Pharmacology Exam 2 PP

8/13/2019 Pharmacology Exam 2 PP

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WPHARM EXAM 2


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3/79

What property o f LAs determine their distribution?

Amides: distribute rapidly, correlate c extent of perfusion (some fat seq

Esters: stay localized and are more rapidly metabolized

What are the esters?

Benzocaine, cocaine, procaine (all have one I in the name)

What are the amides?

Bupivacaine, lidocaine, prilocaine (all have two I in the name)

How are amides metabolized?

In liver via p450 system

How are esters metabolized?

Hydrolyzed in plasma by pseudocholinesterase

How ar e LAs excreted?

Via kidney

LOCAL ANESTHETICS


4/79

What Na channels do LAs prefer to bind to? Higher affinity for active and inactivated than rested channels

What factors will binding? Lower membrane potentials, more rapidly firing axons

What are the effects of Ca and K on the effects of LAs? Ca: membrane potential more rested channels antagoniz

K: depolarizes membrane more inactivated channels poten

How do nerves themselves affect LA actions? Fiber diameter: greater diameter = less effect

Firing frequency: greater frequency = greater effect

Fiber position: outside fibers first

What is the purpose of adding sodium bicarb or CO2 to L intracellular pH and intracellular drug concentration

LOCAL ANESTHETICS


5/79

When should vasoconstrictors NOT be used c LA? In the fingers or toes due to low perfusion

Where does LA instillation take place? Epidural or subarachnoid space

What is regional anesthesia? IV administration in limb c blockage of venous flow

Which Rx have a short duration of action? Procaine and chloroprocaine

Which have intermediate duration? Lidocaine, mepivacaine, prilocaine

Which are long-acting? Tetracaine, bupivacaine, etidocaine, ropivacaine

LOCAL ANESTHETICS


6/79

What are the results of LA CNS toxicity? Sleepiness, visual and auditory disturbance, tongue numbness, nystagm

fasciculations, tonic-clonic convulsions

What is the result of cardiovascular toxicity? Inhibition of Na and Ca channels arrhythmias, (-) inotropic action, v

Which LA does not have (-) inotropic effects and vasodilation? Cocaine: SNS tone HTN and arrhythmias

Which is the most cardiotoxic? Bupivacaine: binding to resting channels b roadened QRS

Which LA may cause a blood toxicity and what is the Tx? Prilocaine metabolite may cause methemoglobinemia

Methylene blue is used for Tx

Which LAs may cause al lergic rxns? Esters (rare c amides)

LOCAL ANESTHETICS


7/79

How is procaine (Novocain) metabolized? An ester that is metabolized by pseudocholinesterase

What is i ts duration of action? Short

What is the metabolite of procaine and its action? PABAinhibits action of sulfonamides

When is it used topically? It is NOT

What is the relative time of onset and action of tetracaine? Long-acting and slow onset of action (>10 mins)

When is it used? Spinal anesthesia and ophthalmologic use

What is tetracaines potency relative to procaine? 10X more potent, but also more toxic

LOCAL ANESTHETICS


8/79

What type of tetracaine preparation is used for spinal anesthes Combined c 10% dextrose to make it heavier than CSF

What type of preparation is used topically? 2% solution

What is benzocaine (Americaine) used for? OTC topically for sunburn, minor burns, and prur itis

When is cocaine used? Topical anesthesia of mucous membranes

What ANS effect does cocaine have? Blocks reuptake of catecholamines into nerve terminals (vasoconstricti

When should cocaine be used cautiously? Pts c HTN, CV disease, or thyrotoxicosis

What is the regulatory classification of cocaine? Schedule II controlled substance

LOCAL ANESTHETICS


9/79

What is the prototype amide c intermediate duration of action? Lidocaine

When is lidocaine preferred? Infiltration blocks and epidural anesthesia

What are its pharmacokinetic properties? Rapidly absorbed and is metabolized in liver by microsomal mixed-fu

(p450)

What is another use of lidocaine? Antiarrhythmic (given systemically)

When is prilocaine used? By injection, but NOT topically or for subarachnoid anesthesia

When should prilocaine be avoided? Cardiac or respiratory disease or methemoglobinemia

Prilocaine causes methemoglbinemia

LOCAL ANESTHETICS


10/79

How is methemoglobinemia reversed? Methylene blue

What is the duration of action of bupivacaine? Long

When is it used? Infiltration blocks and epidural anesthesia

What makes it stand out from other amides? Greater cardiotoxicity

What Rx resembles bupivacaine, but is less arrhythmogenic? Ropivacaine

How does its metabolism differ from bupivacaine? Less lipid soluble and cleared via the liver more rapidly (less adverse e

What are ropivacaines possible Rx interactions? Alfentanil, theophylline, fluvoxamine, cimetidine

LOCAL ANESTHETICS


11/79

What is dissociative anesthesia?

Cataleptic state c profound analgesia, amnesia, unresponsiveness, but lmay move

What Rx causes it? Ketamine

How is depth of anesthesia assessed? Observing reflex activity, reaction to stimuli, breathing, and BP

What IV general anesthetics are used? Barbiturates, benzos, propofol, ketamine, and opioid analgesics

What is the mechanism of action of the 1 st3 mentioned? Act at the GABAA receptor

What is the action of ketamine? Blocks NMDA receptors

What is the effect of inhaled anesthetics?

