Pharm Exam 2

Question 1

Nitroglycerin (NTG)

Answer 1

Organic nitrate (prototype)
Prodrug: metabolized to NO in VSM by mitochondrial ALDH2 (aldehyde dehydrogenase)
Efficacy: prevent and termination of acute angina attacks, improves exercise tolerance, abolishes ST segment depression
No survival benefit/prevention of MI
Adverse: HA (severe), facial flushing, orthostatic hypotension, reflex tachycardia (increases O2 demand negating therapy; suppressed with beta blockers or Ca-ch blockers)
Tolerance
Interactions: ED vasodilator drugs (sildenafil; can precipitate severe refractory hypotension and possible MI within 24h of PDE-5 inhibitors); alcohol (inhibits ALDH2; accentuates orthostatic hypotension)

Question 2

Isosorbide dinitrate

Answer 2

Organic nitrate
Oral and sublingual tablets
Prodrug: metabolized to isosorbide mononitrate
Longer duration (q4-6h) added if angina not controlled by NTG and B-blockers/CCBs
Efficacy: prevent and termination of acute angina attacks, improves exercise tolerance, abolishes ST segment depression
No survival benefit/prevention of MI

Question 3

Organic Nitrates

Answer 3

Prodrug: metabolized to NO in VSM by mitochondrial ALDH2 (aldehyde dehydrogenase) (also used in EtOH metabolism)
MOA: venous > arterial dilation at therapeutic doses, reduces preload (decreased venous return; reduced O2 demand)
Efficacy: prevent and termination of acute angina attacks, improves exercise tolerance, abolishes ST segment depression
No survival benefit/prevention of MI **
CBF: vasodilator action on epicardial (lg) arteries (blood to endothelium); dilation on spastic coronary arteries
CV: usual doses (no inotropic or chronotropic effects nor changes in BP); higher doses (reflex tacky if MAP reduced–baroreceptor reflex); arterioles in face/neck and meningeal arteries sensitive to vasodilation (HA)
Pharmacogenetics: ALDH2 polymorphism (ALDH22 is low activity, high prevalence in Asians, possibly lower efficacy)
PK: sublingual (circumvents 1st pass metabolism, therapeutic levels in 1-2m, rapid relief, duration is <1h); tablets unstable to heat/light/moisture; tingling sensation under tongue (indicates tablet is effective); oral or cutaneous (slower onset 30-60m, longer duration 4-24h)
Contact EMS if angina not gone within 5m
TOLERANCE: nitrate-mediated inactivation of ALDH2; most common with oral and transdermal meds; minimized with eccentric dosing (nitrate-free interval of 10-12h)
Adverse: HA (severe), facial flushing, orthostatic hypotension, reflex tachycardia (increases O2 demand negating therapy; suppressed with beta blockers or Ca-ch blockers)
Interactions: ED vasodilator drugs (sildenafil; can precipitate severe refractory hypotension and possible MI within 24h of PDE-5 inhibitors); alcohol (inhibits ALDH2; accentuates orthostatic hypotension)

Question 4

Calcium channel blockers

Answer 4

Vasodilator. Effect on after load.
MOA: block inward flow of Ca++ through voltage-gated L-type Ca channel (bind channel alpha-1 subunit). Marked decrease in TRANSMEMBRANE Ca current (decreased Ca intracellularly) in VSM, cardiac myosotes, and nodal tissue. Vasodilators in peripheral and coronary arteries (decreased after load –> reduced O2 demand).
Efficacy: prophylaxis against angina attacks (reduce consumption of NTG). Long-acting preps or 2nd gen preferred (immediate release –> reflex tachycardia). As effective as beta-blockers in controlling angina. No survival benefit.
Adverse: Bradyarrhythmia (ver,dil), reflex tachycardia (nifed), cardiac depression (ver,dil), flushing, peripheral edema (nifed), constipation (ver–geriatrics)

Question 5

Nifedipine

Answer 5

CCB (dihydropyridine) (prototype)
Immediate release (causes reflex tachycardia)
Greater inhibitory action on VSM than myocardium.
Less depression of myocardial contractility and minimal effects on SA automaticity and AV conduction velocity (compared to non-DHP)
CYP3A4 metabolism (grapefruit juice)
Adverse: reflex tachycardia, flushing, peripheral edema

