Anti-arrhythmics DSA

Question 1

Class Ia: Na+ Channel Blockers

Answer 1

a) Disopyramide (Norpace)
b) Quinidine
c) *** Procainamide

Double Quarter Pounder

Question 2

Class Ib: Na+ Channel Blockers

Answer 2

a) *** Lidocaine (Xylocaine)
b) Mexiletine
c) Tocainide

Lettuce Tomato Mayo

Question 3

Class Ic: Na+ Channel Blockers

Answer 3

none of these are red

a) Moricizine
b) Flecainide (Tambocor)
c) Propafenone (Rythmol)

More Fries Please

Question 4

Class II: β-Adrenergic Receptor Blockers

Answer 4

a) ** Esmolol (Brevibloc)
b) ** Metoprolol (Lopressor, Toprol XL)
c) Propranolol (Inderal)

Question 5

Class III: K+ Channel Blockers

Answer 5

a) ** Amiodarone (Cordarone)
b) Bretylium
c) Dofetilide (Tikosyn)
d) Ibutilide
e) Sotalol (Betapace)

A Big Dog is Scary

Question 6

Class IV: Ca2+ Channel Blockers

Answer 6

a) ** Verapamil (Calan)

b) Diltiazem (Cardizem)

Question 7

7) Other ACLS Drugs

Answer 7

a) ** Adenosine
b) ** Atropine
c) Anticoagulants
d) ** Digoxin
e) MgSO4
f) Naloxone (Narcan)
g) Vasopressors:
i) Epinephrine, norepinephrine (Levophed), vasopressin (Pitressin), dopamine

Question 8

Normal Cardiac Rhythm

Answer 8

i) Electrical activity initiated in the sinoatrial (SA) node, frequency 60-100 bpm.
(1) Highest degree of automaticity; largely influenced by autonomic nervous system (ANS) as both cholinergic and sympathetic innervations control sinus rate.
ii) Electrical impulse travels to atrioventricular (AV) node.
(1) AV nodal conduction slow (~ 0.15 seconds), allows atria to contract and blood to flow to ventricles; atria and ventricles separated by fibrous AV ring that will not permit electrical stimulation.
iii) Impulse then travels to the His-Purkinje system.
(1) Enters bundle of His, then bifurcates into 1 right bundle and 2 left bundles, then arborizes into the Purkinje system.
iv) Ventricular activation (

Question 9

Transmembrane Potential

Answer 9

i) Resting membrane potential (RMP) determined by concentrations of ions on either side of the membrane and the permeability of the membrane to each ion:
(1) Sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl-).
ii) Ions are unable to cross the lipid cell membrane, must travel through ion channels in response to electrical and concentration gradients. Ion movement produces currents which form basis of cardiac action potential.
(1) Intracellular Na+ Concentration: 5-15 mEq/L, Extracellular Na+ Concentration: 135-142 mEq/L
(a) Both concentration gradient and electrical gradient (0 mV outside; -90 mV inside) would drive Na+ ions into cell.
(2) Intracellular K+ Concentration: 135-140 mEq/L, Extracellular K+ Concentration: 3-5 mEq/L
(a) Concentration gradient of K+ would drive ions out of cell but electrical gradient would drive them in. Inward gradient = outward gradient (equilibrium).
(b) Certain K+ channels (inward rectifier channels) are open in the resting cell but little current flows through due to equilibrium.
(c) ** Extracellular potassium concentration and the inward rectifier channel are major factors determining the membrane potential in the resting cardiac cell.
(3) Additionally, cell must have mechanism for maintaining stable transmembrane ionic conditions.
(a) Establishes and maintains ion gradients. Example: Na+/K+-ATPase.

