness quicker.

Factors Affecting Uptake: see graph slide 30 • Dependent upon the blood supply to the organ.

Ex: brain has high blood supply so they rapidly accumulate here • Concentration of Inspired Gas = variable that anesthetist has direct control

over; this value is ↑ in the induction phase to ↑[] gradient, ↑ passage of drug to body and speed up the process of unconsciousness, then ↓ back down to maintenance levels

• Solubility - partition coefficient • Rate of blood flow to lungs • Cardiac Output • Tissue Distribution

*High blood flow tissues see a higher [] faster, and also are cleared of it faster. Fat, on the other hand, has a less rapid uptake and tends to hang on to the agent for longer as well. Respiratory Effects of Inhaled Agents:

• ↑ RR and ↓TV = regular rhythmic shallow breathing • ↓ respiratory fxn with ↑ depth of consciousness • Reflex response to PaCO2 is blocked by all but nitrous oxide. So, as ↑PaCO2, no

stimulation of repiratory center to ↑RR and blow off excess CO2. Result = ↑PaCO2 with ↑ depth unconsciousness.

Cardiovascular Depression by Inhaled Agents:

• ↓ in BP with ↑ depth of consciousness – this is due to a ↓ in CO – overall trend, not true for desflurane or isoflurane

• overall effect is dep. On the individual patient and their concurrent pathology, cardioactive drugs, and mechanical ventitlation

• Could have Pharmacological effect by: -direct depression - ↓sympathetic outflow - peripheral ganglion blockade - ↓ adrenal catecholamine release - BR attenuation - ↓Ca2+ flux - vagal stimulation

• Nitrous oxide has no significant CV effects when given alone. With ↑ in opioid, nitrous oxide produces CV depression suggesting a sympathomimetic action.

i.v. Anesthetics omitted: slides 38-40

I. Review slides 6-17… Key ideas:

A. Balanced anesthesia

B. formulation problems (b/c lipophilic in aq soln)

1. * except Methohexital & Ketamine –(will dissolve in aqueous soln)

C. complex structures specific R’s – (e.g. sites on GABA receptor; Ketamine on Glu- receptor)

D. * slide 12 pic of sites of axn

E. TMN signalling in wakefulness w/ Histamine vs VLPO signalling in non-REM sleep w/ GABA

F. * slide 15 – graph of time course of i.v. anesthetics

1. * waking ≠ drug metabolized! – just redistributed out of CNS to mm & skin, then fat

2. elim t1/2’s are hrs for all, but wake up ~15-30min

G. majority of these drugs do NOT analgesia (pain relief), so must add opiate.

1. exception: Ketamine, a potent i.m. analgesic, acting on Glu- receptor

II. Induction Agents: Barbiturates – Thiopental, Thiamylal, & Methohexital

A. Mech: prolong binding of GABA to the GABA receptor

1. * linear in depression of CNS w/ dose – easier to die w/ OD than BZ’s (i.e. a dose-dependent response – see graph slide 11)

2. widespread depression of brain activity (rat images)

B. Side Fx:

1. NOT analgesic – in low conc actually sensation of pain

a) Must add Rx for analgesia – here, opiates

2. * Dose-dep resp depression: death w/ OD

3. Can broncho- and laryngospasm @ beg while Rx admin’d

4. Usu no signif CV fx, but...

a) * caveat: Slide 19 – other factors affect CV response to i.v. anesthetics

(1) ANS

(2) Rx – e.g. BB’s, vasodilators

(3) CV pathology

C. Other Problems:

1. Cerebral vasocnstrxn

2. Hypovolemia, BB’s, central anti-hyperT’s (e.g. Clonidine) – all can affect CV stability w/ Rx

3. Enzyme indxn & tolerance – barbiturates induce CYP450 & enlargement of liver due to protein syn

4. Non-aq formulation

5. Allergic rxn

6. Porphyria (demyelination of nn due to drug axn)

III. Induction Agents: Propofol A. looks like skim milk

B. Mech:

1. enhance GABA activity + direct activation of GABA R

2. ALSO: inhib Glu- R

C. *Rapid comp’d to Thiopental

1. recovery is 10x faster

2. only Desflurane is faster

D. FX:

1. NO analgesia

2. lower doses conscious sedation

3. antiemetic – very low incidence of N/V

4. resp & CV fx = barbiturates (i.e. well-tolerated)

5. * intraocular P

6. some m. relaxation…

a) but if req signif m relax for surgery, would use nm blockers

E. Problems:

1. pain on injection

The initiating drugs we talk about are relatively well-tolerated – i.e. no major side fx common, but can have these bothersome side fx… Notice that: Propofol – very low incidenc of N/V. Methohexital & Thiopental – higher incidence of N/V; may req add’l antiemetic drugs.

IV. Induction Agents: Etomidate A. Mech: enhances GABA axn

1. may displace endog inhib’s of binding

B. FX:

1. CV & Resp depression: rare when used alone – well tolerated

a) resp depression w/ inhalational agents or opioids

2. direct, potent cerebral vasoconstrictor

a) can be advantageous in some cases

C. Problems:

1. pain on injection

2. * inhib of steroidogenesis – pt’s showed inhib of hypothal-pit-adrenal axis failure to thrive death

a) ACTH-unresponsive

b) NOT used in ICU!!

V. Ketamine

A. Mech: inhibits *Glu-* (acts on Glu- receptor) – [no direct effect on GABA]

1. diff pattern of depressed CNS activity (specific areas) vs. global fx of barbiturates (rat images)

B. useful IM when IV impractical

C. FX:

1. * potent analgesic

2. Symp stim activity:

a) muscle tone

b) open eyes (may resemble catatonic state) – eyes open, but unconscious & pain-free

c) BP, myocard O2 consump, minimal resp depression

d) intracranial P, intraocular P – may need to avoid according to circumstance

3. Intact pharyngeal/ laryngeal reflexes

4. * Potent bronchodilator – Tx refractory bronchospasm; facilitates good resp fnxn in anesthesia

D. Side Fx:

1. Hallucinations – (?)or using other drugs too

a) young women w/ “h/o vivid dreams” most susceptible

b) may need to give pt short-acting BZ – e.g. Midazolam (Versed) – to control hallucinations while pt emerging from unconsciousness

VI. Benzodiazepines – Diazepam (Valium), Lorazepam, Midazolam (Versed) A. Mech: bind & allosteric change in GABA receptor activity activity of receptor w/ less GABA

(i.e. shift D-R curve to the left)

1. dose vs. CNS depression: max effect levels out graph @ increasing doses; much more difficult to death w/ OD than barbiturates… unless combo w/ EtOH.

B. FX:

1. NO analgesia –(if need analgesia, use as part of drug combo.)

2. anticonvulsant – 1o use

3. anterograde amnesia – pt doesn’t remember surgery or immed prior to surgery

4. use w/ opioids suggests sympathomimetic effect – *slide 26 graph

a) has direct depressive CV effect but balanced by its symp stim no net CV effect

b) … unless used w/ e.g. opiates, which block symp output reveal direct depressive CV fx

(1) recall: same thing happens w/ N2O + opiates

5. wide Tx safety margin

6. * Flumazenil – specific antagonist for BZ – given i.v. to rapidly antag negative fx of BZ’s; only when necessary b/c has its own side fx

C. Problems:

1. Diazepam:

a) 1o drug & active metabolites prolonged sedation

b) * vs. Midazolam :

(1) water soluble

(2) very rapid distribution & metabolism – short duration, rapid recovery

VII. Chloral Hydrate (Aquachlor) – NOT on drug list! – may be w/drawn from market soon.

A. oral/rectal alternative to BZ’s

B. Conscious Sedation: dental procedures & perioperative for antianxiety/sedation

C. Common side fx: vomiting, behavioral changes

1. resp depression possible, esp combo’d w/ EtOH

D. Habit forming: w/drawal seizures, delerium, & death (!) if untreated

E. (alc. dehyd.) Trichloroethanol active product (GABA)

1. trichloracetic acid – suspected renal toxin & carcinogen

VIII. Opioids A. MuORs – in thalamic & spinal cord areas – Mu is involved in dulling pain

1. most effective against dull, poorly localized pain

2. difficult to reliably predict req’d effective dose due to:

a) CO, age, smoking, alcohol

b) morphine conjugates have pharm activity

c) acute tolerance

B. Arguments for/against using opioids as sole anesthetic agent:

1. For:

a) pain relieved but pt arousable

b) NO direct effect on heart

c) maintain nl regional blood flow autoreg

d) airway reflexes (facilitates intubation)

e) NOT toxic to organs – no malignant hyperthermia

2. Against – (it is not used alone now):

a) incomplete amnesia – pt could remember events from surgery

b) CV instability

(1) bradycardia

(2) hypoT (direct) or hyperT (insufficient block of pain symp stim in surgery)

(3) addn of N2O CV depression

c) blood req’s

d) prolonged resp depression in ICU

e) histamine-induced rxns

C. Side Fx:

1. [Assoc’d w/ speed of injection, high conc, & presence of other cardioactive Rx]

2. Bradycardia – via vagus or direct axn on SA/AV nodes

3. Hypotension – 2o to histamine release

4. Hypertension:

a) perhaps due to activation of renin-angio system

b) intense pressor effect w/ Naloxone – catecholamine release?

5. * Resp depression = major side effect (*see graph slide 33 – worse w/ anesthetic + opioid)

a) responsiveness of carotid bodies to rising PaCO2 – do not respond to ventilation

b) breathing driven by hypoxic drive – no O2 admin!! – will get rid of their only drive to breathe

c) reverse w/ opiate antagonists: Naloxone, Nelmefene

(1) * shorter t1/2 than opiate agonist! so must monitor pt for recurrence of resp depression

d) entero-hepatic recirc of opioid

6. muslce rigidity – wooden chest syndrome

7. intracranial blood flow & P – may need to avoid in pt

8. N/V, constipation, miosis…

9. * opiate OD classic s/s = pinpoint pupils, resp, coma

D. Relative narcotic potency:

1. Meperidine 0.1x morphine

2. Morphine is the standard @ 1 – it is used most b/c cheaper

3. Alfentanyl 0.1-0.2x Fentanyl – Fentanyl 75-125x – Sufentanyl 5-10x Fentanyl

a) synthetic, more $$

E. Opioid Combinations:

1. Innovar “neurolept-analgesia”; combo of...

a) Droperidol state of indifference, anti-emetic, anti-convulsant

b) Fentanyl analgesia

c) useful for radiology, endoscopy, to change burn dressings

2. + N2O (65%) “neurolept-anesthesia”

a) pt is now unconscious + pain free + indifferent

b) diff in t1/2 (D 3-6hr; F 1/2hr)

3. other: Atropine + Morphine/Meperidine

F. Remifentanil – a new class of opioids

1. very short-acting

2. very potent analgesic activity

3. rapid onset & peak (~1min); short t1/2 10-20min

a) effects not cumulative b/c so rapid

4. rapid recovery when discontinue admin… but so does the analgesia! … must consider & give other drug for analgesia beforehand so it can take effect

G. Choosing an opioid:

1. Long-lasting analgesia: Morphine – prototypical, very commonly used.

a) poor penetration of BBB (<1%)

b) pain relief correlates w/ CSF drug level

c) peak relief 15-30min

d) N/V is a classical side effect

2. Short-acting: Fentanyl

a) “20-min drug for 20-min procedure”

b) more lipid soluble

c) onset < 30sec!

d) peak relief 2-3min

e) N/V rare – unlike morphine!

IX. Pre-op Drug Sequence – *skipped to talk a/b more w/ ancillary drugs A. pre-op visit + interview

B. night before surgery:

1. BZ p.o.

C. 1-2 hr before surgery:

1. BZ p.o., 150mL water

2. opioid i.m. for analgesia

3. Scopolamine for amnesia & sedation

4. Cimetidine &/or Metoclopramide p.o.

5. Glycopyrrolate or atropine i.m.

D. transfer to surgery:

1. 8-10 add’l drugs in anesthetic regimen

X. Malignant Hyperthermia

A. Mech:

1. causative agent intracell Ca2+ release from SR (sarcoplasmic reticulum) metabolic activity & mm cntrxn

B. Dx:

1. 2-3x in end tidal CO2

2. total body rigidity (mm cntrxn)

3. unexpected tachycardia, tachypnea

4. resp & metab acidosis

5. can unexpected cardiac arrest

a) * primarily in young males w/ unDx’d myopathy 50% mortality

C. Causative Agents:

1. Succinylcholine –(nm blocker) – now labeled NOT for routine use in children

2. other triggers:

a) ALL volatile anesthetic agents! – incl. Desflurane, Sevoflurane

D. Safe Drugs:

1. N2O, local anesthetics, barbiturates, narcotics, tranquilizers, catecholamines, new muscle relaxants (e.g. Mivacurium, Doxacurium)

E. Tx:

1. Dantrolene – (not on list; will be discussed in Tx of mm spasticity) repackaging of Ca2+ into SR

2. stop trigger agent; avoid CCB’s (Ca2+ channel blockers)

3. hyperventilate w/ O2

4. correct hyperK+ & acidosis

5. cool core temp

“Local” Anesthetics Amide-type: (infiltration/injection) Lidocaine Mepivacaine Prilocaine Bupivacaine Levobupivacaine (discont’d) Ropivacaine

Ester-type: (infiltration/injection) Procaine Chloroprocaine Tetracaine Cocaine *Articaine – amide & ester bonds

Topical use only: Benzocaine (ester-type) Dyclonine Dibucaine (amide-type) Pramoxine EMLA TAC

I. “Local Anesthetics” – Reversible blockade

A. Ideal agent:

1. lipophilic and hydrophilic

2. low toxicity

3. short onset t.

4. completely reversible fx

5. active by topical, injection, & infiltration

B. Pros: simple, safe w/in dosing limits, cheap

C. Cons: unsuitability for some procedures, unpredictable surgery, prejudice (pt. & doc)

D. Mech:

1. block voltage-gated Na+ channels prevent neuronal cndxn

a) increase refractory period of nerve; longer t for Na+ to reconfig

b) most bind w/in channel

c) Benzocaine acts w/in memb memb swells occlusion of channel

2. NO effect on resting memb potential, only on depolarization

3. other explanation: Disruption of surface charge of memb by local anesthetics impairs nl depolar mech – this prob. adds to overall activity of these drugs

E. Differential Blockade – i.e. does not block all nerve fibers to the same extent

1. fiber diameter – smaller fibers blocked more easily

2. myelination – must block 3 successive nodes of Ranvier to have complete blockade of cndxn, or impulse just skips over

3. position in nerve bundle

4. nerve activity – change in ion conc’s affect rel polarity of memb change frequency of Na+ channel activity and avail to bind – a frequency-dependent blockade

a) effect in hyperK+ - in pt’s given Lidocaine for cardiac arrhythmias; hyperK+ penetration b/c Na+ channels more freq avail in less polarized memb heart block death!

b) effect in hyperCa2+ - b/c memb more polarized, less activity of Na+ channels to gain access

5. Drugs affect pain & temp before other fnxn’s

a) pain in type Aδ & type C fibers – most sensitive to local anesth

II. Partitioning of local anesthetic:

A. local anesth’s are weak bases – have 3o amine; most can be ionized: pH – pKa= log (unionized/ionized)

1. all else equal, drugs w/ pKa closest to local pH fastest, strongest block!

B. *Ion pooling may occur in inflamed extraneural tissue (more acidic) – w/ same amt drug applied, much less effective & shorter duration (b/c the extraneural drug doesn’t just stay there, and then more drug comes back out)

C. Interneural space pH rel constant pH = 7

*recall: only the unionized form crosses the membrane. III. Anatomical Aspects of Nerve Block:

A. Nerve bundle:

1. outer fibers go to proximal areas

2. inner fibers go to more distal areas

B. Drug applied outside nerve bundle

1. Anesthetic diffuses down conc gradient from outer to inner nn. – block runs proximal distal

2. Diffusion, dispersion, dilution, absorption

3. Conc grad now reversed – highest in center, lowest outer; drug diffuses again back out of n – return of sensation runs distal proximal

IV. Structure of Local Anesth’s: need to understand!

- 3o Amine: imp for axn of the drug - Aromatic ring: gives lipophilicity to penetrate memb’s into n. fiber - Intermediate portion – two groups: ester & amide

* if drug name has “i" anywhere before “–caine” it is an Amide! * if name does not have “i” before “-caine” it is an Ester!

- Changes of this baseline structure: DNTK them, but their purpose is to change pKa, lipophilicity, dynamics of absorp into n. fiber & mech of fx * Articaine – has thiophene ring instead of benzene ring of the others has both amide & ester linkage rapidly metab’d articainic acid (inactive); so very short-acting

V. Amide-type: Hepatic Metabolism – tend to have longer duration

A. affected by:

1. CV status

2. liver dz, can accum & systemic toxicity

3. toxemia of Pg

4. cimetidine

5. volatile anesthetics

6. BB’s

B. elim as urinary metabolites

VI. Ester-type: NON-Hepatic Metabolism by plasma Pseudocholinesterase – shorter duration

A. esterase affected by:

1. liver dz

2. Pg

3. chemoTx – some efficacy of pseudocholinesterase

4. atypical enzyme activity – genetic - systemic toxicity

B. elim as urinary metbolites

VII. Systemic Toxicities:

A. prepare for toxicity when:

1. approaching max dose

2. there is a potential for direct i.v. injections

B. Drug systematization:

note: some goes into blood stream – rate of this systemization is crucial

C. 1st = avoidance!

D. ask pt to report s/s of minor toxicity:

1. ringing in ears

2. metallic taste

3. numbness of lips/tongue

4. … if reported, stop injection immediately!

E. if no warning & high systemic conc,1st sign of toxicity = Seizures

1. Tx:

a) protect airway

b) admin Thiopental or Diazepam

c) Succinylcholine may be needed if severe – protects airway & metabolic acidosis

2. prompt Tx no long-term brain damage

3. delay potential permanent neuro deficit

F. CV less sensitive than CNS, but w/ rapid i.v. large dose Cardiac toxicity (ventric dysrhythmias or fibrillations)

1. worst w/ Bupivacaine – b/c bind Na+ channel for long t

2. possible w/ all local anesth’s

3. Tx:

a) secure airway, 100% O2, artificial circ

b) EPI + defibrillate

c) Bretylium (antiarrhythmic) – 5mg/kg to 30mg/kg

G. Vasoconstrictors: mimize drug systemization

1. w/o vasoconstrictor:

a) drug diffuses from site of application, to n. bundle & removed to blood

2. w/ vasoconstrictor:

a) local blood supply constricted - chance for drug to go to n. bundle

b) duration & intensity of blockade

VIII. Complications & Additives:

A. Epinephrine or Levonordefrin common (vasoconstrictors duration & intensity)

1. Toxic rxns may be evident:

a) in small children & w/ large doses for deep parenteral sedation

b) exaggerated responses w/ other sedating agents

2. Epinephrine interaxn possible w/:

a) BB’s, TCA’s (Imipramine), halothane (sensitizes myocard to Epi)

b) also w/ hyperT, heart block, cerebral vasc insufficiency, uncontrolled hyperthyroidism

3. Aspiration test: pull back on the barrel of the syringe to make sure you haven’t penetrated the vasc.

a) avoid vasc injxn of local anesth & Epi (signif CV fx)

b) but will not always show i.a. placement

B. Ester-type: more likely to allergy

1. rxn to para-aminobenzoic acid (metabolite) – a well-known allergen

2. cross-sensitivity among, not between, esters & amides

C. Rxn to preservatives (sulphites)

1. w/ allergic patient, e.g. asthmatic, use preservative free!

a) 1% diphenhydramine ± 1:100,000 epi – limited success b/c has 3o amine

D. True allergic rxns are rare (<1%)

1. rash, verticaria, laryngeal edema, bronchospasm

2. usu inadvertent i.a. admin

E. Most complications are psych, due to injection anxiety, not pharm:

1. pallor, unrest, sweating, fatigue, palpitations, N/V

2. Vasovagal reaction:

a) s/s – sweating, faintness, pulse changes

b) may cerebral hypoxia, seizures, CV catastrophe

c) Tx is critical: place in recumbent position & give immed. supportive measures

IX. Vial Info:

A. drug conc given as %soln (for anesthetic)

1. e.g. Lidocaine Hydrochloride 2% = 2g/100mL = 2000mg/100mL, 20mg/mL

B. 1:X dilution (for vasoconstrictor)

1. e.g. Epinephrine 1:100000; 1:1 = 1g/mL; 1:1000 = 1mg/mL; 1:100000 = 10ug/mL

Onset – slow/rapid: - speed somewhat due to pKa, amt ionized at physiological pH - drugs w/ less non-ionized form have slower onset b/c conc of avail unionized drug is reduced (e.g. Bupivacaine) Potency - all based on Procaine (1) - note those similar & much more potent Duration – short/intermed/long: - long based partly on kinetics of binding to Na+ channel R – i.e. bind and inactivate it for a longer t DNTM these #’s, but know drugs are sep’d according to onset t, potency, & duration of axn note long-acting drugs – clinically important

X. Common Ester Anesthetics:

A. Cocaine:

1. topical use only – ENT

2. Fx: potent vasocnstrxn – only local anesth that does this

3. Side fx:

a) w/ chronic sniffing, vasoconstrict ischemia & gangrene in nasal passages

b) potentiates cardiac arrhythmias, esp w/ Epi present

B. Procaine:

1. slow onset, short duration – preferrable in some situations

2. this is the standard to measure the others’ potency

C. Chloroprocaine

1. short plasma t1/2

2. this minimizes fetal exposure in OB

D. Tetracaine

1. long axn; slow metab

2. very potent

3. potentially very toxic due to long blockade & potency

XI. Common Amide Anesthetics:

A. Lidocaine:

1. most commonly used local anesthetic

2. more rapid onset, longer duration & intensity vs. Procaine

B. Mepivacaine:

1. resembles axn of Lidocaine, but…

2. no topical effect

C. Prilocaine

1. lower acute toxicity than Lidocaine, but…

2. toxic metabolite (orthotoluidine) methemoglobinemia

a) Ferrous Ferric ion in Hb O2 carrying capacity of Hb low O2 in pt’s predisposed, e.g. w/ COPD

b) blue lips & nail beds

c) antidote: Methylene blue (or ascorbic acid): Ferric Ferrous

D. Bupivacaine & Ropivacaine

1. slow onset

2. long activity (up to 24hrs!) – useful in post-op anesthesia around wound

3. more potent & more cardiotoxic than Lidocaine or Mepivacaine – b/c of long binding

4. Ropivacaine has d cardiotoxicity

XII. Topical Local Anesthetics A. only topical due to poor aq solubility &/ localized toxicity w/ infiltration (irritate local tissue if injected)

1. some of these penetrate w/ low enough conc when used topically to not irritation

B. locations for use: skin & mucus memb’s (some exceptions); mouth, pharynx, larynx, trachea, esophagus, urethra

C. Benzocaine

1. assoc’d w/ Methemoglobinemia (also seen w/ Prilocaine)

2. skin, NOT mucus memb’s

D. Dyclonine

1. skin, NOT mucus memb’s

E. Dibucaine

F. Pramoxine

G. EMLA (Eutectic Mixture of Local Anesthetics)

1. 2.5% Lidocaine + 2.5% Prilocaine, cream

2. apply, wrap, wait, wipe off – ready for procedure

H. TAC (Topical Anesthesia thru Cut skin)

1. liquid applic to lacerations that req stitches

a) ineffective when applied to intact skin

b) rapidly absorbed thru mucus memb’s

2. widely used in pediatric emergency rooms

XIII. Regional Anesthesia: Infiltration

A. inject adjacent to nerve or nerve bundle

B. duration determines agent

1. recall: Epi prolongs fx of all drugs

C. area dictates dose

1. large surf A large volumes of dilute soln

a) e.g. Lidocaine - MTD 5mg/kg: MED 0.3-0.5% - so use 1 mL of 2% soln or 4 mL of 0.5% soln

D. Injection Technique: local anesthetics can be injected w/ little/no pain!

1. use smallest needle

2. inject subQ before raising wheal – subQ tissue can stretch more than dermis

3. solns are acidic stinging pain on injection

a) neutralize w/ NaHCO3 0.1-0.2 mEq/mL pain & may improve onset (1 mEq/ 10mL of 1.5%Lidocaine)

b) don’t come like that b/c of drug stability! – mix immed before use

4. body temp solns better tolerated

XIV. Regional Anesthesia: Tumescent

A. mostly commonly in plastic surgery – liposuction

B. subQ perfusion of large volumes of saline w/ dilute local anesth + Epi (33-55mg/kg)

C. very good outcomes reported, but…

1. comp to Lidocaine infiltration (above), conc much higher b/c then suctioned out w/ fat…

2. but have seen plasma peaks ~8-12 hrs later

3. unexpected deaths in CA attributed to this technique

D. *addl local anesth by any route not recommended for 12-18hrs – may get CNS & cardiotoxicity w/ too much

XV. Regional Anesthesia: i.v. – Lidocaine

A. 1o for upper limb surgery

B. also short-duration foot procedures

C. tourniquet applied to occluded limb

1. entire limb loses sensation

2. tourniquet left on to allow absorp of anesth from the vasc

3. when removed, what is left goes systemic and is metab’d

XVI. Regional Anesthesia: Central Nerve Block (Spinal or Epidural)

A. duration dep on: agent, dose, concurrent vasoconstrictor

B. hyper-, hypo-, or isobaric soln – i.e. additives in vial to make soln more, less, or equally dense than CSF

1. allows migration of drug down/up after injection

C. + Epi: has α2 axn inhibit Substance P release pain transmission

D. + Clonidine: also has α2 axn

E. application of drug can have complications…

1. esp w/ higher than nl epidural dose – must monitor closely

2. * Sympathetic Blockade w/ migration of drug up spinal cord:

a) Heart: symp innerv starts ~T12 chain ganglia; block will not stop heart (has parasymps too), but CO!

b) Resp ~same lower level as heart (T12) respiratory depression

c) Brain – higher profound depression & death

XVII. Systemic Uses for Local Anesthetics – low levels of i.v. Lidocaine:

A. [ineffective orally due to big 1st pass effect; given i.v. by divided bolus dose + infusion]

B. Suppress Grand Mal seizures

1. inhib hyper-excited neurons

C. Intracranial P

1. cerebral vasocnstrxn w/ less hypoT than Barbiturates

D. Analgesia

1. for post-op pain

2. need for opioids/ inhaled anesth

a) (*ceiling effect)

E. Suppress Cough

1. used peri-op

F. Antiarrhythmic: Tx Cardiac Dysrhythmias

G. Orally active congeners of Lidocaine (same mech but have oral bioavail):

1. Tocainide

2. Procainamide

3. Flecainide

H. other info:

a) Na+ channels modulated @ 50-100uM

b) many other effects @ 1-5000x lower conc – area of research

XVIII. Single Enantiomer Drugs:

A. BG: most syn drugs are 1:1 racemic mixtures; removal of inactive enantiomer improve Tx index; may side fx

B. Ropivacaine: pure S-enantiomer

Migraine not included: slides 5-9

I. Acute Migraines: Principles A. use only safe agents

B. choose based on severity of attack

1. mild-mod OTC

2. severe triptans or DHE most effective

C. use MTD before say that Tx does not work

D. w/ N/V, route of admin imp – injection/nasal spray better than oral

E. treat when mild! greater efficacy

1. only if <2 headaches / wk

2. >3d / wk risk analgesic overuse syndrome

[CSD = cortical spreading depression] note: - many different receptor systems involved - targeting α or H3 does NOT signif clinical fx

NSAIDs inhibit COX I & II PG Triptans activate: 5-HT1B vasocnstrxn 5-HT1D block Ca2+ into neuron release of CGRP & SP

II. Acute Migraine Therapy A. Analgesics: oral

1. NSAIDs single agent: Aspirin, ibuprofen, naproxen

a) Mech: inhib COX I & II syn of pro-inflamm mediators

b) take sooner vs. later!

c) Side fx:

(1) chronic use irritate gastric mucosa potentiate migraine-assoc’d N/V

(2) * additive nephrotoxicity! – monitor renal fnxn.