Question 6

Verapamil

Answer 6

CCB (HR lowering) (non-dihydropyridine)
Act on SA and AV nodal issue (decrease HR and contractility; less potent vasodilators than DHPs)
C/i in SICK SINUS SYNDROME and AV nodal block
Adverse: bradyarrhythmia, cardiac depression, constipation (inhibits peristalsis in GI SM by CCB effect, geriatrics)

Question 7

Diltiazem

Answer 7

CCB (HR lowering) (non-dihydorpyridine)
Act on SA and AV nodal issue (decrease HR and contractility; less potent vasodilators than DHPs)
**Less cardiac depression than verapamil; better tolerated
C/i in SICK SINUS SYNDROME and AV nodal block
Adverse: bradyarrhythmia, cardiac depression

Question 8

Propranolol

Answer 8

Beta-blocker (non-selective–blocks B1 and B2)
MOA: decrease HR, contractile force, and BP which decrease myocardial oxygen demand. Increases perfusion during diastole (negative chronotropism). Decreases resting HR; effect on exercise-induced tachy is more pronounced.
Use: maintain resting HR at ~55bpm and limit peak HR during exertion to ~110 (titrate dose to this). Reduce severity and frequency of stable anginal attacks. Reduces mortality** and decrease incidence of sudden cardiac death. Not useful for vasospastic angina (may worsen condition dt unopposed alpha-adrenergic receptor activity)
Adverse: effects on ventricular function (acute, B1); increase airway resistance (B2); precipitate acute MI on sudden withdrawl; c/i in agents with intrinsic B1-receptor agonist activity (pindolol); fatigue, depression, sexual dysfunction

Question 9

Ranolazine

Answer 9

Antianginal effects without changes in HR or BP
MOA: Inhibits “late phase” of inward sodium current, thereby blocking calcium overload–>reduced O2 demand. (increased Na+ influx in ischemic myocytes leads to Ca++ overload (Na-Ca exchanger)–> increases O2 demand, impaired relaxation, and decreased perfusion.)
Use: prophylaxis against angina attacks, anti arrhythmic properties. In combo in pts with uncontrolled angina.
Adverse: prolonged QT-interval. C/i with other drugs that promote this effect. CYP3A4 metabolism.

Question 10

Sildenafil

Answer 10

PDE5 inhibitor (prolongs activity of NO/cGMP)
PDE (break-down cGMP. cGMP causes vasodilation) 
MOA: relax corpora cavernosa SM. No effect in the absence of sexual stimulation (NANC--parasympathetic nonadrenergic noncholinergic--innervation must be intact) 
PK: take 1h before sexual activity. Onset is ~60m. Duration is 2-4h. Onset delayed by a high fat meal. CYP3A4 metabolism. Related agents have longer duration of action. 
Effective in 50-90% of cases.
Adverse: HA and flushing (PDE1), nasal congestion, dyspepsia, abnormal vision (blue color tinge, blurring, light sensitivity (retinal PDE6)), risk of sudden hearing loss, priapism (rare--treat with vasoconstrictors) 
Interactions: potentiate the effects of organic nitrates and alpha blockers.

Question 11

Alprostadil

Answer 11

Prostaglandin eicosanoid (PGE1)
MOA: agonist for EP2 receptor in VSM. Direct vasodilation upon LOCAL administration. Bypasses need for intact NANC innervation. Auto-erection within minutes.
Intercavernous injection or urethral suppository. Short duration of action (<1h)
Alternative to PDE5 inhibitors.
Adverse: pain at injection site and hypotension; priapism and penile fibrosis (rare)

Question 12

JNC 8 guidelines

Answer 12

1. First line: thiazide diuretics, ACE-I, ARB, CCB (DHP)
2. Second-line: higher doses of first-line agents
3. Third-line: beta blockers, loop diuretics, aliskiren, alpha-1 blockers, vasodilators, central alpha-2 agonists, reserpine, aldosterone antagonists