Question 10

Cell Depolarization

Answer 10

i) Phase 0 – rapid depolarization
(1) Abrupt increase in cell permeability to Na+ influx in response to a depolarizing stimulus; overshoots electrical potential resulting in brief repolarization (Phase 1).
ii) Phase 1 – initial repolarization
(1) Transient and active K+ efflux; Ca2+ begins to move into intracellular space at about -60 mV (phase 0) causing slower depolarization which continues throughout phase 2.
iii) Phase 2 – plateau phase
(1) Depolarizing Ca2+ influx currents continue (L channels in myocardial tissue) and are balanced somewhat by repolarizing K+ efflux currents.
iv) Phase 3 – cellular repolarization
(1) Delayed rectifier K+ currents increase with time, membrane remains permeable to K+ efflux, while Ca2+ currents inactivate.
v) Phase 4 – gradual depolarization
(1) Constant Na+ leak into intracellular space balanced by decreasing K+ efflux overtime; slope of phase 4 determines, in large part, the automatic properties of the cell (threshold potential also regulates cellular automaticity).
vi) Refractory period – time between phase 0 and sufficient recovery of Na+ channels in phase 3 to permit a new propagated response.

Question 11

Arrhythmia

Answer 11

a) Deviations in the normal cardiac rhythm; aberration in one or more of the following: site of impulse origin, rate or regularity, conduction.

Question 12

Factors which may precipitate or exacerbate an arrhythmia:

Answer 12

Ischemia, hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine exposure, autonomic influences, drug toxicity (digitalis or antiarrhythmics), over stretching of cardiac fibers, presence of scarred or otherwise diseased tissues.

Question 13

Arrhythmias result from:

Answer 13

abnormal impulse generation

abnormal impulse conduction

Question 14

Abnormal impulse generation

Answer 14

(disturbance of impulse formation) or “automatic” tachycardias.

i) Interval between depolarizations = duration of action potential + duration of diastolic interval.
(1) Shortening of either action potential or diastolic interval duration increases pacemaker rate.
(2) Diastolic interval determined by slope of phase 4 depolarization (pacemaker potential).
(a) Increased slope of phase 4 may be caused by: drugs (digoxin, catecholamines), hypoxia, electrolyte abnormalities (hypokalemia), and fiber stretch.

(b) Increased slope of phase 4 causes heightened automaticity and may compete with the SA node for dominance of cardiac rhythm (rate of spontaneous impulse generation > SA node = automatic tachycardia).
(3) Triggered automaticity: transient depolarization that occurs during repolarization.
(a) Early afterdepolarization (EAD): transient depolarization that interrupts phase 3.
(i) Exacerbated at slow heart rates, contributes to long QT.
(b) Delayed afterdepolarization (DAD): interrupts phase 4.
(i) Often occurs when intracellular calcium is increased, exacerbated by fast heart rates.
(ii) Responsible for some arrhythmias related to excess digitalis, catecholamines, and myocardial ischemia.

Question 15

Abnormal impulse conduction

Answer 15

(disturbance of impulse conduction) or “reentrant” tachycardias.

i) Severe depressed conduction may result in simple block (AV nodal block, bundle branch block).
(1) Because parasympathetic control of AV conduction is significant, partial AV block sometimes relieved by atropine (anticholinergic).
ii) Reentry: impulse reenters and excites areas of the heart more than once.
(1) Three conditions must be met for reentry to occur:
(a) Must be an obstacle (anatomic or physiologic), thus establishing a circuit
(b) Must be a unidirectional block
(c) Conduction time must be long enough that the retrograde impulse does not encounter refractory tissues

Question 16

Principles of antiarrhythmics:

a) Depress autonomic properties of abnormal pacemaker cell.

Answer 16

i) Action: decrease slope of phase 4 depolarization and/or elevate threshold potential.
(1) If rate of spontaneous impulse less than SA node –> restoration of normal cardiac rhythm.

Question 17

Principles of antiarrhythmics:

b) Alter conduction characteristics of pathways of reentrant loop.

Answer 17

i) Action: facilitate conduction (shorten refractoriness) in area of unidirectional block.
(1) Allows antegrade conduction to proceed.
ii) Action: depress conduction (prolong refractoriness) in area of unidirectional block or in pathway with slowed conduction and short refractory period.
(1) Retrograde propagation of impulse not permitted causing bidirectional block.

Question 18

a) Type Ia: Sodium Channel Blockers actions

Answer 18

disopyramide, quinidine, procainamide) – prolong the action potential duration, dissociate from channel with intermediate kinetics.***

(1) Decrease conduction velocity, increase refractoriness, decrease autonomic properties of Na+ dependent conduction tissue.
(2) In reentrant tachycardias, decrease conduction, increase refractoriness, unidirectional block transformed to bidirectional.
(3) Has some potassium blocking properties.
(4) Clinically effective in supraventricular and ventricular arrhythmias.

