Pharmacology of Antiarrhythmias Flashcards
Transmembrane Potential
Resting membrane potential determined by concentrations of ions
Sodium (Na+), Potassium (K+), Calcium (Ca2+), Chloride (Cl-)
Ions unable to cross lipid membrane
Electrical gradient
-90 mV inside
0 mV outside
Gates in the Cell Membrane
Depolarization opens the activation (m) gates If inactivation (h) gates have not already closed, the channels are open and activated Opening brief; open (m) gates very quickly followed by closure of (h) gates and channel inactivation
M- you May come in
H- Heck no!
Cell Depolarization phases
Phase 0- rapid depolarization, abrupt increase in Na+ permeability
Phase 1- brieff repolarization, transient K+ efflux
Phase 2- plateau phase, Ca3+ influx ,balanced by K+ efflux
Phase 3- repolarization, continued K+ efflux
Phase 4- gradual depolarization, Na+ leak balanced by K+ efflux
Impulse Conduction
Heart rate reflects SA node
- Much faster rate of spontaneous firing
AV node much slower
- Ca2+ current
Bundle of His and Purkinje fibers fast
- Large Na+ current
P-wave: depolarization of atria
PR interval: AV nodal conduction time
QRS: depolarization of ventricles, conduction time of ventricles
QT interval: ventricular action potential duration
T-wave: repolarization of ventricles
Abnormal impulse generation
Disturbance of impulse formation
Interval between depolarizations = duration of action potential + duration of diastolic interval
Triggered automaticity:
- Early afterdepolarization – interrupts phase 3
- Delayed afterdepolarization – interrupts phase 4
Abnormal impulse conduction
Depressed conduction
- Simple block
- eg. AV nodal block, bundle branch block
Reentry
- Impulse reenters/excites areas of heart more than once
- Must be an obstacle – establishes a circuit
- Must be unidirectional block
- Conduction time must be long enough that retrograde impulse does not encounter refractory tissues
Antiarrhythmic drugs can:
Induce arrhythmias
- Must weigh benefits vs. risks
Depress autonomic properties of abnormal pacemaker cell
- Decrease slope of phase 4
- Elevate threshold potential
Alter conduction characteristics of reentrant loop
- Facilitate conduction (shorten refractoriness)
- Depress conduction (prolong refractoriness)
Class IA Na+ Channel Blockers
Disopyramide
Quinidine
Procainamide***
Proarrhythmic (TdP) Use-dependence - Open/inactivated channel binding - Block tissues more frequently depolarized (tachycardia) Intermediate kinetics
Procainamide
Slows upstroke of action potential, slows conduction, prolongs QRS, prolongs action potential duration
Extracardiac: ganglion-blocking
PK: Metabolite N-acetylprocainamide (NAPA) with class III activity
Therapeutic Use:
Atrial and ventricular arrhythmias
ADRs:
Excessive APD prolongation, QT prolongation, reversible lupus erythematosus (~33%)
Class IB Na+ Channel Blockers
Lidocaine***
Tocainide
Mexiletine
Not for atrial arrhythmias
Activated and inactivated channel binding
Rapid kinetics
Lidocaine
Decreases action potential duration, shortens phase 3 repolarization
PK:
- Extensive first-pass metabolism (3% bioavailable), given IV
- Therapeutic levels: 2-6 mcg/mL
Therapeutic Use:
- DOC for termination of VT and prevention of VF after cardioversion in setting of acute ischemia
ADRs:
- Least cardiotoxic but associated with neurologic (paresthesias, tremor, nausea, lightheadedness)
Class IC Na+ Channel Blockers
Moricizine
Flecainide
Propafenone
High incidence of drug induced arrhythmias
Cannot be used in structural heart disease
Slow kinetics
Flecainide
Blocks both Na+ and K+ channels but does not prolong action potential or QT interval
