FACTORS AFFECTING ABSORPTION:i. Dose size administered: inc. dose = inc. rate and extentii. SA: inc. SA = inc. rate and extentiii. pH of the absorbing environment: weak acid (more acidic env’t); weak base

(more basic env’t)iv. Degree of perfusion (blood supply) of absorbing env’t: inc. blood supply = inc.

rate & extent Absorption in small intestine >>> stomach ; greatest - lungs :) Can be modified to limit / minimize drug absorption (if it may lead to

toxicity)e.g. Local vasoconstrictors w/ local anaesthestics

Epinephrine + Lidocaine---> constricted blood vessel ---> less systemic absorption, less toxicity

v. Gastric emptying time (GET) - time it takes for the stomach to empty its contentsStomach - poor absorbing env’t except for ASA and Ethanol POReasons: (1) small surface area (2) small blood supply (3) lined with thick

mucusInc. GET = dec. Rate of absorption ; Dec. GET = inc. Rate of absorption (RATE NOT EXTENT!)Thus may affect onset of action of drugs

Factors that increase GET (delay in absorption) high CHON/fat meal Gastric ulcers Stress / heavy exercise Lying on the left side - intervention of certain poisoning cases e.g

INH poisoning (L-side to gavage later) Drugs that impair GI motility - opioids, anticholinergic effecs of

drugs (TCA - may anticholinergic effect)Factors that decrease GET (inc. rate of abs)

Cold food and drinks and hot food (all variations is temp of food decrease GET)

Mild exercise Lying on right side Gastrectomy DM - incretins - affect how glucose is absorbed - they lack this,

so there is rise of glucose in blood due to less GET - lack of incretin affect normal glucagon levels (after eating dapat bababa si glucagon, tataas si insulin, but in DM Px, both tataas)

Drugs that inc. GI motility - cholinomimetic, anti-dopaminergic drugs (metoclopromide Plasil®, Domperidone)

Spicy food Hot meal at 60C

4. DISTRIBUTION - process of drug movement from systemic circulation to different body compartments / parts

- drug reaches the site of action - 'Carrier' of drug to different compartments from the blood

2 important physiologic factors that affect distribution Cardiac output (CO) - volume of blood pumped out by heart in 1 min. = 2.2-3.5

L/min/m2 BSA - expression of rate (how fast blood is moving)

e.g CHF- low cardiac output state - delay in drug distribution in reaching a therapeutic tissue conc’n of drug)

Regional blood flow - fraction of CO that is delivered to specific tissues or organse.g. Liver - 25% CO , kidneys - 25%, lungs - 100%

Areas with poor regional blood flow - not > 1% of CO (bones, adipose)Implication: Tx in these areas, it will take some time to reach tissue

conc’ne.g. Osteomyelitis (bone infection) - 6 weeks or greater Abx treatment [IV] vs. Pneumonia (lung Infection) - 7-14 days [oral]

2 important distribution parameters: Protein binding - binding of drug w/ blood proteins: drug + protein drug-CHON

complex(in blood)Drug (unbound) - can be distributed, can reach site of action and can be

metabolized and excretedBound - stays in systemic circulation- can serve as depot form - store and

slowly release the drugsBlood proteins:

i. Albumin - dominant, structure non-selective, preferentially binds weak acids

ii. Alpha1-acid glycoprotein - structure non-selective, preferentially bind weak bases

iii. Globulin- selective for hormones (specific globulins for different hormones e.g. cortisol binding globulin, thyroxine-binding globulin)

NOTE: displacement interactions - drugs displacing one another from CHON binding ---- are not clinically significant unless there is a concurrent elimination problem, ONLY IF ELIMINATION IS IMPAIRED (e.g. Warfarin and NSAIDs)

Volume of distribution (Vd) - hypothetical or apparent volume of body fluid that is necessary to dissolve given amount or dose or a drug to a conc’n equal to that of plasma conc.

Not a real blood volume (computed only)Conc’n = mass/volume V = m/CVd = D / Co ; Vd = A / Cp

D = dose size administered ; Co = extrapolated drug plasma conc’n at t=0A = amount of drug in the body; Cp = conc’n of drug in plasma at a given time

Important applications of Vd:1. Estimating Loading dose (DL)

e.g. At what DL should a drug be given if the Vd is 5 L/kBW and desired drug plasma conc’n is 5 mg/L. Px weighs 60kg.

Given: Vd = D / Co ----- DL / C target ------- DL = Vd x C target[(5 L/kg) x 60 kg] x 5 mg/L = 1500 mg

2. Predict the likely extent of drug distribution (where is the drug located) - compare Vd with the body fluid volumes if Vd approximates the volume of certain body fluid, then drug is located at that body fluid.

 

Body fluid % BW Given a 70kg Px

Total body fluid1. Intracellular

 2. Extracellular

1. Intravascular2. Interstitial

60%40% 20%5%15%

42 L 28 L 14 L3-4 L10-11 L

e.g. Drugs Vd Extent of drug dist.

a 40L Extent is total body fluid

b 2L Intravascular

C (chloroquine) 5,000L Extent is total body fluid

**** Vd is hypothetical!!!!3. Extent of ditribution

Large Vd - widely distributed ---- extent approximate to Total or intracellular Body fluid

e.g. Chloroquine, atropine, B-blockers, weak bases (in general)

Low/small Vd - extracellular or within intravascular compartmente.g. Warfarin, Midazolam, weak acids (in general)

5. METABOLISM --- biotransformation (one of the two elimination processes)Objective: converts drugs into forms which are less active or inactive, less toxic or non-toxic, polar or water soluble (to be easily excreted)

Exceptions: Prodrug - parent drug that is inactive and has to be metabolized to the

active forme.g. Enalapril (inactive, prodrug) ---hydrolysis Enalaprilat (active, anti-HTN effect) etc.

Active drug with active metabolitese.g Diazepam active --- N-desmethyldiazepam (nordazepam) [active] --- Oxazepam [active] inactive glucuronide

Nontoxic drug metabolized to a toxic druge.g. Acetaminophen (nontoxic) ---CYP1A2--- N-acetylparabenzoquinone imine (NAPQI) [hepatotoxic] ---conjugation with GSH--- inactive nontoxic mercapturic acid form

Important metabolizing organs:o Livero GIT (stomach, intestines)o Blood (plasma: portal, systemic)

o Kidneys - Imipenem (dihydropeptidase enzyme in kidney) dihydropeptidase inh - cilastatin

o Lungso Placentao Aqueous humor of eyes

** First Pass Effect / Metabolism (FPE / FPM) - initial metabolism of a drug BEFORE it reaches the systemic circulation

PO drug - intestines - portal circulation - liver systemic circulation (Sites of FPE in PO drugs: intestines, portal circulation and liver). Significance: FPE can decrease oral bioavailability of a drug

Phases of drug metabolismI. Phase 1 metabolism - functionalization phase (addition or unmasking of a

functional group) Oxidation - DOMINANT

a. CYP-mediated - involves cytochrome P-450 mixed oxidase systemCYP families and their most notable substrates

CYP 1A2

Acetaminophen, TheophyllineCYP1A2 can be induced by Omeprazole, Cruciferous veggies, burnt meat (benzo[alpha]pyrene)