Question 13

Chlorthalidone

Answer 13

Thiazide diuretic
Antihypertensive, not hypotensive
Longer DOA than hydrochlorthiazide
Initial increase in TPR dt RAAS (baroreceptor reflex)
Thought: decreased sodium from vasculature
Hemodynamics: no change in HR or CO
Use: low dose for stage 1 (lower BP 10-15 in 4-6w); reduces mortality; Shallow ANTIHYPERTENSIVE dose-dependence (doses >25mg only increase side effects); in combo with others for mod to severe HTN (synergistic effect); reduce Na+ retention cured by vasodilators and some sympathetics; effective in volume-dependent HTN
Adverse: hypokalemia, hyperuricemia, hyperglycemia, hyperlipidemia, erectile dysfunction

Question 14

Furosemide

Answer 14

Loop diuretic
Modest effect on BP despite brisk diuresis
Shorter DOA than thiazides
Use: malignant HTN, volume-dependent patients with GFR <30mL/min
Adverse: similiar to thiazides (hypokalemia, hyperuricemia, hyperglycemia, hyperlipidemia, erectile dysfunction), OTOTOXICITY, INCREAED EXCRETION OF CALCIUM

Question 15

Captopril

Answer 15

ACE-I
Inhibits ACE, decreases TPR
Use: antihypertensive (even if patient has normal Plasma Renin Activity); no interference with CV reflexes (baroreceptor; no effect on exercise tolerance); safe in pts with bronchial asthma; no effects on lethargy, weakness, or sexual dysfxn
Reduces risk of HTN-related mortality
1st dose phenomenon (function of PRA; start with low doses) (high PRA due to salt restriction possible)
Adverse: hypERkalemia, cough (bradykinin), angioedema, teratogen (category X)

Question 16

Losartan

Answer 16

ARB
MOA: AT1 receptor antagonist; decreases TPR
Use: alternative to ACE-I
Adverse: similar to ACE-I (hypERkalemia, teragogen) but cough/angioedema less prevalent

Question 17

Eplerenone

Answer 17

Aldosterone antagonist
MOA: selective aldosterone antagonist (1. little/no effect on other hormone receptors, 2. promotes excretion of Na+ and water by blocking aldo receptors in kidney; 3. prevents/reverses CV remodeling)
Use: additional decrease in BP in pots taking ACE-I or ARB
Adverse: hypERkalemia, reduced side effects assc with spironolactone

Question 18

Aliskiren

Answer 18

Direct renin inhibitor (DRI)
MOA: blocks conversion of angiotensinogen –> AngI
Use: alone or in combo with other anti-HTN agents
Adverse: hypERkalemia, c/i in pregnancy

Question 19

Nifedpine (anti-HTN)

Answer 19

CCB
MOA: block voltage-gated L-type Ca++ ch in VSM
Decreases TPR, distinguished in regard to cardiac effects
Use: first-line for mild to mod HTN; administered at max doses in “vasoreactive” patients
Adverse: reflex tachy, bradycardia

Question 20

Verapamil (anti-HTN)

Answer 20

CCB
MOA: block voltage-gated L-type Ca++ ch in VSM
Decreases TPR, distinguished in regard to cardiac effects
Use: first-line for mild to mod HTN
Adverse: reflex tachy, bradycardia

Question 21

Nitroprusside

Answer 21

Vasodilator
Compound contains NO and Cyanide (released on decomposition)
MOA: non-enzymatically decomposes to release NO (arterial and venous dilation, mech. similar to NTG but no tolerance develops)
PK: constant infusion (IV); immediate effect; BP can be adjusted by changing infusion rate (monitor this); short DOA; BP returns to pre-treatment levels in 3-5m; unstable and light sensitive in solution
Met: non-enzymatic conversion; CN- metabolized by liver by rhodanase to SCN-; avoid CN- accumulation by admin of thiosulfate (antidote for CN- poisoning)
Use: HTN emergencies (diastolic >120; it never fails!); hypotensive surgery; give furosemide simultaneously to reduce fluid retention
Adverse: excessive vasodilation/hypotension; cyanide toxicity (rare); hypothyroidism (thiocyanate accumulation–goitregernic)

Question 22

Hydralazine

Answer 22

Vasodilator
MOA: arteriolar dilation; NO donor and may decrease Ca++ release
Met: low oral bioavailability (high 1st pass); acetylated by NAT2 (inactivates drug); reduce the dose in slow-acetylators
Use: severe HTN in combo with other agents, HTN crisis, in combo with isosorbide denitrate (BiDil) for CHF/HTN in African Americans
Adverse: Reflex tachy and HA; lupus-like syndrome in slow-acetylators