Hyperpolarize neurons to depress activity of CNS

GENERAL ANESTHETICS


12/79

How do inhaled anesthetics act on excitatory and inhibitory sy

excitatory transmission (inhibit nicotinic receptors and activate K cha inhibitory transmission (facilitation of GABA receptor)

What is the potency of inhaled anesthetics related to? Their lipid solubility

What are the stages of anesthesia? Inhibition of substantia gelatinosa in dorsal horn inhibition of senso

Blockade of small inhibitory neurons causes excitation

Loss of consciousness and reflexes (surgical anesthesia)

Medullary respiratory and vasomotor center depression

What are the effects on BP? due to vasodilation, cardiac depression, blunted baroreceptor reflex,

What are the effects on respiration? respiratory drive, gag/cough reflex, and LES tone

GENERAL ANESTHETICS


13/79

What are the CNS effects?

metabolism, but vasodilation causes cerebral blood flow and intracr

How do they affect body temp and why is it of concern?

Cause hypothermia that may post -anesthetic morbidity

What is a common postoperative Sx?

Nausea an d vomi ting

Which Rx is least l ikely to cause N/V?

Propofol

What Sx occur on emergence from anesthesia?

HTN and tachycardia (may result in myocardial ischemia)

Excitement: tachy, restlessness, crying, moaning, thrashing, shivering

What is used to Tx the excitement?

Opioids (meperidine for shivering)

GENERAL ANESTHETICS


14/79

What determines the concentration of anesthetic in a tissue?

Partial pressure and degree of solubility What factors determine the rate anesthetic gets into the brain?

Solubility of the anesthetic in blood and tissues

Concentration in the inspired gas

Pulmonary ventilation delivering the gas to the lungs

Loss of agent from blood to tissues in the body

What is used to express solubility of a gas? Blood/gas partition coefficient

What does this coefficient represent? The ratio of anesthetic in the blood to the inh aled gas when blood and l

pressures are at equilibrium

How does blood solubility affect rate of delivery to the brain? The faster the blood is saturated, the faster the delivery to the brain

The less soluble the Rx in blood, the faster it becomes saturated (more

GENERAL ANESTHETICS


15/79

What are the relative solubilities of nitrous oxide and halothan

Nitrous oxide (0.4 7): insoluble in blood = rapid onset Halothane (2.3): soluble in blood = slow onset

How can blood saturation and rate of induction be for a parti the concentration ( for maintenance)

How does ventilation affect the partial pressure of the gas in th ventilation [anesthetic] in blood

How can emphysema affect inhaled administration? Less transfer to blood slow induction and recovery

How does pulmonary blood flow affect induction of anesthesia flow from CO means more blood is available to be saturated c anest

will rate of induction

What happens in shock? CO is and ventilation q uicker induction

GENERAL ANESTHETICS


16/79

How does perfusion rate affect delivery of Rx to tissue?

High perfusion means Rx will enter tissue qu ickly and diffuse away quis turned off

What factors affect elimination of a Rx from tissue? Blood flow: fast flow = fast elimination

Solubility: low solubility = fast elimination

Why are combinations of inhaled Rx often used? Decrease concentration of each Rx and minimize side effects

What is used to describe the potencies of general anesthetics? Minimum alveolar concentration (MAC)

What is MAC? [anesthetic] in % in an inhaled gas mix that results in immobility in 50

exposed to noxious stimulus (analogous to ED50 )

How does age affect MAC? in elderly pt

GENERAL ANESTHETICS


17/79

How does MAC change as Rx are mixed?

It is additive (0.5 MAC of Rx -A and 0.5 of Rx-B = 1 MAC) How is MAC affected by adjunct IV Rx?

Decreased (opioids, benzos)

How does MAC relate to potency? Low MAC = more potent

High MAC = less potent

What is diffusion hypoxia? N2O is not very soluble in blood. When administration stops, large amo

alveoli and expand lung volume to crowd out O 2

How is this avoided? Give 100% O2after discontinuing anesthesia

What is the second gas effect? Addition of 2nd gas (N2O) will partial pressure of the other gas in the

delivery and speed induction

GENERAL ANESTHETICS


18/79

What is the MAC and blood/gas of halothane?

MAC = 0.75, blood/gas = 2.54 What is i ts relative time of induction and activity?

SLOW induction, rapid awakening used for maintenance

How does halothane affect the heart? Depresses myocardium and output

Also sensitizes heart to catecholamines arrhythmias

What are other effects? Relaxes uterus, laryngospasm, renal blood flow and urine output

What are serious complications c halothane use? Hepatitis: more often seen c Hx of use and middle-age obese women

Miscarriage (seen c repeated exposure)

What can happen c administration of halothane + succinylcholi Malignant hyperthermia (all inhaled do this, but halothane is the wor

GENERAL ANESTHETICS


19/79

How is malignant hyperthermia treated?

Dantrolene What is the MAC and blood/gas of enflurane?

MAC = 1.63, blood/gas = 1.9

How does its induction compare to halothane? More rapid

What side effects may occur post-op c enflurane? N/V, shiver ing

What can happen at high concentrations? CNS stimulation and seizure

How can it affect the kidneys? Production of fluoride during metabolism may cause reversible kidney

What is the MAC and blood/gas of isoflurane? MAC = 1.17, blood/gas = 1.46

GENERAL ANESTHETICS


20/79

What is the most widely used inhaled anesthetic and why

Isoflurane, due to its low toxicity What is a drawback?