Therapeutic Use:
Supraventricular arrhythmia
ADRs:
Severe exacerbation of arrhythmia
Propafenone
Similar to flecainide + β-blocking activity
Class II β-Blockers
Propranolol
- Esmolol
- Metoprolol
Decrease automaticity
Prolong AV conduction
Decrease heart rate and contractility
Decrease O2 demand
Class II β-Blockers Therapeutic Use:
Tachyarrhythmias Atrial flutter Atrial fibrillation AV nodal re-entrant tachycardia Hypertension Heart failure Ischemic heart disease
Class II β-Blockers ADRs:
bradycardia, heart block, potential worsening of reactive airway disease (nonselective), cold extremities, fatigue, cardiac decompensation if heart relying on sympathetic drive (heart failure)
Metoprolol
B1-selective
PK:
Onset of action: 1-2 hours (oral), 20 minutes (IV); t1/2: 3-4 hours
Significant first pass effect: 50%, CYP2D6 metabolism
ADRs:
Similar to other B-blockers but with reduced risk of bronchospasm and diabetes
Esmolol
B1-selective, ultra-short-acting
PK:
Onset of action: 2-10 minutes; duration of effect: 10-30 minutes
Metabolized by red blood cell esterases
Class III K+ Channel Blockers
Amiodarone ***
Dofetilide
Sotalol
Diminish outward K+ during repolarization
Increase duration of action potential
Prolong effective refractory period
Amiodarone
Prolongs action potential duration (& QT interval), significantly blocks Na+ channels, weak adrenergic and calcium channel blockade; broad activity
Extracardiac effects: peripheral vasodilation
PK:
Bioavailability: 35-65%; hepatic metabolism, major active metabolite
t1/2: 3-10 days (rapid component 50%), several weeks (slower component)
Effect maintained 1-3 months after drug discontinued
ADRs:
Symptomatic bradycardia, heart block (those with preexisting AV node disease), accumulates in tissues, pulmonary toxicity (& fatal pulmonary fibrosis), abnormal LFTs, skin deposits, gray-blue skin discoloration
DDIs: MANY! CYP3A4 blockers (cimetidine) ↑ amiodarone levels; inducers (rifampin) ↓ amiodarone levels; reduce doses of warfarin, statins, digoxin…33-50%
Class IV Ca2+ Channel Blockers
Verapamil
Diltiazem
Decrease inward Ca2+ current
Decrease rate of phase 4 spontaneous depolarization
Slows conduction in Ca2+ dependent tissues (AV node)
Use dependent
Verapamil
Blocks activated and inactivated L-type Ca2+ channels, slows SA node by direct action, suppresses both early and delayed afterdepolarizations
Extracardiac effects: peripheral vasodilation
PK:
Bioavailability: 20% after oral administration
Extensively metabolized in the liver; t1/2: 7 hours
Therapeutic Use:
Supraventricular tachycardia, decreases ventricular rate in AFib and AF, angina, hypertension
ADRs:
Hypotension & VF if given to a patient with VT misdiagnosed as SVT; can induce AV block; constipation, lassitude, nervousness, peripheral edema
Adenosine
Nucleoside, activates inward rectifier K+ current and inhibits Ca2+ current resulting in marked hyperpolarization and increased refractory period
PK:
Metabolized in blood and tissue; t1/2: less than 10 seconds
Adenosine –> inosine –> adenosine monophosphate and hypoxanthine
Therapeutic Use:
DOC for conversion of paroxysmal SVT
ADRs:
Flushing, shortness of breath, chest burning, high grade AV block, atrial fibrillation, headache, hypotension, nausea, paresthesias
Atropine
Blocks actions of acetylcholine at parasympathetic sites, increases CO
PK:
30-50% excreted unchanged in the urine; t1/2: 2-3 hours
Therapeutic Use:
Bradycardia, neuromuscular blockade reversal, cholinergic poisoning
ADRs:
Arrhythmia, tachycardia, dizziness, constipation, urinary retention
Digoxin