Question 19

a) Type Ib: Sodium Channel Blockers actions

Answer 19

(lidocaine, tocainamide, mexiletine) – shorten the action potential duration in some tissues in the heart and dissociate rapidly.***
(1) In diseased tissue, refractoriness prolonged leading to bidirectional block.

(2) Clinically effective in ventricular arrhythmias more than supraventricular arrhythmias.

Question 20

Type Ic sodium channel blockers actions

Answer 20

(moricizine, flecainide, propafenone) – minimal effects on action potential duration and dissociate slowly.***

(1) Profoundly decrease conduction velocity while leaving refractoriness unaltered.
(a) Theoretically eliminates reentry, slowing conduction to point where impulse extinguished.
(2) Clinically effective for ventricular and supraventricular arrhythmias but use in ventricular arrhythmias limited due to risk of proarrhythmias.

Question 21

Type II: Sympatholytic Beta-Blockers actions

Answer 21

i) Decrease conduction velocity, increase refractoriness, decrease automaticity in nodal tissues.
ii) Anti-adrenergic actions.

Question 22

Type III: Potassium Channel Blockers actions

Answer 22

i) Prolong the action potential duration, prolong refractoriness in atrial and ventricular tissues, delay repolarization by blocking K+ channels.
ii) Examples: amiodarone, bretylium, dofetilide, ibutilide, sotalol.

Question 23

d) Type IV: Nondihydropyridine Calcium Channel Blockers actions

Answer 23

i) Slows conduction, prolongs refractoriness, and decreases automaticity where action potential dependent on calcium (SA and AV nodes).

Question 24

Limitations of classification

Answer 24

a drug may have multiple classes of action (usually discussed according to predominant action) and certain agents (adenosine, magnesium) do not fit readily into this scheme.

Question 25

Procainamide MOA

Answer 25

(1) MOA: slows upstroke of action potential, slows conduction, prolongs QRS, prolongs APD (class III action – nonspecific blockage of K+ channels), direct depressant effects on SA and AV nodes.
(a) Extracardiac effects: ganglion-blocking (reduces peripheral vascular resistance, causes hypotension – usually with excessively rapid IV infusion or severe LV dysfunction).

Question 26

Procainamide PK

Answer 26

administered IV, IM, and orally.

(a) Hepatic metabolism to N-acetylprocainamide (NAPA) then renally excreted; t1/2 3-4 hours.
(b) NAPA class III activity  accumulation (renal failure) implicated in Torsade de Pointes (TdP).
(c) Dose reduction required in renal failure (decreased excretion of NAPA) and heart failure (decreased volume of distribution).

Question 27

Procainamide therapeutic use

Answer 27

(a) Atrial and ventricular arrhythmias.
(b) Long-term therapy avoided due to frequent dosing and lupus-like adverse effects.
(c) Used second or third line for sustained ventricular arrhythmias after MI.

Question 28

Procainamide ADRs

Answer 28

excessive action potential prolongation, QT prolongation, induction of TdP, new arrhythmias. Reversible lupus erythematosus like syndrome (~33%) consisting of arthralgia and arthritis (some patients experience pleuritis, pericarditis, or parenchymal pulmonary disease, rarely renal lupus). Increased ANA titer without symptoms is not an indication to stop therapy. Nausea and diarrhea (10%), rash, fever, hepatitis (

Question 29

Lidocaine MOA

Answer 29

: blocks activated and inactivated sodium channels with rapid kinetics; inactivated state blockage ensures greater effect on cells with long action potential (Purkinje and ventricular cells); rapid kinetics at normal resting potential result in recovery from block between action potentials with no impact on conduction. Increased inactivation and slower unbinding result in selective depression of conduction in depolarized cells.

Question 30

Lidocaine PK

Answer 30

extensive first-pass metabolism (only 3% bioavailable) must be given IV; t1/2 1-2 hours.