Pungent odor so not good for induction (also expensive)

What advantages does its low blood/gas coefficient confe Induction and emergence rapid c ability to adjust depth of anes

What indicates depth of isoflurane anesthesia? BP and respiration, HR

Why is it often used in neurosurgery? Less dilation of cerebral vasculature than halothane and cereb

O2consumption

Which inhaled anesthetic has the least effect on the heart Sevoflurane

GENERAL ANESTHETICS


21/79

What is the MAC and blood/gas of sevoflurane?

MAC = 1.8; blood/gas = 0.69 What are its relative induction and recovery times?

Both are rapid

What patients often receive sevoflurane? Those c CV disease and children (low airway irritation)

What is the MAC and blood/gas of desflurane? MAC = 6.60; blood/gas = 0.42

What type of surgery is it used for and why? Outpatient due to very rapid induction and emergence

What are its undesirable characteristics? Very pungent (not for induction), BP, profound respiratory dep

intracranial pressure

GENERAL ANESTHETICS


22/79

How can halogenated hydrocarbons cause liver toxicity?

Chlorine and bromine are removed generating a toxi c metabolite that mimmune response hepatitis

Repeated exposure can lead to induction of hepatic enzymes and formametabolites

Which can release fluoride ions that may cause renal toxicity?

Enflurane and sevoflurane

What is malignant hyperthermia? Rapid rise in temp and O 2consumption due to intracellular Ca causin

muscle contraction

Although rare, which Rx are most likely to cause it?

Halothane combined c succinylcholine

What is the Tx?

IV dantrolene

GENERAL ANESTHETICS


23/79

What is the MAC and blood/gas of nitrous oxide?

MAC = 104; blood/gas = 0.46 What are its effects?

Analgesia(not anesthesia), relaxation, euphoria

When is it used? Dental procedures and c other inhaled anesthetics to rate of induction

What must be done when nitrous oxide is terminated? Give 100% O2at first to prevent diffusion hypoxia

How else can it act in combo c other anesthetics? Reduces the amount of hypotension produced

What are its adverse effects? Chronic exposure may cause peripheral neuropathy , and megaloblast

When is it contraindicated? Do not use w/in 3 months of eye surgery where intraocular gas was use

GENERAL ANESTHETICS


24/79

What are IV anesthetics used for?

Induction of anesthesia When is thiopental contraindicated?

Porphyrias

What are the characteristics of midazolam? Ultrashort-acting benzo that causes sedation and anterograde amnesia

What is the most widely used anesthetic in the U.S.? Propofol

What is i ts mechanism? Facilitates GABA transmission

What makes it such a great anesthetic? Rapid induction and recovery (recovery is 10X faster than thiopental)

In what form is it given and what is the result of this? Given as an emulsion c albuminthat may cause anaphylaxis

GENERAL ANESTHETICS


25/79

What are the drawbacks of propofol?

Allergic rxn Profound respiratory depression

Reaction at site of injection (inject c lidocaine)

What is the mechanism of etomidate? Facilitates GABA transmission

When is it used? Induction of anesthesia in pt c risk of hypotension

What is the mechanisms of ketamine? Blocks NMDA receptors

What are its effects in the patient? Catatonic state, dissociative anesthesia, profound analgesia (not anes

What can happen on emergence from ketamine? Emergence deliriumbizarre dreams , hal lucinat ion, and psychosi s

GENERAL ANESTHETICS


26/79

How does ketamine affect other body systems?

Sympathomimetic, bronchodilation, very little respiratory de

What Rx can be given in a lollipop to children?

Fentanyl

What Rx class does it belong to?

Opioid

GENERAL ANESTHETICS


27/79

What are the endogenous opioids and their function in the brai

Enkephalinsdecrease pain Beta-endorphins pain an d cause euphoria

Dynorphin Amay sensitivity to pain in spinal cord

What is the function of nociceptin?

Antagonizes analgesia @ receptors, but may be involved in reward sy

What are the 3 opioid receptors and their roles?

Mu ()most important receptor for analgesia

Kappa ()some anesthesia and dysphoria

Delta ()may cause dysphoria

What are all opioid receptors coupled to?

G i/ oproteins that close voltage-gated Ca channels on presynaptic nerve

Results in NT release

OPIOIDS AND ANTAGONIST


28/79

In addition to closing Ca channels, what other channels do rece Open K channels causing hyperpolarization

What are the relative affinit ies of the opioids for the 3 receptors? : endorphins > enkephalins > dynorphins

: enkaphalins > endorphins and dynorphins

: dynorphins >> endorphins and enkephalins

How do opioids cause analgesia? both sensation of pain and reaction to pain while maintaining propriocept

pre ss ure sensa tions Does tolerance to analgesia develop?

Yes

How does morphine act different from other opioids in overdose? Morphine causes CNS depression , while others cause excitement and conv

Does tolerance develop to the sedative effects of opioids? Yes



29/79

How can opioids cause N/V in some patients?

Stimulate chemoreceptor trigger zone (CTZ) in brain What non-analgesic effect do opioids cause that is useful?

Antitussivesuppress cough

Which Rx are most effective at cough suppression and which hantitussive effect? Codeine and dextromethorphan are most commonly u sed

Meperidine (Demerol) has NO effect on cough

How do opioids affect respiration? Cause respiratory depression (more common in overdose) by the brai

response to CO2

This makes them useful in Tx of what? Pulmonary edema

When should opioids not be used? In pt c head trauma or intracranial pressure (causes intracranial pr e



30/79

What happens to the eyes c opioid overdose?