(a) inhib COX PGE2, PGI2 renal blood flow & ET-1

d) Drug interaxns:

(1) attenuate diuretics, BBs, ACEIs, vasodilators, central α2 agonists, periph α1 & Angio II blockers

(2) adjust dose in pt’s on NSAIDs

(3) elderly at ’d risk

2. NSAID combinations: Acetaminophen/Aspirin/Caffeine + Butalbital = Fioricet, Fiorinal

a) G6PD deficieny: imp w/ chronic high doses b/c aspirin hemolytic anemia in these pt’s

b) Butalbital (a barbiturate)

(1) Mech: thalamic GABA enhancement sedative-hypnotic fx

(2) Fx: drowsiness, sedation, cerebral fnxn

(3) Side fx:

(a) * analgesic overuse syndrome – strongly linked!

(b) enzyme inducer (CYP450)

(c) CNS & respiratory depression

(d) Porphyria (demyelination of nn due to drug axn)

(4) Contraindicated w/ ethanol & sedatives

c) Caffeine

(1) cerebral vasocnstrxn

(2) useful esp in caffeine w/drawal

(3) Side fx: potential CV interaxns (stimulant)

B. Triptans: oral; sooner is better!

1. Sumatriptan (oral, nasal, or S.C.) – does not cross BBB, but active against migraine!?

a) may have axn outside CNS?

b) migraine pt’s may have compromised BBB! …so maybe it does cross the BBB.

2. Zolmitriptan

3. Naratriptan inactive products, so has least problem w/ side fx

4. Rizatriptan

5. Newer analogs oral dosing, onset t, CNS penetration, duration

6. Mech: triple axn! (also see pic above)

a) selective intracranial/extracerebral vasocnstrxn

b) inhibit trigeminal n. activation by vasoactive peptides

c) inhibit trigeminal cervical complex activation

d) note: 5-HT1B & 5-HT1D specific axns – contrast w/ ergots! – (chart slide 18)

(1) i.e. the Ki values for 5-HT1B & 5-HT1D are much lower than w/ any other R’s

(2) fnxn’l activity (50% efficacy) varies slightly by analog

7. Metabolism:

a) by MAO: Suma-, Zolmi-, & Riza- – interaxns w/ MAOIs!

b) by CYP450: Nara- – interaxns w/ anything that inhibits CYP450!

8. * Tx: first line for moderate/severe attacks & non-responders!

a) * max usage = 2d/wk

9. Side fx: [only signif problem: Side fx ’d compliance]

a) sleepiness/tiredness (50%)

b) difficulty thinking (25%)

c) racing HR (25%)

d) dizziness (20%)

e) can coronary & periph vasospasm

(1) * contraindicated in: coronary or periph vasc dz, uncontrolled hyperT, or IBD (ischemic bowel dz)

(2) vasospastic fx additive w/ ergot alkaloids – do not give w/in 24 hrs: 2 triptans or triptan + ergot

C. Ergot alkaloids: parenteral (S.C., I.M., I.V.) or I.N.

1. Drugs:

a) Ergotamine

(1) moderate doses contrxn of smooth muscle (e.g. in small aa); used to…

(a) control hemorrhage

(b) promote uterine cntrxn

(c) Tx migraine headaches!

(2) large doses paralyze motor n. ending of symp. NS (“ergotism”)

(a) s/s = mental disorientation, convulsions, m. cramps, dry gangrene of extremities

b) Dihydroergotamine (DHE)

2. * Tx: limited to severe migraines – use other less toxic Rx for milder migraines

3. Mech: agonist on 5-HT1 & 2, α1 & 2, D2 (specific Ki’s slide 18)

4. Hepatic metabolism renal elimination

a) metab by CYP450… so, caution w/ impariment or concurrent CYP3A4 inhibitors

(1) SSRIs – fluvoxamine

(2) HIV drugs – saquinavir

(3) azoles – intraconazole

5. Fx: Complex

a) central (5-HT) & peripheral (α) vasocnstrxn + amine reuptake inhibition

(1) * contraindicated w/ any vasospastic predisposing condition: periph vasc dz, CAD, sepsis, MI, uncontrolled hyperT, etch

b) BP fx unpredictable

(1) capacitance >> resistance vessels

(2) dose-dependent fx

(3) α antagonist w/ dose

6. Side fx:

a) many drug interaxns!

(1) do not use w/in 24hrs of triptans – additive vasospastic fx

(2) do not use w/ sympathomimetic vasoconstrictors

(3) do not use w/ tobacco – (vasoconstricts)

(4) do no use w/ Propranolol – blocks vasodilation

(5) antagonizes: nitrates, BBs, CCBs

b) Catogory X! – do not use in lactation! – excreted in milk, affects infants’ CV/BP

c) chronic use valvular heart dz

D. Narcotics (Opiates): Butorphanol – I.N.

1. Mech:

a) all 3 ORs (mu, delta, kappa) agonist/antagonist in spinal cord & higher CNS centers

b) hyperpolarizes endplate; cAMP

(1) blocks release of SP from n. ending

2. Side fx:

a) Respiratory depression, bradycardia, histamine release, QT prolongation, constipation (recall: no tolerance to this effect)

b) CYP3A4 substrate signif hepatic drug-drug interaxns

c) N/V common (as w/ all opiates)

(1) avail w/ promethazine (anti-emetic)

3. * special consideration: severe migraines do NOT need narcotics!

a) 80% of migraines allodynia (hypersensitivity to touch & other sensations) – Triptans are ineffective for this type of migraine.

b) >50% of ppl who go to ER for migraine receive a narcotic analgesic!

c) Ketorolac is an injectable NSAID

(1) effective & avoids narcotics (habit-forming)

(2) (also used in ancillary anesthesia for analgesia)

d) Narcotics should only be given as a last resort!

E. Migraine & Pregnancy

1. common, most in 1st trimester – * when fetus @ greatest risk for abortifacent & teratogenic drugs!!

a) Acetaminophen – mainstay for 1st trimester attacks

b) Opioids – may be added for migraines in later trimesters

2. DHE: contraindicated

3. other classes used only when unavoidable

4. chronic migraine is rare and most difficult to treat

F. Antiemetics: Metoclopramide, Prochlorperazine, Promethazine, Chlorpromazine – I.V.

1. Emesis:

a) assocd w/ migraines &/ ergot use

2. Mech – work in 1/3 ways:

a) block signals to & from vomit center

b) block gut receptors that trigger nausea in the brain

c) act directly on stomach rate of emptying

3. Metoclopramide

a) cheapest, most common

b) Mech:

(1) central D2 blockade

(2) Ach release from post-gang fibers peripherally

(a) stimulates gastric emptying

c) Side fx:

(1) CNS: drowsiness, fatigue, confusion, restlessness

(2) PL secretion (D2 pituitary effect) gynecomastia

(3) oral drug interactions: e.g. aspirin, tetracycline, lithium, & digoxin

4. Prochlorperazine & Chlorpromazine

a) Mech:

(1) D2 block in CTZ(chemoreceptor trigger zone) & adverse extrapyramidal effects

(2) Ach & α-adrenergic block

(a) sedation, muscle relaxation, hypoT, headache

b) Side fx:

(1) D2 block tardive dyskinesia – avoid in Parkinsonism

(2) α2 block hypoT – caution w/ CV dz & elderly

(3) Ach block glaucoma, urinary retention, prostatic hypertrophy

(4) additive fx w/ CNS drugs – e.g. sedatives, anti-seizure, anticholinergic

(5) seizure threshold in predisposed pt’s

5. Promethazine (Phenergan)

a) Mech:

(1) H1 antag (GI, uterus, smooth m.)

(2) weak D2 antag

(3) central Ach antag in CTZ

b) Side fx:

(1) * fatal respiratory depression <2 yoa!

(2) Ach antag glaucoma, urinary retention, prostatic hypertrophy

(3) D2 antag drowsiness, seizure risk, Parkinson-like symptoms

III. Chronic Preventive Migraine Therapy

Note: preventive Tx is controversial… when? how long? which drugs? always required? how many migraines per month indicate need?

A. Considerations:

1. recurrent migraine interfering w/ daily routine despite acute Tx

2. very frequent headaches w/ risk of rebound

3. acute meds: failure, contraindication, or signif side fx; overuse

4. special: hemiplegic migraine, risk of perm neuro injury

5. patient preference

B. How to procede:

C. Amitriptyline (a TCA)

1. Mech:

a) inhibit reuptake of NE & Serotonin

(1) metabolite Nortriptyline also inhibits NE reuptake

b) strong anti-cholinergic axn

2. Side fx – typical anticholinergic:

a) aggressiveness, irritability, sedation

b) tachycardia, palpitations

c) cycloplegia

d) xerostomia, constipation, urinary retention

e) endocrine dysfnxn, weight gain

D. Divalproex (Depakote) & Valproic Acid (Depacon)

1. anticonvulsant; multiple mech’s

a) inhibit voltage-gated Na+ channels

b) GABA metabolism/ reuptake

2. Side fx:

a) highly protein bound – displacement can [free drug] & toxicity

b) CYP2C9 substrate – potential interaxns, e.g. warfarin, losartan, phenobarbital

c) * Teratogen

d) other: N/V, indigestion; pancreatitis or hepatotoxicity; sedation; derm rxns; /weight

E. BBs: Timolol & Propranolol

1. 50-70% effective to prevent migraine

2. Fx:

a) prevent aa dilation; inhibit renin secretion

b) block catecholamine-induced lipolysis AA syn PG prdxn

c) O2 delivery to tissues

3. Side Fx:

a) lethargy, GI upset, exercise intolerance

4. Contraindications:

a) asthma, AV block, sinus bradycardia, diabetes mellitus

F. Topiramate (Topamax)

1. 50% effective to prevent migraine

2. Antiepileptic agent – blocks spread of seizures

3. Complex Mech

a) block voltage-gated Na+ channels

b) enhance GABA axn

c) inhibit Glutamate axn

4. PKs:

a) long duration of action

b) narrow therapeutic window: metab and/or excretion toxicity

c) limited hepatic metab (CYP450)

(1) interaxns w/ CYP450 inhibitors

d) renal excretion

(1) decreased renal fnxn toxicity

G. Botox

1. Tx: spasticity, cervical dystonia, blepharospasm, strabismus, 1o hyperhydrosis

2. Speculated mech: direct release of mediators or indirect mm. activation of nn.

3. Admin: symmetrical injxn into glabellar frontalis & temporalis mm

4. Fx: incidence & severity of all headaches

a) no adverse fx!! – no vascular or systemic fx!!

b) But, high placebo rate

H. Cafergot (=Caffeine + Ergotamine) – oral/ rectal

1. act synergystically

2. Mech:

a) additive cerebral vasocnstrxn? (both do this)

b) * enhanced GI absorp of ergotamine tartrate

(1) absorp rate & peak plasma levels

3. PKs:

a) rectal bioavail 20x oral

b) Tmax ~2 hrs post-oral admin

c) relief w/in 1-2 hrs of admin

IV. Analgesic Overuse Syndrome A. Fulfiling…

Headache for >15 days/month (char depends on the drug) + headaches began/progressed in severity while taking meds + headache resolves or reverts to previous pattern w/in 2 mos after discontinuation of chronic drugs

B. Regular medication overuse >3 mos…

1. Ergotamin, Triptans, Opioids, & combination NSAIDs >10 days/month

2. Simple analgesics (NSAIDs: aspirin, ibuprofen, naproxen) >15 days/month

3. Note:

a) mean duration of drug overuse can be years

b) monthly doses highest for least expensive agents – analgesics

C. Trigeminovascular system sensitization

1. due to incomplete initial drug Tx, or…

2. by direct drug-effects on modulatory pathways in CNS

D. drug-induced in 5-HT levels 5-HT2 receptor upregulation

E. Cellular adaptation – changes to already aberrant internal signaling

F. Free radical damage in periaqueductal grey

1. * may be irreversible if extensive

G. Level of Association of drugs w/ analgesic overuse syndrome:

H. Three-Facet Approach:

1. Transition or bridging program (60-90% success)

a) 1st control migraines themselves w/ Ergotamine; prophylaxis w/ Propranolol

2. Biofeedback therapy

3. Prophylaxis to incidence of migraines:

a) TCA (Amitriptyline), SSRI, BBs (Timolol, Propranolol), anti-epileptics (Divalproex, Valproic acid, Topiramate), NSAIDs (Aspirin, Ibuprofen, Naproxen)

I. Overuse of medicine accounts for the majority of chronic dz headaches

1. need to raise physician awareness

2. avoid the syndrome in the 1st place!

Prior to surgery, a 37 year-old patient receives ranitidine to:

A) Produce sedation B) Reduce tracheobronchial secretions C) Empty the stomach D) Reduce vagal stimulation E) Reduce stomach acid secretion

Which of the following produces vasospasm and is contraindicated in a migraineur with uncontrolled hypertension or coronary artery disease?

A) Butalbital

B) Valproic acid

C) Ibuprofen

D) Dihydroergotamine

E) Butorphanol

Anti-Cancer Agents Assessment 8

1

Principles of Cancer Cell Growth • Cancer is the clinical manifestation of carcinogenesis • Carcinogenesis is the dz

o Caused by dysregulation of the cell cycle (ex: multiple mutations) o Oncogenes = encode proteins that tell the cell to divide o Tumor Suppressor Genes = proteins that detect damage repair or apoptosis.

• Cell-Kill Hypothesis (from Skipper’s Model)

o Chemo follows log-kill model: constant % cells killed regardless of tumor size First-order kinetics Ex: if there are 1010 cells and chemo has a log-kill power of 4, how many

cells will be left? Answer: 106 o Skipper failed to take into account vascularization or drug resistance.

• Growth as size - a sigmoidal relationship (Gompertzian Model). Why? b/c tumor

outgrows blood and nutrient supply. • Vascularization: - Good: more effective drug delivery

- Bad: risk of metastasis

• Drug Resistance: the major obstacle to successful cancer chemo. (Goldie-Coldman) o Acquired via random mutation (NOT b/c of response to drug). o Tx with combination chemotherapy to achieve cell-kill and avoid drug resistance o Beware Narrow Therapeutic Window!

• Treatment Options

o Best Tx is surgery – remove it all. (Easier said than done) o Systemic adjuvant or neoadjuvant chemo to de-bulk tumor before surgery. o Systemic chemo if dz is disseminated (ex: leukemia, metastasis) o Evolving Drug Choice

Older drugs interact with DNA inhibit synthesis cell death Newer drugs target specific molecular targets

• IMPORTANT GENERAL TOXICITIES OF ANTINEOPLASTIC CHEMOTHERAPY

o Myelosuppression thrombocytopenia o Secondary Malignancies – all that DNA damage risk for another tumor o Nausea/Vomiting + Diarrhea o Organ toxicity o Tumor Lysis Syndrome – lysis of tumor cells releases purine, K+, etc kidney

is overwhelmed uric acid & calcium phosphate deposition RENAL FAILURE Tx: Hydration Allopurinol – blocks xanthine oxidase (cf gout lecture) Rasburicase – urate oxidase (converts uric acid soluble allatoin)

Anti-Cancer Agents Assessment 8

2

Alkylating Agents • What are Alkylating Agents?

o Have chlorethyl (alkyl) group that reaches out and binds DNA o Usu @ N7-Guanine o The binding causes miscoding and DNA strand breakage G2 Block

Thus, replicating cells are the most susceptible, like… • Cancer cells • Bone Marrow • GI diarrhea • Hair allopecia

Cells in earlier cell cycle stages may have time to repair damage. • O6-alkylguanine-DNA alkyltransferase (AGT) is an endogenous

enzyme that takes the alkyl grp off the DNA (suicide enzyme). o General/Common Side Efx of Alkylating Agents

N/V Tx with Ondansetron (serotonin antagonist) Lung fibrosis (progressive, may show up years later) Secondary Malignancies Teratogen

• Nitrogen Mustards

o Cyclophosphamide MOA: chlorethyl group alkylates DNA

• Prodrug coverted in liver + kidney to aldophosphamide (active) • Alternate use: immunosuppression (transplants + stubborn RA)

Common Side Efx plus: • Renal Failure • Urotoicity severe hemorrhagic cystitis + bladder tumors

o Tx with Mesna – conjugates toxic acrolein (metabolite) o Ifosfamide

Renal Failure Urotoxicity tx w/ Mensa CNS toxicity: altered mental status, ataxia, seizures, coma

o Mechlorethamide

• Busulfan (an alkyl sulfonate)

o MOA: same as cyclophosphamide, just different structure Oral or IV hepatic metabolism

o Common Side Efx plus: Addison-Like efx: asthenia, hypotension, normal corticosteroid levels. Hepatic Toxicity veno-occlusive liver dz (see below)

Anti-Cancer Agents Assessment 8

3

• Nitrosoureas – only alkylators for brain tumors b/c lipophylic ∴ can cross BBB

o BCNU (Carmustine) 2 MOA’s: (parenteral)

• Alklates O6-Guanine DNA breakage • Isocyanate protein metabolite inhibits DNA repair

Side Efx: • Injection site rxn • Pulmonary Fibrosis • CNS toxicities! 1) endocrine dysfunxn (hypothyroidism, etc)

2) seizures, dementia, encephalopathy • Hepatic Toxicity – veno-occlusive dz

o alk.phosphatase, transaminase, + hyperbilirubenemia b/c endothelial damage

o Sx: abdominal pain, hepatomegaly, jaundice o Treat with Defibrotide.

o CCNU (Lomustine) MOA: alklator

• Thiotepa o MOA: polyfunctional alkylater (IV, IVe, or IC)

Rapidly metabolized in liver to TEPA loses an aziridine group forms interstrand DNA cross-links

o Side Efx: Neurotoxic symptoms: seizure, coma Injection site rxn Local bladder toxicities if IVe: dysuria, retention, hemorrhagic cystitis

• Mitomycin C (antibiotic) o MOA: bio-reductive alkylator

Also generates free radicals Comes from Streptomyces Metabolically activated (∴ vulnerable to reistance)

o Side Efx: myelosupression, injection site rxn, hemolytic anemia o Overall, this drug’s effectiveness in recent trials has been disappointing.

Anti-Cancer Agents Assessment 8

4

• Drugs with Platinum (and Chloride atoms) that Alkylate

o Cisplatin

MOA: alkylates intrastrand DNA links; 1º at N7-Guanine. • IV only; renal elimination

Side Efx: • Ototoxic • Nephrotoxic tx with Amifostine. • N/V pretty bad tx with Ondansetron • Progressive neuropathy (motor + sensory) even after stop drug • Secondary Malignancy: AML (acute myeloid leukemia)

o Carboplatin

MOA: same; also IV only Much less reactive than Cisplatin ∴ severity of side efx

(myelosuppresion is still dose-limiting factor)

• Dacarbazine o MOA: methylates DNA at O6-Guanine. (does not use Cl-)!

Metabolically activated; IV only Temozolomide is similar oral form

o Common Side Efx. (myelosuppression, N/V, etc)

• Procarbazine o MOA: methylates DNA at O6-Guanine

Prodrug activated in liver (CYP) Resistance rapidly develops when used alone!

o Side Efx: Myelosuppression Weak MAO inhibitor beware drug-drug interaxns!!!! Disulfriam-like actions (pt feels malaise if they drink alcohol)

• Review Alkylation Agents:

o Which two drugs can cause fatal liver toxicity? o Which drugs have CNS side efx? (name at least 4) o Which alkylator is not synthetic? o Which drugs methylate instead of using chloride as the alkylator? o Which drugs favor O6-Guanine instead of the N7 one? (name at least 3)

Anti-Cancer Agents Assessment 8

5

Anti-Metabolites mimic RNA + DNA (get inserted) but difference in structure foils transcription.

• Folic Acid Analogs o Methotrexate – our DMARD friend

MOA: • inhibits DHFR (which is necessary for folic acid to be able to

provide carbon groups for purine synthesis). • inhibits thymidylate synthase • When active drug enters cell, it gets polyglutamated

o This form is active, too o Can’t get out of cell

• doesn’t cross BBB Resistance: uptake, efflux, polyglutamation Toxicity: Bone marrow hemorrhage

o Renal Toxicity o Pneumonitis

Rescue with Leucovorin – a reduced folate that doesn’t need DHFR.

o Pemetrexed (Alimta) Strongly inhibits GART: glycinamide ribonucleotide formyltransferase Good to tx mesothelioma

o Trimetrexate (Neutrexin) - BBB crossing, tx Pneumocystis carinii.

• Pyrimidine Analogs (Cytosine, Thymine, & Uracil) Mnemonic? Pyramid Cytings of Gems, Capes, and Fluorine?

o Fluorouracil (5-FU) – IV only MOA: inhibits thymidylate synthase (TS)

requires a triple complex: enzyme + reduced folate + FdUMP Leucovorin enhances the enzyme part potency of 5-FU!

Resistance: 5-FU activation; TS synthesis Toxicity:

• Angina • Myelosuppression • Hand-Foot syndrome: erythema + desquamation

o Capecitabine – oral precursor of 5-FU Hand-Foot more frequent

Anti-Cancer Agents Assessment 8

6

o Cytarabine MOA: interferes w/ base stacking ∴ inhibits chain elongation

• Prodrug converted to ARA-CTP (active) • S-phase specific

Resistance: conversion to ARA-CTP or ARA-UMP (inactive) Toxicity: potent myelosuppression

o Gemcitabine

MOA: locks up cell division (similar to Cytarabine but not S-phase specific)

Toxicity: myelosuppression o *flu-like syndrome o liver transaminases o interstitial pneumonitis

• Purine Analogs and Friends (Guanine, Adenine) o 6-Mercaptopurine (Purinethol) - oral

MOA: ??? Resistance: HGPRT, alkaline phosphatase, uptake, efflux, etc. Toxicity

• Myelosuppression • hepatic enzymes jaundice • You MUST do genotyping to check for lack of TPMT! (slide 52,54)

• DRUG INTERACTION: Allopurinol slows deactivation! Reduce dose of Mercaptopurine.

o Thioguanine – similar to 6-MP; no allopurinol conflict

o Pentostatin – parenteral MOA: inhibits adenosine deaminase apoptosis Myelosuppression is dose-limiting.

o Cladribine and Fludarabine

MOA: oral prodrugs metabolized by deoxycytidine kinase to active triphosphate apoptosis

Resistance: deoxycytidine kinase activity Toxicity: myelosuppression, lingering immunosuppression (>1yr)

Anti-Cancer Agents Assessment 8

7

Natural Products (plant alkaloids and molds) (Slide 57ff)

do not assume that similar drug structure = same spectrum of activity. a lot of these guys have a huge structure good for taking up space

• Vinca Alkaloids o Vinblastine - IV

MOA: bind β-tubulin, preventing polymerization metaphase arrest hepatic metabolism

Resistance: P-glycoprotein or binding site of β-tubulin mutation Toxicity:

• Neurotoxicity (neural microtobules): numbness, reflexes, weakness dose has seizures + irreversible coma

• Alopecia and local cellulitis

o Vincristine and Vinorelbine MOA: same as Vinblastine Toxicity: Leukopenia, alopecia, local cellulitis

• Camptothecin analogs – “The Happy Tree” o Topotecan

MOA: bind and inhibit Topoisomerase 1 strand breakage • Hepatic metabolism via glucaronidation; renal elimination.

Resistance: eflux, change in Topo-1 expression, or Topo-2 this is why you give concurrent Topo 1+2 inhibitors!!!

Toxicity: • *Gilbert Syndrome: pt can’t glucaronidate anything ∴ can’t

metabolize the drug toxicity • Neutropenia, diarrhea, N/V • hepatic enzymes

o Irinotecan

MOA & Resistance: same (inhibit Topo-1) Toxicity:

• Same as Topotecan, plus… • *Acetylcholinesterase inhibition Ach efx, including acute

diarrhea that doesn’t respond to Loperamide (give Atropine!)