CYP 2C19

Omeprazole (PPIs), Propranolol

CYP 2C9

Warfarin, phenytoin

CYP 2D6

*most studied CYP* antidepressants, antipsychotic, codeine, dextromethorphan, debrisoquin - will be discussed in genetic polymorphism (US - leading causes of hospitalization/morbidity are psychosis and depression)

CYP 3A4, 5, 7

*super family- very big group, major metabolism of more than 50% of commercial drugs* amiodarone, azole antifungals, CCBs, macrolides, grapefruit

b. CYP - independento MAO o Alcohol and aldehyde dehydrogenase

Reductiono Nitro reduction - chloramphenicolo Carbonyl reduction - antagonist of opioids - Naloxone

Hydrolysiso Esters - ASA, ester -type local anethesia (LA), ACE-io Amides - procainamide, lidocaine, amide type LA

II. Phase 2 metabolism - Conjugation reactions / synthetic phase; Involves addition of a POLAR conjugate

Glucuronidation (dominant) - enzyme: glucuronosyl acyltransferase [GluCAT] (poorly expressed / few in amount in neonates - not more than 28 days) -

o Grey baby syndrome - Chloramphenicol - inability to metabolize by glucuronidation the chloramphenicol metabolites

o Kernicterus in neonatal hyperbilirubinemia - excess bilirubin - Types of bilirubin: (1) Unconjugated / indirect which is lipophilic (cross BBB) thus kernicterus ; prevented by enzyme GlucAT (2) conjugated / direct - H2O so’lb (cannot cross BBB)

Acetylation - N-acetyl transferaseo Hydralazineo Isoniazid- undergoes phase II metabolism first before Phase Io Procainamide

Glutathione conjugation Glycine conjugation

Enzyme induction - stimulate activity or production of enzymesEffects: i. If substrate is prodrug - increase in activity of prodrug & risk of toxicity (e.g codeine morphine active)ii. If substrate has a toxic metabolite - increase toxicity (e.g. Acetaminophen NAPQI hepatotoxic)iii. If substrate is active with inactive metabolite ----- decreased activity

Enzyme inducers: general - rifampicin, phenobarbarbital, carbamazepine, CYP1A2 inducers - most important substrate is acetaminophen (risk of NAPQI) --- cruciferous veggies (brussel sprout, brocolli), omeprazole, char-boiled meat (benzopyrene), cigaretteCYP3A4 inducer - St John's wort (adjunctive therapy for anxiety)

Enzyme Inhibition - decreased activity or production of metabolizing enzymeEffects: i. If substrate is prodrug ---- decreased activity / efficacyii. If substrate is active with inactive metabolites --- increased activity / efficacy or risk of toxicity (e.g warfarin inhibition --- if metabolism is inhibited then Px has risk of bleeding)

Enzyme inhibitors: General- azole antifungals (ketoconazole, fluconazole) macrolides (erthromycin, clarithromycin except azithromycin)

CYP3A4 inhibitors: antiviral agents (indinavir, saquinavir) grapefruit

GENETIC POLYMORPHISM - variability in the expression or production of enzymes based in genetic characteristics

3 groups based on quantity of enzymes produced or expressed: EM = extensive metabolizers (produce normal or adequate amount of enzymes) UM = ultra metabolizers (produce excessive amounts of enzyme) PM = poor metabolizers (produce inadequate amount of enzyme)Examples:

NAT2 polymorphism - N-acetyl transferase 2 enzyme - catalyzes acetylation (3 substrates yung HIP)

i. EM - rapid acetylators (asians)

ii. PM - slow acetylators (>50% of caucasian) consequence - poorly metabolize INH, hydralazine, procainamide- most assoc. With SLE-like Sx in caucasians [thus higher risk for SLE-like SE with substrates]

6. EXCRETION - final loss of drug from the bodyGeneral requirement: water solubleMechanisms/ route: (1) Renal (2) Biliary (3) lungs - for volatile lipophilic substance (4) skin and sweat glands (5) mammary glands (6) GIT

a. Renal - dominant excretory mechanismRequirement: (1) polar (2) small MW <400-6002 important processes that contribute to renal excretion

Filtration (1st order - concentration dependent) -major renal excretory process ; dependent on renal function (GFR)

If GFR goes down, then filtration goes down (filtration is impaired thus drug is retained in body)Estimation of the GFR: measure Creatinine clearance (CLcr); MDR - modified renal diet method

24-hr urine collection : CLcr = [Ucr / Pcr] x [vol (mL) of urine in 24 hrs. / 1,440 mins]

Ucr = urine creatinine conc’n; Pcr= plasma creatinine conc’ne.g. Urine creatinine conc’n = 24mg/dL Plasma creatinine conc’n = 1.2 mg/dL Volume of urine in 24 hrs = 2880mLAnswer: 40mL/min

Cockroft and gaultCLcr (male) = [(140 -age in yr) (BW kg)] / [72 x Pcr in mg/dL] this is in mL/minCLcr (female) = CLcr male x 0.85

Application: dose adjustment of renally excreted drugs among Px with Renal insufficiencyNormal: 80-120 mL/min or 100 mL/min (ave)Dose adjusted = [(CLcr Px) / (CLcr normal)] x dose regular

= [(CLcr Px) / (100mL/min)] x dose regular Tubular secretion - carrier mediated (saturable) [pls see graph above]

e.g. β-lactams - inhibited by Probenecid (good effect of probenecid is that it lengthens the duration of action of β-lactams.

Digoxin - inhibited by quinidine (never given together because of risk of digoxin toxicity) 

b. Biliary excretion - requirement - polar, MW >400-600*** if a drug is excreted through the bile, there is a possibility of drug reabsorption (biliary recycling / enterohepatic recirculation) --- bile is excreted in duodenum so drug can still be reabsorbed in duodenum, jejunum and ileum

PHARMACOTHERAPEUTICS-study of rational use of drugs in the Mx of diseases

I. Autonomic drugs (variety of clinical uses)a. Anatomy and physio of Autonomic nervous system (ANS)

b. Sympathetic drugsc. Parasympathetic drugs

Anatomy and Physiology of ANS ANS is an effector of the CNS (ANS performs the function of the CNS) NOTE: other

effector of CNS is Somatic NS CNS - brain and SC Key difference of ANS from somatic NS

a. ANS is a 2-neuron system while Somatic NS is a 1-neuron system second neuron has the cell body outside the CNS (in Somatic NS, body is

in CNS)preganglionic fiber is axon of neuron #1 while postganglionic fiber is the axon of neuron #2

b. Presence of ganglia in ANS (absent in Somatic NS) ganglion - collection of nerve cell bodies located outside the CNS

c. Action/effect: ANS - automatic, independent, involuntary ; Somatic NS - voluntary (skeletal muscle)

Synaptic Neurotransmission - describes the transmission of impulses across an interface (interface between Neurons and between Neuron and its target organ)

3 important parts of synapse (the interface) o Presynapse - important in synthesis, storage and release (by exocytosis) of

NT ; may contain presynaptic receptors (role in regulatory / “autoreceptors” - when stimulated will inhibit further release of NT)

o Synaptic cleft - where NT are released and may be the site of metabolism of NT (e.g acetylcholinesterase acting on Ach)

o Postsynapse - primary location of majority of receptors (if it is not specified what kind of receptor it is, assume that it is postsynaptic unless otherwise specified) ; metabolism of NT(postsynaptic enzyme)

NOTE: role of Ca -- induce release of NT ; increase in presynapse during neurotransmission and will stimulate the process of exocytosis of NT

Different synapses : ANS - 2 synapses ; SomNS - 1 synapseNomenclature:

Divisions of the ANSo Sympathetic

o Parasympathetico Enteric - 3rd division of ANS ; intrinsic (found at that site only) autonomic

innervation of the intestines; discovered in isolated tissue experiments - intestines preserved their secretions and activity ; The extrinsic are the symp and parasympathetic

Mediated by 2 plexuses (nerve networks): Auerbach Meissner (both are responsible for motility and

secretions Involves different set of NT:

ATP VIP (vasoactiveintestinal peptide) Substance P Neuropeptide Y

 

Criteria Sympathetic = adrenergic Parasympathetic = cholinergic

a. Anatomic {draw}i. Origin / roots of fiberii. Location of ganglia {draw}iii. Length of fiber

Pregang.Postgang.