(a) Therapeutic plasma level: 2-6 mcg/mL, levels of great value in adjusting infusion rate.
(b) Occasional patients with MI or other acute illness require higher doses due to increased plasma α1-acid glycoprotein (an acute phase reactant) binding lidocaine making less free drug available.
(c) Patients with heart failure, volume of distribution and total body clearance may both be decreased necessitating lower bolus and maintenance doses.
(d) Patients with liver disease have decreased clearance and increased volume of distribution, maintenance dose should be decreased but loading doses can still be given.
(e) Liver disease impacts lidocaine drug concentrations while renal disease has no major effect.

Question 31

Lideocaine therapeutic use

Answer 31

(a) Drug of choice (DOC) for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. However, prophylactic use of lidocaine may increase total mortality by increasing incidence of asystole. Most administer lidocaine only to those with arrhythmias

Question 32

Lidocaine ADRs

Answer 32

least cardiotoxic of Na+ channel blockers. Proarrhythmic effects, including SA node arrest, worsening of impaired conduction, and ventricular arrhythmias uncommon. Large doses may cause hypotension (especially in patients with pre-existing heart failure). Most common adverse effects are neurologic (paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbance, slurred speech, convulsions). Effects dose-related and occur most commonly in the elderly. Otherwise well-tolerated if levels

Question 33

Mexiletine

Answer 33

: orally active congener of lidocaine.

(1) Therapeutic Use:
(a) Ventricular arrhythmias, off-label use for chronic pain.
(2) ADRs: neurologic (tremor, blurred vision, lethargy), nausea.

Question 34

Flecainide

Answer 34

(1) MOA: potent blocker of sodium and potassium channels but does not prolong action potential or the QT interval.
(2) Therapeutic Use:
(a) Supraventricular arrhythmias.
(3) ADRs: severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with previous MI.

Question 35

Propafenone

Answer 35

sodium channel blocking kinetics similar to flecainide but with weak β-blocking activity, does not prolong the action potential.

(1) Therapeutic Use:
(a) Supraventricular arrhythmias.
(2) ADRs: metallic taste, constipation, arrhythmia exacerbation.

Question 36

Amiodarone MOA

Answer 36

markedly prolongs action potential duration (and QT interval) by blocking IKR, chronic administration results in IKS blockage. Does not have reverse-use-dependence (prolongs action potential over a wide range of heart rates). Also significantly blocks sodium channels, weak adrenergic and calcium channel blockade. Broad spectrum of activity may account for high efficacy and low incidence of TdP.
(a) Extracardiac effects: peripheral vasodilation (prominent during IV administration – may be related to action of vehicle?).

Question 37

Amiodarone PK

Answer 37

: variable absorption, bioavailability 35-65%.

(a) Hepatic metabolism, major active metabolite desethylamiodarone.
(b) Elimination t1/2 has rapid component 3-10 days (50%) and slower component several weeks.
(c) After drug discontinuation, effects maintained 1-3 months.
(d) Pharmacologic effects achieved rapidly by IV loading, QT prolongation modest whereas bradycardia and AV block may be significant with IV administration.
(e) ** MANY drug interactions: ↑ amiodarone levels with CYP3A4 blockers (cimetidine), ↓ amiodarone levels with CYP3A4 inducers (rifampin); results in increased drug levels of statins, digoxin, warfarin (must reduce warfarin dose by 33-50%). **

Question 38

Amiodarone Therapeutic use

Answer 38

(a) Atrial fibrillation, prevention of recurrent ventricular tachycardia, not associated with increased mortality in patients with CAD or heart failure, used as adjunct with implanted cardioverter-defibrillator (ICD) to reduce the frequency of uncomfortable discharges.

Question 39

Amiodarone ADRs

Answer 39

symptomatic bradycardia, heart block in those with preexisting sinus of AV node disease. Accumulates in heart (10-50x more than plasma), lung, liver, skin, and concentrates in tears. Most important ADR: pulmonary toxicity, fatal pulmonary fibrosis (1%). Abnormal LFTs, skin deposits, photodermatitis, gray-blue skin discoloration in sun-exposed areas, corneal microdeposits. Blocks peripheral conversion of thyroxine (T4) to triiodothyronine (T3), may result in hypo- or hyperthyroidism.

Question 40

Dronedarone

Answer 40

structural analog of amiodarone with iodine atoms removed. Designed to eliminate action of parent drug on thyroxine metabolism and modify t1/2 of drug. Multi-channel actions: IKr, IKs, ICa, INa, and β-blocking actions.