Anti-Cancer Agents Assessment 8

8

• Podophyllotoxins (slide 68 – Mandrakes) o Etoposide (Toposar)

MOA: inhibits Topo-II (forms ternary complex with it) • prevents re-sealing of normal DNA break ∴ inappropriate

breakage of DNA • Oral • Renal elimination (dose correction for creatinine clearance)

Resistance: typical: efflux, mutation Side Efx: myelosuppression, alopecia

o Teniposide (Vumon)

MOA: inhibits Topo-II (same) • IV • Extensive metabolism, then renal elimination (no dose fix)

Side Efx: myelosuppression, N/V

• Taxanes (from the Western Yew)

o Paclitaxel (Taxol) MOA: bind β-tubulin, preventing de-polymerization

mitosis arrest • Needs surfactant for solubility • If the cell isn’t cycling, paclitaxel has no efx. • Hepatic metabolism

Side Efx: • Cremaphor EL (surfactant) microembolism chest pain

o Tx prophylactically with antihistamines + steroids!!! • Myelosuppression • *Stocking-glove sensory neuropathy

b/c efx microtubules in nerves Cisplatin has similar side efx; do NOT give in combo!

o Docataxel (Taxotere)

Semi-synthetic taxol more potent than paclitaxel less surfactant problems b/c uses Polysorbate 80 instead. Side Efx:

• Neutropenia • Fluid retention perif + pulmonary edema

Tx prophylactically with oral Dexamethasone

Anti-Cancer Agents Assessment 8

9

• Anthracyclines “-rubicin” o Doxorubicin (Adriamycin)

MOA: • Inhibits Topo-2 (large planar ring structure gets in groove) • Makes free radicals • Apoptosis (via p53, caspases, FAS)

Resistance: typical Toxicity

• Myelosuppression, alopecia • Etravasational necrosis • Cardiac toxicity cumulative

o Acute is reversible o Chronic is irreversible CHF o PROTECTION with Dexrazoxane (iron chelator that

binds up free radicals, preventing cardio damage) • Red urine (not toxic, just weird)

o Daunorubicin (Cerubidine) – same as Doxorubicin

o Epirubicin (Ellence) – less cardiotoxic , but less effective anti-cancer .

o Valrubicin (Valstar) - non-cardiotoxic; used IVe for bladder carcinoma.

o Idarubicin (Idamycin)

o Mitoxantrone (Novantrone) (the only one without “rubicin” but it has “anthr” in it…)

MOA: • Inhibits Topo-2 • Binds cytoskeleton protein (cytokeratin 8) • Not enough free radicals for anti-tumor efx

but still enough for cardiotoxicity IV dosing, hepatic elimination Blue urine

Anti-Cancer Agents Assessment 8

10

• Bleomycin (Blenoxane) o MOA: drug-Fe complex causes oxidative damage to the deoxyribose

effectively same as if blocking Topo DNA breaks IV or IM high drug levels in skin + lung

o Resistance: typical o Toxicity

Pulmonary fibrosis + dry cough (may be latent) Cutaneous toxicity: hyperpigmentation, hyperkeratosis, etc.

• Actinomycin-D (aka: Dactinomycin, Cosmegen) o MOA: intercalates DNA (ie, inserts itself between a G-C base pair)

Single strand DNA breaks via Topo-2 axn IV dosage

o Toxicity: Pancytopenia, anorexia, N/V, diarrhea, alopecia Extravasational necrosis Dermatalogical manifestations, subject to X-ray (erythema,

desquamation, inflammation).

• Asparaginase (Elspar) from E. coli o MOA: protein synthesis o Toxicity:

protein synthesis • Beware drug interaxns • Immunosuppression • insulin hyperglycemia

Pancreatitis (note that amlase and lipase levels may be normal!) Hypersensitivity (10% have a potentially fatal rxn)

• Review o Which drugs inhibit Topo-1? Which ones inhibit Topo-2? o Factoid: Mandrakes come from the same plant family as Atropa belladonna

(Atropine), tomatoes, potatoes, and eggplant. (thank you, Wikipedia). o Which drug group requires prophylactic steroid tx? Why? o Which drugs can cause neurotoxicities?

Anti-Cancer Agents Assessment 8

11

Drugs with Specific Molecular Targets

• Hydroxyurea (Hydrea) o MOA: interferes with conversion of ribonucleotides deoxyribonucleotides

by stealing the free radical from ribunocleotide reductase. Rate-limiting step in DNA synthesis. Oral Resistance: reductase

o Toxicity Desquamative interstitial pneumonitis Myelosuppression used against various myeloproliferative disorders.

• Thalidomide (Thalomid)

o MOA: NK cells (via IL-2 + IFN-γ) inhibits anti-apoptosis (ex: NF-κB) angiogenesis prevents tumor cell adhesion

o Side Efx: Sedation Constipation peripheral sensory neuropathy teratogen!

• Tretinoin

o Specifically tx Acute Promyelocytic Leukemia (APL) also used for acne + psoriasis b/c promotes desquamation

o MOA: promotes differentiation and disrupts the chimeric gene being over-expressed in APL.

Oral Hepatic metabolism

o Toxicity Retinoic Acid Syndrome: fever, dyspnea, wt gain, pleural effusion Teratogen liver enzymes

• Glucocorticoids: Dexamethasone and Prednisone

o MOA: anti-inflammatory + immunosuppressive via synth of PG + leukotrienes Small, lipophilic, with cytoplasmic receptor gene transcription High doses suppres T-cells (and B-cells)

Anti-Cancer Agents Assessment 8

12

• Antibodies: biological response modifiers they all cause apoptosis and ADCC (antibody-dependent cell cytotoxicity) o Rituximab (Rituxan)

MOA: binds CD-20 B-cell depletion • Directly binds & dimerizes cell surface receptors apoptosis • Fc region provides target for complement Big MAC • Fc region provides target for macrophages

Tx cancer and RA

o Alemtuzumab (Campath) Binds CD-52 T-cell depletion

o Trastuzumab (Herceptin)

Monoclonal Ab binds EGFR-2 and Her-2/NEU Tx breast cancer (30% have the aggressive Her-2 mutation) Side Efx: Cardiomyopathy

o Cetuximab (Erbitux)

Binds EGFR-1 and Her-1 Tx colorectal cancer

o Bevacizumab (Avastin)

Monoclonal Ab that blocks VEGF anti-angiogenesis • Note: does not target/kill tumor cells, just limits its growth

Side efx: HTN CHF + pulmonary hemorrhage + GI perf.

o Interferon-α2a (Roferon) MOA: acts like endogenous INF antiviral + anti-neoplastic

• Cell cycle arrest in G0 • Apoptosis • cytotoxic T-cells + NK cells • pegylated form needs hepatic metabolism; renally eliminated.

Toxicity: • *Neuropsychiatric • *Flu-like sx • CYP450 inhibition

Anti-Cancer Agents Assessment 8

13

• Tyrosine Kinase Inhibitors

o Gefitinib (Iressa) and Erlotinib (Tarceva) MOA: prevent EFGR TK from phosphorylating ∴ no signal passed on

• Cell cycle arrest + inhibits angiogenesis • Oral w/ hepatic metabolism

RAPID RESISTANCE via expansion of clones w/ mutated targeted TK Side Efx: fatiue, rash, N/V, anorexia, diarrhea

o Imatinib (Gleevec) and Dasatinib (Sprycel)

MOA: oral TK inhibitor Resistance to Imatinib is high; Dasatinib is 2G drug w/ different

binding site

o Bortezomib (Velcade) MOA: inhibits the ubiquitin-proteasome pathway

• prevents degradation of IκBα o IκBα restrains NFκB (who is a pro-proliferation guy) o Result: no proliferation

• Activates caspases • Inhibits binding of myeloma cell to stroma • angiogenesis • inhibits cytokine interactions

o Tocicity: Thrombocytopenia, Peripheral neuropathy

Drug Associations (randomly inserted here b/c there was room)

Oncology Agent Concurrent Agent Consequence Tumor Lysis Syndrome Allopurinol, Rasburicase uric acid ∴ renal protect

Cyclophosphamide Mensa Protect from acrolein Cisplatin Amifostine Cytoprotection

MTX Leucovorin Metabolic Rescue 5-FU Leucovorin Enhanced action! 6-MP Allopurinol INCREASES TOXICITY

Anthracyclines Dexroxazone Iron chelator ∴cardiotox Bone Metastasis Pamidronate, Zoledronate bone pain & fractures

Anti-Cancer Agents Assessment 8

14

Hormones as anti-tumor agents

• Leuprolide (Lupron) and Goserelin o MOA: GnRH agonists initial hyperstimulation desensitization (castration)

Avoid initial flair with AR blockers o Side Efx: sweat, libido, hot flashes, nausea

• Neilutamide and Flutamide

o inhibit androgen binding (but circulating levels remain high) o Side Efx: gynecomastia

• Estramustine

o MOA: alkylating agent that targets cells with estrogen receptors binds microtubules ( disassembly), DNA breakage, apoptosis

o Side Efx: N/V + diarrhea is dose-limiting

• Anti-Estrogen Therapy

o Fulvestrant – Selective Estrogen Receptor Downregulator (SERD) MOA: completely suppresses ER genes Resistance: molecular cross-talk b/t ER + growth factor signals

o Tamoxifen and Raloxifene – Selective Estrogen Receptor Modulator (SERM)

MOA: • Estrogen agonist @bone • Estrogen antagonist @ mammary tissue

Side Efx: endometrial hypertrophy endometrial cancer

o Aromatase Inhibitors – 3rd Generation drugs Non-Steroidal: Anastrozole and Letrozole – competitively inhibit

aromatase Steroidal: Exemestane – irreversibly binds aromatase Oral w/ hepatic metabolism Side Efx:

• *more arthralgia & diarrhea than Tamoxifen, but fewer gynecological symptoms

• no affect on adrenal steroids or other hormones.

MuscleRelaxants Assessment8

1

Notehowthebodyhandlesthedrug(hepaticmetabolism,etc)Noteotherclassesofdrugsthathavepotentialinteractions.Reviewthetableonthebackpageofthehandout.GeneralSideEffects

‐ impairedbalanceespeciallyintheelderly‐ operationofmotorvehicles‐ additiveCNSdepressionwhenusedwithotherCNSdepressants(gofigure).‐ anti‐cholinergicactions(secretions,urinaryretention,blurredvision)‐ potentialdrugdependencystoppingdrugcancausereboundpain!

TxofSpacticity

• Baclofen (Lioresal) o MOA:  GABA agonist   hyperpolarization     muscle tension 

alsoinhibitsSubstanceP oralorintrathecaldosing renallyeliminated

o FDAIndications:multiplesclerosis,musclespasm,spasticity,cordtrauma

o DrugInteractions&SideEfx.

Renalfailure bloodglucose(bewareanti‐diabetics!) drowsiness,confusion,dizziness

• Dantrolene (Dantrium) o MOA: blocks ryanodine receptor on sarcopasmic reticulum    

prevents Ca++ release   restores Ca++ balance by allowing repackaging     muscle axn 

OralorIV(needssurfactant) Hepaticmetabolism

o FDAIndications:MalignantHyperthermia,NeurolepticMalignantSyndrome,

multiplesclerosis,andofcoursespasticity.

o DrugInteraxnsandSideEfx *Livertoxicity,esp.w/estrogensregularliverfxntests *Injectionsitephlebitis *Crossesplacentafloppybabysyndrome DoNOTusewithCa++channelblockersV‐fib Rarely:seizures,pericarditis,pulmonaryedema

MuscleRelaxants Assessment8

2

• Tizanidine (Zanaflex) o MOA: pre­synaptic α2 receptor agonist 

muscletonebutNOTmusclestrength! Efficacytotxspasticity=BaclofenBUT…

• Moresedation• Lessadversemuscleweakness

EfficacytotxHTN<<Clonidineo FDAIndications:MS,spasticity,spinalcordtraumao SideEfx

Don’tusewithotheranti‐HTNdrugsb/chypotension α2stuff:weakness,xerostomia,dizziness,sedation

• Quinine 

o MOA:refractoryperiodandmotorendplateexcitability Alsogreatanti‐protozoal

o Uses:txMalaria,txnocturnallegcrapms

• OtherDrugsfromOtherLectureso Clonidineo Gabapentino Diazepamo Botulinum toxin–clipsV‐snares∴preventsAchvesiclereleaseatNMJ

ptmaydevelopantibodiesagainstit;justswitchtypeAB.ThesedrugsjusttxSpasm(ie,drugsthatrelaxskeletalmuscle)–mostactintheCNS

• Carisoprodol (Soma) o MOA:CNS axn on reticular activating system in spinal cord

Nodirecteffectonperipheralnerves,muscleexcitability,etc Oral Hepaticmetabolism(CYP2C19)urinaryelimination

o SideEfx:

Druginteraxn:Rifampinwillpotency;Ketoconazolewillpotency CNSefx:drowsiness,dizziness,insomnia,vertigo,ataxia Mydriasis Orthostatichypotension

• Chlorzoxazone (Paraflex) 

o MOA:CNS‐unknown Oral *Noanticholinergicaxns

o SideEfx:

MuscleRelaxants Assessment8

3

Hepatictoxicity∴monitorliverenzymesandavoidacetaminophen• Cyclobenzaprine (Flexeril) 

o MOA:CNSatlevelofbrainstem oral (fibromyalgiaoff‐labeluse)

o SideEfx: Significantanticholinergicefx:drowsy,xerostomia,dizziness,

constipation,N/V,blurredvision Cardiacefxfalling

• Metaxolone (Skelaxin) 

o MOA:CNSgeneralsedativeaxnandalteredpainpercption Oral Hepaticmetabolismmonitorenzymelevels! (urinaryelimination)

o SideEfx Fattymealsplasmadruglevels Typicalstuff:additiveCNSdepression,N/V,GIupset,drowsiness Headache,irritability

• Methocarbamol (Marbaxin) 

o MOA:sameasMetaxolonebutcanbegivenoral,IV,orIM Cantxmusclespasmandtetanus

o SideEfx Phlebitisb/cofsurfactantformulation(propyleneglycol) Typicalstuff

• Orphenadrine (Flexoject) 

o MOA:generalizedsedativeaxninmedullaandcerebralmotorcentersSimilarstructuretodiphenhydramine(Benadryl)

• analgesia+localanesthetic• mildanti‐cholinergicaxns• anti‐histamine

Alsousedoff‐labeltotxParkinsonism Oral,IV,IM Hepaticmetabolism

o SideEfx:anti‐cholinergicstuffTxofFibromyalgia‐Pregabalin (Lyrica)

• MOA:GABA analogue at α2δ  subunits of Ca++ channelso neuronalcalciumcurrentsneuropathicpain+anxietyo renalelimination,virtuallyunchanged

• SideEfx:

MuscleRelaxants Assessment8

4

o reboundworsening@withdrawalo swellingofhands+feet,dizziness,xerostomia,sedation,wt.gain

GI Drugs Assessment 9

1

Laxatives Note: laxative abuse & overuse can lead to thorough constipation. • Bulk-Forming Laxatives

o Methyl psyllium (Metamucil) and Methyl cellulose (Citrucel) MOA: dissolve in water form a gel.

• In intestines, they attract water and swell ∴ H2O in stool. • Side efx: reduce absorption of other drugs and nutrients.

o Polycarbophil (Mitrolan) – (not on drug list)

• Surfactant Laxatives

o MOA: Stool softener water tension b/t stool and GI tract reduce strain of defecation Do not use long-term b/c of mucosal irritation

o Docusate sodium (Colace, Surfak) – anionic surfactant

o Poloxamer 188 – non-ionic surfactant

o Castor oil – anionic surfactant AND stimulates myenteric plexus (peristalsis)

Converted to active form (ricinoleic acid) in small bowel Used for catharsis (complete bowel evacuation) Can induce uterine contraction in pregnancy

• Stimulant Laxatives

o Most Potent Class of Laxatives o 3 MOA’s:

permeability of intestinal mucosa allow back diffusion stimulate myenteric plexus peristalsis prostaglandin synthesis and intestinal secretions

o Bisacodyl (Dulcolax and Modane) - prodrug, converted by enteric bacteria

o Sena (Senekot)

Natural product; more gentle than Dulcolax. Promotes colonic motility Pink urine

GI Drugs Assessment 9

2

• Osmotic Laxatives o Laxatives with Magnesium

2 MOA’s: • non-absorbable osmotic effect retains water in lumen • cause release of CCK intestinal motility and secretion

Magnesium sulfate (Epsom salt)

Magnesium hydroxide (Milk of Magnesia)

Magnesium citrate (Citroma) – cathartic

o Laxatives with Phosphate Buffered phosphate (Fleet Enema… or oral) – cathartic

o Nondigestible sugars and alcohols

Lactulose (Cephulac) • 2 MOA’s:

o osmotic (non-absorbed semi-synthetic disaccharide) o Fecal acidifier (acidic metabolism products via enteric

bacteria) can help liver failure pt excrete ammonia.

Glycerine – osmotic and lubricant effects; suppository.

(Golytely) polyethylene glycol electrolyte solution (not on drug list)

• Nasty: dissolve into 4L and drink for complete evacuation.

• Other Laxatives o Cascara sagrade extract (not in lecture)

o (Haley’s) Mineral Oil – penetrates and softens stool

o Lubiprostone (Amitiza) – (not on drug list)

secretions by activating Cl- channels, which also causes motility. Great for tx chronic idiopathic constipation (ex: IBS).

GI Drugs Assessment 9

3

Anti-Diarrheals • Tegaserod (Zelnorm) – on quiz but not in lecture

o 5-HT4 antagonist motility stimulant o withdrawn from US market in 2007 (but can be acquired for emergencies)

• Metamucil (also see above)

o In intestines, they attract water and swell ∴ H2O in stool, except this time somehow, this encourages stool to form instead of being a laxative. ???

• Bismuth subsalicylate (Pepto-Bismol)

o Adsorbs harmful bacteria, viruses, and/or toxins

• Attapulgite (Kaopectate) – same as Pepto Bismol

• Opiates as Anti-Diarrheals 4 MOA’s of opioids:

• secretions • muscle tone stiff anti-spasmotic (tx cramps)

sphincter tone urgency • motility contact time • does not cross BBB ∴ CNS efx ∴ specific for diarrhea

o Paregoric – camphorated extract of opium (0.04% morphine)

o Diphenoxylate + atropine (Lomotil) – atropine added to thwart abuse

o Loperamde (Imodium) – binds calmodulin

• Anti-Cholinergics as Anti-Diarrheals o MOA: block Ach from Vagus N. ∴ block signals for GI motility + secretion.

Note that doses high enough to block these signals would be toxic. *These drugs are use as anti-spasmodics to alleviate cramps.

Don’t cross BBB ∴ CNS efx

o Propantheline (Pro-Banthine) – not on drug list; also tx urinary incontinence

o Dicyclomine (Bentyl) – not on drug list

o [a different anti-cholinergic] + Benzodiazepine = (Librax) sedative

GI Drugs Assessment 9

4

Anti-Emetics Review: CNS involvement in the vomiting reaction (slide 24 + 25)

• Scopolamine (Scop-Dur) - anti-cholinergic o MOA: blocks muscarinic receptors on CN VIII as it travels to CTZ (?) o Tx: prophylaxis for motion sickness o Dose: transdermal patch behind ear o Side Efx: sedation, drowsiness, dry mouth

• Anti-Histamines as Anti-Emetics Remember: 1st Gen. H1 blockers also exhibit anti-cholinergic efx. MOA: anti-cholinergic part can act at any of the M1 receptors in the diagram.

o Dimenhydrinate (Dramamine) – OTC prophylaxis for motion sickness

o Cyclizine (Marezine) - OTC prophylaxis for motion sickness

o Meclizine (Antivert) – requires Rx

Tx Vertigo and Meniere’s Dz b/c has depressant efx on ear labyrinth

o Promethazine (Phenergan) - potency; tx severe N/V or use pre-surgery

GI Drugs Assessment 9

5

• Anti-Dopaminergics as Anti-Emetics o Chlorpromazine (Thorazine)

2 MOA’s: anti-dopaminergic + anti-cholinergic low doses highly effective for N/V… and intractable hiccups

o Prochlorperazine (Compazine) – not on drug list o Thiethylperazine (Torecan) – not on drug list; used at hospitals b/c injectable

o Droperidol (Inapsine) - Blocks D2 receptors in CTZ; Tx Post-op N/V

o Metoclopromide (Reglan)

2 MOA’s: • Blocks D2 receptors • gastric emptying (prokinetic)

Tx chemo-induced & Post-op N/V.

o Trimethylbenzamide (Tigan) - extrapyramidal side efx ∴ use short-term

• Serotonin Antagonists as Anti-Emetics MOA: 5-HT3 antagonist (see above figure)

• block receptors in GI • block receptors in CTZ

*Most effective anti-emetics allow chemo dosing *Potency even more if co-administered with dexamethasone

o Ondansetron (Zofran) – class rep; IV, oral o Granisetron (Kytril) – more potent; oral o Dolasetron (Asemet) – longer t½

• Miscellaneous Anti-Emetics and Adjuvants o Delta 9 THC (Dronabinol) – marijuana derivative

Tx intractable N/V in chemo pts (only in CA)

o Corticosteroids: Dexamethazone and Methylprednisolone Anti-emetic AND reduce side efx of other drugs via prostaglandins

o Aprepitant (Emend) – substance P antagonist; crosses BBB to act on CTZ

o Lorazepam (Ativan) – benzodiazepine, used for anticipatory vomiting

GI Drugs Assessment 9

6

Great drugs to tx Peptic Ulcer Dz Antacids

• Magnesium-aluminum Hydroxide (Maalox) o MOA: weak bases that neutralize HCl ∴ prevent pepsin activation o Uses: simple reflux, or adjunct w/ H2 Blockers and/or PPI’s. o Side Efx: drug interactions b/c Δ pH; Frequent dosing is inconvenient

• Mg-Al Hydroxide + alginic acid (Gaviscon)

o alginic acid is a floating gel to help prevent reflux

• Calcium Carbonate (Tums) o Side efx: acid reflux (b/c pH so fast reflex acid secretion )

H2 Antagonists

• Ranitidine (Zantac) o MOA: comptetitively inhibit H2 receptors (in stomach) ∴ acid secretion

• Famotidine (Pepcid AC) – most popular b/c most Potent and Longest t½

• Niatidine (Axid) – comparable to Famotidine

• Cimetidine (Tagamet) – not on drug list. No reason to ever give it b/c its least

potent, shortest t½ and side efx (CYP450) can be avoided using the other 3.

Proton Pump Inhbitors (PPI’S) • MOA: covalently bind & inhibit hydrogen ion pump (90% effective!).

o Irreversible modification of sulfydryl group on H/K-ATPase on parietal cells o Requires acidic pH for activation o Drug trapping (b/c covalent) o Best to use short-term b/c long-term efx unknown

• Omeprazole (Prilosec) – oral, long t½

• Esomeprazole (Nexium) - oral, long t½

• Lansoprzole (Prevacid) – less effective

• Rebperazole (Aciphex) - metabolized less by CYP450 ∴ lasts longer in pts

taking other Rx’s.

GI Drugs Assessment 9

7

Cytoprotective • Bismuth subsalicylate (Pepto Bismol)

o 4 MOA’s: secretion of mucous and HCO3 inhibits pepsin forms protective barrier at base of ulcer inhibits H. pylori

o Uses: GERD, PUD, and diarrhea

• Sucralfate (Carafate) o Forms sticky viscous gell at base of ulcer o Requires acid pH (prevent pneumonia in nocosomial chronic users)

• Misoprostol (Cototec) – PGE1 analog

o secretion of mucous and HCO3 o Side efx: intolerable (ex: diarrhea)

Antibiotics (for attacking H. pylori) a multi-drug regimen (slide 30): PPI + 2 Abx • Clarithromycin - Macrolide that inhibits microbe protein synthesis

• Metronidazole – synthetic abx for obligate anaerobes (resistance is a problem)

• Tetracycline – second-line drug (stagger dosing if w/ Bismuth)

o Not much resistance problem, but it turns kids adult teeth brown

• Amoxicillin – for G- bacilli

• Furazolidine – nitrofuran that is antibacterial and antiprotozoal

Drugs for portal HTN and Encephalopathy

• Lactulose (Cephulac) – see “laxatives”; acidification of stool systemic NH4

• Neomycin – give enema to colonic bacteria

GI Drugs Assessment 9

8

Drugs to Tx GERD Two-pronged approach to Tx GERD:

1) postural & dietary therapy (smaller meals, no mexican food, elevate bed) 2) prokinetic drugs to enhance peristalsis (keep that food down!)

(Note: anti-secretory drugs (H2-R + PPI) can be used to healing, but do not affect LES pressure)

D2 Receptor Blockers • Metoclopramide (Reglan)

o MOA: anti-D2 removes inhibition ∴ local Ach (5HT4 can now signal) smooth muscle stimulation (Slide 39).