Miosispinpoint pupils are charac teristic What is the exception to this?

Meperidine does NOT cause miosis

How can the miosis be reversed? It is a parasympathomimetic effect so it is blocked by atropine

Does tolerance develop to miosis? NO

How do they affect muscles, when does it happen, and how is i May cause truncal rigidity that can interfere c respiration

Most common c highly lipid soluble Rx life fentanyl give IV

Prevented using neuromuscular blockers

What is the CV effect? May cause bradycardia (no direct effect), BP, and ort hostatic hypote



31/79

Which opioid may cause tachycardia?

Meperidine What are the GI effects of opioids?

Constipation, gastric motility, biliary colic, constriction of sphincter

What are the GU effects?

Antidiuretic effect as a result of renal blood flo w

sphincter tone = harder to urinate

ureteral tone = harder to pass kidney stone

How does it affect the uterus?

May prolong labor (meperidine does not)

What are the endocrine effects?

ADH, prolactin, and somatotropin

LH, FSH, cortisol, and testosterone



32/79

What may cause itching in some patients receiving opioids?

Causes release of histamine itching, flushing, sweating More common if they are injected

Treated or prevented c antihistamines

How can pain perception be changed c chronic use of opioids? Hyperalgesiathe sensat ion of pain is c chronic use

Tolerance develops to which effects? Tolerance to analgesia, sedation, euphoria, N/V, respiratory depression

Does NOT develop to miosis, constipation, seizures

When does addiction to opioids normally develop? If they are underprescribed. The goal is to prevent pain and not treat it

becau se this resu lts in stimulation of the reward syst em

What opioid withdrawal Sx are seen? Dysphoria, anxiety, insomnia, anorexia, vomiting, diarrhea

No t a li fe -th reatening wi thdrawa l



33/79

How can withdrawal Sx be reduced?

Use of clonidine or another opioid (methadone) What opioid antagonist is used in overdose?

Naloxone

Use c what antidepressants should be avoided? MAOIscause hyperpyrexic coma

Which opioids are the worst for this?

Meperidine and dextromethorphan How do opioids affect liver enzymes?

Inhibit CYP2D6

What are the consequences of this? Those c to little CYP2D6 or those taking SSRIs (also inhibit) m

experience sufficient analgesia c codeine derivatives



34/79

Which SSRIs are the most potent CYP2D6 inhibitors?

Fluoxetine and paroxetine When are opioids contraindicated?

Use of partial agonist c full agon istimpairs analgesia or causes withd

Pt c head injury, pregnancy, impaired pulmonary function, hepatic or re

What is the prototype opioid? Morphinestrong agonist of all opioid receptors

Although it can be give through many routes, what is the most

Injection due to high first-pass metabolism What is the standard therapeutic dose of morphine?

10mg SC or IM

How is it metabolized? Metabolized by CYP2D6: conjugated to morphine-6-g lucuronide (poten

morphine-3-glucuronid (major metabolite) eliminated in u rine (90%)



35/79

How does hydromorphone compare to morphine?

More potent Metabolites dont accumulate (good in renal dysfunction)

Less likely to cause histamine release

What are the characteristics of methadone? Long half life (15-60 hrs), stimulates receptors, blocks NMDA recept

inhibits NE/5-HT reuptake

What are its uses?

Useful in long-term control of pain (neuropathic, cancer) Maintenance Tx of addictsused to wi thdrawal Sx

When is meperidine (demerol) used? For very briefcourses in patients

How does it differ from other opioids? Anticholineric tachycardia, mydriasis ; no cough suppression



36/79

What are the Rx interaction of meperidine?

TCAs, SSRIs, MAOIs (phenelzine, selegiline, linezolid) serotonin s What toxicity can result from long term meperidine use?

Metabolized to normeperidinethat may cause seizures Caution in renal failure

What are the characteristics of fentanyl? Very lipid soluble and hig hly potent (high abuse potential)

Short duration of action and half-life

What are the moderate-to-strong agonists? Hydrocodone and oxycodone

What are the moderate agonists? Codeine and tramadol

What are the mixed agonist -antagonists? Buprenorphine and pentazocine



37/79

What Rx is often combined c acetaminophen?

Hydrocodone (+ acetaminophen = Vicodin) What is i t often combined c to reduce abuse potential?

Homatropine (in antitussive products)

How is it metabolized? By CYP2D6 to a metabolite c some analgesic effects

What is the result of this metabolism? Doesnt work well in pt on SSRIs (fluoxet ine, paroxet ine)

What is i ts scheduling classification? Schedule II (alone) or schedule III (c acetaminophen)

What is oxycodone often combined with? Acetaminophen (Percoset) or aspirin (Percodan)

How is it metabolized? CYP2D6



38/79

What is the schedule of oxycodone?

Schedule II How is codeine often used?

As a cough suppressant

What is responsible for its analgesic effects? Partial metabolism to morphine by CYP2D6

What is the schedule of codeine? Schedule II (alone), III (when combined), IV (in antitussives)

What is the mechanism of pentazocine? Kappa receptor agonist and receptor partial agonist

What is i t used for? Oral or IV administration for moderate pain

What advantage does it have? Less sedating, less respiratory depression, fewer GI Sx, low abuse pote



39/79

What is the result of pentazocine being a receptor agon

May cause dysphoria How might it act in a pt dependent on opioids?

May cause withdrawal due to partial agonist activity at recept

What is the schedule? IV

What is the mechanism of buprenorphine?