Thoracolumbar (exit together with T1-T12 and L1-L5) Near the Spinal Cord (paravertebral, pre-vertebral chains) ShortLong

Craniosacral (CN 3,7,9, 10) and S1-S4 Near target organ  LongShort

b. NTi. Pregangii. Postgang

 AchNE [NOR-epi means NO CH3 at Nitrogen], Epi [with CH3], Dopamine

 AchAch (both Ach that’s why it’s ‘cholinergic’)

c. Receptors (postsynap)i. Ganglionic

 Ii. Target organ

 Nicotinic (Nn) **Nm - predominantly found in somatic NS, in neuromuscular endplate Alpha, beta, dopamine (D)

 Nicotinic (Nn) thus pag ganglionic blocker you block both Muscarinic (M), nicotinic (N)

d. Responses / effectsi. General response

 ii. Specific

HeartEyes PupilsBronchiGIT walls

sphincters

 Fight/flight/fright responses - all stresses (always think sympathetic) Inc HR (tachycardia)Dilate (mydriasis)BronchodilationRelaxation

 Rest and digest responses - all maintenance  Dec HR (bradycardia)Constriction (miosis)Bronchoconstriction ContractionOpening (both may lead to

Synapse type Presynapse name Postsynapse name

ANS 1st synapse Preganglonic fiber Ganglion

ANS 2nd synapse Postganglionic fiber Target organ

SomNS (the only synapse is called the NMJ)

Somatic nerve Neuromuscular endplate

Urinary bladder DetrussorTrigone

 Sweat glands

Closure (both may lead to constipation = ileus) RelaxClosure (both will lead to urinary retention) Apocrine (palms and soles) - inc. sweating

peristalsis) 

ContractionOpening (both will lead to urination = enuresis = micturation)Eccrine Sweat glands (thermoregulation and widely distributed) - inc. sweating

SYMPATHETIC DRUGS1. Biosynthesis of cathecolamines2. Receptors, location and responses3. Sympathomimetics = agonists4. Sympatholytics = antagonist

1. BIOSYNTHESIS OF CATECHOLAMINESLocations: sympathetic postgang. fiber, adrenal medulla, CNSSteps:

Active uptake of precursor amino acid (aa) = tyrosine Conversion of tyrosine to DOPA [ tyrosine ---Tyrosine Hydroxylase---> DOPA

(dihydroxyphenylalanine) *rate limiting step - slowest* Can be inhibited by metyrosine (methyl tyrosine)

Formation of 1st cathecolamine = dopamine [ DOPA ---DOPA decarboxylase---> dopamine *central, peripheral - may limit availability of DOPA in BBB*

Vesicular uptake of dopamine at presynapse – dopamine should be stored in vesicles right away (rationale: MAO enzyme readily destroy dopamine at the presynapse)

Can be inhibited by reserpine (thus inh. sympathetic response) Vesicular metabolism of dopamine to NE within the vesicles [ dopamine ---

dopamine B-hydroxylase---> NE (major sympathetic (symp.) NT)]**happens only at adrenal medulla, not in Sympathetic Postgang. fiber**

NE ---PENMT (phenylethanolamine N-methyl transferase---> Epi (adrenaline) [see structure above]

Exocytotic release of NT *postgang symp fiber ----> NE* Can be inh by guanethidine and guanadrel Can be stimulated by ephedrine, amphetamines, angiotensin II

(important in DI), tyramine ( we don’t get HTN since we have MAO at the presynapse, unless Px is on MAOi)

FATE OF CATHECOLAMINE (NE) AT THE CLEFT Binding to postsynap receptors Metabolism by COMT and MAO Re-uptake of NE via Uptake 1 transporter (it goes back to presynap)

NE is conserved and returned to presynapMajor mechanism of loss of NE from cleft (70%)

Can be inh. by drugs such as Cocaine, TCA (tricyclic antidepressants), NaRI or NRI (NE or noradrenaline reuptake inhibitor)

2. Receptors, Locations, Response

Receptors Location Response

1. Alphai. Alpha 1 (Gq

linked)       

ii. Alpha 2 (part of vascular s.m. tone / vasomotor area - continuous releases of NE and causes b.v. To be constricted)

 2. Beta

i. Beta 1 (Gs linked)      

ii. Beta2 (Gs linked)            

 Smooth muscles [VP of RP]

Vascular s.m. (blood vessels)

Prostatic s.m. &bladder trigone and sphincter

Radial muscles of iris (move away from pupils [see drawing]

Pilomotor s.m.  Presynaptic (Gi linked) CNS – inh. release of NE Postsynap (Gq linked) Vascular s.m.  [HJ]

Heart (dominant adrenergic receptor)  

  Juxtaglomerular (JG)

apparatus Smooth muscles [BUVS]

Bronchial s.m. Uterine s.m.

  Vascular s.m. Of blood

vessels that supply the skeletal muscle

Skeletal m. (Somatic NS)o NM endplate

(postsynap) 

 ContractionVasoconstriction

Contraction ---> urinary retention (esp. when prostate is enlarged)Contraction ---> shortened radial m. ---> mydriasisContraction ---> goosebumps / gooseflesh Sedation, depressionPeripheral vasodilation Peripheral vasoconstriction   Inotropism - inc. in strength of contractionChronotropism - inc. in HR (tachycard.)Dromotropism - inc. rate of conduction across AV node[see drawing] shorten delay Renin release 

RelaxationBronchodilationUterine relaxation (for pre-mature labor)= tocolysisVasodilation(so you can tolerate exercise longer otherwise, easy fatigability) Musc. Contraction ---> tremors (Inderal® - controls tremors)

  

iii. Beta3 

3. Dopamine (D)i. D1

  

ii. D2-D4

o Muscle cells     adipose [R & S b.v. ; GIT & CNS]Renal and splanchnic (abdominal) b.v. Peripheral = GIT  

  CNS  

Movement of K into cell (inward K conductance)or transcellular shift of K into cells ---> Hypokalemia (musc. Weakness) SE of β2 overstimulation Lipolysis  Vasodilation (renal vasodilation - inc. filtration so GFR is inc. ---> diuresis) Loss of peristalsis ---> nausea and vomiting (stretching of stomach stimulates irritant chemicals that may cause vomiting) Levo-dopa ---> causes nausea and vomiting (SE)Behavior and perception regulationModulation of motor activities (shuffling gait, rigid if low Dopamine)

3. SYMPATHOMIMETIC DRUGS (adrenergic agonist)a. Direct acting adrenergic (directly stimulate the receptors)b. Indirect (produce a sympathetic response by inc. levels of cathecolamine)c. Centrally-acting sympathomimetics