Inhibits Na+/K+ ATPase, results in positive inotropy, increased intracellular Na+, decreased Ca2+ expulsion, increased free Ca2+. Decreased HR, increased refractory period, decreased conduction velocity
PK:
65-80% absorbed after oral administration
Not extensively metabolized, ~66% excreted unchanged by the kidneys. Must be dose adjusted in renal impairment
t1/2: 36-40 hours
Therapeutic Use:
AFib, supraventricular tachycardia, heart failure
ADRs:
Nausea, vomiting, diarrhea, disorientation, visual disturbances, aberration of color perception, delayed afterdepolarization
Supraventricular Arrhythmias
originate above the Bundle of His; characterized by normal QRS complexes Sinus bradycardia Sinus tachycardia Paroxysmal supraventricular tachycardia Atrial flutter Atrial fibrillation Wolff-Parkinson-White Premature atrial contractions
Ventricular Arrhythmias
originate below the Bundle of His
Premature ventricular contractions
Ventricular tachycardia
Ventricular fibrillation
Conduction Blocks
based on their level or location
Supraventricular: 1st, 2nd, or 3rd degree AV block
Ventricular: right or left bundle branch block
Atrial Fibrillation - description and appropriate drugs
Depolarization from ectopic focus or re-entrant circuit impact atria. No single pacemaker in control. “Irregularly irregular”
Acute: IV CCB, BB, or digoxin
B-blockers (propranolol, metoprolol, esmolol) 1st choice in high catecholamine states. Should not be used acutely in systolic heart failure.
Non-DHP CCB’s (verapamil, diltiazem) IV produce rapid effects 4-5 min.
Digoxin has much slower onset (max effect 6-8 hours), less effective than BB/CCB in increased sympathetic tone.
Chronic: oral BB, CCB
Digoxin if intolerable adverse effects to others
Atrial Fibrillation Long-term strategy:
Rate control > rhythm control +/- anticoagulation (CHA2DS2-VASc score)
Rhythm control indications – continued symptoms with adequate rate control, rate not adequately controlled, or intolerable adverse effects
Atrial Fibrillation Chemical vs. electrical cardioversion
Direct current cardioversion most effective
Chemical options: ibutilide IV, propafenone PO, flecainide PO, amiodarone PO/IV, dofetilide PO
Atrial Fibrillation Maintenance of NSR:
FDA indication – flecainide, dofetilide, dronedarone
Others – propafenone, amiodarone
*safe to use in patients with HF
Paroxysmal Supraventricular Tachycardia (PSVT) - descripation and appropriate drugs
AV nodal re-entry
Valsalva maneuver
Acute treatment: IV adenosine (DOC), verapamil, or diltiazem
Alternative – BB or digoxin if others fail
Chronic: radiofrequency catheter ablation potentially curative
Drugs – verapamil, diltiazem, BB, or digoxin
Premature Ventricular Contractions (PVCs)- description and appropriate drugs
Ventricular arrhythmias arise from irritable foci within ventricular myocardium
Asymptomatic: do not use class Ic agents CAST trial associated with ↑ mortality
B-blockers within first 24 hours after MI if no contraindications (improves survival)
Sustained Ventricular Tachycardia- description and appropriate drugs
Hemodynamic instability: synchronous cardioversion
Stable VT patients: procainamide, sotalol, amiodarone
Implantable cardioverter/defibrillator for:
Survivors of cardiac arrest caused by VF or hemodynamically unstable sustained VT
LVEF less than/ = 35%, prior MI at least 40 days after event and NYHA Class II or III
LVEF less than/ = 30%, prior MI at least 40 days after event and NYHA Class I
After ICD, prophylactic ablation or adjunctive anti-arrhythmic drugs may be necessary depending on number of discharges
Torsades De Pointes
Hemodynamic compromise: electrical cardioversion
Hemodynamically stable: MgSO4 Alternative: class Ib agents