Partial agoniston and maybe When is it normally used?

To reduce cravings in opioid addicts

Why is it often combined c naloxone? Naloxone is not absorbed subl ingually, which prevents pt from

tablet in water and injecting solution



40/79

What is the mechanism of tramadol?

Weak agonist and inhibits reuptake of NE/5-HT What are the Rx interactions?

With antidepressants seizures

With MAOIs, SSRIs, TCAs serotonin syndrome

What is its schedule? Not a scheduled Rx

What is the mechanism of dextromethorphan? Blocks NMDA receptors and 5-HT reuptake

What is the DOC in opioid overdose? Naloxone

How is it administered? Must be injectedgive until pupils dilate



41/79

What is the duration of action of naloxone?

Short duration (2 hrs)may require multiple doses in long-actin How does naltrexone differ?

It is effective orally and is long acting (24 hrs)

How is it used? In recovering addicts to prevent them from getting high

Also decreases cravings in recovering alcoholics

What is its adverse effect? May cause liver toxicity c chronic use

How is nalmefene different? Similar to naloxone c slightly longer duration and less liver tox



42/79

What is physical dependence?

Behavior and physical Sx occur if drug is withdrawn DOES NOT indicate addiction

What is psychological dependence? Dysphoria and intense craving occur following the withdrawal

What are pharmacokinetic and pharmacodynamic toleranc Pharmacokinetictolerance due to metabolism of a drug

Pharmacodynamictolerance due to changes in receptor What are the reward pathways in the brain?

DA is released from ventral tegmentum to different centers: Nucleus accu mben s: + reward an d pleasure

Frontal cortex: decision making, impulse control

Amygdala: negative reward, fear

DRUG ABUSE

DRUG ABUSE


43/79

What is the mechanism of amphetamines? Sympathomimeticpromo te release of newly synthesized catecholami

presynap tica lly

What are the effects? : alertness, energy, anxiety, irritability; appetite

Psychosis may occur

How does smoking amphetamines affect the activity of the dru rapidity of action

What are the toxic effects? Neurotoxic: per si st en t damage to dopaminergic and serotoninergic neur

Fatalities due to cardiac toxicity

Dental problemsmeth mo uth

What kind of tolerance and dependence occur c meth use? Physical dependence occurs when brain creates a higher setpoint

Need more dru g to feel normal

DRUG ABUSE


44/79

DRUG ABUSE


45/79

What is the mechanism of nicotine? Activates nicotinic receptors in CNS and periphery 5-HT and DA

What are the peripheral effects? BP and HR, GI tone

What are the CNS effects? DA and 5-HT release have antidepressant and reinforcingeffects

DA may activate endogenous opioid pathways

Nico tinic ac tivat ion memory, lea rning, and al er tnes s

What type of dependence is seen? Psychological and physical

What are the Sx of withdrawal? Craving, irr itability, anxiety, restlessness

How does opioid tolerance develop? Receptor sensitization

DRUG ABUSE

DRUG ABUSE


46/79

What are the Sx of opioid withdrawal? Restlessness, fever, chills, vomiting, piloerection, mydriasis

How does naltrexone work? Blocks opioid receptors

What long-acting opioid is used for heroin and morphine addic Methadone

What Rx can suppress opioid withdrawal Sx? Clonidine

What is the mechanism of marijuana? THC binds cannabinoid receptor and DA

What kind of dependence develops? Psychological. Does NOT cause physical dependence

What are the adverse effects? Paranoia, testosterone levels, sperm produ ction and motility, bronch

DRUG ABUSE

DRUG ABUSE


47/79

What is the mechanism of LSD? Binds to 5HT

2A

or 5HT1C

receptors

What are the effects? Profound CNS effects c minimal peripheral actions:

Euphoria and visual hallucination

Labile mood, bad trips c severe anxiety, or flashbacks may occur

What type of dependence does it produce? NONE

What is the mechanism of MDMA? Stimulates release/inhibits reuptake of 5HT; some in DA/NE release

What are the effects? Peacefulness, empathy, feelings o f closeness

What are the adverse effects? Hyperthermia, dehydration , HR/BP, confusion, paranoia, panic

DRUG ABUSE

DRUG ABUSE


48/79

What happens c long -term MDMA use? Degeneration of serotonin neurons leads to memory loss and depression

What is the mechanism of PCP/ketamine? NMDA receptor an tagonist s

What are the effects of PCP? Profound analgesia , aggression, hallucinations , slurred speech, mydri

What are the toxic effects? Amnesia, coma, hyperthermia, rhabdomyolysis

What are the effects of ketamine? Dissociative anesthesiaf loating, high doses cause del irium and amn

What are the toxic effects? Tachycardia, hyperthermia, hallucinations, nystagmus

What are the effects seen c long term inhalant use? Toxicity of liver, kidney, peripheral nerves, bone marrow depression, a

DRUG ABUSE

DRUG ABUSE


49/79

What are the toxic effects of nitrous oxide?

Overdose results in unconsciousness and death

Chronic use can cause peripheral neuropathy

What effect do amyl and butyl nitrite have in the body?

Smooth muscle relaxants

What changes are seen?

Hypotension c reflex tachycardia

Euphoria, dilation of genital vessels for enhanced sexual ple

DRUG ABUSE

ANALGESICS AND


50/79

How are the eicosanoids made?