A. DIRECT ACTING SYMPATHOMIMETIC ADRENERGIC AGONIST -directly act on receptor

i. Non-selective agonists – stimulate more than 1 general receptor (alpha + beta +/- D) Natural Cathecolamines (NE, Epi, Dopamine)

Pharmacodynamics: greater affinity for β than for α. (B = β ; A = α)LOW DOSES ---> stimulate BHIGH DOSES ---> stimulate B + stimulate A (e.g. Epi: B1 = B2 (low dose) A1 (high dose) ; NE: B1 A1 ; Dopamine: D1 B1 A1 **[NO NATURAL A2 AGONIST, ONLY EPI STIM. B2)**

Pharmacokinetics: very poor PO bioavailability thus routes are parenteral (IV, SQ), inhalational

Poor oral bioav. - they are very acid labile, very extensive First Pass effect, can limit their own absorption (THEY'RE ALL A1 AGONIST thus they are all vasoconstrictors less perfusion)

Metabolism: (1) COMT (2) MAOCommon metabolite: VMA- vanillyl mandelic acid (3-methoxy-4-hydroxy-mandelic acid) - important in Dx of Pheochromocytoma (adrenal medulla)

Clinical Uses of Cathecolamine: Epinephrine (Adrenin®, Epicaine® - with Lidocaine) - 1st

line cardiac stimulant (1st choice in Advanced Cardiac Life Support - use of drugs and machine that introduce electric shock) [1-3 mg every 3-5 mins (give it until Px is revived) IV]

a. Anaphylactic shock / anaphylaxis, and anaphylactoid reaction [0.3-0.5 mg SQ every 15-20mins up to 3 doses] anaphylaxis / anaphylactic shock and anaphylactoid – there is excessive histamine release from cells but anaphylaxis & anaphylactic shock are IgE mediated(allergy); anaphylactoid - NOT allergic/IgE mediated (can be a direct effect of opioids)

NOTE: additional benefit of Epi - stabilize mast cell membrane (thus prevent further release of histamine)

b. Local vasoconstrictor given with local anesthetic (lidocaine) dec. systemic absorption of the anesthetic

c. Mx of glaucoma [Dipivefrin (Alcon®)- pivalic ester derivative of Epi and is hydrolyzed in aqueous humor to release Epi. The addition of pivaloyl groups to the adrenaline molecule enhances its lipophilic character and as a consequence, its penetration into the anterior chamber. Dipivefrin hydrochloride is converted to adrenaline inside the human eye by enzyme hydrolysis. The liberated adrenaline, an adrenergic agonist, appears to exert its action by decreasing aqueous production and by enhancing outflow, thus lowering intra-ocular pressure.]

Norepinephrine (Inotrop®, Levolin®, Levophed®, Norepin®, Norphed®) - 1st line inotropic in the mx of septic (infection) shock (hypotension that does not resolve or improve with IV fluid) route: IV infusion

Dopamine (Cardiofast®, Dokard®, Dopamax®, Myocard®) - route: IV infusion

Dose Effects

1-3 mcg/kg/min Stimulate D1 receptor renal vasodilation (inc GFR ) ---> diuretic

2-5 mcg/kg/min Additional B1 stimulation inotropic effect

>/= 5mcg/kg/min

Additional A1 stimulation vasoconstriction

Use: Mx of septic shock, cardiogenic shock(hypotension due to cardiac problem), acute heart failure that are complicated by oliguria (<500mL urine in 24 hrs) /anuria (<50mL urine in 24 hrs) /low GFR

Common Toxicity of Cathecolaminesa. B1 overstimulation ---> tachyarrhythmiasb. A1 overstimulation ---> peripheral vasoconstriction ---> digital

necrosis

ii. Selective - stimulate 1 general type (alpha or beta or D)**almost always synthetic**

1. B-nonselective agonist - selective for B but does not choose bet. B1 and B2

Isoproterenol - synthetic catecholamine; alternative inotropic IV infusion for shock states or acute Heart failure

Historical use: bronchial asthma (1st drug for bronchial asthma to become available as metered dose inhaler) SE: tachyphylaxis (rapid development of tolerance) to B2 but not to B1 effect therefore Px keep on inc. dose Px died earlier due to B1 overstimulation (tachyarrhythmia) that’s why now, ots only used for its B1 effect

2. B1 selective agonist Dobutamine (Cardomin®, Dobuject®, Dobulex®, Dobutrim®) - IV

infusion ; 1st line drug in Mx of cardiogenic shock and acute HF3. B2 selective agonist

Tocolytics - ritodrine, isoxsuprine (Duvadilan®, Duvaprine®, Isoxilan®), terbutaline (Bricanyl®, Bricalin®, Pulmonyl®, Pulmolin®, Terbulin®) - control premature labor

Mx of bronchial asthma (and sometimes COPD)1. SABAs - short acting B2 agonist - 1st line

bronchodilators in acute asthma attacksSalbutamol (US - albuterol) ; terbutaline,

metaproterenol,pirbuterol (3-4 hrs)Route: inhalational (metered dose inhalers MDI) whatever device you use, there is no advantage, they all have the same effect; P.O 2-3 tabs per day.; Terbutaline only – SQ

Salbutamol - Activent®, Ventolin®, Combivent® and Duavent® (+ Ipratropium), Pulmovent® (+ guaifenesin) ; Metaproterenol - Alupent® (NA), Pirbuterol - Maxair® (NA)

2. LABAs - long acting B2 agonist - Alternative controllers in bronchial asthma

Salmeterol (MDI), formoterol (MDI), bambuterol – PO (12 hrs or more)

Recent recommendation: Px should be removed from LABAs due to inc. hospitalizations and death (but ok pa din for COPD)

Salmeterol - Salmeflo®, Seretide® (+ fluticasone in diskus), Formoterol - Atock®, Foradil®, Symbicort® (+ budenoside)

Other uses: Adjuncts in the Mx of hyperkalemia (to make K+ go into

cell) Terbutaline - Mx of symptomatic bradycardia (has more

significant B1 effects than the other - hindi sila pure B2 ha, preferred lang, pero meron pa din, may ratio lang - binding affinity is greater in one receptor over the other

SE: tachycard, palpitations (augmented by other agents with inotropic or chronotropic activity) ; hypokalemia (muscle weakness), tremors, tolerance (fenoterol never given as single agent)

4. A1 selective agonist - hypertensive agentsPhenylephrine [Bioflu®, Neozep® and Decolgen Forte®(+ chlorphenamine and paracetamol), No drowse Decolgen (no chlorphenamine) Dimetapp® (+ Brompheniramine), Tuseran Forte® (Dextrometorphan paracetamol)], propylhexedrine (Benzedrex®, Obesin®) both NA, methoxamine, oxymetazoline (Drixine®), tetrahydrozoline (Tyzine® NA), Xylometazoline (Otrivin®), [Eye-mo red eyes® and Visine refresh® - Tetryzoline]

Effects: vasoconstrictionRisk: Urinary retention Clinical uses:

nasal decongestants (colds) - Dimetapp®- PPA replaced by PE; Decolgen® Neozep® etc. (PO or intranasal)

Mx of hypotension (IV) Local vasoconstrictors (SQ) together with local anesthetics Ocular decongestants - eye redness Methoxamine - stimulate few A1 receptors in the heart Mx of

arrhythmiaSE / Toxicities:

Systemic agent (PO / parenteral) exacerbate HTN due to vasoconstricting effect - elicit Hx of

HTN from Px - avoid if Px has Hx of HTN and if with concurrent use of MAOi (remedy: intranasal)

Precipitate urinary retention in Px with BPH (remedy: intranasal)

Tolerance - as nasal decongestant given only for nmt 5 days (beyond 5 days, decongestant effect is lost)

Nasal spray Rhinitis medicamentosa (rebound congestion / rebound

hyperemia) when intranasal A1 agonist is used beyond 3

days) you give vasoconstrictor to reduce space and permit air but in rebound casodilation, blood vessels will dilate even more. Rebound - worse than the original. Congested b.v are dilated, mucus narrow down passage way so give vasoconstrictor but beyond 3 days, may tolerance so b.v will dilate even more.