* accelerate gastric emptying * LES pressure esophageal peristalsis amplitude

o Side Efx: other D2 R’s get blocked (tardive dyskinesia) ∴ use only 1-2 wks

• Domperidone (motilium) – same as Metoclopramide

Drugs to Tx Inflammatory Bowel Dz Local Anti-Inflammatory Agents

• Sulfsalazine (Azulfidine) o MOA: prodrug that is broken down into two metabolites

5-ASA active sulfapyridine side efx: anemia, rash, impotence

• ASA-Dimer (Rowasa)

o MOA: prodrug that is metabolized to two molecules of 5-ASA o Fewer side efx but weaker anti-inflammatory

• Glucocorticoids: Prednisone

Antibodies for TNFα

• Infliximab (Remicade) - monoclonal IgG Aby for TNFα bind TNFα

• Etanercept (Enbrel) - MOA: soluble TNFα receptor bind TNFα

Endocrine Drugs Assessment 10

1

Pituitary: Natural Hormones and Associated Drugs • Somatotropic Hormones (slide 9 & 10) – pulsatile release

o Growth Hormone (GH) stimulates liver et al (via tyrosine kinase) to release IGF-1 growth deficiency pituitary dwarfism excess gigantism or Acromegaly Dx deficiency: hypoglycemia (insulin-induced) GH; high glucose GH

Somatropin (Serstim, Genotropin, Humatrope, etc) – same as hGH Somatrem (Protropin) = GH + methionine

• (Methionine added at terminal end of GH peptide to extend patent) Sermorelin acetate (Geref)

• the first 29aa of GHRH (44 total) • for testing, not for replacement therapy

Side Efx

• Less in children but include: leukemia, ICP, nausea • Adults: carpal tunnel, peripheral edema, arthralgia, myalgia

o IGF-1 (Insulin-like Growth Factor)

deficiency looks like GH BUT does not respond to hGH. Tx with: Mecaserin (Increlex) – IGH binding protein combo (1+3)

• Provides the IGF binding protein AND t½. excess causes Acromegaly. Tx with:

Pegvisomant (Somavert) – GH Receptor antagonist IGF-1 • covalently bound polyethylene glycol (PEG) renal clearance ∴ t½

o Prolactin (PRL) – no therapeutic use, but… o Dopamine Receptor Agonists to DA prolactin tx hyperprolactin-

emia from pituitary adenomas Pergolide (Permax) - 1° tx Parkinson’s. Least expensive. Cabergoline (Dostinex) - affinity, t½ Quinagolide [not in US] Bromocriptine (Parlodel)

• Somatostatin Analogs

Somatostatin normally negatively regulates secretion of GH + TSH excess GH = Gigantism or Acromegaly. Best tx is surgery; drugs are 2°.

o Octreotide (Sandostatin) – short t½ (3x daily injxn) Side Efx: diarrhea, nausea, abdominal pain

o Lanreotide (Somatuline LA) – long acting, slow release, same side efx

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• Glycoprotein Hormones o Thyrotropin (TSH) o Luteinizing hormone (LH) – ovulation occurs 36 hrs after LH surge o Follicle-Stimulating Hormone (FSH)

Menotropin (Pergonal, Humagon, Repronex) – give IM • urine from post-menopausal women; contains FSH + LH • tx female infertility

Recombinant FSH – give SubQ - also tx female infertility • Follitropin α (Gonal-F) or Follitropin β (Puregon, Follistim)

o Chorionic Gonadotropin (hCG) Diagnostic kits – target hCG-β Human excreted CG (Pregnyl, Profasi)

• From pregnant women’s urine. Mimic LH ∴ tx female infertility Menotropin – same as above

o RISK of multiple pregnancy with gonadotropins!

• Pro-opiomelanocortin (POMC)-derived Hormones o Corticotropin (ACTH) o α-MSH & β-MSH (melanocyte stimulating hormones)

• Posterior Pituitary Hormones: Oxytocin, Vasopressin (ADH), Desmopressin

Hypothalamus: Releasing Hormones

• Gonadotropin Rleasing Hormone (GnRH) stimulates FSH + LH stimulate gonads ∴ necessary for fertility

o Synthetic GnRH (Factrel, Lutrepulse) - t½ = 2-4 min Use Factrel to DDx pituitary vs. hypothalamic defect when pt has

hypogonadotropism Use Lutrepulse (pulsating IV) to tx male infertility (try androgens 1st).

o Analogues of GnRH – longer t½ tx prostate cancer & precocious puberty by surge downregulation

Goserelin acetate (Zoladex), Triptorelin (Trelstar), Leuprolide (Lupron) Histrelin (Supprelin) & Nafarelin (Synaral)

o Cetrorelix (Cetrotide) and Ganirelix (Antagon) = GnRH Antagonists used to delay LH surge ∴ delay ovulation to allow collection of ova for

use in in vitro fertilization

• Growth Hormone Releasing Hormone (GHRH) stimulates AP to release GH • Thyrotropin Releasing Hormone (TRH) (Protirelin) – used for diagnostics (slide 37) • Corticotropin Releasing Hormone (CRH) – used for diagnostics (Cushings vs. ectopic)

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Adrenocorticosteroids • ACTH

o Natural (HP Acthar Gel) – from animal sources (POMC peptide) o Cosyntropin (Cortrosyn) – synthetic (aa 1-24), preferred

Major clinical use is to test integrity of HPA axis (negative feedback to hypothalamus & pituitary, slide 10) – does pt need supplemental steroids?

• Glucocorticoids gluconeogenesis & anti-inflammatory (block Phospholipase A2)

o Cortisol = Hydrocortisone – short t½ o Cortisone Acetate – short t½ o Prednisone (Deltasone) & Prednisolone – medium t½ o Methylprednisolone – medium t½ o Dexamethasone (Decadron) – long t½ o Betamethasone – long t½, tx asthma o Triamcinolone – long t½, tx asthma o Budesonide (Pulmicort) – tx asthma or IBD o Side Efx of Glucocorticoids

*Suppression of ACTH and TSH production don’t stop tx abruptly! lipolysis, redistribute fat (Cushing-oid) diabetes risk (b/c opposes insulin) peptic ulcers perforation risk b/c steroids suppress the pain CNS arousal, euphoria, insomnia Blood: Hgb + RBC + PMN’s; lymphocytes + eosinophils In MEN: hypogonadism In WOMEN: stop ovulation, dysmenorrhea, osteoporosis In CHILDREN: inhibit IGF-1, osteoporosis

• Mineralocorticoids Na+ Retention

o Aldosterone – Stimulated by 1) angiotensin II & 2) K+ Axn: distal convoluted tubule Na+ resorption; K+ & H+ secretion Side Efx: edema, HTN, cardiomyopathy, CHF, hemorrhage

o Fludrocortisone – synthetic aldosterone o Spironolactone – aldosterone antagonist.

• Inhibitors of Adrenocorticoids

o Aminoglutethimide – inhibits CYP450 in synthetic pathway inhibits overproduction of cortisol tx Cushings.

o Ketoconazole – anti-fungal; also inhibits CYP450 tx Cushings.

potency b/c no efx on mineralocorticoid receptors

Endocrine Drugs Assessment 10

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Gonadal Hormones • Estrogen birth control (BC) & tx prostate cancer

Bones: closes epiphysial plates; osteoclasts (tx osteoporosis) Cancer Risk: stimulates what’s already there breast, endometrial hepatic protein synthesis clotting factors thromboembolism HDL, LDL (good)

o Natural Estrogens – 1st pass metab Estradiol – most potent; principal ovarian steroid Estrone – like estradiol, it is made from androgen via aromatase. Estriol – least potent; principal placental steroid

o Ethinyl Estradiol & Mestranol – synthetic 17α bonds allow 1st pass metab. oral use for contraception

o Estrogen Esters: conjugated (Premarin), from estradiol (Delestrogen et al) IM injection to tx menopause (Premarin = Pregnant Mare Urine)

o Estropipate (Ogen) crystalline estrone sulfate o Non-steroidal Estrogens – avoid 1st pass efx

Diethylstilbesterol (DES) - teratogenic Clorotrianisene

o Selective Estrogen Receptor Modulators (SERM) tissue selective

Tamoxifen, Raloxifene, & Toremifene • agonist in bone, brain, + liver • antagonist in breast + endometrium (∴ tx breast cancer)

o Anti-Estrogens: Clomiphene & Fulvestrant

antagonist in all tissues (bind ERα+β) Axn: block feedback inhibition GnRH induce ovulation

• Progestin estrogen Precursor, maintains Pregnancy Norethindrone Norgestrel Levonorgestrel

o Anti-Progestins Mifepristone – RU 468 – blocks P receptor; morning-after pill (49 days) Onapristone – more pure antagonist

o Selective Progesterone Receptor Modulator – Asoprisnil – experimental

o Aromatase Inhibitors tx breast cancer (after Tamoxifen fails) (slide 32) Anastrozole & Letrozole

• HDL, LDL (bad) CHD • thickens cervical mucus & oviduct motility • tx endometrial cancer • morning-after pill (Levonorgestrel)

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• Androgens o Testosterone:

3 MOA: • bind androgen receptor • conversion in some tissues to 5α-dihydrotestosterone (DHT),

which is more potent. • conversion to estradiol binds estrogen receptor

Side Efx: masculinize females, feminize men, risk CHD, hepatic carcinoma

o Testosterone Derivatives (slide 53) Methyltestosterone Testosterone propionate Testosterone cypionate Testosterone enanthate Fluoxymesterone Danazol – tx endometriosis; masculinizing side efx

• Androgen Receptor Antagonists

o Cyproterone acetate – tx acne + baldness o Flutamide, Bicalutamide, & Nicalutamide – tx prostate cancer

Nicalutamide is less hepatotoxic, longer t½

• Inhibitors of 5α-Reductase – Finasteride – blocks testo converstion to DHT o Tx BPH (benign prostatic hyperplasia) and male-pattern baldness o Teratogenic

• Anabolic Steroids athletes abuse ‘em

o Side efx: Testo levels, libido, sperm, liver toxic, CHD (HDL+LDL). o Oxandrolone – less conversion to estrogen (so its better?) o Androstenedione

• Loose Ends (not on drug list)

o Spironolactone – aldosterone antagonist – competes for testo receptor o Ketoconazole – antimycotic – inhibits CYP450 inhibits testo synthesis (note

that this is a side effect, NOT therapeutic use) o SARM: selective androgen receptor modulators – experimental

Bind androgen receptors to stimulate muscle + bone growth

• Review: Use in Cancer Chemotherapy (slide 31) o Breast Cancer tamoxifen, aromatase inhibitors o Endometrial Cancer anti-estrogens, progestins o Prostate Cancer estrogens, anti-androgens

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Monomer (no hexamer with zinc) ∴ faster onset + shorter t½

Pancreatic Hormones and Anti-Diabetic Drugs • Natural Regular (soluble) Insulin – for IV injection

o Porcine – differs from human by only 1 aa o Bovine – differs by 3 aa o Ovine (sheep) – differs by 3 aa

• Modified crystal size insulins (slide 23)

o NPH insulin – intermediate axn use twice daily (B-fast + Supper) o Lente insulin (also intermediate axn) = 30% semilente + 70% ultralente

Semilente insulin – short-acting Ultralente insulin – long-acting b/c has larger crystals

• Synthetic Insulins – slide 31!

o Recombinant DNA Human Insulin (Humulin) – made in bacteria/yeast o Human Insulin made by switching AA of Porcine insulin (Novolin)

o Insulin lispro (Humalog) o Insulin aspart (NovoLog) o Insulin glulisine (Apidra)

o Insulin glargine (Lantus) – long-acting – asparagine 21 replaced by glycine o Insulin detemir (Levemir) – long-acting – acidic solution neutralized at injxn

crystals precipitate slow absorption

• Sulfonylureas promote hypoglycemia by efx of insulin on glucose uptake o Metabolized in liver, excreted by kidney, use is controversial. o Axn is enhanced by NSAIDs

1st Gen • Tolbutamide • Chlorpropamide • Tolazamide • Acetohexamide

2nd Gen – more potent all start with “Gli” filled with Glee for being better than 1st Gen

• Glyburide – can be combined w/ Metformin • Glipizide • Gliclazide • Glimepiride

• Meglitinides: Repaglinide & Nateglinide promote hypoglycemia by insulin secretn

o short t½ ; used to control post-prandial glucose level. (Beware hypoglycemia)

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• Biguanides promote hypoglycemia by hepatic glucose production

Does not affect insulin secretion, ∴ no hypoglycemia o Phenformin – withdrawn b/c lactic acidosis o Metformin (Glucophage)

• Thiazolidindiones (“the glitter zone”) promote hypoglycemia by binding PPARγ

receptor ∴ insulin sensitivity o Troglitazone – withdrawn b/c severe liver toxicity o Rosiglitazone (Avanida) – black box warning o Pioglitazone (Actos)

• α-glucosidase Inhibitors promote hypoglycemia by inhibiting α-glucosidase (in

epithelial brush border) ∴ carbohydrate absorption o Acarbose o Miglitol

• Incretins insulin secretion

o What’s an Incretin? Endogenous compounds (GIP & GLP-1) that post-prandial blood glucose. Usu secreted w/ oral food intake.

o Exenatide (Byetta) – more potent than GLP-1 (from Gila monster venom) o Sitagliptin Phosphate (Januvia) – inhibits inactivation of Incretins

• Amylin Analogues – Pramlintide – augments endogenous amylin

o What’s amylin? Similar axns to GLP-1 but different receptors: slows gastric emptying, satiety, inhibits glucagon.

o Benefits: pt loses weight and needs less insulin.

• Diazoxide – inhibits insulin secretion (but not synthesis) tx hypoglycemia • Octreotide – long-acting somatostatin analogue inhibits insulin, glucagon, GH, &TSH

o Tx insulinomas, glucagonomas, acromegally, etc. • Drug Combinations… add it with Metformin for a happy cocktail

o + Glyburide o + Rosiglitazone o + Pioglitizone o + Glipizide o + Sitagliptin

• The Future: Tyrosine Kinase Inhibitors (like Imatinib) to tx Type 1 DM.

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Calcium Regulating Hormones • Parathyroid Hormone

o Teriparatide (hPTH 1-34) – short t½ o Full-Length hPTH (1-84)

• Calcitonin

o Synthetic human calcitonin hCH o Natural calcitonin from salmon (Calcimar)

Abys may develop; use prednisone. o Use: excess Ca++ from Hyperparathyroid

(short-term use), Paget’s Dz, Osteoporosis

• Vitamin D (Calcitriol) Cholecalciferol = Vitamin D3 (fish liver oils) Ergosterol (similar to cholesterol) Ergocalciferol (after irradiation) = Vitamin D2 25-OH cholecalciferol Calcipotriol – analog of Calcitriol; tx psoriasis Dihydrotachysterol (reduced VitD2, DHT)

• Less active, but more effective w/ dose good tx osteoporosis Paricalcitol – MOA: PTH secretion 22-Oxacalcitriol – MOA: PTH synthesis

* plasma Ca++ (bone, kidney, GI) * MOA: cAMP (urine test)

* plasma Ca++ * comes from C-cells in thyroid * opposes efx of PTH

Actions of Calcitriol * plasma Ca++ (GI, kidney, bone) * synth. in skin * most important Ca++ regulating hormone! Therapeutic Uses: * hypoparathyroid * rickets/osteomalacia * osteoporosis

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• Bisphosphonates inhibit bone resorption o Tx: Paget’s Dz, Osteoporosis, Hypercalcemia (long- term tx – for weeks) o Dose: must take after overnight fast w/ glass of water, no food for 30 min. o Side Efx: osteonecrosis of the Jaw! (esp w/ 3G)

gingival swelling and loosening of teeth; surgery makes it worse!

1st Gen – Etidronate – less effective orally (infusion better to Ca++)

2nd Gen – more potent • Alendronate (Fosamax) – tx osteoporosis • Pamidronate • Ibandronate (Boniva)

3rd Gen – even more potent! Risedronate (Actonel) & Zoledronate

• Calcium Sensing Receptor (CaSR) Mimetics (aka: calcimimetics) o Cinacalcet

MOA: binds allosterically to CaSR ∴ suppresses PTH at lower [Ca++]. Tx: hyperparathyroid, PT-carcinoma

• Fluoride – binds Ca++ o Cavity prophylaxis (∴ in our drinking water) o Prevent blood clotting o Prevent osteoporosis o Toxicity: osteosclerosis (but no cancer risk, which is nice).

(one more page!)

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Thyroid and Anti-Thyroid Drugs • The Natural Hormone – tx hypothyroidism

T4 = tetraiodothyronine = the form synthesized in the thyroid gland T3 = triiodothyronine = active form metabolite of T4. rT3 = reverse T3, inactive form Axns: growth, metabolism, HR Side Efx: monitor levels closely to avoid /-thyroidism

o Desiccated animal thyroid preparations (T4+T3) – not preferred b/c variability o Levothyroxine (L-T4) (Synthroid) o Liothyronine Sodium (L-T3) o Liotrix (both T4+T3)

• Anti-Thyroid Drugs (Thioureylenes) – tx hyperthyroidism

o Propylthiouracil (PTU) 2 MOA:

• inhibits I- organification ∴ it can’t bind to thyroglobulin • inhibits peripheral conversion of T4 T3.

Side Efx: uncommon (agranulocytosis, rash)

o Methimazole MOA: only inhibits I- organification. More potent and longer t½ than PTU Side Efx: crosses placenta (bad b/c fetus needs thyroid for happy brain)

o Carbimazole

• Iodine & Friends o Iodine

MOA: large doses inhibit iodine metabolism ∴ rapidly blocks T4 release Tx: thyroid storm

o Radioactive Iodine (Na131I)

concentrates in thyroid destroys parenchyma Tx: big thyroid (ex: Graves Dz, goiter, carcinoma?)

o Iodinated Contrast Media (off-label use for hyperthyroidism)

MOA: inhibit peripheral conversion of T4 T3 Diatrizoate Iohexol

Anti-Lipid Drugs Assessment 10

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Synthetics: FAR

Drugs that (primarily) Lower LDL Cholesterol (and coronary events) • Bile Acid Sequesterants

o MOA: anionic ∴ bind (-) bile acids in gut interrupt bile recycling makes liver think it needs to excrete more cholesterol safe, non-systemic, ok for kids & liver dz

Colestipol – big tablet Cholestyramine - Colesevelam – more potent; forms hydrophilic gel ∴ drink water!

o Side Efx: unpleasant sandy texture, flatulence, constipation; drug interaxns

• Statins = HMG-CoA Reductase Inhibitors o MOA: up-regulate hepatic LDL-receptors via SREBP-2 transcription

extensive 1st pass metabolism BUT ok b/c liver is the target organ! o Tx: LDL, TG

Simvastatin – prodrug, intermediate efx Pravastatin – safer but w/ low potency, low efficacy Fluvastatin - safer but w/ low potency, low efficacy; Gemfibrozil ok Atorvastatin – potency; renal clearance Rosuvastatin – most potent Lovastatin – prodrug (needs CYP3A4)

o Side Efx: Generally well-tolerated, may have GI distress or sleep issues CYP3A4 (get out that plastic card) LOTS of drug interaxns!!! Not for renal dz (except Atorvostatin OK) Teratogenic Rhabdomyolysis: if it gets systemic CPK muscle lysis acute

renal failure death. Myositis (muscle weakness + incr CPK)

• Cholesterol Absorption Inhibitors Ezetimibe o MOA: blocks internalization of NPC1L1 (niemann-pick) inhibits cholesterol

absorption (50%) in small intestine hepatic cholesterol up-regulates LDL receptors LDL + TG & HDL biliary excretion.

o Side Efx: Usu. well-tolerated (minimal steatorrhea) GI distress, fatigue, gallstones Plasma Levels if: elderly, female, liver insufficency Drug interaxns: CYP3A4, bile acid sequesterants, etc (slide 35) Pregnancy Category C; excreted in breastmilk ∴ do not use

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Drugs that (primarily) Lower Triglycerides (TG) & Raise HDL-Cholesterol

• Fibric Acid Derivatives (Fibrates) o MOA: activate PPAR-α (FA oxidation). (Note: γ-targeted ones are for diabetes)

LPL, ApoA1, but bile cholesterol excretion causes gallstones

Gemfibrozil – safe (at low doses) for renal + liver dz • side efx: reflux, diarrhea, myopathy if used w/ statins (so

either use Fluvastatin, OR switch to Fenofibrate). • +benefit to CHD (esp if TG (go figure) or diabetes)

Fenofibrate – has active metabolite • side efx: transaminases, GFR (azotemia) ∴bad for renal dz

Clofibrate – side efx: gallstones + cancer o All are Teratogenic

• Nicotinic Acid (Niacin)

o Aka: pyridine-3-carboxylic acid = vitamin B3 Immediate Release (IR) (Niacor) - side efx Sustained Release (SR) (Slo-Niacin) – slow release but hepatitis Extended Release (ER) (Niaspan) – t½ 4-6hrs Niaspan + Simvastatin (Simcor)

o MOA: unknown, something about FFA mobilization o +benefit to CHD, esp combined w/ simavastatin. o Side Efx:

Hepatotoxicity (∴ max 2g/day) Flushing w/ “ants” Eye issues: conjunctivitis, retinal detachment insulin resistance look for acanthosis nigricans Other: GI irritation, gout, dry skin, Pregnancy Category C

• Omega-3 Polyunsaturated fatty acids (Fish Oil)

o MOA: TG (nil efx on HDL or LDL) o +benefit to CHD antiplatelet, hypotensive, antiarrhytmic

• Investigational HDL-raising Drugs – just FYI, not for test.

Anti-Parasitic Drugs Assessment 10

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Drugs to Tx Protozoal Infections • *Metronidazole – requires metabolic activation

o MOA: block Pyruvate:ferrodoxone oxidoreductase (parasite specific). Equally active in dividing and non-dividing cells. bioavailability, BBB penetration, hepatic metabolism

o Tx: amoeba (tissue), giardia, trichomonas, anaerobic bacteria (B.fragilis) o Side Efx: GI, heatache, metallic taste, dizziness, disulfriam-like o Contraindications: Lithium, Coumadin

• Atovoquone

o MOA: inhibits electron transport ∴ pyrimidine synthesis o Tx: pneumocystis, toxoplamsa, amoeba, trichomonas, P.falciparum.

• *Eflornithine

o MOA: inhibits ornithine decarboxylase (a parasite essential) o Tx: W. trypanosoma o *Side Efx: anemia, leucopenia, diarrhea… convulsions, GI pain, alopecia

• Paramomycin

o MOA: aminoglycoside abx o Tx: amoeba (DOC), tapeworms, leishmanias, (giardia if pregnant) o Side efx: diarrhea, GI upset, not for renal dz

• Iodoquinol – MOA unknown

o Tx: tapeworms, amebas (lumen), and maybe anti-protozoal. o Side efx: diarrhea, iodine toxicity (but no neuropathy) o Contraindicated for optic neuropathy, renal dz, thyroid dz

• Pentamide - MOA unknown, may inhibit DNA

o Tx: 2nd line for pneumocystis, leishmania, & trypanosoma (blood stage) o Side Efx: 50% toxicity = hypoTN, hypoglycemia, blood dyscrasias,

cardiotoxicity, nephrotoxicity

• Sodium Stibogluconate o MOA: interferes with trypanothine redox system (IV or IM) o Side Efx: overall ok, but pancreatitis, myelosuppression, muscle pain

• Melarsoprol

o MOA: arsenic inhibit trypanothione reductase (always give IV) o Tx: trypanosoma brucei (CNS stage) o Side Efx: toxicity = fever, reactive encephalopathy (5%), neuropathy

prevent w/ prednisone prophylaxis

∴ Paramomycin is preferred

Anti-Parasitic Drugs Assessment 10

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Drugs to Tx Malaria

• Blood schizontocides o Chloroquine

MOA: unclear, something about 4-aminoquinolines, or DNA, or heme. • Widely distributed, sloooow clearance (months-years)

Tx: Plasmodium (except resistance via efflux pump); non-GI amebas Side Efx: high doses permanent blurred vision + retinal pigment. Q: use for prophylaxis? Hallucinations?

o Quinine

MOA: block DNA synthesis Tx: adult Plasmodium; gametes of P.vivax + P.malariae More toxic and less effective than chloroquine; used if resistant bug.

• Cinchonism: tinnitus, blurred vision, headache, hearing • Muscle: heart, dilate BV and uterus • Rifampin causes faster clearance of Quinine

o Quinidine gluconate

MOA and Tx parallel Quinine; more effective for falciparum. Side Efx: anticholinergic ∴ A-V Block. Use only for severe falciparum

o Halofantrine MOA unknown, but do NOT administer w/ food! (absorption) Tx: multi-drug resistant falciparum Side Efx: prolonged QT interval; arrhythmias; long elimination time

o Mefloquine

MOA ~ like quinine and maybe chloroquine (:-P); excreted in bile. Side Efx: Gi, vertigo, insomnia, β-blockers, convulsions

o Artemisinins – from Chinese herb

MOA: free radicals damage macromolecules (like iron) in Plasmodium Tx: severe Plasmodium, Leishmania, Toxoplasma, Schistosomiasis

o Lumefantrine – effective for falciparum w/ cardiotoxicity, but expensive.

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• Tissue schizontocides (liver stage, esp. vivax & ovale) o Primaquine

MOA: unknown, 8-aminoquinoline structure Tx: prophylaxis; kill gametes, cure vivax and ovale in liver

only anti-malarial that kills falciparum gametes Side Efx: toxicity w/ chronic use; G6PD deficient hemolytic anemia

o *Pyrimethamine + sulfadoxine = Fansidar (never used alone)

MOA: inhibits DHFR Tx: Plasmodium; Toxoplasma gondii. Side efx: resistance, megaloblastic anemia, bad skin stuff

Drugs to Tx Helmintic (Worm) Infections

• Benzimidazoles MOA: inhibits microtubule assembly (affinity for parasite tubulin)

∴ larval development and immobilize worm let go and fall off Teratogenic!!!

o Albendazole – erratic absorption o *Mebendazole – oral, broad-spectrum nematodes (whip, pin, hook)

• Pyrantel Pamoate

o MOA: bind nicotinic receptors depolarizing blocade spastic paralysis side efx in host minimal b/c so poorly absorbed ∴ stays in GI lumen.

o Tx nematodes, Ascaris, moniliformis

• Ivermectin – o MOA: inhibits Glutamate and GABA hyperpolarized nerve paralysis o Oral, no metabolism, long t ½ , excreted in feces o Tx: Strongyloidiasis, River Blindness (onchocerca), other nematodes o Side Efx: GI, itchy, dizzy, allergic/inflammatory rxn to dying bugs

• Diethylcarbamazine

o MOA: unknown o Tx elephantitis o Side Efx: mild anorexia, nausea, headache

• Praziquantel

o MOA: Ca++ permeability spastic paralysis ok for humans b/c 1st pass metabolism (dose w/ liver dz)

o Tx tapeworms, schistosomiasis (not if ocular), other flukes o Side Efx: GI pain, diarrhea, headache; hepatic metabolism.

A 57-year-old man is brought to the ER. Vital signs include temperature 103, BP:190/120, HR:184, SOB, confusion and delerium. Thyrotoxicosis 2° to a thyroid tumor is diagnosed and propranolol [Inderal] is administered. The purpose of this is to:

A) block parenchymal cell receptors for thyroid hormoneB) block release of hormone from the thyroidC) inhibit thyroid hormone synthesisD) lessen the dangerous 2° signs/symptoms of thyroid hormone excessE) lower TSH levels

A 62 year-old woman at high risk from osteoporosis is started on alendronate [Fosamax] therapy. For this drug and the other bisphosphonates, a serious adverse effect is:

A) CholelithiasisB) EsophagitisC) Fluid/electrolyte loss from extreme diarrheaD) Hepatic necrosisE) Renal calcium deposits

Which of the following endocrine / metabolic disorders is most likely to arise in some patients taking bisphosphonates for Paget’s disease of the bone?