Long chain FAs are cleaved b y phospholipase A 2 arachidonic acid Arachidonic acid (AA) cleaved by multiple enzymes:

Cyclooxygenases (COX-1 and COX-2) thromboxane (TXA) and prost

Lipoxygenases leukotrienes

Other 2 routes not important for this lecture

How do COX-1 and COX-2 d iffer?

COX-1 is constitutively expressed , COX-2 is inducible

COX-2 is an immediate early response gene whose expression is stimulfactors, tumor promoters, and cytokines

Which is mainly responsible for prostacyclin synthesis in endo

COX-2

What type of receptor do the eicosanoids bind to?

G-protein 2nd messenger

ANTIINFLAMMATORIES

ANALGESICS AND


51/79

What 2 G-protein receptors do they act on?

Gs: cAMP protein kinase phosphorylate Ca pumps intracellular Ca

Gq: IP3 free intracellular Ca

What are the effects of TXA and PGE/PGI on smooth musvasculature, bronchial muscle, and GI? Vascular

TXA2mitogenic, vasoconstrictor

PGE/PGIvaso dilation by intracel lular Ca Bronchial

TXA and PGFcontract

PGE/PGIrelax

GI Both cause cramps (longitudinal muscle contracted, circular muscle

ANTIINFLAMMATORIES

ANALGESICS AND


52/79

What is the source of PGs in semen?

Seminal vesiclefunction unknown but PG levels are high in fertile m What is the function of PGE 1on male genitalia?

Relaxes smooth muscles in corpus cavernosum to enhance erection

What are the roles of PG in females?

PGE 2and PGF2have potent oxytocic actions that promote uterine cont

Soften the cervix by proteoglycan content and properties of collagen

How is it used pharmacologically? For 1st and 2nd trimester abortion and priming cervix for abortion

How do PGs affect platelets?

May enhance or inhibit aggregation

What effect do they have in the kidneys?

GFR by vasodilation

ANTIINFLAMMATORIES

ANALGESICS AND


53/79

What Rx will stimulate COX activity in the kidneys?

Loop diuretics

What Rx can diminish this effect?

COX inhibitors (like ASA)

What role doe PGs play in the ANS and CNS?

Produce fever

Inhibit the release of NTs

Facilitate release of TSH, ACTH, FSH, and LH

What effect do they have on bones

Facilitate bone resorption

What are the clinical uses of PGE 2?

Used for abortion, facilitating labor, and Tx of dysmenorrhea

ANTIINFLAMMATORIES

ANALGESICS AND


54/79

What are the clinical uses of alprostadil (PGE1)?

Given intracavernosal or as urethral suppository for Tx of ED Used in pediatrics to keep PDA open before surgery

What are the side effects caused by PGE 1used for ED Tx Penile pain and priapism

Trazodone also causes priapism

What are the uses of prostacyclin in the lungs? Produce vasodilation in primary pulmonary HTN

Sildenafil and Bosentan also used

What is latanoprost and its action? Analog of PGF2 uveoscleral resorption of aqueous humor

How is it administered? Topically in combo c timolol to produce complete additive syn

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What are the side effects of latanoprost? Blurred vision, conjunctival hyperemia, foreign body sensation, iridial

irritation What is the mechanism and use of zileuton?

Lipoxygenase inhibitoreffective in asthma

How is montelukast different? It is a leukotriene receptor inhibitor

What is the mechanism and use of misoprostol? PGE

1analogreduces gastric acid secretion in ulcers

Where does ASA act centrally to reduce fever and malaise? Hypothalamus

When is ASA not very effective? As an analgesic in non-inflamed painful conditions

How does ASA affect body temp? Lowers temp ONLY in febrile patients, but not normal patients

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ANALGESICS AND


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What is the ASA mechanism of action? Irreversible inhibition of COX-1and COX-2

How well does ASA cross placenta and the BBB? Readily crosses placenta and slowly crosses BBB

What is the plasma concentration of ASA? Low due to rapid hydrolysis

What Rx does it compete c for plasma binding sites?

T3, PCN-G, thiopental, bilirubin, phenytoin, naproxen How is it metabolized?

Low dose = 1 st order kinetics; high doses = zero order kinetics

Excreted mostly by the kidney

How can renal excretion be promoted? Alkalinization of the urine

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ANALGESICS AND


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What are the GI effects of ASA? GI upset, gastritis, ulcers, bleeding, inhibit secretion of mucus, acid p

What can be used to protect the stomach in long term ASA ther MisoprostolPG analogue

What are the adverse effects on the kidneys? Renal damage, acute renal failure, interstitial nephritis, nephrotic synd

How can ASA affect male fertil i ty? PGs in semen that are necessary for sperm motility. Subfertile males

adversely affected by ASA

What is a fatal dose that could cause acute salicylate poisoning 20 grams

What are the signs of salicylism? H/A, dizziness, tinnitus, thirst, hyperventilation, skin eruption, CNS pr

Salicylate jagmental disturbance resembling EtOH inebriation s euelation

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ANALGESICS AND


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What are the ASA hypersensitivity rxns? Skin rash, asthma, and anaphylactic rxns

What is Reyes syndrome? Cerebral edema in children c viral infection caused by ASA

What is the DOC in children? Acetaminophen

How do nonacetylated salicylates differ? Effective anti-inflammatories c less analgesic effects than ASA and no

COX inhibition

How does diflunisal differ? Salicylic acid derivative that is NOT metabolized to salicylic acid

What is the prototype COX-2 specific inhibitor? Celcoxib (Celebrex)

How does COX-2 inhibition differ? It is reversible

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ANALGESICS AND


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What are the adverse rxns of celecoxib? GI upset and ulceration (although less risk) , h ypersenstivity, risk of

What are the contraindications? GI disease, asthma, breast f eeding, pregnancy, renal failure, sulfonamid

hypersensitivity

What is the non-specific NSAID c the best side effect profile? Ibuprofen

What is the worst? Indomethacin

What effect does indomethacin have on WBCs? Reduces PMN migration

What is i ts mechanism? Inhibits phospholipase A

What is i t often used for? To maintain PDA

ANTIINFLAMMATORIES

ANALGESICS AND

O S


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What is the advantage of sulindac?