Question 23

Minoxidil

Answer 23

Vasodilator (dangerous; rarely used)
MOA: arterial dilation by opening K+ ch on VSM (K+ efflux causes hyper polarization, reducing contraction; reflex increase in HR and contractility)
Prodrug: met in liver to minoxidil sulfate
Use: seldom; add-on for severe HTN; topical to promote hair growth (Rogaine)
Adverse: edema (salt/water retention; may need a loop); pericardial effusion (boxed warning; tamponade); reflex tachy (use with Beta blocker); Hypertrichosis (hair growth on face, back, arms, and legs)

Question 24

Epoprostanol

Answer 24

Prostacyclin (PGI2)
MOA: mimics effect of PGI2 on VSM; binds to receptor and stimulates cAMP synthesis; promotes vascular relaxation, suppress growth of VSM; inhibits platelet aggregation
Use: Pulmonary arterial hypertension (PAH) (improves short-term survival)
Infusion pump, kept cold (difficult to use)
Adverse: flushing, HA, nausea, risk of bleeding

Question 25

Bosentan

Answer 25

Endothelin-1 antagonist (endothelial-derived vasoconstrictor peptide; mirror image of NO) ET-1 induces infl, fibrosis, and proliferation of VSM MOA: competitive antagonist of ET-a and ET-b receptors Use: PAH; toxicity restricts use Adverse: teratogenic, hepatotoxic

Question 26

Clonidine

Answer 26

Sympatholytics Centrally-acting alpha-2 adrenergic agonist Decreases sympathetic outflow by stimulating alpha-2 receptors in NTS Also binds imidazoline receptor Compensatory Na+/water retention Use: for patients not responding to other drugs; no evidence for reducing risk of adverse CV events Adverse: dry mouth, sedation, sexual dysfxn, postural hypotension; c/i in depressed pts Abrupt withdrawal syndrome: rebound HTN, HA, tachy

Question 27

Methyldopa

Answer 27

Sympatholytic Alpha-2 adrenergic agonist Metabolized to methylNE; effects similar to clonidine Adverse: dry mouth, sedation, sexual dysfxn, postural hypotension; c/i in depressed pts; (similar to clonidine but without rebound effect); positive Coomb's test Safely used during pregnancy

Question 28

Propranolol (HTN)

Answer 28

Beta-blocker (non-selective) B1 blockade: reduces CO, reduces TPR long-term despite B2 blockade (inhibits renin release), reduces sympathetic outflow (CNS) Use: no longer recommended unless specific indication (MI, CHF, SIHD); less effective in African-Americans and geriatric patients; prevent reflex tachy in severe HTN treated with vasodilators Used most widely: metoprolol and atenolol (cardioselective) Adverse: bradycardia (reduced contractility and AV conduction); bronchoconstriction; reduced exercise capacity; sexual dysfxn