A) Cushing’s disease (Cushingoid symptoms)B) Diabetes insipidusC) Diabetes mellitusD) HyperparathyroidismE) Hyperthyroidism

Paget’s disease of the bone can be successfully treated with a naturally occurring substance called:

A) CalcitoninB) CortisolC) EtidronateD) Parathyroid hormoneE) Thyroxine

A 73 year-old diabetic is taking oral medication for this condition. One day she goes without eating for 18 hours and is brought to the ER in a critical condition with a blood glucose level of 48 mg/dL. Which of these potential oral medications most likely contributed to her present condition?

A) AcarboseB) GlyburideC) MetforminD) PioglitazoneE) Rosiglitazone

A 57 year-old retired pilot with TB is developing signs of severe acute adrenal insufficiency. This condition will most likely produce:

A) a moon faceB) dehydrationC) hyperglycemiaD) hypertensionE) hyperthermia

Which of the following endocrine processes can be tested by the administration of metyrapone?

A) Pancreatic islet alpha cellsB) Pancreatic islet beta cellsC) Pituitary adrenal axisD) Testicular Leydig cellsE) TSH effects upon thyroid gland function

A 35 year-old woman with systemic lupus erythematosis abruptly stops taking here glucocorticoids because she feels well and doesn’t want to gain weight. After severaldays she presents at the ER, “feelin terrible.” Which of the following results would be found if serum from this patient was analyzed?

A) Elevated ACTHB) Elevated cortisolC) HypernatremiaD) HypokalemiaE) Hypoglycemia

Leuprolide is used to treat a 75 year-old man with prostate carcinoma. This drug works by:

A) inhibiting 5-alpha reductaseB) acting as an antagonist at androgen receptorsC) competitively inhibiting LHD) acting like GnRHE) acting like testosterone

A 39 year-old woman with a 2-year history of pulmonary and extra-pulmonary TB collapses while out shopping and is brought to the ER. She complains of recent weight loss, increasing fatigue and muscle weakness. Dark spots have appeared over her knuckles and in her mouth. Significant clinical signs include: hyponatremia, hyperkalemia, low plasma aldosterone, high plasma renin. She fails to respond physiologically to cosyntropin challenge. Select the most appropriate long-term management for this individual.

A) ACTH replacementB) AlbuterolC) AldosteroneD) Insulin and a glucose infusionE) Hydrocortisone plus fludrocortisone

An adrenal tumor has resulted in Cushing’s disease in a 47 year-old man. Which of the following drugs would most likely reduce the signs and symptoms of this man’s disease?

A) BetamethasoneB) CortisolC) FludrocortisoneD) KetoconazoleE) Triamcinolone

Which of the following corticosteroids has the highest anti-inflammatory potency?

A) CortisolB) DexamethasoneC) FludrocortisoneD) PrednisoneE) Triamcinolone

A 55 year-old man with benign prostatic hyperplasia and male pattern baldness seeks help from his physician who replies that he can certainly help both problems, and with a single drug! He is thinking of:

A) cortisoneB) estradiolC) finasterideD) gonadotropinsE) testosterone

A man with type-2 diabetes is taking combination oral drug therapy for his condition. If he become hypoglycemic, ingesting sucrose (sugar) will work less well and take longer to restore blood glucose levels if he is taking:A) acarboseB) glyburideC) metforminD) repanglinideE) rosiglitazone

Propylthiouracil is prescribed for a 32 year-old woman with Grave’s disease, a small goiter and “mild-to-moderate” symptoms. The patient needs to be followed closely forwhich of the following side effects?

A) AgranulocytosisB) Cholestatic jaundiceC) GoutD) Renal tubular necrosisE) Rhabdomyolysis

A 60 year-old man is given pioglitazone to treat his type 2 diabetes. The ability of this agent to lower blood glucose is based upon it:

A) increasing insulin secretionB) causing glycosuriaC) increasing target sensitivity to insulinD) increasing hepatic gluconeogenesisE) blocking intestinal carbohydrate absorption

Endometriosis in a 27 year-old woman is treated with danazol. Which of the following is the most likely adverse effect for which a physician should be monitoring?

A) Anemia from excessive vaginal bleedingB) Abnormal liver function testsC) PsychosisD) ThrombocytopeniaE) Weight loss

Ritodrine infusion is started in a 22 year-old woman in imminent danger of delivering a premature infant. Which other drug should be administered prepartum specifically for the purpose of reducing the risks and complications of the newborn’s immature respiratory system development?

A) AlbuterolB) BetamethasoneC) ErgonovineD) IndomethacinE) Magnesium sulfate

Many insulin preparations contain modifications to the structure of “regular” insulin. These include recombinant modifications in amino acid sequence, conjugation withneutral protamine, or addition of zinc. The common result of each of these modifications is:

A) elimination of allergenicityB) enabling intravenous and subcutaneous administrationC) selective effects on glucose metabolism but no effects on lipidsD) reactivation of endogenous insulin synthesis and releaseE) modulating onset time and duration

A 31 year-old woman is diagnosed with epilepsy and is started on phenytoin therapy. For several years she has successfully used an oral contraceptive (estrogen/progestin). Which of the following is the most likely consequence of adding the phenytoin?

A) Agranulocytosis or aplastic anemia requiring the abrupt stopping of both medicationsB) Breakthrough seizures from increased phenytoin clearanceC) Rapidly appearing phenytoin toxicityD) A dramatic increase in craniofacial abnormalities in the developing fetusE) Reduced contraceptive efficacy

A 23 year-old woman seeks a prescription for an oral contraceptive and you have to decide between recommending an estrogen/progestin combination and a “mini-pill” comprised only of progestin. You recall that, compared to combination products, minipills:

A) Have a higher risk of thromboembolismB) Have direct spermicidal activityC) Cause more menstrual irregularities (length, amenorrhea, spotting, etc)D) Are more effective contraceptivesE) Must be taken on an irregular cycle, rather than daily, so compliance is an issue

Which of the following adverse or side effects of oral contraceptives is due to estrogen excess arising from the estrogen component?

A) FatigueB) HypertensionC) HypomenorrheaD) Increased appetiteE) Weight gain

Your 20 year-old patient would like to take an oral contraceptive but is concerned about the risks of thromboembolism. Which of the following drugs could you prescribe that would carry a lower risk of this adverse effect?

A) A combination drug with high estrogen componentB) A combination drug with high progestin componentC) A combination drug with low estrogen componentD) A combination drug with low progestin componentE) A single component, estrogen only product

A 27 year-old woman has hypercortism. It is important to determine whether cortisol production is independent of pituitary gland control so you decide to administer a high potency glucocorticoid to suppress ACTH. You would select:

A) DexamethasoneB) HydrocortisoneC) MethylprednisoloneD) PrednisoneE) Triamcinolone

A 67 year-old man with multiple cardiovascular problems is receiving multiple drug therapy. He complains of muscle aches and tenderness. Clinical examination reveals myoglobinuria, a rise in serum creatinine kinase levels and a decline in creatinine clearance. Which of the following drugs is most likely responsible for these findings?

A) Captopril being taken for hypertension and heart failureB) Nitroglycerin being taken for exercise-induced anginaC) Procainamide being taken to control atrial fibrillationsD) Atorvastatin being taken for high LDL cholesterol levelsE) Furosemide as adjunctive therapy for congestive heartfailure

Which of the following is ineffective in reducing plasma triglyceride levels?

A) Rosuvastatin [Crestor]B) Nicotinic acid [Niaspan]C) Cholestyramine [Questran]D) Fenofibrate [Tricor]E) N-3 fatty acids [Max-EPA]

Which one of the following drugs/foodstuffs doesNOT increase the risk of statin-induced myopathy by interference with the function of the CYPs responsible for statin metabolism?

A) Nefazodone [Serzone]B) Ezetimibe [Zetia]C) Erythromycin [generic]D) Grapefruit juiceE) Gemfibrozil [Lopid]

A 35 year old female is found to have hypercholesterolemia.Total cholesterol is 270 mg/dL, HDL-C is 85 mg/dL, Triglyceride 120 mg/dL, and LDL-C is 161 mg/dL. Other than a positive family history of coronary heart disease [father and paternal uncles], she has no risk factors for coronary disease. Her 10/year risk of a coronary event is < 1% [or < 0.1% per year] based on the Framingham study calculations. She plans to have several children over the next few years. Which of the following would you recommend as the safest initial therapy of her hypercholesterolemia. with appropriate modification during pregnancy and lactation?A) Pravastatin [Pravachol]B) Gemfibrozil [Lopid]C) Nicotinic acid [Niaspan]D) Simvastatin [Zocor]E) NCEP (National Cholesterol Education Program) Phase II diet

A 52-year-old Greek immigrant is to receive primaquine to treat an active Plasmodium vivax infection. This drug is generally well tolerated, but you are concerned for an increased risk in this individual and test for:

A) a normal electrocardiogram

B) creatinine clearance

C) glaucoma

D) G6PD status

E) nystagmus

Which of the following drugs is most appropriate to treat the exerythrocytic phase of a Plasmodium vivax infection?

A) Chloroquine

B) Primaquine

C) Pyrimethamine

D) Quinidine

E) Doxycycline

Which of the following drugs produces reactive encephalopathy as an adverse effect and in consequence is reserved for late stage E. African trypanosomiasis infection

A) Atovoquone

B) Eflornithine

C) Melasoprol

D) Metronidazole

E) Paromomycin

Which of the following drugs requires metabolic activation under anaerobic conditions?

A) Atovoquone

B) Eflornithine

C) Mebendazole

D) Metronidazole

E) Pyrimethamine

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Drug Abuse Introduction and Miscellaneous • Definitions

o Addiction = compulsive drug seeking behavior and use Can be caused by the drug, the user, or the environment. Reinforcement: dopamine reward pathway: VTA nucleus accumbens

prefrontal cortex o Tolerance = need for intoxication OR efx with same dose o Dependence

• Marijuana (Cannabis sativa)

o Endogenous Anandamide & 2-arachidonyglycerol o From Plants THC (tetrahydrocannabinol) - psychoactive

Δ9-THC is more like anandamide o Rx Dronabinol & Nabilone

MOA: 7TM cannabinoid receptors • CB1: brain (basal ganglia + limbic system) + testes • CB2: immune (spleen)

receptors activate multiple pathways o K+ extracellularly o Block Ca++ entering cell (∴ Ca++ extracellularly) o cAMP

Approved Medical Uses • Antiemetic (cancer) • AIDS wasting syndrome

o Side Efx: CNS

• Acute: memory, confusion, depersonalization, hunger, REM, balance, dry mouth

• Chronic: amotivational syndrome (apathy, judgment, concentration + memory, etc)

Cardiovascular: HR (dose-dependent) bloodshot eyes Immune: T-cells ∴ immune response Endocrine: LH+FSH Testo, testes, + libido; GH, Prl,

ACTH Respiratory: acute bronchodilates, but chronic constricts Tolerance: receptors; dependence is mild

• Withdrawal sx: irritable, nausea, insomnia, sweating o Hazards

Psychotoxicity Carcinogenic Teratogenic

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• Hallucinogens o LSD (lysergic acid diethylamide)

• Sympathomimetic • Psychedelic hallucinations (colors, loss of time, etc) • Persistent Adverse Rxn: prolonged psychosis, flashbacks

o Mescaline MOA: serotonin and dopamine agonist (from the peyote cactus) Efx:

• Sympathomimetic • Hallucinations, unusual time perception • Adverse: paranoia & fear

o Phencyclidine (PCP, Angel Dust) 3 MOA:

• NMDA receptor antagonist same MOA as Ketamine (Special K) + dextromethorphan

• sigma receptor agonist • dopamine/norepi reuptake inhibitor

Efx: • Sympathomimetic • sensitivity to stimuli w/ loss of proprioception; restlessness,

disorientation, detachment, anxiety • Adverse: flashbacks, psychosis, dependence, OD

o Natural Derivatives

Mushrooms: psilocybin + psilocin like LSD + panic attacks Salvia divinorum (mint family) dissociation from self

o Drugs with Hallucinogenic Properties

MDMA (Ecstasy) • MOA: blocks NTM reuptake @ synapse

Cathinone • Physical Efx: HTN, HR, arrhythima, MI • CNS: insomnia, cerebral hemorrhage • Psychic: hallucinations (visual + auditory), mania, euphoria,

aggressive, anxiety, emotionally unstable

• OTC o Dextromethorphan (Delsym) - cough suppressant; NMDA receptor antagonist o Dimenhydrinate (Dramamine) – tx motion sickness

can also cause Disorientation, Delirium, and Delusions

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• Inhalants o Options

Volatile Solvents: paint thiner, dry-cleaning, glue, markers Aerosols: spray paint, PAM, etc Gases: ether, chloroform, nitrous oxide (laughing gas) Nitrites: (sexual enhancers)

o MOA: activate dopamine (∴CNS depressants) o Problems

Neurotoxicity demyelination Motor incoordination immune system (makes AIDS worse) Sudden Sniffing Death cardiac arrhythmias Other causes of death: choking, suffocation, asphyxiation

___________________________________________________________________ Nicotine

• Nicotine o Bolus activates addiction. No bolus, no addiction! o Neuronal receptors: pentameric, ligand-gated w/ subunits α2-α9, β2-β4

• Cigarette tobacco o effective drug delivery system – large nicotine bolus in <10 sec.

• Nicotine Replacemnt Therapies (NRT’s) o nicotine gum (Nicorette)

Efficacy: o Short-Term: 24% abstinence @ 6 mo o Long-Term: 18% abstinence @ 1 yr

Best if used w/ Buproprion Suggested termination of use after 6 mo.

o nicotine transdermal patch (Habitrol, Nicotrol, Nicoderm CQ, ProStep) Efficacy: 16.8% (double placebo) @ 24 wks Overall well tolerated; may have sleep disturbance or skin irritation.

o nicotine inhaler (Nicotrol NS) Efficacy: ~25% (~ double placebo) @12 wks Goal: disrupt behavioral associations (best if used in combo). Side Efx: nasal irritation Use >3 mo = useless (no further change)

o low- or no-nicotine “cigarettes” (Eclipse, Accord, Quest) exposure to smoke-related toxins by heating tobacco w/o burning it. Ineffective overall (b/c smokers don’t want to use them)

o Smokeless tobacco (Snus) “somewhat similar to snuff” Efficacy: works in Sweden.

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• Non-nicotine cessation compounds Regardless of which drug is used, abstinance > 1 yr is low (~10%) In contrast to other drugs, the more times you try to quit, the more successful you’ll be

o Buproprion (Wellbutrin, Zyban) MOA: unknown, but has anti-depressant efx Efficacy:

• 60% abstinence @ 9 wks (double placebo) • 24% abstinence @ 1 yr (4x placebo), esp in combo.

Side Efx: well-tolerated, potential for abuse, BUT beware CYP450! • Do NOT give w/ βB, tricyclic antidepressant, seizures, anorexia

o Barenicline (Chantix)

o Mecamylamine

MOA: non-selective antagonist at non-α7-nicotinic cholinergic receptors crosses BBB ∴ risk side efx (in clinical trials)

Efficacy: inconclusive

o Rimonabant MOA: CB1 antagonist Efficacy: yes short term, but not more than other tx. Try as 2nd line? Side Efx: severe depression

o Clonidine – our old anti-hypertensive friend; also a 2nd line “quitter” drug

MOA: α2 agonist; crosses BBB, t½ ~ 1hr

o Nortriptyline – a Tricyclic Anti-Depressant MOA unconfirmed but blocks NorEpi; crosses BBB; long t ½ Efficacy: highest in depressed pts.

o Vaccines

MOA: Aby’s trap nicotine in plasma ∴can’t cross BBB to reward center Efficacy: lasts just a few months ∴ only tx initial quitting, or relapse.

• Therapeutic Potential: Epibatidine pain reduction

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Alcohol • Alcohols

o Ethanol MOA: alters ion channels Zero-order kinetics Metabolized in Liver:

• 1 = alc. dehydrogenase • 2 = ALDH (inactive in 50% of Asians)

Side Efx:

• CNS tolerance develops (but not liver ∴ toxic) • CNS damage:

o BeriBeri/Werkicke-Korsakoff thiamine deficiency peripheral neuropaty

o Cerebellar degeneration ataxia o Central Pontine Myelinolysis dysarthria, confusion o Marchiafava-Bignami Syndrome apathy, dementia o Pellagra = niacin deficiency Dermatitis, Diarrhea,

Dementia, Dizzyness, and Depression • Hepatomegaly encephalitis, esophageal varices • Acute vasodilation • Cardiomyopathy • gastric damage of NSAIDs ulcers + gastritis

also sensitizes pt to acetaminophen toxicity. • Pancreatitis • Anemia + Immune suppression • Fetal Alcohol Syndrome (inhibition of cellular proliferation) • Women have 1st pass metabolism ∴ [blood alcohol] • Cross-tolerance w/ barbiturates + benzodiazepines

Withdrawal: • Early: agitation, confusion, hyperactive autonomics, seizures • Late: delirium tremens hyperthermia, hallucination, coma

EtOH(1)Acetaldehyde(2)AcetateCO2+H2O

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o Methanol (wood alcohol) Oxidized like Ethanol but yields formaldehyde Result: blindness, irreversible acidosis death Tx: ethanol + dialysis

o Isopropanol (rubbing alcohol)

Oxidized to acetone (ie, a desperate second choice) Result: CNS toxicity, severe gastritis, nausea, pain Tx: hemodialysis

• Tx CNS Alcohol Toxicity

o Thiamine

• Tx Chronic Alcoholism o Naltrexone opioid receptor antagonist; helps relapses

o Ondansetron 5-HT3 antagonist; helps craving

o Acamprosate NMDA-R antagonist (no studies in US); helps relapses

Reduce dose w/ renal insufficiency

o Topiramate AMPA-R antagonist & GABA-R modulator Adverse efx ∴ titrate dose

o Disulfiram acetaldehyde dehydrogenase antagonist [acetaldehyde]

same thing as a bad hangover. (It also blocks NE synthesis) Acetaldehyde syndrome: HR, flushing, hypotension, N/V, headache No efx on craving Side Efx: hepatotoxicity, depression, psychosis

• Tx Alcohol Withdrawal Rx Tremulousness Sx Seizures Delirium Tremens Benzodiazepines Atenolol Clonidine Phenytoin

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Toxicology • Some general methods of decontamination

o SDAC = Single Dose Activated Charcoal Tx oral toxin ingestion via SA (protect airway) NOTE: no evidence of improved outcome

o Ipecac promotes emesis; but no evidence of improved outcome. Side Efx: dehydration, cardiotoxicity

o Gastric Lavage Side Efx: perforation, aspiration

o Whole Bowel Irrigation w/ isotonic fluid rapid elimination of gut contents o Hemodialysis only if toxin is water–soluble

Ex: methanol, ethylene glycol, salicylates, lithium, sotalol. o Hemoperfusion = pass blood through charcoal cartridge filter

Ex: carbamazepine, Phenobarbital, phenytoin, theophylline • How does the poisoned patient die? (slide 31) • Supportive Lab Tests anion gap = Na – Cl – HCO3 • Nerve gas… carbamate… herbicide intoxication… ? • National Poison Control Center: 1-800-222-1222

Toxin Antidote Acetaminophen

• Sx: appear after 24hrs RUQ pain • Death: hepatic failure

N-acetylcystine • When: <10 hrs • MOA: replace liver enzyme (?) • Adverse: N/V, bad taste, anaphylaxis

Aspirin (acetylsalicylic acid)

• Sx: N/V, tinnitus, sweating lethargy + respiratory failure resp.alkalosis metab.acidosis more ASA crosses BBB worse

• Death: neurologic decline

Tx options: • Charcoal (bad choice?) • Fluids + dextrose • Na-Bicarb ionizes drug ∴ no BBB • Hemodialysis

Benzodiazepines

• Sx: drowsy, confused, incoordinated • Death: if taken w/ alcohol

Supportive Care = 1° choice Flumazenil - not routinely used

• N/V, dizzy, panic attack, seizures Barbiturates

• lethargy resp. depression + shock • Phenobarbital & Aprobarbital………

ABC = airway, breathing, circulation … tx via urinary alkalinization (ion trapping)

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β-Blockers & Ca++-channel blockers • BB Sx: HR, hypoTN, QRS widening,

seizure, resp, hypoglycemia, K+ • CCB Sx: HR, AV block (Verap + Dil)

Vasodilation (-pine)

If immediate release gastric lavage If sustained release whole bowel Atropine for bradycardia Glucagon reverses contractility + HR NorEpi for vasopressor

Digoxin

• Sx: malaise, vomiting, abd. pain, arrythmias

Digibind • Corrects hyperkalemia… • …but serum [digoxn] (from tissues)

Opioids (Rx or Street)

• Sx: unconscious, resp. depression • Supportive Ventilation = 1° choice • Naloxone – reverses resp. depression

but can cause withdrawal sx. Tricyclic Antidepressants (TCA)

• Sx: w/in 2hrs; cardiotoxic, seizures Charcoal + gastric lavage Bicarb: pH displaces drug from Na+ channels Vasporessor + IV fluids

Theophylline

• Tachycardia, vomiting, hypoTN, seizures if blood levels really high.

• Supportive Care • Aggressive gut decontamination + βB

Hemodialysis if blood levels really high Anti-Cholinergics

• Sx: flushed, dehydrated, delirious, tachycardia, pupils dilated

• Supportive care • Physostigmine (in small doses IV;

beware heart block + seizures) Intoxication by Gas Gas Toxicity Sx + Tx CO Binds Hgb ∴ O2

capacity Sx: headache, N/V, seizures Tx: 100% O2

Irritants: chlorine, ammonia, sulfur dioxide

Corrosive efx on + airways

Sx: cough, stridor, pneumonia Tx: O2 + bronchodilators

Cyanide Blocks O2 binding Sx: headache, N/V, seizures Tx: antidote kit (nitrite + thiosulfate)

Hydrogen Sulfide Similar to Cyanide Sx: cyanide + smell of rotten eggs Tx: nada

Nitrogen oxides Methemoglobinemia Sx: Dyspnea, cyanosis, syncope, seizure Tx: methylene blue

Hydrocarbons (solvents) Sx: cough/choke, headache, lethargy Tx: ABC’s, supportive care

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Insecticides & Herbicides Insecticides + Nerve Gas • Organophosphates:

o Diazinon o Malathion o Parathion

Atropine + Supportive Tx Pralidoxime (2PAM)

Caustic Acids & Alkalis (slide 66) – not on drug list Heavy Metal Poisoning (slide70) Lead

• Sx: colic, constipation, anemia, fxn proximal tubule, encephalopathy

Chelators [blood]; do not reverse damage • Succimer for mild cases • Dimercaprol for severe cases

Arsenic • Source: herbicide, paint, insecticide,

electrical manufacturing • Acute Sx: N/V, colic, psychosis, rash,

cardiomyopathy, seizures • Chronic Sx: Mee’s Lines (nails), hair

Dimercaprol (in peanut oil) = 1° choice • nephrotoxic; beware G6PD deficiency

Succimer • hydration important b/c renal exretn

Mercury Succimer Copper Penicillamine

• use b/c of toxicities (slide 83) Iron

• MOA: impairs Ox-Phos cell death • Sx: hematemesis, diarrhea liver

damage, metabolic acidosis, GI scar

Deferoxamine = 1° choice IV • MOA: chelates iron • Sx: red urine, HR, hypoTN, fever

Deferasirox: tx transfusion pts w/ iron • Sx: diarrhea, headache, cough

Venom Rattlesnake

• Dx: fang marks, local tissue damage • Sx: hemorrhage, ecchymosis,

necrosis, inflammation, coagulopathy

Anti-Venom = CroFAB

Brown Recluse Spider • Venom: sphingomyelinase D2 • Sx: pain, itchy, enlarging blister

Most bites resolve w/out tx. (anti-venom use questionable)

Black Widow Spider • Venom: α-latrotoxin binds ion

channels affects Ach • Sx: hours later muscle cramping,

headache, anxiety, fatigue, insomnia

Tx: • Anti-spasmodics (benzos) • Opiates • Anti-venom (high-risk pts only)

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Sedatives & Hypnotics • Vocab – Basics

o Sedative = excitement o Hypnotic = drowsiness

• Benzodiazepines, in general:

o MOA: freq. of Cl- channel opening ∴ enhances GABAA-receptor-induced Cl- channel opening postsynaptic inhibition.

Membrane hyperpolarization Absorbed rapidly, cross BBB, and do not induce CYP450. anxiolytic; fatal CNS depression ∴ high therapeutic index all benzo’s are equally effective

o Tx: Anxiety Disorders, Panic Disorder, Acute Stress. o General Efx:

Sedation Anti-convulsant Muscle relaxation (via CNS) ∴ not for Myasthenia Gravis pts! Amnesia Sleep awakenings, stage 2, stage 3+4, bizzare dreams

beware rebound insomnia Withdrawal: anxiety, insomnia, irritable, panic, anorexia. (slide 17)

must taper dose if used many weeks o Contraindications:

sleep apnea alcohol consumption potentiates depression (deadly) pregnancy + lactation Drugs that Benzo efx: (metab.) cimetidine, disulfriam, & estrogen Drugs that Benzo efx: antacids & rifampin

• Short-Acting Benzo’s worse chance for rebound anxiety + insomnia

o Midazolam [Versed] – full agonist; t½ = 2 hr no active metabolites Use: conscious sedation; adjunct anesthesia; skeletal muscle relax. Side Efx: hypotension, headache, amnesia.

o Alprazolam [Xanax] o Lorazepam [Ativan] o Oxazepam [Serax] o Triazolam [Halcion]

Pro’s: less daytime sedation b/c fast acting Con’s: more frequent amnesia & rebound insomnia; hostility at doses

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• Long-Acting Benzodiazepines worse chance for day after “hangover” o Diazepam [Valium] o Chlordiazepoxide [Librium] o Flurazepam [Dalmane] – hypnotic; sedation hangover especially notorious o Clonazepam [Klonopin]

• The “Z” drugs

abuse potential ∴ limit use to 2-3 nights reduce dose 50% if elderly or pregnant

o Zolpidem [Ambien]

MOA: not a benzo! It acts at omega-1 benzo receptor • Short-acting (~2 hr) • No active metabolites (true for all 3 “Z drugs”)

Efx: • Hypnotic + sedative • NO anticonvulsant/muscle relaxing efx. • Well tolerated in elderly • sleep time but NO CHANGE in sleep architecture (<20mg) • worsens sleep apnea

o Zopiclone [Lunesta] o Zaleplon [Sonata]

• Discussed but not on drug list (NODL): o Flumazenil (Romazicon) benzo competitive antagonist @ GABA-A receptor

Use: reverse benzo sedation; VERY short t½ o Temaepam (Restoril) intermediate duration benzo for hypnotic o Estaolam (ProSom) intermediate duration hypnotic (slide 30).