Less nephrotoxic than other NSAIDs (but severe GI effects including p

What is the mechanism of diclofenac?

Potent COX inhibitor; AA bioavailability

What Rx is often combined c it?

Misoprostol to GI effects

What is ketorolac often used for?

As an analgesic in postsurgical pain

How is it administered and what is i ts 1/2 life?

Given orally, IV, or IM c a 1/2 life of 4 -8 hrs

Often combined c opiates

What is i ts typical time frame of use?

After 5 days causes frequent GI upset

ANTIINFLAMMATORIES

ANALGESICS AND

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What happens when ibuprofen is combined c ASA?

Decreases the effect of ibuprofen

What is the mean plasma 1/2 life of naproxen?

13 hrs

How is it excreted?

Largely in the urine, but some in the feces

Who should not take it?

Pregnant womenreadily crosses placenta

What accounts for its adverse Rx rxns?

Extensively binds plasma protein, displacement causes adverse rxns

What effects does piroxicam have on WBCs?

Inhibits PMN migration and lymphocyte function

Decreases oxygen radical production

ANTIINFLAMMATORIES

ANALGESICS AND

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What characterizes the pharmacokinetics of piroxicam?

Long half life, high incidence of GI side effects What is unique about nabumetone?

Requires conversion to active metabolite

Half life long enough for once daily administration

Fewer adverse GI effects than others

What characterizes phenylbutazone?

Very potent c serious side effects, not marketed in U.S.

Why is acetaminophen preferred to aspirin?

Tolerated better, lacks ulcerogenics, blood clotting defects, otot

What happens c acetaminophen overdose?

Fatal hepatic necrosis

ANTIINFLAMMATORIES

ANALGESICS AND

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What is the plasma binding capacity of acetaminophen? Low (20-50%)

How is it metabolized and secreted? Metabolized in liver, conjugated, and excreted renally

What enzyme eliminates free radicals produced by acetaminph GSH

How do its ph armacodynamics differ from the NSAIDs? NO an ti-inflammatory effec tsnot effective as an antirheumatic

What is i ts antipyretic mechanism? Inhibits the action of endogenous pyrogen @ the hypothalamus by inhib

product ion

What dose is required for hepatotoxicity in adults? 10-15 grams (25 grams may be fatal)

When does the toxicity become serious? When the metabolites exceed the available reduced glutathione in the b

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ANALGESICS AND

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What can increase the toxicity of acetaminophen? Chronic EtOH consumption

What is the Tx of acetaminophen intoxication? Gastric lavage, diuresis, hemodialysis

N-acetylcysteinegive parenterally w/in 10-12 hrs after intoxi

What is aurothioglucose (a gold salt) used for? Inhibit phagocytosis, uncouple oxidative phsophorylation

Stabilize lysosomal membranes and inhibit lysosomal enzymes

React c proteins, inhibit proteolytic enzymes of leukocytes

Prevent PG synthesis

Suppress cellular immunity

What is its toxicity? Bone marrow damage , dermatitis, enterocolitis , jaundice, neur

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ANALGESICS AND

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What is penicillamine and its uses? A chelating agent effective i f RA and Wilsons disease

What may contribute to its antirheumatic effects? Inhibits formation of collagen and circulating IgM rheumatoid

How does it differ from cytotoxic immunosuppressants? Does not levels of absolute serum immunoglobulins

How does penicillamine affect lymphocytes? Depresses T-cell activity but not B-cells

What are the adverse rxns? Pruritis, rash, alteration in taste

Pancytopenia, proteinuria, hypoalbuminemia

Lupus like disease, Goodpastures, myasthenia gravis

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ANALGESICS AND

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What are the effects of hydroxychloroquine?

Antihistamine, anticholinesterase, antiprotease

Inhibits PG synthesis, inhibits response to chemotactic stimuli and pha

Where is it concentrated in the body?

High affinity for melanin epidermis and retina

What is the half-life?

50 days

What is i ts toxicity?

Pruritis, hemolyis (G6PD deficiency), ototoxicity, retinopathy, neuropa

How does sulfasalazine compare to penicillamine for Tx of RA

As effective and less toxic

What should be monitored c sulfasalazine administration?

Hepatitis and marrow suppression

ANTIINFLAMMATORIES

ANALGESICS AND

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What is infliximab used for?

Crohns and RA when combined c methotrexate

What is i ts mechanism?

Monoclonal Ab against TNF-

How is it administered?

IV

What are the contraindications?

Pregnancy, breast feeding, children, infections

What is the mechanism of rituximab?

IgG that binds to CD20 B-cells of non-Hodgkin lymphoma

What is the mechanism of adalimumab?