5. A2 agonistClonidine - Catapres® (apraclonidine - “Iopidine” NA, brimonidine - Alphagan®, Combigan® (+ timolol) ; methyldopa (Aldomet®, Dopamet®) ; guanfacine (Tenex® NA), guanabenz (Wytensin® NA)

Effects: presynaptic CNS A2 receptorsSE: sedation, depression (for sedation - practical note – don’t give them

to Px with occupations requiring full mental alertness. For pilots, the only drugs allowed for allergy are Loratadine and Fexofenadine) (for depression - do not give to Px with Hx of depression)

Common clinical use: Mx of HTN - hypotensive agents / anti-HTN

i. Clonidine - active drug by itself (Route: PO, IV, Intranasal)PO and IV effects: stimulation of postsynaptic A2 in the peripheral b.v. vasoconstriction (when in systemic circulation) -initial but transient response ; Stimulation of presynaptic CNS A2 receptors vasodilation(when in brain) cross BBB - final longer lasting effect. You see both but at different times. So in the product inserts, it should be indicated: may initially cause transient inc. In BP

Clinical Uses: Alternative in Mx of HTN - useful in HTNsive crisis

and Mx of HTN in Px on hemodialysis (practically non-functional kidneys machine clean blood – directly. But the drug is in the blood - removed also in the blood. But clonidine’s anti-HTN effect is in the brain so you could still give it :) and you do not hemodialyse the brain. Ahahaha. So for Px on Hemodialysis, give a drug that will act not on the b.v since they will just be removed. Give a drug that will control BP areas in the brain.

Nasal spray (local effect) - nasal decongestantRelated drugs: apraclonidine, brimonidine (act only on nasal mucosal bv)

Alternative in Mx of ADHDSE: will talk about this later

** Clonidine-withdrawal-induced-rebound HTN (even worse than untreated state, higher BP)

- Can occur even in just 1-2 missed doses- Remedies: simply re-institute clonidine (drink

missed dose) ; give other drugs - Labetalol ;

give Na Nitroprusside IV infusion if Px goes into HTNsive crisis

ii. Methyldopa - alpha-methyl-DOPAMOA: prodrug cross BBB in the brain =

metabolized to yield active drugMetabolism in the brain: α-Methyl-DOPA ---DOPA decarboxylase---> α-methyl Dopamine ---Dopamine-β-hydroxylase---> α-methyl NE [which is the active drug, it is a false NT (looks like NE which can stimulate A1 and B1 but NOT A2 receptors) but since this is a false NT, it has NO A1, NO B1 but HAS A2 effect]

Clinical Use: Mx of HTN in pregnancy (very few anti-HTN drugs

can be given to pregnant women) but NOW, Nifedipine, hydralazine, labetalol are also used for HTN (pre-eclampsia, eclampsia, gestational HTN, chronic HTN in pregnancy)

SE: Sedation, depression (of course!) Hepatotoxicity at doses > 2g/day (limit dose) Positive Coombs test - indicate presence of Ab that

can cause hemolytic anemia - can be caused by methyldopa and pens (immunohemolytic anemia – associated with pens)

6. D1 - selective agonistFenoldopam (Corlopam® NA)

Effect: vasodilator (IV) esp. in abdominal vesselsUse: adjunct or alternative in Mx of HTNsive crisisCommon SE: diuresis and natriuresis (but not that common)

B. INDIRECT-ACTING SYMPATHOMIMETIC / ADRENERGIC AGONISTEffect: Inc. in conc’n or level of NE at the cleft

i. Re-uptake inhibitor - inhibits the mechanism of loss of NE from cleft [TCA, cocaine, NRI]

ii. Releasers – stimulate exocytotic release of NE [amphetamine, ephedrine]

Ephedrine - "ma huang"Dual MOA

Direct receptor agonism at the A1, B1, and B2 (nonselective) Stimulate release of NE into the cleft (more significant mechanism)

Clinical Use: Nasal decongestant - involves direct application into the nostrils

(ephedrine sol’n) Mx of acute Hypotension esp. during surgery (IV bolus)

SE: Exacerbate HTN - risk of HTNsive crisis in Px on MAOi (Contraindicated

even as nasal decogestant) Risk of tachyarrhythmia Palpitations

Illicit use: performance enhancer and fat burner

C. CENTRALLY-ACTING SYMPATHOMIMETICSAmphetamine (methamphetamine), methylphenidate/mephenidate (Concerta®, Ritalin®), phentermine (Duromine®), phenmetrazine (Preludin® NA), PPA = phenylpropanolamine (Disudrin®, Sinutab Extra Strength ® (+ Chlorpheniramine maleate paracetamol)

Clinical Use: Mx of Attention deficit Hyperactive disorder (ADHD)

[DOC: methylphenidate ; alternative: amphetamine - can cause adult onset ADHD, clonidine, TCAs, SSRI]

Mephenidate MOA: unkown, proposed MOA: release more NE until stores are depleted NE levels will drop

Anorexiants / appetite suppressants - 'dieting pills' [phentermine, phenmetrazine] Ionamine - phentermine in different dosage forms (ion exhange resin)

Mx of narcolepsy [amphetamine, phentermine]SE:

Risk of addiction (they are ‘uppers’) amphetamine - most addictive (US - ADHD secondary to addiction)

PPA - inc. hemorrhagic stroke in young women (used as dieting pills) Phentermine - inc. risk of primary pulmonary HTN in young women (due

to dieting pills) - will die in 2-3 yrs when already symptomatic

4. SYMPATHOLYTICS = ADRENERGIC ANTAGONISTa. Alpha-blockers (A-adrenergic antagonist)b. B-blockers (B-adrenergic antagonist)

 a. ALPHA BLOCKERS

Effects: Vasodilation Relieve urinary retention

Types:i. Nonselective A-blockers - block both A1=A2

a. Irreversible: Phenoxybenzamine (Dibenzyline® NA)b. Reversible: Phentolamine (Regitine®)

ii. Selective A1-blockers (-zosin) – Prazosin (Vasoflex® NA), Doxazosin (Alfadil XL®), Alfuzosin (Xatral®, Fozal®, Profuzosin®), Terazosin (Hyzin®, Hykor®), Tamsulosin (Harnal®, Prozelax®, Pimax®)

iii. Selective A2-blockers - Yohimbine, Rauwolscine or α-yohimbineClinical Use:

Mx of HTN inPx with Pheochromocytoma Mx of Sx in Px with Raynaud's syndrome Mx of HTN and urinary retention in BPH Phenoxybenzamine - Mx of Sx of Carcinoid syndrome Phentolamine - Mx of erectile dysfunction (injected directly to penile shaft)