Question 29

Terazosine

Answer 29

``` Alpha-1 blocker MOA: block a-1 on VSM Salt and water retention Use: anti-hypertensive Adverse: first-dose effect (postural hypotension); reflex tachy; nasal congestion; inhibits ejaculation ```

Question 30

HTN Treatment Algorithm (JNC8)

Answer 30

1. Lifestyle Changes (first) 2. Drugs when sustained BP ≥140/90 despite lifestyle changes 3. Goal: maintained BP 20/10 6. Comorbid conditions req more aggressive tx 7. Multi-drug tx: enhanced efficacy, dose reduction, offset compensatory responses

Question 31

Atorvastatin calcium

Answer 31

HMG-CoA reductase inhibitor (rate-limiting step in chol biosynthesis) 3-hydroxy-3-methylglutarate --HMg-CoA reducatse--> mevalonate Long half-life, 3A4 and 2C9 Increase synth of hepatic LDL-R and increase removal of LDL particles form circulation. Enhance clearance of LDL precursors (VLDL and IDL). Lower LDL by 20-55%. Decrease TG by 20%. Increase HDL by 5-10%. Use: first line tx for hypercholesterolemia (elevated LDL) Cardioprotective (lower CRP, anti-infl., enhance NO synthesis, stabilize plaques, reduce lipoprotein oxidation, reduce platelet aggregation) PK: oral, in evening, first-pass metabolism in liver, statins are excreted by liver into bile Interactions: CYP3A4 and 2C9 (fibrates, digoxin, warfarin, macrolides); pravastatin avoids P450 interactions Adverse: GI irritation, HA, rash, hepatotoxicity, myopathy (creatining phosphokinase levels >10x ULN; enhanced by fibrates and niacin) C/i: Category X, liver disease

Question 32

Colesevelam (WEL-CHOL)

Answer 32

Bile acid-binding resin Less GI irritation, more pleasant to take MOA: prevent bile acid reabsorption, increased breakdown of hepatic cholesterol (decreases feedback inhibition of enzyme converting cool to bile acid), increased catabolism of chol --> increased LDL-R (similar to statins, except slight increase in HMG CoA reductase activity) Lower LDL (10-20%), small rise in HDL (5%), no effect on VLDL Use: familial or primary hypercholesterolemia or very high LDL, in conjunction with HMG CoA reductase inhibitors PK: not absorbed by GI tract Interactions: Bild acids bind many drugs and interfere with absorption (take other meds 1h before or 3-4 days after) Adverse: bloating, dyspepsia, constipation, mild steatorrhea (decreased compliance) C/i: pregnancy (category B)

Question 33

Ezetimibe

Answer 33

Cholesterol absorption inhibitor Inhibits cholesterol transport protein (NPC1L1) (inhibits reabsorption of chol excreted in the bile) Reduces [LDL] (25%) Use: combination prep no more beneficial than a statin alone, so primarily used in pts who are statin-intolerant PK: well absorbed, excreted in feces unchanged (78%), rest is conjugated by liver (glucuronidation), t1/2 18-30h. Interactions: other anti-lipidemic drugs, fibrates increase risk of cholelithiasis, levels increased by niacin (increased risk of myopathy), increase prothrombin time with warfarin Adverse: diarrhea, low incidence or reversible impaired hepatic fxn C/i: category C

Question 34

Fenofibrate

Answer 34

Fibric acid derivatives (PPAR-alpha activators) Peroxisome proliferator activated receptor-alpha MOA: increase FA oxidation, increase activity of lipoprotein lipase (catabolizes VLDL), Lower [VLDL]--> lower TG (40-55%) [HDL] increases (10-25%) Variable effects on LDL Use: type III hyperlipoproteinemia, severe hyper-TG (>1000) at risk for pancreatitis, hyper-TG with low HDL PK: rapid/efficient absorption (90%), t1/2 from 1-20h, MORE INFORMATION IN SLIDES Interactions: oral anticoagulant tx may be enhanced, in combo with statins (myositis-flu-like illness, myopathy) Adverse: GI disturbance (frequent), skin rash, urticaria, hair loss, myalgia, fatigue, HA (infrequent) C/i: pregnancy and lactation (category C), children, renal failure, hepatic dysfunction

Question 35

Niacin

Answer 35

Nicotinic acid (water-soluble B vitamin--B3) MOA: in adipose tissue** it inhibits lipolysis of TGs by hormone-senstiive lipase (reduces transport of FFA to liver) In liver**, reduces TG synthesis (inhibits synth and esterification of FA's) Red. TG synth red. hepatic VLDL prod Raises HDL by decreasing fractional clearance of HDL-apoA-I rather than enhancing HDL synth Lower TG by lowering VLDL (35-50%) Lowers LDL more slowly (25%) Increases HDL (15-30%) Use: hypertriglyceridemia and elevated LDL, esp if HDL is low PK: absorbed from intestines, t1/2= 60m, liver metabolism, excreted unchanged Interactions: myopathy with statins Adverse: cutaneous flush and pruritis, GI disturbance, hepatic toxicity, activation on peptic ulcer, hyperglycemia, decreased glucose tolerance, hyperuricemia C/i: pregnancy (category C), hepatic disease, peptic ulcer, gouty arthritis

Question 36

ACE Inhibitors

Answer 36

Decrease production of AngII --> lower aldo and SNS. AngII levels return to baseline with sustained use ("angII escape") but efficacy remains (bradykinin-related effects--vasodilation, decrease remodeling) High dose: reduce mortality

Question 37

Aldosterone Antagonists

Answer 37

K+ sparing Inhibit remodeling Reduce mortality Hyperkalemia possible

Question 38

Angiotensin (AT1) Receptor Blockers

Answer 38