• “Other” hypnotics – slide 39 o Chloral Hydrate (NODL) – only works short term b/c dependency/tolerance o Diphenhydramine (Benadryl) – our anti-histamine friend is also a sedative! o Doxylamine (Unisom) – OTC anti-histamine o Hydroxyzin (Vistaril) – Rx anti-histamine

causes drowsiness, but not effective for insomnia o Melatonin (NODL) – jet lag, etc o Valerian (NODL) - sedation

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Anti-Depressants and Mood Stabilizers • Pharmacology of Depression: adaptive changes in monoamine signaling (NE, 5-HT) • BLACK BOX WARNING: risk of suicide in kids + adolescents

• Tricyclic Antidepressants (TCA) “gold standard”. Newer drugs…

MOA: inhibit reuptake of (∴potentiate) NE + 5-HT @ presynaptic terminals - potentiates NE + 5-HT - also block mAch, 5-HT, & histamine receptors side efx.

o α-adrenergic antagonism othostatic hypotension o mAch antagonism tachycardia, confusion, fluid (dry eye,

constipation, urinary retention). o Histamine + α-AR antagonism sedation

- Other Side Efx: arrhythmia, worse CHF, acidosis, delerium, seizures - Potentiated by alcohol = bad combo

o Amitriptyline (Elavil) o Imipramine (Tofranil) o Nortriptyline (Pamelor) o Clomipramine (Anafranil) o Desipramine (Norpamin) o Doxepin (Sinequan) o Protriptyline (Vivactil) o Trimipramine (Surmontil)

• Atypical Antidepressants (2nd + 3rd generation) “heterocyclics” o Amoxamine – mixed inhibition of NET>SERT~DAT

Use for depression in psychotic patients (b/c analog of loxapine)

o Maprotiline (Ludiomil) – NorEpi reuptake inhibitor (NRI) risk of seizures

o Bupropion (Wellbutrin) – weak blocker; active metabolite blocks NE reuptake

Side Efx: anxiety, restlessness, seizure; can aid smoking cessation

o Venlafaxine (Effexor) – Serotonin & NorEpi Reuptake Inhibitor (SNRI) No TCA-like side efx! •Does have mild HTN. •Short t½ (~5 hr).

o Duloxetine (Cymbalta) – most potent SNRI

CYP metabolism; t ½ ~12 hr; 95% protein bound

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o Mirtazepine (Remeron) - enhances release of serotonin & NE by antagonizing presynatpic α2-AR’s

also has anti-histamine axn sedation wt. gain, but less GI + sexual problems than SSRI’s.

o Trazodone (Desyrel) & Nefazodone – moderate 5-HT reuptake inhibitors

use to tx depression w/ sleep disturbance & anxiety inhibit CYP3A4

• Selective Serotonin reuptake inhibitors (SSRI) ∴ potentiate serotonin first-line tx for major depresion

o Efx: initial CNS stimulation, euphoria after a few weeks, sx improve High therapeutic window; overall fewer side efx

• Adverse Efx: nausea, libido • Bad idea if you take it with a MAOI Serotonin Syndrome

o Serotonin Syndrome = overstimulation of 5-HT1A in midbrain Sx: temp, hyperreflexia, tremor, myoclonus, agitation, seizures,

confusion, delerium, cardiovascular collapse, coma, death Tx: discontinue medication immediately!

o Citalopram (Celexa) o Fluoxetine (Prozac) – t½ ~ a week o Fluvoxamine (Luvox) o Paroxetine (Paxil) – teratogenic! o Sertraline (Zoloft)

• Monoamine Oxidase Inhibitors (MAOI) only use if other anti-depressants haven’t worked, or to tx panic disorder

Tranylcypromine (Parnate) Isocarboxazid (Marplan) Phenelzine (Nardil)

o MOA: irreversibly inhibit oxidative metabolosm of monoamines (NE, 5-HT) t½ = 1-3 weeks!

o Efx: initial CNS stimulation, euphoria after a few weeks, sx improve o Adverse Efx: orthostatic hypotension, sleep disturbance; don’t eat cheese.

• Mood Stabilizers tx Bipolar (Manic Depression)

o Lithium – DOC, but rapid t½ w/ NARROW tx window!! o Valproate (Depacon) – anti-convulsant; helps both phases of Bipolar. o Carbamazepine (Tegretol) – anti-convulsant

1. 2.

3. 4.

5. 6.

7. 8.

9. 10.

11. 12.

13. 14.

15. 16.

17. 18.

19. 20.

21. 22.

23. 24.

25. 26.

27. 28.

29. 30.

31. 32.

33. 34.

35.

Different Rx select for different mutations of reverse transcriptase

Anti-Virals Disclaimer: some of these facts were taken from the HIV Micro lecture.

Retrovirus (HIV) • Fusion Inhibitors no viral entry into host cell

o Enfuvirtide – binds gp41 of viral envelope ∴ no “zipping” SubQ 2x/day (inconvenient) risk pneumonia Resistance develops, but no cross-resistance w/ other drugs Only for tx-experienced pts failing HAART

o Maraviroc – CCR5 antagonist (a chemokine receptor on macrophages) needs CYP3A4 (beware drug interaxns) resistance via P-Glycoprotein pump works well BUT only against the R5 serotype Side Efx: cough, rash, dizziness, liver and cardiac “problems”.

• Nucleoside Reverse Transcriptase inhibitors (NRTI) analogs of nucleosides act as competitive inhibitors ∴ block elongation.

This helps protect uninfected cells (tough luck if already infected) all nucleosides must be phosphorylated x3 for efx

Zidovudine pyrimidine (T), aka AZT; perinatal transmission, gets

glucaronidated, avoid fat meal, myelosuppression Stavudine pyrimidine (T) – worst side efx (above) PLUS

peripheral neuropathy, pancreatitis Lamivudine pyrimidine (C) Didanosine purine (A,G) – don’t take w/ food; diarrhea,

peripheral neuropathy, pancreatitis Abacavir purine (G) – EtOH dehydrog. metab. ∴ beware genetics

all can cause GI distress, & lactic acidosis due to mitochondrial toxicity

• Non-nucleoside reverse transcriptase inhibitors allosteric binding causes conformational change in active site ∴ no synth. (Note that this does not require Phosphorylation) Side Efx: maculopapular rash

o Delavirdine – CYP450 inhibitor. o Nevirapine – CYP450 inducer fever, fatigue, nausea, hepatotoxic. o Efavirenz – CYP450 inducer neuropsychiatric, teratogenic.

(more anti-retroviral drugs)

• Nucleotide Inhibitor Tenofovir – inhibits reverse transcriptase o only requires 2 phosphorylations for efx. Oooooh. o Side Efx: N/V, diarrhea, weakness, GI upset, liver enzymes

• Integrase Inhibitor Raltegravir – HIV can’t get into host genome o Only for tx-experienced pts o orally bid (t½ = 9hr) o Metabolism: glucaronidation in liver (not CYP450)

• Protease Inhibitors most effective ART available! (-navir) selective, competitive inhibitors of protease binding site

no cleavage ∴ no viral maturation ∴ no infectious particle each drug selects for different mutations in specific protease codons

General Side Efx: • Hyperlipidemia • GI distress: vomiting, diarrhea • Diabetes • Lipodysrophy = fat wasting and redistribution • Many drug interactions b/c inhibit CYP3A4 (slide 43) • Oral bioavailability varies widely

o Lopinavir – just your run-of-the-mill PI - Like other PI’s, it has high plasma

protein binding & low renal excretion b/c CYP metabolism

o Atazanavir – hyperbilirubinemia jaundice + heart block

o Ritonavir – potent CYP inhibitor used to plasma [drug] of other ART’s. Hepatotoxic at high doses (go figure)

o Saquinavir – lowest CYP inhibition – maybe best choice for interaxns

o Indinavir – alopecia, kidney stones, notorious lipodystrophy

o Nelfinair – efx if taken w/ meal

o Amprenavir – not on drug list and manufacture is discontinued.

Herpesvirus Drugs (Herpes Simplex, Varicella, Cytomegalovirus) “cyclovir” acyclic nucleoside analogs that inhibit viral DNA polymerase ∴ chain termination

require activation via (P) by viral thymidine kinase = magic bullet doesn’t work if virus mutates its DNA polymerase or doesn’t have TMK.

• Acyclovir – purine analog – headache, nausea, diarrhea (renal+CNS toxic @ dose) • Valcyclovir – purine analog, acyclovir prodrug (orally hydrolyzed)

• Ganciclovir w/ Valganciclovir – 100x potency than acyclovir ∴ tx CMV retinitis

o Take together b/c valganciclovir is a prodrug activated by ganciclovir o Side Efx: myelosuppression, teratogenic

• Famciclovir – prodrug form of penciclovir • Penciclovir - guanine analog ∴ competitive inhibitor ∴ no chain termination

o Can also be used against HBV post liver transplant o Best bioavailability (~70%)

• Cidofovir – cytidine nucleotide analog; use if acyclovir resistant b/c…

o worse side efx: Nephrotoxic, neutropenia, carcinogenic

• Foscarnet – pyrophosphate analog ∴ inhibits DNA polymerase by blocking cleavage o Side Efx: nephrotoxic, N/V, anemia, fatigue

Hepatitis B + C

• Adefovir – nucleotide adenosine analog ∴ inhibits viral DNA polymerase o Side Efx:

rebound hepatitis with discontinuation nephrotoxicity (b/c low protein binding renal excretion) lactic acidosis severe hepatomegaly w/ steatosis

• Lamivudine – use in combo w/ adefovir potency; ok to use w/ liver problems • Interferons - activates Jak-Stat anti-viral, anti-immune, anti-proliferative.

o Also can Tx Kaposi Sarcoma o Side Efx: myelosuppression, N/V, neurotoxic, serum creatinine

Micro says it can also cause alopecia & depression/suicide. • Ribavirin – competitively inhibits GTP 5’ capping of viral mRNA

o Side Efx: hemolytic anemia, teratogenic. o Works better with specific HCV genotypes (2+3) (micro)

Influenza Virus • Uncoating Inhibitors block HA glycoprotein binding ∴ no internal acidification

o Amantadine - o Rimantadine -

These work on Influenza A only • Viral Release Inhibitors inhibit viral neuraminidase ∴ no cleavage of sialic acid ∴

no detachment from host cell reduce viral spread o Zanamivir – low oral bioav o Oseltamivir -

These work on Influenza A & B. Review:

Hey, that’s handy…

- all drugs ending with “-fovir” are nucleoTIDE analogs - protease inhibitors (“-navir) are SNARLIng imagine a mean protein w/

lipodystrophy

Anti-Psychotic Drugs - Used to tx: Psychosis, Depression, Anxiety, and Mania Typical Anti-Psychotic Drugs MOA: inhibition of Dopamine (D2) receptor binding… And others, too.

• Phenothiazenes o Chlorpromazine – oldest; aliphatic side chain ∴ low potency

side efx: anti-diuretic, insulin, jaundice o Triflupromazine - aliphatic side chain ∴ low potency o Thioridaine – piperdine ring o Mesoridazine - piperdine ring o Fluphenazine – piperazine group ∴ potency o Trifluroperazine – piperazine group ∴ potency

• Thioxanthenes:

o Chlorprothixene - aliphatic side chain ∴ low potency o Thiothixene - piperdine ring

• Benzepines: Loxapine – potent

• Butyrophenones: Haloperidol – potency

• Indolones: Molindone & Oxypertine – potent

• Other: Butaclamol -

Atypical Anti-Psychotic Drugs MOA: 5-HT2 affinity (low D2 affinity) inhibition risk Type2 DM (and can mortality in alzheimers? – Slide 9)

• Clozapine – low potency; beware blood dyscrasis w/ leucopenia prodrome o Olanzapine o Quetiapine

• Risperidone – 5-HT2/D2 antagonist, but limited EPS at low doses o Only approved agent for children + teens

• Paliperidone – active metabolite of Risperidone • Ziprasidone – 5-HT2A, 5-HT1A, 5-HT2C/D2 antagonist; limited EPS • Aripiprazole – 3 MOA (below) with fewer side efx

o D2 partial agonist (∴ axn of full agonist) o 5-HT2A antagonist o 5-HT1A partial agonist

Pharmacokinetics (slide 30) • lipophilic & protein-bound bioav. If IM injection AND crosses placenta/milk • peak efx in ~2 hrs, efx last 24hrs, but elimination ~30hrs ∴ once daily dosing.

Potential Side Efx

• General: Neuroleptic Syndrome o Suppression of spontaneous movements and complex behaviors o Reduced initiative + interest in environent o Decreased manifestations of emotion or affect o Psychotic symptoms disappear over time

• CNS Efx o Cerebral Cortex: seizure threshold (esp potency phenothiazines) o Basal Ganglia: (tolerance builds over time)

EPS= Extra-Pyramidal Symptoms • Acute Dystonia – muscle spasms, facial grimacing, torticollis • Akathesia – “ants in my pants” • Parkinsonian Syndrome - movement, masked face, tremor • Neuroleptic Malignant Syndrome – rare (slide 39) mortality • Perioral Tremor – rare “rabbit syndrome” • Tardive Dyskinesia – tic-like movements; no tx just stop Rx.

DA metabolism Ach turnover Ach sx: dry mouth, blurred vision, constipation,

orthostatic hypotension (see heart) o Limbic System: site of anti-psychotic effects o Hypothalamus: prolactin secretion; no tolerance develops o Brainstem: respiration OK; reflexes; no N/V b/c DA at CTZ

• Renal – chlorpromazine may be antidiuretic • Liver – may worsen liver dz • Endocrine - risk of Type 2 Diabetes with Atypical drugs • Heart – orthostatic hypotension (yes tolerance)

o More efx: chlorpromazine, thioridazine o Less efx: haloperidol, loxapine, risperidone

• Mild Physical Dependence: malaise, difficulty sleeping • Skin: urticaria, photosensitivity • Weight Gain • Drug Interactions

Drug Choice based on trial-and-error side efx. Misc. Uses: N/V, alcohol hallucinations, movement disorders (Tourette’s, Huntington’s, intractable hiccups)

Anti-Epilepsy Drugs lessen symptoms but do not cure disease mono-therapy is recommended (and start w/ low dose) b/c of so many drug interactions suicide risk w/ these drugs Type of Seizure 1st Choice 2nd Choice Partial (simple or complex) simple = retain consciousness complex = LOC

Carbamazepine Phenytoin, Valproate, Lamotrigine, Gabapentin,

Zonisamide, Levateracetam Tonic-Clonic (grand mal) Carbamazepine Phenytoin, Valproate Absence (petit mal) 3 Hz spike

Ethosuximide Valproate, Lamotrigine

Myoclonic, Atonic, Atypical Absence Valproate Lamotrigine, Clonazepam Status Epilepticus Diazepam (I.V.) Lorazepam, Phenytoin Refractory generalized seizure Clonazepam • Hydantoins

o Phenytoin – stabilizes inactive Na+ channels. Narrow Window: nystagmus, ataxia, arrhythmias (dose), coarsened

face, hirsutism, gingival hyperplasia, peripheral neuropathy, teratogenic o Fosphenytoin – water-soluble phosphoester of phenytoin ∴ parenteral

Arrhythmias, esp in elderly o Methphenytoin – prodrug nirvanol (active).

Worse side efx than Phenytoin. o Ethotoin – use for pts hypersensitive to phenytoin. Less efx.

• Barbiturates

o Pehonbarbital – MOA: prolong opening of GABA receptor Cl- flux Side Efx: sedation, lethargy, nystagmus, rash, megaloblastic anemia (b/c

folate ), VitD o Mephobarbital – N-methyl Phenobarbital, demethylated in liver to active form o Primidone – rapidly converted to Phenobarb + active metabolite (PEMA).

• Iminostilbenes

o Carbamazepine – inhibits Na+ channel recovery also used to tx HD “most likely to reduce clinical efficacy of concurrent Rx’s” Side Efx: blood dyscrasias, N/V, diplopia, ataxia, drug interactions

o Oxcarbamzepine – inhibits Na+ channel recovery Less potent (and less toxic) than Carbamazepine.

• Succinimides – DOC for absence seizures o Ethosuximide – inhibits T-type Ca++ channels ∴ prevents 3 Hz spike/wave

Side Efx: N/V, lethargy, dizziness, euphoria, hiccups, fatigue, tolerance o Phensuximide –

• Branched-Chain Carboxyllic Acid = Valproic Acid (Valproate)

o 3 MOA: stabilizes inactive Na+ channels (like Phenytoin) Ca++ current (like Ethosuximide) stimulates GABA synthesis + inhibits GABA degradation

o Side Efx: nausea, abdominal pain, heartburn, liver toxicity, teratogenic

• Benzodiazepines MOA: ease of opening the Cl- channel potentiate GABA receptor Side Efx: sedation, lethargy, tolerance

o Clonazepam - tx refractory generalized seizures o Diazepam (Vallium) – DOC Status Epilepticus o Lorazepam – longer acting than diazepam

• Miscellaneous

o Gabapentin – GABA axn (analog). Mild side efx: dizzy, ataxia o Lamotrigine – slows recovery of Na+ channels; adjunct; 1% get Stevens-Johnson o Levetiracetam – MOA unknown; mild side efx o Tigabine – GABA b/c inhibits reuptake. May make absence seizures worse. o Topiramate – inhibits Na+ channels & Ca++ current. Kidney Stones. o Felbamate – GABA & inhibits NMDA. Adjunct drug. Aplastic Anemia = bad. o Zonisamide - inhibits Na+ channels & Ca++ current. Broad spectrum axn.

Comparing Pharmacokinetics – it’s like masochism, only for a grade. Drug Bioav. Onset t½ Albumin Metabolism Drug Interaxns

Phenytoin varies 3-12 hr 12-36 hrs.

High Dose-Dependent CYP2C9

Induces CYP 2C + 3A; Valproate, Warfarin, Oral Contraceptn

Barbs 100%, slowly

5 days 50% CYP2C9 Induces CYP2C +UGT Oral Contraceptn

Carbamazepine 100% 6-8 hr 30 hr 70% CYP2C9 Induces CYP’s + UGT MANY INTERAXNS.

Ethosuximide 100% 3-7 hr 40 hr no Glucaronidation Valproate

Valproate 80% 2 hr 9-18 hrs

high affinity

UGT + oxidation Inhibits UGT (itself). Inhibits CYP2C9. Protein binding.

Benzo’s Good Rapid 40 hr binds active products

Drugs to Tx Neurodegenerative Disorders Alzheimer’s Disease

• Problem: not enough Ach (also low levels of 5-HT + NorEpi) • Solution: reversible CNS Acetylcholinesterase inhibitors!

o Tacrine – don’t use it b/c bioav. and side efx: hepatotoxic. o Donepezil (Aricept) – long t½ = 70hr o Rivastigmine – short t½ = 1.5 hr o Galantamine – medium t½ = 7 hr o Side Efx: N/V, diarrhea, insomnia (wild dreams), bradycardia.

• The other Problem: too much glutamate (excitotoxic) • The Solution: block NMDA-type glutamate receptors!

o Memantine (NaMenDA) – low affinity for NMDA (100% bioav.) allows normal hippocampus activity but blocks excitotoxic levels. Side Efx: confusion, headache, insomnia, agitation… cystitis, libido

Huntington’s Disease

• Problem: trinucleotide repeat expansion of CAG (more = worse) loss of cholinergic & GABAergic neurons in striatum (basal ganglia) indirect path

this is, like, the opposite of Parkinson’s • Rx for depression

o Fluoxetine (Prozac) & Carbamazepine • Rx for chorea anti-pychotics with extra-pyramidal (∴ parkinsonian) side efx

o Reserpine – depletes CNS dopamine stores o Tetrabenazine – degrades DA o Chlorpromazine – DA antagonist o Haloperidol – DA antagonist

Amyotrophic Lateral Sclerosis (ALS)

• Problem: impaired glutamate reuptake too much glutamate excitotoxicity

• Riluzole – CYP450 metabolism, t½ = 12hr o Side Efx: nausea, fatigue, sedation, liver dz

Multiple Sclerosis (MS) autoimmune abys attack myelin sheath

• Interferon β-1α - anti-inflammatory restores BBB ∴ [cytokines] in CNS • Natalizumab – anti-inflammatory, more effective than Interferon, BUT…

o Side efx: progressive multifocal leukoencephalopathy. • Glatiramer – myelin decoy; beware injxn site rxns • Mitoxantrone – anti-neoplastic • Alemtuzumab – anti-neoplastic - Aby against CD52 on T-cells

3 MOA reduce glutamate 1. block inactive Na-channel 2. block activated Ca-channel 3. block NMDA channel

Parkinson’s Disease – damage to Dopamine-producing cells in the substantia nigra less DA inhibitory D2 receptors in basal ganglia don’t get stimulated failure of inhibition ∴ failure of “fine-tuning” bradykinesia + hyporeflexia

The 5 main strategies for the treatment of Parkinsonism

Dopamine Replacement Tx [DA] • L-DOPA (Levidopa) – converted to DA by endogenous L-AAD

o First-line tx for Parkinson’s – but wait till sx appear cuz only works 3-5 yrs. o Adverse Efx: N/V, anorexia, orthostatic hypOtension, Afib

• L-DOPA + Carbidopa (Sinemet) –peripherally inhibits L-AAD (can’t cross BBB) o 75% more effective per gram! o Adverse Efx: depression, anxiety, delusions, chorea, “on-off phenomenon” o Interactions: Vit.B6, MAO-I, glaucoma, psychosis, ulcers

DA Receptor Agonists counteract that inhibition failure

o These drugs are best for early Parkinson’s Dz tx. • Bromocriptine – D2 agonist D1 partial agonist • Pergolide – D1/D2 agonist more effective than Bromocriptine • Pramipexole – D2 selective free radical scavenger? • Ropinirole – D2 selective CYP450 metab.

Enhancement of DA Release

• Amantadine – antiviral w/ unknown MOA; efx are modest & short-lived. o Adverse Efx: restless, depression, psychosis…… seizures, heart failure

Inhbition of DA metabolism

• MAO-B inhibitors retard breakdown of DA o Selegiline – interacts w/ TCA, SSRI’s, meperidine (opioid), & L-DOPA o Rasagiline – new, more potent axns

Use these in pts w/ response to L-DOPA. (Minimal efx used alone). • COMT inhibitors prolong axn + bioav. of L-DOPA & prevent its fluctuations

o Entecapone - peripheral only; preferred over Tolcapone o Tolcapone – peripheral + central axn; beware liver failure.

Anti-muscarinics alter DA/Ach balance by blocking cholinergic activation of striatum

o Used in early PD or as adjunct to L-DOPA o Adverse Efx: drowsy, inattention, delusions, hallucinations, “Ach dryness”.

• Benztropine Diphenhydramine (Benadryl) Trihexphenidyl The Future: L-type Ca2+ channel antagonists.

Anti-Microbials • No single drug is useful for all infections. • cidal vs. static both rely on host defenses to aid eliminating bug. • Combination Abx: tx resistant, mixed, or severe infxns; usu not necessary

b/c cost & toxicity. • Ideal Abx: obvious things + cidal, narrow spectrum, acid stable, oral, bones

Inhibitors of Bacterial Cell Walls all are bactericidal. 1. Penicillins • MOA: bind cell wall enzymes β-lactam “square” & 5-membered ring w/ Sulfur • Pharmacology:

o Hepatic metabolism o Renal excretion glomerular filtration & tubular secretion

• Prophylactic use: gonorrhea, syphilis, rheumatic fever, or heart valve dz w/ surgery. • General Side Efx:

o Rash delayed rxn ∴ appears in ~2 days. (tx w/ cephalosporin instead) o Accelerated allergic rxn = within 48 hrs hives, wheezing, edema o Acute allergic rxn anaphylaxis, bronchospasm o Neurotoxicity (worse w/ renal impairment)

Bug Drug Bioav. Side Efx Factors Resistance

Penicillin G paren-teral

renal impairmnt add procaine or benzathine to prolong t½.

(G+) Naturals (staph, strep, spirochetes)

Penicillin V oral

β-lactamase in staph

Nafcillin p electrolytes Oxacillin Cloxacillin

Penicillinase Resistant Staph

Dicloxacillin o

Ampicillin p/o diarrhea, rash Amoxicillin

Extended Spectrum: G+ & some G- Cyclacillin

o

acid stable

β-lactamase in G- bugs

Carbenicillin Ticarcillin electrolytes Mezlocillin

(G-) Anti-pseudomonal (& influenza)

Piperacillin

o

Combined w/ aminoglycoside if serious infx

Augmentin = amox + clav a.

o N/V, diarrhea, rash

tx resistant staph & URI’s

Unasyn = ampi + sulbactam

tx flu, mixed, comm. pneumo.

Timentin = ticar + clav a.

tx anaerobes (B. fragilis)

Combo: penicillin with a β-lactamase inhibitor

Zosyn = piper + tazobactam

p

tx G- hospital infxn, not pseudo

2. Cephalosporins o MOA: Block cell wall synthesis

Chemistry: β-lactam square & 6-membered ring w/ sulfur. o Renal tubular excretion ∴ delayed excretion w/ probenecid (except Taz) o General Side Efx:

Hypersensitivity similar to penicillins, but less anaphylaxis Diarrhea, phlebitis, IM pain, nephrotoxic, rare superinfections.