** while Viagra® & Andros®- Sildenafil citrate, Cialis® Tadalafil, Levitra®Vardenafil. All are PDE-5 inhibitors - PO**

pheochromocytoma - hypersecretory tumor or hyperplasia of adrenal medulla excessive release of NE & Epi (NE > Epi kasi hindi na nakoconvert si NE to Epi, narerelease na agad)

Clinical manifestations: Hypersympathetic state (paroxysmal HTN, tachycardia, palpitations,

nervousness, inc. hostility (rare), sweatingDiagnosis:

Radiographic = MRI or CT Scan (showing adrenal medulla or tumor) Biochemical = demonstrate excessive conc’n of catecholamines -

check urine or serum VMA assayManagement of HTN (there is proper sequence of Tx)

Give A-blocker first then add a B-blocker If reversed (B-blocker before A-blocker): you will worsen HTN

NE 100 mole. 70B receptors

  70A receptors

They will all go up to B receptors first (higher affinity dito), so 30 na lang pupunta sa A.**if mauna A, 70 punta agad sa A thus vasodilation right away kasi blocked na si vasoconstricting effect ng A1. If sabay si A at B, ibablock si B agad, so may 30 lang na punta sa A, thus may vasoconstriction pa din, hindi kasi lahat blocked.Choice of A-blockers: Phenoxybenzamine, Phentolamine, A1-blockersBlocking A2 receptors will worsen pheochromocytoma (since vasodilating effect is blocked so worse HTN)

Raynaud's syndrome - digital vasospasm in response to a cold environmentIf (+) pain = (+) ischemia ongoing need to treat: vasodilators ; if mag-infarct na necrosis (irreversible)

Tx: A-blockers, CCBs Carcinoid syndrome - malignancy or CA involving enterochromaffin cells (storage

sites of serotonin - 90% of all serotonin) of the intestines. There is hyper secretion of serotonin

Clinical Manifestation: Flushing Watery diarrhea Severe HA

Can’t be operated on – this is already malingant if symptomaticTx: control serotonin Sx (palliative treatment - symptomatic relief na lang)

5-HT antagonist phenoxybenzamine - has 5-HT blocking effectSE:

A1 blocker - first dose phenomenon: orthostatic / postural HTN + syncope (transient loss of consciousness)Seen with the very first dose, any sudden inc. in dose and concurrent use of other anti-HTNsiveRemedies: give all doses at bedtime (Px will not lose consciousness because he is aready asleep) ; start low go slow; avoid use of other anti-HTNsive (A1 blocker is the DOC for HTNsive Px with BPH) 

b. B-blockers

Classification:i. Based on selectivity

1. Nonselective B - the rest of olols and alols are here2. B1 selective = cardio selective BB (alols and olols)

Bisoprolol (Concore®, Ziac® (+ Hydrochlorothiazide)), Betaxolol (Betoptic®, Kerlone®, Oxol®)Esmolol (Brevibloc® NA) – shortest acting so given as IV onlyAcebutolol (Sectral®NA, Prent® NA), Atenolol (Tenormin®, Tenoretic® (+ Chorthalidone)Metoprolol (Neobloc®, Angimet®, Cardiotab®)

NOTE: all BBs (cardioselective, nonselective) are generally CI in BA and COPD (they still have an effect on the alpha receptor even if they have preferential binding for the Beta receptor)

ii. Based on intrinsic sympathomimetic (agonist) activity = partial agonist = mixed agonist-antagonist

Carteolol (Mikelan®)Labetalol (Normodyne®NA, Trandate® NA)Acebutolol (less common A more common si atenolol)Pindolol (less common P more common si propanolol) (Pyndale®, Visken®, Viskaldix® (+ clopamide))

Advantage: less associated with rebound tachycard./HTN when withdrawniii. Based on membrane stabilizing activity = local anesthetic effect = quinidine-

like effect (class IA antiarrhythmic - Na channel Blockers)PindololAcebutololLabetalolPropranolol (Inderal®)Metoprolol

Disadvantage: cannot be given as topical opthalmic drops (with local anesthetic effect foreign bodies not recognized due to anesthesia ulceration and infection of cornea)

iv. Based on the presence of alpha-blocking activity Mixed A-B blockers (e.g. Labetalol &Carvedilol (Betacard®, Cardipres®,

Carvid® Xicard®, Psicardiol®)

Clinical Uses: First line drugs for HTN esp. useful if with prior Hx of MI

MOA: i. MAJOR MECHANISM -Ability to block B1 receptor in JG

apparatus dec. in renin releaseii. Blockade of B1 in the heart dec. in inotropic activity

Mx of Angina PectorisDOC in long-term Mx of CSAP (chronic stable angina pectoris)

Mx of arrhythmias (Propranolol, Esmolol, Acebutolol) Mx of stable CHF - do not require ICU admission anymore (if ICU - unstable) ;

Px have responded very well to at least 2 weeks of anti-CHF Tx regimen Add on Tx, given at very low doses ONLY THREE DRUGS FOR CHF: Metoprolol (2.5-10mg/day)

**for HTN, use 50mg/day**, Bisoprolol, Carvedilol Mx of glaucoma

Mx of sympathetic Sx of hyperthyroidism (with additional MOA: blocks peripheral conversion of T4 to T3)

Prophylaxis for migraine Familial tremors / stage fright / performance anxiety

 SE: Mask Sx of hypoglycemia (autonomic Sx) - tachycardia., palpitations,

diaphoresis (cold sweats), tremors - all due to Epi in response to hypoglycemia epi goes up ** NOTE: counter regulator hormones in response to hypoglycemia -(1) Epinephrine (responsible for initial manifestations of hypoglycemia) ; (2) glucagon, (3) growth hormone, (4) cortisol [first 2 are fast acting, latter 2 are slow acting] CNS phase : coma & death

UNFORTUNATELY: BB BLOCK THESE SX! So Px will feel sleepy then he dies

CAUTION: advise DM Px on hypogly. therapy to monitor blood sugar more frequently if they are on BBs (BBs are very helpful for DM Px in controlling BP)

Bradycardia and heart block Dyslipidemia Hyperuricemia Withdrawal of therapy: rebound tachycard./HTN if abruptly withdrawn

[REMEDY: taper dose over 10-14 days before stopping Tx] - less risk if you use PAL – Pindolol, Acebutolol, Labetalol

 CI: i. canadian and australian guideline: should NOT given to age > 65 yrs ;

HR < 60 ; with pre-existing heart blockii. Current Tx of a non-DHP CCB (diltiazem, verapamil ---> same affect na

kasi sila)iii. Unstable CHF (CHF with ongoing exacerbation ; CHF Px not yet

stabilized on conventional Tx)iv. Reduced exercise tolerance

C. PARASYMPATHETIC DRUGS1. Biosynthesis2. Receptors, location, response3. Parasympathomimetics / cholinergic agonist4. Parasympatholytics / cholinergic antagonist

1. BIOSYNTHESIS OF Ach:Location: in all preganglionic fiber (Symp at Parasymp) ; parasym postgang fiber ; somatic nerves ; CNS (brain)Steps:

Active uptake of choline into the presynapse - Rate-limiting step (slowest)

Can be inh. by hemicholiniums Formation of Ach (single step metabolism)