``` Block AT1 (GPCR) but not AT2 receptors. Maintains beneficial AT2-mediated effects. Avoids AngII escape Use when intolerant to ACE-Is reduces mortality ```

Question 39

Beta blockers

Answer 39

Improvement in CHF and decreased mortality (weird: beta-blockers reduce contractile force) Mechanism: Unclear Prevent ischemia and tachyarrhythmias Inhibit cardiac remodeling; reduces renin secretion Reduce EF in short term but increase EF in long-term Cardioselective: metoprolol, bisoprolo, carvedilol Initiate tx at very low doses (<1/10 of final dose) and titrate

Question 40

Diuretics

Answer 40

Reduce Congestive symptoms (decrease water and Na+ retention) Reduced Preload without reduction in CO Dietary salt restriction Efficacy determined by daily body weight No reduction in mortality Loop diuretics: work when GFR is low. K+ depletion. Less effective in later CHF stages. Thiazides: ineffective with low GFR. K+ depletion. Aldosterone antagonists: K+ sparing. Hyperkalemia (esp. with ACE-I/ARB)

Question 41

Vasodilators

Answer 41

Nitrovasodilators: reduce preload; tolerance Hydralazine: reduces pulmonary and systemic vascular resistance (reduces afterload); positive inotropic effect Isosorbide dinitrate-hydralazine (BiDil): reduces mortality; AA patients

Question 42

Digoxin

Answer 42

Cardiac glycoside Digitalis glycoside (foxglove: Digitalis lanata) Increase strength of myocardial contraction (pos. inotropy) Increased contractile force --> Increased CO No decrease in mortality Inhibits Na/K/ATPase (alpha subunit: reduces Na extrusion and increases cytosolic [Na]) Reduced activity of Na/Ca exchanger (NCX) Cytosolic Ca increaes Hyperkalemia: reduces digoxin binding Hypokalemia: increases efficacy (and toxicity), promotes Ca overload WATCH K+ LEVELS Enhances PNS (vagal) tone, reduces SNS outflow AV node: decreases conduction velocity Toxic levels: enhances SNS tone --> reentry arrhythmias Toxic: calcium overload --> DADs PK: long half life, excreted unchanged by kidneys, skeletal muscle distribution (dose on lean body mass), Eubacterium lentum (in gut) metabolizes digoxin in 10% Use: LV systolic dysfunction plus A fib Toxicity: T.I. = 2 (monitor dig (<1ng/mL) and K+ levels); arrhythmias (DAD); SA/AV nodal block Mgmt: anti arrhythmic drugs (lidocaine, atropine), FAB Warning signs of toxicity: GI (nausea/vomiting, anorexia), CNS (fatigue, visual disturbances) Interactions: diuretics (hypokalemia), ACE-I/ARB (hyperkalemia), antiarrhythmics (quinidine and verapamil can increase [dig] plasma)

Question 43

Digoxin immune FAB

Answer 43

Prevents digoxin from binding to ATPase

Question 44

Quinidine

Answer 44

Class 1a: Na ch blocker Moderately slow dissociation (1sec < t < 10 sec) Moderate reduction in phase 0 and conduction velocity Prolong AP duration (K+ ch effect) Widened QRS, prolonged QT Low [K+] --> enhanced proarrhthmagenicity (longer AP) 1. Blocks Na ch 2. Blocks K ch (prolonged refractory pd) 3. alpha-adrenergic blockade 4. anticholinergic (atropine-like) Use: A flutter and fib; suppress SVT and VT Effects: prolonged QT (risk TdP) Interaction with dig (increased [ ]) Cinchonism (HA, tinnitus) at high dose

Question 45

Procainamide

Answer 45

Class 1a: Na ch blocker Moderately slow dissociation (1sec < t < 10 sec) Moderate reduction in phase 0 and conduction velocity Prolong AP duration (K+ ch effect) Widened QRS, prolonged QT Low [K+] --> enhanced proarrhthmagenicity (longer AP) 1. avoid long-term use 2. Metabolism: N-acetyl procainamide (NAPA) blocks Na+ ch and is pro-arrhythmic (long QT0 3. Lupus-like syndrome (ANA ab) esp in slow acetylators