• First Generation similar to ampicillin = G+ cocci, many G- bacilli o Cefazolin o Cephalexin

• Second Generation less G+, more G- o Cefoxitin o Cefuroxime o Cefaclor

• Third Generation enteric G-, crosses BBB Reserve for serious infxns: meningitis, septicemia

o Cefotaxime o Ceftriaxone – hemodialysis OK. o Ceftazidime – excretion via glomerular filtration o Cefpodoxime (prodrug)

• Fourth Generation broad spectrum w/ activity for G+, β-lactamase organisms Use to tx Pseudomonas, Klebsiella, E.coli.

o Cefepime

3. Carbapenems β-lactam square & 5-membered ring with Carbon and a dbl bond. broadest spectrum of any β-lactam abx. Gets in CSF only if meninges are inflamed convenient?

• Imipenem - always give with cilastin to prevent breakdown ∴ renal damage o Side Efx: seizures, nephrotoxicity, CNS toxicity, & typical penicillin stuff

• Meropenem – don’t need cilastin; seizures, efx for G+ • Ertapenem – don’t need cilastin; longer t ½, efx pseudomonas & acinetobactr

4. Aztreonam (Azactam)

• MOA: blocks cell wall synthesis by binding PBP’s o A Monobactam = monocyclic bacterially produced β-lactam. o Narrow spectrum G- bacilli only, parenteral only. o Use in combo w/ broad-spectrum abx.

• Side Efx: GI, skin

Renal elimination

5. Vancomycin • MOA: inhibits cell wall synth (cidal), but different site from other β-lactams • Target: G+ bugs, #1 for MRSA. • Resistance: alteration in binding site; plasmid mediated (esp. enterococcus) • Side Efx:

o Does not cross BBB unless meninges are inflamed o Nephrotoxicity b/c glomerular filtration o Ototoxicity, esp w/ loop diuretics o Red Man Syndrome from histamine release vasodilation & shock o Reduced efficacy in patients w/ Multiple Myeloma b/c [IgA].

6. Fosfomycin

o MOA: blocks formation of cell wall precursors cidal o Pharm: rapid oral, concentrates in urine o Target: uncomplicated UTI o Side Efx: generally good; expensive, diarrhea

Daptomycin inhibits cell membrane, not cell wall

o MOA: alters charge of cell membrane of G+ bugs b/c it is lipophillic. Cidal. o Target: G+ bugs unresponsive to other tx.

(ex: vanc resistant enterococcus; methicillin-resistant staph) o Resistance: none o Side Efx:

Muscle pain/weakness serum creatine kinase Interaxns: binds serum albumin (90%); renal elimination.

Rx that Inhibit the Bacterial Ribosome 1. These inhibit the 50s ribosomal subunit mostly static.

• Dalfopristin-Quinupristin (Synercid) 70:30 combo o MOA: binds ribosome peptidyltransferase ∴ blocks tRNA o Why together? Alone they are static; together they are cidal. o Target: Vanc-resistant E. faecium (only). o Side Efx: inhibits P450; arthralgia, myalgia, conj. bili

• Linezolid (Zyvox)

o Target: Vanc-resist entero. (static @ staph & entero; cidal @ strep.) o Resitance: pt mutation in 23s RNA of the ribosome o Side Efx: N/V, diarrhea, pseudomembranous colitis o Pharmacology: 100% oral bio. OK for liver & kidney BUT inhibits MAO.

contains aspartame ∴ bad for phenylketonuria

• Macrolides/Ketolides

o Erythromycin MOA: binds reversibly to 50s ribosome ∴ static. (t½ = 1.6 hr) Target: G+ bugs when can’t use penicillin (narrow spectrum)

• DOC for Legionaire’s Resistance: rapid, via plasmids, ∴ ensure dose & compliance. Side Efx: Cholestatic hepatitis

o conc. in liver & excreted in bile o GI pain o CYP450 inhibitor

o Clarithromycin (t½ = 4 hr) Think “erythro plus” better b/c: GI efx & acid stable DOC for mycobacterium avium complex (MAC)

o Azithromycin (t½ = 40 hr) Think “erythro plus” better b/c: GI efx & acid stable DOC for: Legionella, MAC, campylobacter, lyme dz.

o Telithromycin MOA: ketolide that binds ribosome at two sites ∴ affinity Resistance: low Target: lungs ∴ tx community acquired pneumonia Side Efx: liver toxicity, prolonged QT, inhibits CYP3A4

o Clindamycin Acid stable; slow resistance. Side Efx: pseudomembranous colitis; GI; rash.

• Chloramphenicol – static

o Resistance: plasmids share inactivation via enzymatic acetylation o Target: broad spectrum, similar to tetracycline o Side Efx:

Liver: glucaronidation metabolism (t½ = 4 hr), but inhibits CP450 Renal: filtered & secreted Bone Marrow Toxicity

• dose related reversible • aplastic anemia (with mortality) even months later.

Gray baby syndrome

2. And these inhibit the 30s ribosomal subunit most are cidal

• Tetracyclines static o Tetracycline – the drug in the class called “tetracyclines”.

MOA: enter cell via passive diffusion through porin channels Target: broad spectrum ∴ G+ & G-, aerobic & anaerobic Resistance: slow but via transport in or efflux out. Side Efx:

• Chelates cations (+) easily o Esp Ca++ in bone discolors teeth if <8 yo. o Don’t give w/ milk/dairy or iron supplements!

• Efx gut flora avitaminosis or superinfections • Vestibular toxicity vertigo • Photosensitivity • Liver toxicity

o Doxycycline - Severe liver damage if parenteral, but GI pain & # doses. o Minocycline – prophylaxis for meningitis; bad vomiting & vertigo. o Demeclocycline - ? o Tigecycline (not on drug list)

MOA & Side Efx: similar to tetracyclines; broad spectrum ∴tx MRSA Resistance: low b/c it can bind other sites and evade efflux pumps.

• Aminoglycosides cidal

MOA: aminosugars diffuse through porin channel ∴ energy dependent • Not acid stable ∴ don’t give it orally or mixed with β-lactams • t½ = 30-90 min

Resistance: inactivation or O2/energy (ie, doesn’t work in anaerobes) Note: resistance to one does not mean resistance to all.

It’s pretty toxic, so only use for severe aerobic G- bugs • Ototoxicity (irreversible) • Nephrotoxicity (glomerular filtration) • Neuromuscular blockade

o Gentamicin – great for enterococcs endocarditis o Tobramycin – great for P. aeruginosa o Amikacin – great for strains resitant to Gentamycin & Tobramycin. o (Streptomycin – 2nd line for TB)

Cidal drugs work best in growing microbes. Static drugs inhibit growth. Concurrent use is counterproductive.

Metabolic Analogs prevent folate metabolism • Sulfonamides

Resistance is slow Distribute to CSF, placenta, breastmilk Renal excretion Classic allergic rash Crystalline aggregates in urinary tract

o Sulfamethoxazole – rapidly absorbed, o Sulfsoxazole – rapidly absorbed, DOC for UTI o Silver sulfadiazine – rapidly absorbed, topical,

tx eye infxns o Sulfasalazine – poorly absorbed ∴ good for IBD o Sulfadoxine – t½ = 1 week (not on drug list)

• Trimethoprim o MOA: prevents reduction of di- to tetra-hydrofolate

Penetrates CSF; concentrates in prostate & vaginal fluid t½ = 11 hr

• Bactrim = Trimethoprim + Sulfamethoxazole o Static alone, cidal together! 20:1 ratio (sulfa:trimethoprim) o Skin rash common o Targets: UTI, URI, neisseria, influenza, Legionella, P. jiroveci, nocardia

Inhibitors of Nucleic Acid Synthesis (Fluoroquinolones) cidal

• MOA: inhibit DNA gyrase; t½ = 4 hr o Resistance: porin proteins or efflux of drug

• Side Efx: Gi, dizzy, photosensitivity, teratogenic, seizures w/ NSAIDs. • Target: alternative for more toxic broad-spectrum drugs.

1st Gen Naldixic acid Cirioxacin

Tx uncomplicated UTI Rapid resitence

2nd Gen Ciprofloxacin Enoxacin Grepafloxacin Lomefloxacin Norfloxacin Ofloxacin

G- & systemic axn Improved pharmacokinetics side efx BUT… …prolong QT & inhibit CYP450 good CSF penetration

3rd Gen Gatifloxacin Levofloxacin Moxifloxacin Sparfloxacin

More axn at G+ Broader G- coverage

4th Gen Truvafloxacin additional anaerobe axn

1

Hematopoietic Agents Growth Factor Agonists

• Erythropoietin (more RBC’s, please) o Epoetin α & Darbepoetin α

MOA: recombinant human erythropoietin ∴ act on committed progenitor cells to RBC production. (give IV or SC)

• Supplement w/ iron dextran Tx: AIDS, chemo, preemies, chronic inflammation, renal failure. Side Efx: high dose heart problems, renal dz, death.

• Myeloid Growth Factors (go bone marrow, go!) o Sagramostin (GM-CSF) - GM = Granulocytes & Monocytes

Tx: shortens period of iatrogenic neutropenia (transplant, chemo) Side Efx:

• granulocytes need frequent blood counts • bone pain; rash • flu-like sx, malaise, fever, diarrhea, dyspnea

o Filgrastim (G-CSF) - G = Granulocytes

Tx: severe neutropenia (iatrogenic or hereditary) Side Efx:

• granulocytes need frequent blood counts • bone pain; rash

o Pegfilgrastim (Neulasta) – like filgrastim w/ a longer t½ .

• Megakaryocyte (makes platelets) o Thrombopoietin

MOA: selective megacaryocytopoiesis rapid #platelets Tx: improves other anemia therapies (currently in clinical trials).

Basically, always use it w/ a myeloid GF and erythropoietin.

o Oprelvekin MOA: recombinant form of IL-11 lymphoid & myeloid growth Tx: thrombocytopenia Side Efx: fatigue, dizziness, dyspnea, arrhythmia, edema

2

Vitamins & Minerals

• Iron o Ferrous Sulfate – DOC for iron deficiency anemia; oral

Others: Ferrous Gluconate, Ferrous fumarate. Side Efx: heartburn, nausea, GI discomfort, constipation, diarrhea Iron Poisoning: pain, diarrhea, vomiting brown/bloody stomach

contents, pallor/cyanosis, hyperventilation (acidosis), shock.

o Parenteral Iron (Ferric gluconate in sucrose; Iron dextran; Iron sucrose) give only if oral not tolerated or absorbed (ex: renal dz w/ Epoetin) Side Efx: different from oral iron

• Headache, malaise, fever, lymphadenopathy, arthralgia, urticaria, worsens RA, anaphylactic shock (rare)

o Deferoxamine (iron chelator)

Tx: iron poisoning; hereditary hemochromatosis

• B12 Cyanocobalamin & Hydroxycobalamin o Both used to tx Vitamin B12 deficiency (impaired DNA synth

megaloblastic anemia). o o/p (injection preferred)

• Folic Acid

o Deficiency: Classic patients are either pregnant or taking folate-chelating drugs Classic complications: neural tube defects, homocystine,

megaloblastic anemia o Folic Acid - o/p

May counteract efx of anti-epileptics o Folinic Acid – F-formyl derivative of tetrahydrofolate

This is important b/c it can circumvent any inhibition of DHFR (like methotrexate), so you can keep taking that drug AND fix the anemia.

Also note that if your chemo drug is an anti-folate drug, this will put a rather large damper on the efx of that other drug.

• General advice: o Give both B12 and Folate in case the pt needs both. o Treat the specific deficiency instead of giving a “multivitamin.”

Dietary Supplements • Massive industry 22 million in 2006 • Age Range highest % use in young children and retired folks. • Problems with Supplements:

o patients think “natural = safe” (wrong!) o lower safety/testing standards; active ingredients and potency may vary. o the manufacturer is responsible for supplements’ safety o patients don’t always think to tell you they’re taking them ∴ risk of drug

interactions (especially elective surgeries)

Supplement Clinical Implications Intended Use Kava-Kava sleeping aid, anti-anxiety Comfrey bone + muscle; kidney stones Germander Wt loss, general tonic Green Tea Ext.

hepatotoxicity

anti-oxidant, anti-inflamm. Ephedra cardiovascular toxicity Herbal wt. loss Chaparral tonic, arthritis, wt. loss Borage rheumatoid arthritis, HTN Senna

hepatotixicity & carcinogenic Laxative

Licorice Pseudo-aldostronism Peptic ulcers; flavoring Garlic anti-platelet axn

Ginkgo Biloba anti-platelet inhibits CYP1A2 & 2D6

prevent Alzheimers (doesn’t work)

Anise Celery Chamomile Fenugreek

natural coumarin derivatives

Red Clover natural coumarin derivaative estrogen-like ∴ risk cancer

Meadowsweet Poplar Willowbark

natural salicylate

Capiscum hypocoagulability b/c fibrinolytic axn St. Johns Wort Induces CYP3A4 & CYP1A2

Echinacea Induces CYP3A4 Inhibits CYP1A2 & 3A4 (intestinal) Antagonize immunosuppressants

Ginseng Antagonize immunosuppressants prolonged bleeding inhibits CYP2D6

Bitter Orange Inhibits CYP3A4

Pomegranate juice mean PSA doubling time Inhibits CYP3A4 rhabdomyolysis ( risk w/ statins)

Cranberry GI upset, diarrhea urinary tract health Caffeine stimulant!

In lecture but not on drug list: Supplement Clinical Implications of excess Intended Use

Vitamin A (retinol) N/V, blurred vision, birth defcts, may mortality (so can E).

Vitamin D N/V, constipation, arrhythmia, calcium deposition in soft tissue

Vitamin E & K antagonize warfarin (anticoag.)

fat-soluble vitamins

Vitamin C kidney stones, iron, GI upset Vitamin B-3 (niacin) flushing, GI upset Vitamin B-6 peripheral neuropathy + pain

Note: does not slow cognitive decline in Alz.

Folic Acid (Vit. B-9) may hide sx if B12 deficient Prevent birth defects

Omega-3 fatty acids high intake bleeding halitosis

HDL

Chromium no proven efx in diabetes or body wt.

enhance insulin axn & metabolism

Selenium improve cancer or HIV antioxidants

Zinc diarrhea, healing of gastric ulcers, sickle cell sx.

cofactor in your body

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Anti-Fungal Agents Rule of Thumb: if it disrupts the cell membrane, it’s cidal.

• Polyene Anti-fungals

o Amphotericin B MOA: binds ergosterol in fungal cell membrane forms a pore

K+ & Mg++ leak out cidal. • Lipid-based formulations have side efx • Give IV, binds to β-lipoprotein • Excreted unmetabolized in urine & bile • Resistance is rare

Target: deep fungal infxns in pregnant woman Side Efx:

• Nephrotoxicity – dose limiting • Fever, chills, shock-like hypotension

o Nystatin – static or cidal, depends on dose.

• 5-Flucytosine

o MOA: prodrug that inhibits thymidylate synthesis & DNA synthesis cidal/static efx are dose dependent Give in combo w/ amphotericin B prolongs t½

o Resistance: lack of permease; defective cytosine deaminase (no activation) o Side Efx:

Glomerular filtration ∴ adjust for renal dz Hematological toxicity Colitis

• Azoles

MOA: inhibit synthesis of ergosterol (∴ defective membrane) Resistance: rapid if used alone Side Efx:

• All are teratogenic • All inhibit CYP450

o Voriconazole >Itraconazole =Ketoconazole >>Fluconazole o Fluconazole – penetrates CSF; t½ = 22 hr; renal excretion o Itraconazole - needs acid for absorption ∴ H2RB’s reduce efx. t½ = 36 hr

Target: broader spectrum than fluconazole Side Efx: liver toxicity (excreted in bile), GI disress, CHF

o Voriconazole – visual disturbance (transient), photosensitivity, liver toxicity o Ketoconazole – N/V, testosterone/steroid problems o Topical Azoles (for mucocutaneous use) Miconazole & Clotrimazole

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• Terbinafine o MOA: inhibits squalene epoxidase (needed for ergosterol synthesis)

Lipophilic ∴ protein bound and concentrates in keratin hair & nails o Side Efx: headache, GI, taste changes, cholestatic hepatitis (liver toxicity)

• Caspofungin

o MOA: inhibits α(1,3)D-glucan synthesis (integral component of cell WALL). IV infusion that takes 1 hr – yikes Excreted in feces & urine

o Target: 2nd line for invasive aspergillus or candida o Side Efx: Histamine sx; teratogenic

• Griseofulvin

o MOA: disrupts mitotic spindle in fungal cells static. o Target: dermatophytes o Side Efx: headache, GI, photosensitivity, hepatic metabolism (ex: OC’s)

Anti- Tubercular Agents These bugs grow slow, live intracellularly, and develop resistance easily.

First-Line Tx for Mycobacterium (takes ~ 24 wks) M. tuberculosis M. avium complex

1. Isoniazid 2. Rifampin 3. Pyrazinamide 4. Ethambutol or streptomycin

1. Clarithromycin 2. Ethambutol or clofazimine or

cipro or amikacin

• Isoniazid

o MOA: blocks mycolic acid synthiesis disrupts cell wall cidal. Penetrates to intracellular space… and CSF, placenta, & breastmilk Efx limited to static if slow-growing or walled off (caseous necrosis). Metabolism in liver (n-acetylation); excreted in urine

o Resistance is rapid ∴ never use alone! o Side Efx: peripheral neuropathy; hepatotoxicity, antacids & corticosteroids

make it less effective.

• Rifampin o MOA: binds β subunit of RNA polymerase cidal.

Penetrates CSF; metabolized in liver & induces CYP450 o Resitance is rapid ∴ never use alone! o Target: TB, MRSA, meningitis, & best anti-leprosy. o Side Efx: Orange-red body fluids, GI, fever, hepatotoxic, OC’s

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• Ethambutol

o MOA: unknown… maybe block RNA synthiesis? It does require actively dividing bugs. Regardless, it’s static. But resistance is latent, so that’s nice.

o Side Efx: optic neuritis visual acuity

• Pyrazinamide o MOA: bugs convert drug to pyranzinoic acid pH bug can’t grow.

Cidal or Static (dose dependent) Resistant bugs are smart and don’t convert it to an acid. Gets into CSF; metabolized in liver; urine excretion

o Target: bugs in acid environment of lysosome/macrophage (ie, slow-growing). o Side Efx: hepatotoxicity, hyperuricemia & gout, arthralgia.

• Cycloserine

o MOA: analog of D-alanine ∴ blocks cell wall synthesis. cidal/static = dose depenent. Broad spectrum, but use only when others fail. Renal excretion

o Side Efx: CNS problems (headache, bertigo, confusion, psychosis, seizures)

• Capreomycin o MOA: unknown, but it’s static. Give IM o Target: last ditch effort b/c side efx: nephrotoxicity

• Ethionamide

o MOA: inhibits peptide synthesis (analog of isoniazid but works different) Penetrates CSF

o Target: last ditch effort b/c of toxicity o Side Efx: GI, hepatic, thyroid

REVIEW: Antimicrobial Sites of Action

Cell Membrane daptomycin polymyxins polyene antifungals imidazole antifungals

Ribosome (30s) inhibitors aminoglycosides tetracyclines spectinomycin

Cell Wall Synthesis penicillins cephalosporins monobactams carbapenems vancomycin bacitracin caspofungin isoniazid

RNA polymerase rifampin

Folic Acid Metabolism trimethoprim sulfonamides

DNA gyrase inhibitors fluroquiniolones

Ribosome (50s) inhibitors macrolides chloramphenical clinamycin synercid linezolid

CNS Stimulants • Indirect Dopamine Agonists

o Amphetamine (Adderall) & Dextroamphetamine (Dexedrine) Tx: obesity, narcolepsy, ADHD Efx:

• Incr BP, arrhythmias, angina, headache • Incr alertness, decr fatigue, incr self-confidence, insomnia • Releases Dopamine in reward pathways incr risk abuse • Neurotoxic

OD: convulsions, coma, cerebral hemorrahge, wt loss, schizophrenia o Methamphetamine (“Ice”)

Take a pinch of red phosphorus, a smidgeion of ephedrine, a dash of iodine and a skosh of lye. Add some distilled water and simmer for a few hours and hope it doesn’t explode and kill you. Voila!

High CNS stimulation w/ decr. peripheral efx. o Methylphenidate (Ritalin)

Think Meth, but milder CNS stimulation. Still has abuse potential. Tx uses: narcolepsy, ADHD

o Cocaine Stimulates VTA nucleus accumbens prefrontal cortex t ½ = 50 min (but the perceived “high” is shorter) metabolites detectable in urine 2-10 days after use. Cocaine + Alcohol metabolized to cocaethylene

• Incr & prolonged euphoria • Incr cardiotoxicity

Preferable Efx: • Vasoconstriction (b/c blocks noradrenergic transporter) • Local Anesthetic (b/c blocks voltage-gated Na+ channels) • Incr. HR & BP • Incr. arousal, alertness, & Euphoria

Less desirable Efx: • Efx of Long-Term Use: motor spasms, paranoia, irritability • Tolerance to euphoric efx. • Heart: arrhythimas, ischemia, myocarditis, aortic dissection • Sex: decr. libido; premature labor (sex makes babies…) • Brain: vasoconstriction/ischemia, seizures, paranoia, addictive

o Withdrawal Sx: depression, fatigue, craving, decr. HR o Mazindol (Sanorex)

Similar MOA as cocaine but more specific for NorEpi. (not DA?) Tx: obesity Side Efx: allergic rxn, insomnia, dry mouth/eyes (glaucoma)

• And ones like cocaine: arrhythmia, incr. BP, anxiety, impotence. • Drug interaxns: MAO-I’s, TCA’s, Guanethidine

• Phentermine (Adipex, Fastin) - indirect Serotonin Agonist o Tx: obesity (short-term use only!) o Good: lower risk of abuse than amphetamine o Bad: atherosclerosis, HTN, hyperthyroid, hx of drug abuse, MAOI’s.

• Atomoxetine (Strattera) – indirect NorEpi Agonist (ie, reuptake inhibitor)

o Tx: ADHD (only drug specifically approved for adults) o Low abuse potential o Side Efx: anorexia, insomnia, incr HR & BP, not as effective as stimulants

• Caffeine (methylxanthine) –

o MOA: adenosine receptor agonist incr DA & NE, inhib. Phosdiesterase Rapid tolerance Mild withdrawal: fatigue, sedation, headaches, nausea NOT ADDICTING (according to APA).

• Others

o Sibutramine MOA: blocks reuptake of dopamine, NorEpi, & Serotonin. (dcr. abuse) Tx: obesity Contraindicated with: MAOI, Anorexia Nervosa, HTN Side Efx: Serotonin Syndrome

o Modafinil MOA unknown. T ½ = 15 hrs. Tx: narcolepsy No efx on Dopamine so no abuse potential. No GI or heart side efx. Side efx: Induces CYP450, headaches (for a week)

o Ephedrine MOA: increase release of DA & NorEpi potent stimulant.

• t ½ = 5 hr. Tx: narcolepsy, bronchoconstriction, depression Side Efx: HTN, stroke, MI, insomnia, tachyphylaxis (rapid desensitization)

o Strychnine MOA: glycine receptor antagonist

• Disinhibition • Convulsions & impaired respiration pesticide axns (fatal) • Found in street drugs b/c stimulates “all portions of CNS”

Tx: respiratory support & diazepam (anti-convulsant)

• No longer on the Market (or your drug list) o Fenfluramine – withdrawn from market b/c cardiac toxicity. o Pemoline – ADHD drug withdrawn from market b/c liver toxicity.

1) A 59 year-old woman is diagnosed with TB. Before prescribing a drug regimen, you take a careful history because one of the drugs used to treat TB is an hepatic CYP450 inducer. Which drug is it? A) Ethambutol B) Isoniazid C) Pyrazinamide *) Rifampin E) Vitamin B6 2) Prior to surgery for a prosthetic heart valve, a 67 year-old man with multiple antibiotic resistances is given a prophylactic IV dose of antibiotic to protect against endocarditis. As the drug is infused, the patient’s skin becomes flushed red over most of his body. The drug he most likely received is: A) Erythromycin B) Gentamicin C) Penicillin G D) Tetracycline *) Vancomycin 3) An intoxicated elderly man is brought to the ER where it is determined that he is in urgent need of antimicrobial treatment for an infection. You wish to avoid a disulfiram-like reaction that might precipitate cardiovascular or respiratory sequelae, bearing in mind his inebriated state. Assuming each of these drugs would be suitable for the infection, which is most likely to produce the described adverse effect? A) Amoxicillin *) Cefotetan C) Erythromycin D) Linezolid E) Penicillin G 4) A 19 year-old is being treated for leukemia when she develops a fever indicative of an infection. You give her several agents that will cover fungal, bacterial and viral etiology. After 48-hours, serum creatinine is rising and acute renal failure ensues. Which of the following drugs is most likely responsible? A) Acyclovir *) Amphotericin B C) Ceftazidime D) Penicillin G E) Vancomycin 5) A 21 year-old woman with UTI due to E. coli is prescribed sulfamethoxazole/trimethoprim [Septra 800/160]. Trimethoprim works by: A) binding to beta-lactamase B) binding to the 50s ribosomal subunit C) inhibiting renal dihydropeptidases *) inhibiting dihydrofolic acid reductase E) inhibiting RNA synthesis 6) A 72 year-old man is receiving drug therapy for TB. Two weeks following the initiation of drug therapy, he returns to his PCP to complain that his sight is “going funny” and that his gout is worsening. Which of the following drugs would most likely produce these symptoms? *) Ethambutol B) Isoniazid

C) Pyrazinamide D) Rifampin E) Vitamin B6 7) Fungal cytosine deaminase converts flucytosine to: A) Ergosterol B) Mycolic acid *) 5-Fluorouracil D) Porphyrin E) Sulfacetamide 8) Azole antifungal agents work by: A) binding to ergosterol and forming “pores” in fungal membranes *) inhibiting P450 14alpha-demethylation of lanosterol C) binding to the 50s ribosomal subunit D) inhibits squalene epoxidase E) inhibits alpha (1,3)-D-glucan synthesis 9) Low hemoglobin and a low hematocrit are found in a G6PD-patient receiving drug therapy for TB. Which of the following drugs would most likely produce these symptoms? A) Ethambutol *) Isoniazid C) Pyrazinamide D) Rifampin E) Vitamin B6 10) Gynecomastia is a consequence of treatment with: A) Amphotericin B B) Caspofungin C) Griseofulvin *) Ketoconazole E) Terbinafine 11) Terbinafine is used to treat which type of fungal infections? A) Aspergillus *) Onchomycosis C) Cryptococcus D) Histoplasmosis E) Disseminated Candida albicans 12) Which of the following binds to and inactivates bacterial transpeptidase, thereby inhibiting cross-linking of peptidoglycan subunits? A) Clindamycin B) Levofloxacin *) Penicillin G D) Doxycycline E) Trimethoprim 13) Resistance to beta-lactam antibiotic occurs through a number of mechanisms, including the production of bacterial beta-lactamases. Which of the following is a beta-lactam antibiotic that is resistant to beta-lactamase expressing bacteria? *) Aztreonam B) Amoxicillin

C) Pipercillin D) Ampicillin E) Ticarcillin 14) Which of the following drugs is effective against MRSA, VRSA, and vancomycin-resistant E. faecium and E. fecalis? A) Azithromycin B) Cefaclor *) Daptomycin D) Dalfopristin/Quinipristin E) Oxacillin 15) The class of antimicrobials known as penicillins has many members. Which of the following is considered to be acid stable with an extended spectrum of activity? *) Amoxicillin B) Ticarcillin C) Cloxacillin D) Nafcillin E) Penicillin G 16) Which of the following works by inhibiting bacterial DNA gyrase? A) Amoxicillin B) Cefaclor C) Linezolid D) Demeclocycline *) Levofloxacin Identify the INCORRECT statement regarding herbal remedies.