Choline + acetyl CoA ---Choline acyl transferase or ChAT---> Ach Vesicular uptake of Ach (at the presynapse) - Ach molecules are concentrated

within vesicles (each vesicle can contain 10k-50k Ach molecules)

Can be inh. by Vesamicol Quantal release of Ach into the cleft (quantal - millions of Ach being released

at any given time)Can be inh. By Botulinum toxin / botox

FATE OF Ach AT THE CLEFTo Can bind to postsynap receptorso Metabolism by Acetylcholinesterase (AchE) - (most important fate) ---> highly

efficient (that's why you need quantal release of Ach)Ach ---AchE---> choline + acetate

CHOLINESTERASES:a. Acetylcholinesterase - true cholinesterase = RBC cholinesterase ; Very

specific for Achb. Butyrylcholinesterase - Pseudo cholinesterase = PLASMA cholinesterase ; not

specific - can act on any ester except Ach

2. Receptors, Location, Response

Receptors Location Response

1. Muscarinici. M1

 ii. M2

  

iii. M3 (Gq linked)                  

 Nerves that supply gastric glands (branches of vagus nerve CN10)Nerves that supply the heart (branches of vagus nerve) Smooth muscles

Eyes (circular musc. of pupils)

Eyes (ciliary muscles) 

Bronchial s.m. GIT (walls) GIT (sphincters)

Urinary bladder (detrussor muscle)

Urinary bladder (sphincter and trigone)

 Gastric acid secretion 

Bradycardia, (-) dromotropism(slow rate of conduction across AV node [vagotonic response] Pupilloconstriction (miosis)Contraction = accommodation (ability to recognize objects that are near your face)Bronchospasm / bronchoconstrictionContraction (thus lead to peristalsis)Relaxation = opening (thus lead to peristalsis)Contraction (thus lead to urination)

Relaxation = opening (thus lead to urination)**diuresis – inc. urine volume not pass out urine or inc. excretion of urine. Passage of urine is micturition ; enuresis is incontinence or involuntary passage of urine**

 2. Nicotinic (N)

i. Nn (neural)

ii. Nm (muscular – this is somatic not autonomic)

 

Exocrine glands Lacrimal Salivary Bronchial GIT Eccrine sweat gland

 

 Ganglia, CNS (both found in Symp &Parasymp)NM endplate

 SecretionLacrimationSalivationInc. bronchial gland secretionInc. GIT secretionSweating   Stimulation (may it be Sym/Para)

Skeletal m. contraction

 3. PARASYMPATHOMIMETICS = CHOLINERGIC AGONIST

a. Direct-acting Cholinergic agonists - stimulate directly cholinergic receptorsi. Choline ester

Acetylcholine (M, N) Bethanechol / Urecholine Butanechol (M) Methacoline (M, N) Carbachol (N, M)

ii. Cholinergic alkaloids Pilocarpine (M) Muscarine (M) Nicotine (N) Lobeline (N)

 b. Indirect-acting cholinomimetic - do not stimulate receptors BUT can inc. conc’n

of Ach in the cleftMOA: inh. AchEsterase [anti-cholinesterases]

i. Short-acting anti-cholinesterase - duration of action does not exceed 30mins (15-20 mins on ave.) Chemical structure: amino alcohols Inhibition: reversible

e.g. Edrophonium (Tensilon®)ii. Intermediate-to-long-acting (2 hrs up to less than 24 hrs - 2<X<24)

Chemical: organocarbamates (carbamyl esters) Inhibition: reversible

e.g. Neostigmine (Prostig®, Prostigmin®), Physostigmine (from Calabar bean Physostigma venenosum), pyridostigmine (Pyrinon®), ambenonium (Mytelase® NA), demecarium (Humorsol® NA)

iii. Very long-acting agents - duration is days to weeks Chemical: organophosphates Inhibition: depends on duration of exposure

1st 24-48 hrs ---> potentially reversible

> 24-48 hrs -----> definitely Irreversible (due to "aging" of PO4 bond which is a covalent bond - it is like forming a new molecule)

e.g Ecothiophate, Malathion & Parathion (both seen in insecticides), IsofluorophateSarin, Tabun, Soman (nerve gases for chemical warfare)

iv. Miscellaneous agents - useful for AD (alzheimer's dementia)e.g. Rivastigmine (Exelon®), Tacrine (Cognex® NA),

Donepezil (Aricept®, Donezel®)

Clinical Uses of cholinergic agonists: Dx and Mx of Myasthenia Gravis Mx of neuromuscular blocker toxicity -useful to counteract effect of curare

derivatives (atracurium etc.) respiratory paralysis o Edrophonium - more commonly used in clinics (curare effect is

short lived, Neostigmine for arrow poision! yey! ) but this is long acting so Px may develop cholinergic crisis. That’s why edrophonium is used as antidote since it is only short-acting

Mx of glaucomao Drugs: ecothiopate, carbachol

Mx of non-obstructive ileuso Pilocarpine (direct acting cholinergic alkaloid) combined with

physostigmine(indirect acting), bethanechol Mx of atropine poisoning (previously: physostigmine - 1980's)

1990's - higher risk for CNS effects than benefit by physostigmineNOW: Neostigmine (quaternary ammonium Peripheral agents), pilocarpine, Physostigmine no longer used in severe cases

If with seizure, give anticonvulsant (diazepam) Mx of urinary retention in BPH

o Bethanechol = urecholine Smoking cessation

o Nicotine, lobeline (pharmacognosy answer) Mx of AD

o Rivastigmine, Tacrine, Donepezil

Myasthenia Gravis Autoimmune disease characterized by presence of Ab that are directed vs.

Ach receptors - "anti-ACR antibodies" ACR that are commonly destroyed are the Nm receptors Associated with hyperfunctioning/tumor of thymus gland (big when young,

responsible for maturation of Tcell/T lymphocyte) SSx: progressive muscle weakness

Initial: late afternoon drooping of eyelids (subject to fatigability) late afternoon weakness (can’t seem to rise from a seated position) generalized muscle weakness (paralysis)

Final: paralysis of the diaphragm (put on mechanical ventilator to survive) Dx:

o Immunologic - documenting/ assaying presence of anti-ACR Ab

o Pharmacologic - Tensilon® test (short lived improvement in muscle strength): inject tensilon in a matter of minutes, she will regain strength 15-20 mins. eyelids droop again and can’t stand up again

NOTE: another use of Tensilon® in MG is to differentiate bet. CHOLINERGIC CRISIS and MYASTHENIC CRISIS

Now able to walk, move about etc. then all of a sudden weak again even on treatment, consider if (1) overtreating Px / cholinergic crisis OR (2) undertreatment / myasthenic crisis

If Px is weak and then becomes weaker with Tensilon® - Too much Tensilon® causes skeletal muscle contraction spasm weakness : OVERTREATMENTIf Px is weak then becomes strong with Tensilon® : UNDERTREATMENT

Tx: o Neostigmine, Pyridostigmine, Ambenonium - (Indirect cholinergic

agonist)o Immunosuppressants (prednisone at high dose)o Removal of thymoma or thymus remnants (thymic stripping)

Cholinergic SE and toxicities:o Diarrheao Urinationo Miosiso Bradycardiao Bronchospasmo Emesiso Lacrimationo Salivation & Sweating

Mx of Toxicities:o Primary Tx (DOC) for toxicities with ALL cholinergic agonist - Initial

Tx is Atropine (base treatment)o For organoPO4 poisoning ONLY - special Tx - when organoPO4 is