(1) PK: t1/2 24 hours; food increases absorption two-threefold.
(a) Non-renal elimination; both substrate and inhibitor of CYP3A4, should not be co-administered with potent inhibitors (azoles, protease inhibitors).
(2) Therapeutic Use:
(a) Atrial fibrillation (restores sinus rhythm in

Question 41

Sotalol:

Answer 41

both β-adrenergic blocking actions and action potential prolonging actions. Racemic mixture, L-isomer responsible for β-blocking activity, both L- and D-isomers responsible for action potential prolongation. β-blocking effects non-cardioselective.

(1) PK: well absorbed, 100% bioavailable.
(a) Not metabolized, not bound to plasma proteins; excreted predominately by the kidneys in unchanged form; t1/2 12 hours.
(2) Therapeutic Use:
(a) Life-threatening ventricular arrhythmias, maintenance of sinus rhythm in atrial fibrillation. Treatment of supraventricular and ventricular arrhythmias in the pediatric age group.
(3) ADRs: dose related incidence of TdP (6% at highest recommended max doses).
(a) Further depression of LV function in patients with heart failure.

Question 42

Dofetilide

Answer 42

dose-dependent blockade of rapid component of delayed rectifier potassium current IKr and the blockage of IKr increases hypokalemia. Slow recovery from blockage, little dependence on stimulation frequency.

(1) PK: 100% bioavailable; 80% eliminated unchanged by the kidneys, remainder eliminated as inactive metabolites by kidney.
(a) Initiated in hospital after baseline measurement of rate-corrected QTC & serum electrolytes.
(b) Relative contraindications: QTC > 450 ms, bradycardia of

Question 43

Verapamil MOA

Answer 43

blocks both activated and inactivated L-type calcium channels. Effect more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on calcium current (such as SA and AV nodes). AV node conduction and effective refractory period are consistently prolonged. SA node slowing by direct action, but hypotensive action may result in small reflex increase of SA rate. Suppresses both early and delayed after depolarizations.
(a) Extracardiac effects: peripheral vasodilation.

Question 44

Verapamil PK

Answer 44

bioavailability 20% after oral administration.

(a) Extensively metabolized by the liver, t1/2 7 hours.

Question 45

Verapail Therapeutic Use

Answer 45

(a) Supraventricular tachycardia, reduces ventricular rate (rarely converts) in atrial fibrillation and atrial flutter. Others: angina, hypertension.

Question 46

Verapamil ADRs

Answer 46

: hypotension and ventricular fibrillation if administered IV to a patient with ventricular tachycardia misdiagnosed as supraventricular tachycardia. Can induce AV block in large doses – can be treated with atropine and β-stimulants. Other ADRs: constipation, lassitude, nervousness, peripheral edema.

Question 47

Diltiazem

Answer 47

similar efficacy to verapamil.

(1) PK: t1/2 4-5 hours when given as continuous infusion.
(a) Bioavailability 40% after oral administration; hepatic metabolism, extensive first-pass effect.
(2) Therapeutic Use:
(a) Supraventricular tachycardia, angina, hypertension.
(3) ADRs: edema and headache. Can induce AV block, bradycardia, hypotension.

Question 48

Adenosine *

Answer 48

i) MOA: nucleoside which activates the inward rectifier K+ current and inhibits Ca2+ current causing marked hyperpolarization and suppressing calcium-dependent action potentials. Directly inhibits AV node conduction and increases refractory period when given as a bolus dose.
ii) PK: t1/2

Question 49

Atropine*

Answer 49

i) MOA: blocks actions of acetylcholine at parasympathetic sites, increases cardiac output.
ii) PK: t1/2 2-3 hours.
(1) 30-50% excreted unchanged in the urine.
iii) Therapeutic Use:
(1) Bradycardia, neuromuscular blockade reversal, cholinergic poisoning.
iv) ADRs: arrhythmia, tachycardia, dizziness, constipation, urinary retention.
c) Magnesium
i) MOA: may influence Na+/K+ ATPase, sodium channels, certain potassium channels, and calcium channels. Has antiarrhythmic effects in patients with normal Mg levels.
ii) Therapeutic Use:
(1) Digitalis-induced arrhythmias if hypomagnesemia present, TdP even if Mg normal.