IgG for TNF-

Approved for monotherapy of RA (unlike infliximab)

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ANALGESICS AND

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What is the structure of adalimumab? 100% human derived

How is it administered? Subcutaneously

What is the structure of etanercept (Enbrel)? NOT a monoclonal Ab

Made of extracellular binding portion of human TNF-receptor linked portion of Ig

What is i ts action? Binds TNF-but does not affect its production or serum levels

What are the pharmacokinetics? Given subQ c 1/2 life of 102 hrs

What is the structure of abatacept? Fully humanrecombinant fusion protein

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ANALGESICS AND

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What is the structure/action of anakinra?

Recombinant IL-1 receptor antagonist

ANTIINFLAMMATORIES

GOUT


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What Rx are used for acute gout attacks? Colchicine and NSAIDs

What are primary causes of gout? Over production of uric acid

Underexcretion or uric acid

What are secondary causes of gout? Accumulation of uric acid due to another disease (leukemia, polycythem

What is the pathogenesis of gout? Deposition of uric acid tophi in peripheral joints are phagocytosed by s

that initiate an inflammatory rxn mediated by PGs and immune cells

What are the analgesic effects of colchicine? NONE!

How does it urate? It DOES NOT

GOUT


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What is the mechanism of colchicine? Binds to tubulin and inhibit s the assembly of microtubules

Inhibits leukocyte migration, phagocytosis, and formation of leukotrien

When is it used? To reduce pain and inflammation in an acute attack

Prophylactically at initiation of Tx c uricosuric agents

What are the pharmacokinetic properties? Oral administration (IV: toxicity), effective in 12 -24 hrs

What are the adverse effects? Diarrhea, N/V, ab d pain

What is the primary NSAID used in gout? Indomethacin

What others are also used? Naproxen and su lindac

GOUT


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What NSAIDs are contraindicated in gout and why? ASA, salicylatesdecrease urate excretion

What is the mechanism of uricosuric agents? urinary excretion of uric acid by blocking active reabsorption in the prox

What are the uricosuric agents? Probenacid and sulfinpyrazone

How must the urine be modified c administration of uricosuric ag Maintain a pH >6.0 (alkalinize) and maintain large amounts to minimize the

kidney stone formation

Why arent they used for acute attacks? They can aggravate or trigger an attack

How is this avoided? Give c prophylactic colchicine

What are the side effects? GI irritation

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How is probenacid administered? Orally, but not until 2 -3 weeks after an acute attack

What are the Rx interactions? Decrease excretion of many acidic compounds

PCN, methotrexate, glucuronides of NSAIDs

What are the additional interactions and adverse effects of sulfcompared to probenacid? Inhibits platelet aggregation and inhibits liver metabolism of warfarin

What are the xanthine oxidase inhibitors? Allopurinol and febuxostat

What are the side effects? Vasculitis, agranulocytosis, and hypersensitivity

What Rx are they often administered with? Colchicine to prevent an acute gouty attack

GOUT


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What are the Rx interaction of allopurinol/ febuxostat? Aluminum hydroxide the absorption of allopurinol

effect of chemotherapeutic mercaptopurines the effect of cyclophosphamide

Inhibits elimination of chlorpropamide

Inhibits metabolism of warfarin and probenacid

Inhibits activation of fluorouracil

What is rasburicase and its mechanism Recombinant form of urate oxidase (not found in humans)

Catalyzes oxidation of uric acid to allantoin , a readily secreted metabolite

When is i t often used? To prevent tumor lysis syndrome after initiation of chemotherapy

How is i t given? IV infusion

What are the side effects? Severe hypersensitivity rxns (anaphylaxis), N/V/D/C, fever, H/A

MIGRAINES


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What is the mechanism of migraines? First phase of vasoconstriction of intracranial arteries causing ischemic

Second phase is vasodilation of extracranial arteries causing the H/A duvasoactive materials

What is the prototype -triptan? Sumatriptan

What is i ts mechanism of action? Selective 5-HT1D agonist of intracranial vessels causing vasoconstrictio

of sensory neuropeptides

What are the pharmacokinetics? Give PO or SC

1/2 life is 2 hrs; H/A recurs w/in 24-48 hrs

What are the toxicities? Coronary artery vasospasm, arrhythmias, cerebral vasospasm intracr

Peripheral or bowel ischemia, GI upset

MIGRAINES


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What is the mechanism of ergotamine tartrate?

Vasoconstriction:

Partial agonist on 5-HT receptors

Partial agonist on 1receptors

How are the ergot alkaloids administered?

Orally, inhalation, sublingual, or parenteral routes

What are the adverse effects?

More potent vasoconstrictor than the -triptans:

Acute: N/V/D, CV toxicity

Chronic: ergotism + CNS Sx

What are the contraindications?

Thromboangiitis obliterans, atherosclerosis, severe HTN, ischemic hear

Allergy, renal or hepatic disease, malnutrition, peptic ulcers. pr egnancy

MIGRAINES


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What are the characteristics of dihydroergotamine? Similar to ergotamine, given IV

When is methylsergide used? In migraine prophylaxis

What is its mechanism? It is an ergot alkaloid (5-HT partial agonist) but a weak vasocon

What are its pharmacokinetic properties? High first pass metabolism 13% bioavailability

What are other Rx used for prophylaxis? Beta blockers (propranolol), Ca channel blockers (verapamil),

antidepressants (amitriptyline), clonidine, anticonvulsants (valptopiramate), botox, ARBs

Pharmacology Exam 2 PP

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