Question 46

Lidocaine

Answer 46

``` Class 1b: Na ch blocker Fast dissociation (t < 1 sec) Reduces rate of phase 0 depolarization/excitability in depolarized cells Minimal effects on EKG 1. Blocks Na ch (ventricle selective) Use: IV tx for ventricular arrhythmias Concern about increased mortality Not useful for atrial arrhythmias Effects: CNS (seizures with rapid admin, paresthesias, tremor, drowsiness); cardiac depression Local anesthetic ```

Question 47

Flecainide

Answer 47

Class 1c: Na ch blocker Very long dissociation (t > 10sec) (marked effect on phase 0 depolarization) Wide QRS, prolonged PR, prolonged QT 1. blocks Na ch (high rate) 2. Blocks K ch (prolonged RP) Use: SVT, ventricular arrhythmias (life-threatening) Increased mortality in pts recovering from MI Effects: blurred vision, pro-arrhythmic (severe heart disease), blocks Ca ch (suppresses LV fxn, worsens CHF)

Question 48

Propafenone

Answer 48

Class 1c: Na ch blocker Very long dissociation (t > 10sec) (marked effect on phase 0 depolarization) Wide QRS, prolonged PR, prolonged QT Beta-adrenergic blockade (bradycardia, bronchospasm) CYP2D6 (increased blood levels in slow 2D6 metabolizers)

Question 49

Metoprolol

Answer 49

Class 2: beta blocker Blocks B1-R regulated activity of Ca++ and K+ ch in myocardium Blocks sympathetic infl on automaticity Blocks sympathetic-induced EAD and DADs Increases RP of AV node (incr PR) Use: decrease mortality, suppress tachyarrhythmias (A fib/flutter, exercise/emotional induced), PSVT (AV nodal reentry or WPW) Effects: SA and AV nodal block, sudden withdrawal syndrome, decrease ventricular fxn (negative inotropic)

Question 50

amiodarone

Answer 50

Class 3: prolong refractory period 1. blocks K+ ch (prolongs RP in fast response tissue) 2. Blocks Na+ ch (decreases excitability, increased RP) 3. Blocks Ca++ ch (increased RP) 4. non-competitive adrenergic R blocker 5. Prolonged PR (Ca), QRS (Na), and QT (K) Use: V tachy or fib. To maintain sinus rhythm in A fib. Effects: pulmonary fibrosis (long term use at 400 mg/day dose), thyroid dysfxn (analog of TH) PK: highly lipophylic, long half-life, inhibition of CYP 3A4/2C9 and P-glycoproteins

Question 51

Sotalol

Answer 51

Class 3: prolong refractory period Non-selective B-blocker that also blocks K+ ch Ventricular tachy or severe atrial flutter or fib Adverse: TdP in overdose, B-blocker assc.-toxicities, NOT approved as a anti-HTN or antianginal

Question 52

Dofetilide

Answer 52

Class 3: prolong refractory period "pure" K+ (delayed rectifier) ch blocker No extra cardiac effects Maintain sinus rhythm in pts with A fib (with MI/HF) TdP (only used under super close monitoring)

Question 53

Verapamil

Answer 53

Class 4: Ca ch blocker 1. blocks Ca ch (L-type); decreases SLOW tissue automaticity and excitability 2. Effects similar to B-blockers 3. Depresses AV nodal conduction Use: control ventricular rate in atrial flutter/fib, SVD (dt AV nodal reentry) Effects: depressed cardiac force (c/i in CHF), constipation Interactions: drugs that inhibit SA and AV nodes, B blockers, dig (bradycardia and AV block)

Question 54

Adenosine

Answer 54

1. Stimulates adenosine A1 GPCR (Gi): decrease cAMP 2. Activates K ch in sa and AV! nodes (hyperpolarization, decreased automaticity, (inward rectifier)) 3. Reduces AV node Ca++ (Go) 4. Increased PR Use: termination of AVNR, WPW (c/i if A fib present) Effects: safe dt short action (5 sec asystole); flushing, metallic taste Rapid IV bolus (10-20sec), inactivated by adenosine deaminase, interaction with caffeine (blocks A1 receptors)