<24-48 hrs duration - Regenerator compounds: OximesPAM (pralidoxime) ; DAM (diacetyl monoxide) - but you still have

to give atropine

4. PARASYMPATHOLYTICS = CHOLINERGIC ANTAGONISTa. Anti-muscarinic = anticholinergic = atropine-like effects or SE

Prototype: anti-muscarinic all throughout = Atropine Effects due to M1 block- dec. in GIT secretion M2 block – tachycardia and (+) dromotropism Vagolytic effect

(remember vagotonic?) M3 block:

o smooth muscle s.m. relaxationo Eyes - mydriasis, Cycloplegia/loss of near vision (Blind as

a bat) Cycloplegia - relaxation/paralysis of ciliary

muscle move towards each other can

close canal of schlemm absolute CI: narrow-angled glaucoma

Ciliary muscles contract - move away from each other - open canal of schlemmCiliary muscles relax - move towards each other - close canal of schlemm

Glaucoma - problem is inc. in IOP due to inc. aqueous humor volume

may be overproduction (normal drainage) - angle is open or open/wide-angle glaucoma

problem in drainage (normal production) - narrow-angle glaucoma

Complication if given cycloplegic angle will close acute angle closure glaucoma (can cause blindness in 24-48 hrs retina will be impinged (there are many b.v here, as well as the optic nerve)

o Bronchi - bronchodilationo GIT - constipation & ileuso Urinary bladder - urinary retentiono Exocrine glands - dec. secretion (lacrimal, saliva, etc.) /

drying effect (Dry as a bone)Anhydrosis - absence of sweating (eccrine - thermoregulator)

Complication: hyperthermia / atropine fever (potentially fatal in children) – (hot as a hare / hot as hell)

Flushing / cutaneous vasodilation (so that heat will be released) - red as a beet

o CNS effects (atropine can cross BBB)CNS agitation, confusion, seizure, acute psychotic

reaction – (mad as a hatter) - give diazepamClinical Uses of Atropine

Topical: mydriatic-cyclopegic Systemic (IV): Mx of symptomatic bradycardia or heart block Mx of anti-Ach overdose (organoPO4) Given with diphenoxylate (opioid anti-diarrheal - can cross BBB

minimal euphoria, loperamide cant cross BBB) to minimize risk of addiction with diphenoxylate

e.g. 10 tablets they will experience the ‘alice in wonderland’ due to atropine toxicity so they will stop :) ahahahaha 

Other anti-muscarinics

1. CNS-actinga. Scopolamine

Sedative (dreamless sleep) Use: anti-motion sickness Historical use: obstetric anesthetic - "twilight sleep"

Scopolamine(sedative) + morphine(analgesic)b. Biperiden (Akineton®), Benztropine (Cogentin® NA), Trihexyphenidyl

(Artane® NA)Use: adjuncts in tx of parkinsonism; Mx of some Sx of EPS(extrapyramidal Sx) assoc. With anti-psychotic tx

2. Eyes - mydriatics-cycloplegicAtropine (Anespin®, Isopto Atropine®) - topical (effect lasts for 72 hrs), Homatropine (Lesopen®), Tropicamide (Mydriacyl®, Sanmyd-P® (+ Phenylephrine)), Cyclopentolate

Mydriatics: indicated to allow full exam of retina (if pupils are constricted, it will be hard to examine retina)

Cycloplegics - to relax ciliary muscle in the Mx of eye pain due to ciliary spasms (infections/inflammation)

CI: Px with narrow-angled glaucoma as mentioned a while ago

3. Bronchi = bronchodilatorsIpratropium Br - usually combined with salbutamol (albuterol in US) - Combivent®, Oxytropium, Tiotropium (Spiriva®)

Choice bronchodilator in COPD Alternative adjunct bronchodilator in BA

4. GIT and urinary bladdera. M1-selective blockers - useful for hyperacidity (adjuncts)

Pirenzepine (Gastrozepin® NA), Telenzepineb. M3-blockers - useful for GIT and urinary bladder conditions

Hyoscine-N-butylbromide (Buscopan®), Dicycloverine (Relestal®), Glycopyrrolate (Robinul® NA), clidinium (Librax® NA (+ chlordiazepoxide)), dicyclomine (Bentyl®), Methscopolamine (Pamine® NA)

Hypermotility disorders ---> abdominal cramps Urinary incontinence, abdominal colic

b. Anti-nicotinic - with specific group namesi. Neuromuscular blockers

Target receptor: Nm (these drugs act on somatic NS)a. Depolarizing ('stimulate') irreversible/non-competitive Nm blocker

e.g. Succinyl choline MOA: irreversibly STIMULATE Nm receptor

2 phases of effects Phase 1: continuous and tetanic skeletal muscle

contraction [cycle of contraction-relaxation] w/o relaxation (with succinyl choline, it’s just pure contraction, no relaxation) therefore, muscle contraction is INEFFECTIVE muscle fatigue and loss of Ca2+ ions

Phase 2: skeletal muscle paralysis (flaccid paralysis) because there’s no more Ca2+ to stimulate Contraction

b. Non-depolarizing reversible competitive Nm blockerMOA: directly INHIBIT Nm receptor skeletal muscle paralysis right away

e.g. Curare derivatives (from natural product L-tubocurarine)

2 classes: Isoquinoline structure (-curium): Atracurium

(Atracor®, Tracrium®), mivacurium Steroidal nucleus (-curonium): Pancuronium

(Pavulon® NA), vecuronium (Norcuron®)Clinical Uses:

Skeletal muscle relaxants during surgery (muscles should be retracted in abdominal surgery)Side Effects / toxicities:

Shared toxicity: diaphragmatic muscle paralysis- in case of prolonged paralysis - antidote: edrophonium (clinics)

and neostigmine (board exam) Succinyl choline

SE: muscle pain myositis or rhabdomyolysis (break down of muscles)

HYPERKALEMIA (cells burst/breakdown and so K will be released) heart may stop

myoglobinemia (myoglobin is toxic to renal tubules) = acute tubular necrosis (ARF)

lactic acidosis due to severe muscle contraction malignant hyperthermia = Neuroleptic (anti-psychotics)

Malingnant Syndrome **congenital defect in Sarcoplasmic Reticulum which is the one storing and providing Ca2+ that is required for muscle contraction massively release Ca when they are exposed to succinyl Ca released super super contraction muscle breakdown and metabolism body temp goes up (Fatal)

DOC: Dantrolene (Dantrium®) Alternative: Bromocriptine (Parlodel®) - dopamine agonistFor succinyl choline toxicity: Ca2+ supplement IV

Tubocurarine SE: anaphylactoid rxn (due to direct histamine releasing effect of

tubocurarine on mast cells) 

ii. Ganglionic blockersTarget receptor: Nn in the gangliaNon-specific (block both Sym and Parasym ganglia)

No longer used clinically due to non-spec. effectsHistorical use: Alternatives in HTNsive emergency cases

Hexamethonium, Mecamylamine (Inversine® NA), Trimethaphan camsylate (Arfonad® NA)

Effects: (mixed) Mydriasis, tachycardia, constipation, urinary retention (all

are parasym block) Vasodilation (sym block) anhydrosis (both para and sym

block)ALL TISSUES ARE DOMINANTLY INNERVATED BY THE PARASYMPATHETIC EXCEPT BLOOD VESSELS & SWEAT GLANDS