A) Herbal medications are covered drugs and under DSHEA, manufacturers are not

required to demonstrate efficacy before marketing a particular agent or combination

product

B) There are insufficient clinical studies to document dosing for herbal medications

C) Herbal medications produce pharmacological effects, and thus, may produce drug

interactions and side effects

*) The FDA regulates herbal medications in the same manner that it regulates OTC

products and medical devices. Which of the following agents was removed from the market because of its association

with hemorrhagic stroke?

A) Echinacea

B) Ginko biloba

C) Garlic

D) Kava

*) Ephedra Your diabetic patient was previously managing their condition quite well but lately blood sugar levels have been erratic. In questioning your patient about recent changes in their life that might explain this development, they tell you that they have recently begun taking an herbal product. Which of the following is most likely responsible for the effect? A) Ginkgo *) Ginseng

C) Red clover D) Sawtooth palmetto E) Valerian Which of the following contains estrogen-like constituents and would therefore be relatively contraindicated in a woman with hormonally-responsive breast cancer? A) Ginkgo B) Ginseng *) Red clover D) Sawtooth palmetto E) Valerian A 45 year-old woman is pancytopenic following adjunctive chemotherapy for breast carcinoma. Her physician prescribes a drug that will selectively stimulate megakaryocyte proliferation to increase her platelet count. Such a drug is: A) Epoetin alfa [Epogen]. B) Folic acid. *) Oprelvekin; rh-IL-11 [Neumega]. D) Sargramostim; GM-CSF [Leukine]. E) Vitamin B12. A 27 year-old vegan has pernicious anemia. Lifetime supplementation is necessary with which of the following drugs to correct the anemia and to prevent irreversible neurologic damage? *) Cyanocobalamin [Berdoz]. B) Deferoxamine [Desferal]. C) Ferrous sulfate. D) Folic acid. E) Ferretin.

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Drugs for the Prevention and Treatment of Arterial Thrombosis Big Picture:

• Anti-platelet drugs (aspirin & clopidogrel) – most effective in preventing arterial thrombosis (stroke, MI, etc); less effective in preventing venous thrombosis.

• Anti-coagulants (heparin & warfarin) prevent both arterial and venous thrombosis (DVT, pulmonary embolism, arterial thrombi).

• Thrombolytics (Fibrinolytics) lyse both arterial and venous thrombi. Anti-Coagulants Indirect Thrombin Inhibitors (via Anti-Thrombin III)

• Heparin o MOA: activates antithrombin III inactivates thrombin (binds Exosite 2)

Only works for soluble thrombin (clot-bound has hidden binding site) Monitor dose w/ PTT

o Side Efx: immune response mounts after 5-10 days of use (b/c platelet 4 binds heparin & abys bind to the new complex) thrombocytopenia (HIT).

• LMWH (Low Molecular Weight Heparin): Enoxaparin, Dalteparin, Ardeparin, & Danaproid

Smaller, active pieces of heparin with a longer t ½. (give SubQ) ∴ anti-Xa axn & anti-platelet axn (∴ don’t need to monitor)

• Fondaparinux

o MOA: Factor Xa is the single molecular target of this drug.

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Direct Thrombin Inhibitors • Hirudin

o MOA: irreversibly binds at the active site and Exosite 1 of thrombin Independent of antithrombin III. Axn against free (soluble) AND clot-bound thrombin Unaffected by factors that neutralize heparin

o Origin: leech spit o Use: heparin-induced

thrombocytopenia

• Lepirudin – a recombinant derivative of Hiruden.

• Melagatran/Ximegalatran MOA: reversibly binds the active site of thrombin.

Vitamin K Antagonists: Coumarin/Warfarin

• MOA: competes w/ Vitamin K epoxide reductase fibrin formation • Side Efx: skin necrosis, bleeding

Give heparin while waiting.

aka Prothrombin Time

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Anti-Platelet Drugs • COX inhibitors

o Aspirin – non-selective COX 1&2 irreversible inhibitor (∴efx last 4-7 days) Antipyretic, anti-inflammatory, analgesic, antiplatelet

Block COX 1 no TxA2 from platelet no platelet aggregation Block COX 2 no PGI2 from endothelium Use: CHD Side Efx: GI bleed, hemorrhagic stroke, asthma (b/c leukotrienes)

o Other NSAIDS - non-selective COX 1&2 reversible inhibitor

Anti-platelet efx not nearly as good as aspirin. (∴don’t CHD)

o Celecoxib – selective COX-2 ∴ no anti-platelet efx. (CHD = bad!)

o Acetaminophen – COX-3? (very weak COX 1&2) ideal antipyretic/analgesic for pts taking warfarin or heparin.

• Drugs that platelet cAMP

o Phosphodiesterase Inhibitors Dypyridamole

• MOA: blocks phosphodiesterase (enzyme that degrades cAMP) cAMP inhibits aggregation & adenylate cyclase.

• Also a potent vasodilator • Use: makes aspirin better; weak anti-platelet used alone. • Side Efx: headache, dizziness, GI upset

Cilostazol • MOA: PDE IIIb inhibitor (reversible) & vasodilator. • Not a 1° antiplatelet drug.

o Adenylate Cyclase Activators: Prostacyclin (PGI) & Organic Nitrates

(indirect)

• Drugs that Inhibit ADP (∴ prevent aggregation) o (Ticlopidine – 1stGen – neutropenia, TTP, & aplastic anemia. Bad. Off market.) o Clopidorgrel – a thienopyridine prodrug.

MOA: prevents ADP from activating GP IIb/IIIa Receptor no platelet activation no aggregation

• Anti-platelet efx = aspirin (but $$ & don’t use ‘em together) Side Efx: bleeding (but not those bad ones of Ticlopidine)

• Drugs that block GP IIb/IIIa Receptor

o Eptifibidate – synthetic peptide, prevents binding of fibrinogen, give IV o Abciximab – Aby for the receptor, give IV

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Thrombolytic Drugs These all convert plasminogen plasmin, which degrades fibrin & fibrinogen. “Clot-Busters” – work in ~60% of coronary thrombosis pts. Give aspirin and heparin concomitantly to prevent re-thrombosis. beware Systemic Lytic State intracranial hemorrhage! (occurs in ~3%)

• Sreptokinase o 1st Gen - Comes from hemolytic streptococcus o MOA: forms “activator complex” with plasminogen; non-specfic o Good: cheap; additive efx w/ aspirin. o Bad: lytic state; triggers immune response ∴ one-time use only

• Urokinase

o 1st Gen - Comes from cultured human fetal kidney cells (∴ not antigenic) o MOA: serine protease that cleaves plasminogen into plasmin; non-specific o Use: acute massive unstable PE o Side Efx: lytic state (b/c non-specific)

• tPA

o 2nd Gen – recombinant endogenous serine protease from vascular endothelium o MOA: tPA, fibrin, & plasminogen form a ternary complex specific axn

against fibrin clot o Use: MI, PE, or stroke w/out hemorrage.

• Reteplase

o “r-PA” – a deletion variant of tPA w/ longer t½. o works about the same as tPA but incidence of hemorrhagic stroke (yikes).

When to NOT give these drugs:

- pt >75 yo - recent surgery, biopsy, or CPR - uncontrolled HTN

Over the Counter Drugs

General: OTC or Rx – who decides?

1. FDA decides if drug is safe for direct selling – via Non-prescription Drug Advisory Committee (NDAC).

a) Does the drug in question treat a condition that consumers can diagnose and manage themselves

b) Is the drug sufficiently safe for use by consumers without direct supervision by the physician

c) Does the label clearly explain the potential adverse effects and conditions with clear and understandable directions

d) The variability in decision-making criteria between candidate drugs calls into question the transparency of the process.

Rx to OTC switch has allowed Americans a more active role in their healthcare. Changing role =

1. Original intention – relieve symptoms 2. Now – many of them were once rx agents to treat or cure the illness 3. Key to successful use = select correct product – but NOT easy – must

recognize symptoms, judge severity, choose and assess tx options

OTC – Labels – a large % of consumers don’t read label! 1. Product name 2. Active Ingredients 3. “Purpose” – antacid, antihistamine, cough suppressant 4. “Uses” – symptoms or dz to be treated 5. “Warnings” – when not to use, to stop, to see a doctor 6. “Directions” – how to take, how much, how long 7. “Other info” – storage conditions 8. “Inactive ingredients” – binders, coloring, flavoring

Misperception = increasing dose beyond what is recommended, re-dosing earlier, or taking more drug in a day than recommended brings great and quicker relief.

1. This is NOT true!! 2. This misperception is pervasive across all age groups – even with adults. 3. Primary rule of safety for any med = to give right does at right time.

Significant Problems = drug interactions with food and beverages, potential

problems with dzs, alcohol + OTC = not good, anti-coag tx, CNS acting drugs might not mix with OTC agents, and careful with NSAID dose

Prescription drugs were the 3rd most used drugs amongst teens in 2005 behind

marijuana and inhalants.

Reasons for OTC Use:

Typical uses = allergies, arthritis, athletes foot, common cold, constipation, cough, diarrhea, drowsiness, eye problems, fever, GI, HA, hemorrhoids, jock itch, menstrual pain, muscle pain, pain, poison, ring worm, scalp itch, skin problems, sleep disorders, sore throat, ulcer, upset stomach, vomiting

Analgesics/NSAIDs – very commonly used OTC

1. Safe when taken as directed for short-term use (7-10 days) 2. Studies have shown toxicity in kidney, liver and GI tract 3. FDA proposed Label Changes:

a) Products with acetaminophen include warnings for liver tox, particularly when used in high doses, with other acetaminophen products, or with 3+ alcohol drinks a day.

b) OTC NSAIDS include warning for stomach bleeding in people over 60, those who have had ulcers, taken a blood thinner or more than one NSAID, or those who take them with alcohol or longer than directed.

c) To help consumers track consumption, FDA also wants “acetaminophen” or “NSAID” to be prominent on the package. Consumers taking a pain reliever may not know that a cold med also has the ingredient.

Acetaminophen (Tylenol) –

SE = hepatic toxicity Interactions = hepatotoxic drugs (azoles, macrolides,

warfarin), CYP inducers Cautions = cirrhosis, poor nutrition, alcohol use, anti-coag Dosing = 10-15 mg/kg/dose q4-6 hr with no more than 5

doses in 24 hr; max daily dose = 80 mg/kg/day – tox reported at lower doses

NSAIDS (Bayer, Advil, Naprosyn, Orudis)

SE = tinnitus, diarrhea, N, gastritis, GI bleed, renal failure Interactions = Warfarin, ACEIs Cautions = renal failure, CHF, cirrhosis, gout, aspirin

sensitive asthma

Allergy Meds

1. Anti Histamines – runny nose, sneezing, watery eyes Loratadine (Claritin, Alavert, Zyrtec) Marketed as “non-sedating” Push too high and CNS effects will occur 1st generation drugs used for motion sickness = diphenhydramine,

dimenhydrinate, cyclizine Alternative to the sedating agents:

Brompheniramine (Dimetane) Chlorpheriramine Diphenhydramine (Benadryl) Clemastine

2. Coughs and Colds

Anti-Cholinergic Antistamines (Benadryl)

SE = cognitive dysfxn, hallucinations, insomnia,

xerostomia, constipation, impaired diaphoresis, ↑ thirst, mydriasis, anuresis, seizures, arrhythmia, heat stroke

Interactions = Anti-parkinsonian drugs, TCAs, phnothiazines, oxybutynin

Cautions = closed angle glaucoma, dementia Pseudoephedrine (Sudafed)

SE = HTN, vasospasm , arrhythmia, stroke, seizure, hallucinations, chronic Has, insomnia, tremor

Interactions = BBs, digoxin, MOAIs Cautions = CHD, HTN, thyroid dz, diabetes, prostatic

hypertrophy, urinary retention, closed-angle glaucoma Topical Nasal Decongestants (Afrin, Neo-Synephrine)

SE = rhinitis medicamentosa, HTN Interactions/Cautions = same as for pseudoephedrine

3. Anti-Tussives – for dry irritating cough Benzonatate

Local anesthetic like action; limited efficacy SE = sedation, mild dizziness, and HA, mild GI upset

Codeine, Hydrocodone – BY PRESCRIPTION ONLY!!!

MOA = direct action on the cough center of the medulla Suppression is achieved at lower doses than those

producing analgesia Drying effect and ↑ viscosity of respiratory secretions NO well controlled studies demonstrate efficacy – report

of peds deaths and other adverse SEs Dextromethorphan – found in >125 OTC products

MOA = binds to non-opiate Rs in cough center At normal doses (15-30mg q6-8 hr) has NO sedative,

analgesic, or addictive properties Demethylated by CYP2D6 and enzyme deficient in some

individuals leading to rapid acute tox Excess = dry mouth and throat, ↑HR, warm feeling,

inability to concentrate With > 2mg/kg (5-10x normal dose) you get phencyclidine

like effects --- out of body state, disorientation, depersonalization, confusion, somnolence, stupor, impaired coordination, disorientation of speech, dissociative anesthesia; addiction is problematic

Combo products = contain ingredients that limit dosing (guaifenesin) or have toxicity (chlorpheniramine)

4. Expectorants – productive cough, congested

Guaifenesin = only FDA approved OTC agent High dose effects = N/V, dizziness, HA, rash

5. Conclusions:

a) Anti-tussives have ? clinical efficacy b) Centrally acting agents are dangerous, esp in young kids c) Decongestant/anti-H may ↓ post-nasal drip and ↓ cough

OTC Products Affecting BP

Ephedrine Epi Ibuprofen Phenylephrine Pseudoephedrine Racinephrine Theophylline

OTC Stimulants (Diet Aids) – Caffeine

Coffee Decaf Tea Cold Remedies Analgesic Preparations Stimulants Weight Loss Aids

a) > 300mg/day ↑ spontaneous abortion, low birth weight,

metabolizing enzymes absent in newborn b) Caffeine withdrawal syndrome = HA, sleepiness, drowsiness,

irritability, confusion, etc. c) At normal doses, no arrhythmogenic link with CV dz.

Orlistat

a) GI lipase (covalent) inhibitor for obesity management b) Blocks the absorption of dietary fat -- ↓calorie intake leads to

negative E balance and weight loss c) Minimal systemic absorption d) Adverse effects, esp. with >30% fat calories = flatulence with

discharge, fecal urgency/incontinence, steatorrhea, oily spotting, oily evacuation

e) Pt. needs to adhere to recommended diet plan f) Psyllium fiber adjunct can ↓ some GI side effects g) Hypovitamnosis – can be prevented through use of daily mv

that contains fat soluble vitamins

Benzocaine Gum – numbs the taste buds removing the pleasure of eating OTC Dyspepsia and Heartburn

1. Antacids [Maalox, Mylanta, Rolaids, Tums]

SE = electrolyte imbalance, diarrhea, constipation, kidney stones

Interactions = Ibuprofen, sulfonylurea drugs, ferrous sulfate, tetracycline, ciprofloxacin, INH

Cautions = kidney stones, hyperCa, renal failure, CHF

2. H2 Receptor Antagonists [Tagamet] and PPIs [Prilosec]

SE = liver dz. tachyphylaxis Interactions = a ton Cautions = cirrhosis, anti-coag.

Anti-Diarrheals

1. Bismuth Subsalicylate [PeptoBismol, Kaopectate]

SE = discolored feces and tongue, fecal impaction Interactions = warfarin, tetracycline, steroids,

valproic acid, uricosuric drugs, antacids Cautions = anti-coag and inf. D

2. Loperamide [Imodium]

SE = electrolyte imbalance, fluid loss, dehydration,

paralytic ileus No interactions Cautions = cirrhosis, inf. D

OTC Constipation Products

1. Bisacodyl [Dulcolax] and Senna [Ex-lax]

SE = electrolyte imbalance, cathartic axn No interactions No cautions

2. Magnesium Hydroxide [MOM] and Magnesium Sulfate [Epsom salts]

SE = electrolyte imbalance, edema DI = quinolones, azoles, thyroid drugs, digoxin Cautions = renal failure, bone dz

Insomnia – Sleep Disturbances

OTC Sleep Aids = have 1st gen. anti-histamines – Diphenhydramine, Doxylamine

Lack of consistency in action – tolerance Daytime drowsiness, dry mouth palpitations, blurred

vision, urinary retention (problems with an enlarged prostate)

Special Patient Populations –

1. Women

Transplacental passage occurs in pg. – adverse teratogenic or pharmacological effects possible

*Acetaminophen is DOC for short-term pain relief NSAIDs/Aspirin – developmental/delivery problems 3rd trimester = heartburn is common; chronic antacid

use = hyper, or hypoMg and hyper Ca; H2 blockers have shown anti-androgenic effect t/f direct patients to antacids because safety data is stronger

2. Neonate

Acetaminophen + NSAIDs provide safe pain relief Aspirin in milk = rashes and neonatal bleeding Anti-Histamines (H1 and H2) – eliminated in the

milk – H1 = sedation, irritability, crying, sleep disturbances, ↓ milk production; H2 = AAP accepts with no risks involved

Al or Mg antacids don’t enter milk

3. Children

OTC drugs are safe when used appropriately Kids are not just small adults – follow dosing instructions

and DON’T DOUBLE THE DOSE b/c child seems sicker than last time the OTC product was used

Acetaminophen = DOC for pain relief Avoid aspirin = risk of Reye’s syndrome Decongestants – use correct dose Antacids widely used but safety not established H2 blockers are safe – liquid formulations are not OTC!

4. Fetus – see chart slide 35 – list of drugs and effects on fetus

5. Elderly ↑ risk NSAIDs and kidney dz/ GI bleeding ↑ risk glaucoma/UT block with pseudoephedrine Interactions with anti-histamines may be significant –

worsen asthma, narrow angle glaucoma, prostatic enlargement, confusion, delirium, dizziness (falls and fractures)

More susceptible to adverse effects of GI drugs: (Diarrhea/dehydration (Mg) or constipation (Al) Mg antacids are best if no remal impairment Drug interaction with cimetidine most likely

1) Streptokinase is administered as part of the immediate therapy for a patient presenting with acute MI. The drug works by: A) Activating the conversion of fibrin to fibrinsplit products *) Activating the conversion of plasminogen to plasmin C) Inhibiting the conversion of prothrombin to thrombin D) Inhibiting the conversion of fibrinogen to fibrin 2) A patient on heparin therapy is bleeding profusely from the i.v. site after treatment is terminated. Protamine is administered to reverse the effects of heparin. It does this by: A) hydrolyzing heparin B) changing the conformation of antithrombin III to prevent heparin binding C) activating the coagulation cascade, overriding the actions of heparin *) combining with heparin as an ion-pair, thereby inactivating it 3) Clopidogrel is administered to a 67 year-old man to guard against another stroke. When employed in this manner, clopidogrel works by: A) Inhibiting platelet thromboxane production *) Antagonizing the ADP receptor C) Antagonizing glycoprotein Iib/IIIa D) Inhibition of vitamin K-dependent coagulation factor synthesis E) Activation of plasminogen to plasmin 4) In patients receiving warfarin, the antithrombotic effect is decreased when they are given which of the following drugs? A) Chloral hydrate B) Heparin C) Aspirin *) Cholestyramine E) Clopidogrel 5) Which of the following drug pairings represents a pharmacokinetic drug interaction? A) Propranolol - Isoproterenol B) Nalmefene - Morphine *) Acetaminophen - Ethanol D) Neostigmine – Tubocurarine 6) In the Facts & Comparisons A to Z Drug Facts book, one reads that: "effects of felodipine [Plendil] may increase if given with grapefruit juice." The mechanism responsible for this interaction is: A) increased stomach acidity *) decreased metabolism in the intestinal wall C) decreased stomach emptying D) increased rate of tablet dissolution E) decreased renal excretion

7) Drug X is a CNS-active product that is converted to a single inactive metabolite by a CYP: 2C19 (P-450) mediated biotransformation. Which of the following statements regarding this process is CORRECT? A) Concurrent cimetidine exposure will shift the dose-response curve of drug X to the left and increase its half-life B) Concurrent rifampin exposure will reduce the affinity of drug X for its receptor C) Concurrent rifampin exposure will shift the dose-response curve of drug X to the right and decrease its half-life D) Concurrent cimetidine exposure will increase the affinity of drug X for its receptor E) Neither cimetidine nor rifampin will have any effect upon the activity of drug X 8) The abuse liability of stimulants is thought to result from: A) stimulation of norepinephrine transmission B) inhibition of serotonin transmission C) simulation of GABA-A receptors D) inhibition of AMPA receptors *) stimulation of dopamine transmission 9) Which anti-narcolepsy drug has relatively little abuse liability? *) Mazindol (Mazanor) B) Methamphetamine (Ice) C) Methylphenidate (Ritalin) D) Amphetamine (Dexedrin) E) Modafinil (Provigil)

Heparin: A) has thrombolytic activity B) has the most prolonged activity when administered orally *) acts by inhibiting antithrombin D) inhibits the aggregation of platelets caused by TXA2 E) acts by blocking hepatic vitamin K regeneration Warfarin: A) acts rapidly when given orally B) is potentiated by barbiturates C) is antagonized by protamine sulfate *) affects the activity of clotting factors E) is potentiated by platelet factor 4 The risk of bleeding in patients receiving heparin is increased by concurrent aspirin treatment because aspirin: A) inhibits heparin anticoagulant activity *) inhibits platelet function C) displaces heparin from plasma protein binding sites D) inhibits prothrombin formation E) causes threombocytopenia When given concurrently, which of the following drugs decreases the antithrombotic effect of warfarin? A) Chloral hydrate B) Heparin C) Aspirin *) Cholestyramine E) Clopidogrel Aspirin can: *) prevent TXA2 formation B) prolong whole blood clotting time C) shortens bleeding time D) inhibits fibrinolysis E) inhibits the effects of warfarin If bleeding became a problem in a 67 year-old man receiving warfarin for prophylaxis of a recurrent venous thromboembolism, which of the following would most effectively reduce the clotting time? A) Aspirin B) Heparin C) tPA *) Vitamin K E) Fibrinogen

Alteplase is prescribed for a 54 year-old man with an acute MI. This drug works by: A) blocking platelet ADP receptors B) inhibits platelet TXA2 formation C) blocking the metabolic formation of vitamin K-dependent coagulation factors D) blocking glycoprotein IIb/IIIa receptors *) promoting conversion of plasminogen to plasmin Which of the following tests would show an abnormal value in a patient taking aspirin on a chronic basis? A) Activated Partial Thromboplastin Time (APTT) *) Bleeding time C) INR (International Normalized Ratio) D) Platelet count E) Prothrombin time OTC Drugs. 1. How are OTC products regulated? 2. When used as directed, what are the side effects or toxicities and possible interactions with prescription drugs? In a patient who is self-medicating with NSAIDs for rheumatoid arthritis, which of the

following OTC antidiarrheal agents would give MOST cause for concern of a drug

toxicity?

A) Loperamide

*) Bismuth subsalicylate

C) Kaolin

D) Calcium carbonate

E) Alumina powder Which of the following OTC drugs is known to reduce milk volume in mothers with

suckling infants?

A) cimetidine [Tagamet]

B) aspirin

*) diphenhydramine [Benadryl allergy sinus]

D) metamucil

E) tums or rolaids Factors affecting drug action. 1. What factors affect drug action? 2. What impact do they have? 3. Can you manipulate them? The renal clearance of drug X is < GFR when ammonium chloride is administered

concurrently, but is > GFR when sodium bicarbonate is administered concurrently.

Which of the following BEST characterizes the properties of drug X?

A) Strong organic base

B) Non electrolyte

*) Weak organic base

D) Weak organic acid

E) Strong organic acid In the Facts & Comparisons A to Z Drug Facts book, one reads that: "effects of felodipine [Plendil] may increase if given with grapefruit juice." The mechanism responsible for this interaction is: A) increased stomach acidity *) decreased metabolism in the intestinal wall C) decreased stomach emptying D) increased rate of tablet dissolution E) decreased renal excretion 2) Drug X is a CNS-active product that is converted to a single inactive metabolite by a CYP: 2C19 (P-450) mediated biotransformation. Which of the following statements regarding this process is CORRECT? *) Concurrent cimetidine exposure will shift the dose-response curve of drug X to the left and increase its half-life B) Concurrent rifampin exposure will reduce the affinity of drug X for its receptor C) Concurrent rifampin exposure will shift the dose-response curve of drug X to the right and increase its half-life D) Concurrent cimetidine exposure will increase the affinity of drug X for its receptor E) Neither cimetidine nor rifampin will have any effect upon the activity of drug X