Antiarrhythmic Drugs Flashcards
Bundle of Kent
Accessory Pathways
Some individuals possess accessory electrical pathways that bypass the AV node eg, bundle of Kent. The impulse is conducted more rapidly through the bundle of Kent than the AV node and thus the ventricular tissue receives impulses from both the normal and the accessory pathway.
Drugs Used to Treat Arrhythmias
Class I (Na+ channel blockers)
- Class IA:* quinidine, procainamide, disopyramide
- Class IB:* lidocaine, mexiletine
- Class IC:* flecainide, propafenone
Class II (B-blockers)
propranolol, metoprolol, esmolol
Class III (K+ channel blockers)
amiodarone, sotalol, dofetilide
Class IV (Ca2+ channel blockers)
verapamil, diltiazem
Miscellaneous
digoxin, magnesium, atropine
Class I Antiarrhythmics
(Na+ Channel Blockers) The Class I drugs act by modulating or blocking the sodium channels, thereby inhibiting phase 0 depolarization. Three different subgroups have been identified because their mechanism or duration of action is somewhat different due to variable rates of drug binding to and dissociation from the channel receptor:
- Class IA drugs are intermediate in terms of the speed of binding and dissociation from the receptor.
- Class IB drugs have the most rapid binding and dissociation from the receptor.
- Class IC drugs have the slowest binding and dissociation from the receptor.
By blocking Na+ channels, automaticity is decreased by shifting the threshold to more positive potentials and decreasing the slope of phase 4 depolarization. The block of Na+ channels leaves fewer channels available to open in response to membrane depolarization, thereby raising the threshold for action potential firing and slowing the rate of depolarization.
During faster heart rates (eg, tachyarrhythmias), less time exists for the drug to dissociate from the receptor, resulting in an increased number of blocked channels and enhanced blockade. (Use/State Dependence)
Because nodal tissue action potentials do not rely on fast Na+ channels for depolarization, Class I drugs do not have any direct effect on nodal tissue.
Name the 3 Class IA Drugs and their General Clinical Applications
(Quinidine, Procainamide & Disopyramide)
Class IA drugs, due to their intermediate kinetics may or may not affect conduction at normal heart rates. They also block K+ channels (phase 3) resulting in a prolongation of the refractory period in both the atria and ventricles (ie: reflected as QT interval elongation). Myocardial excitability is reduced by an increase in threshold for excitation and inhibition of ectopic pacemaker activity.
The antiarrhythmic effects of the Class IA drugs are also modified due to the anticholinergic and negative inotropic actions of the drugs. Quinidine has moderate anticholinergic properties, procainamide weak, whilst disopyramide has strong anticholinergic effects.
One difference between the drugs is that quinidine and procainamide generally decrease vascular resistance, whereas disopyramide increases vascular resistance.
In addition, N-acetyl-procainamide (NAPA), a metabolite of procainamide, has little Na+ channel blocking activity, while retaining K+ channel blocking ability. Thus, NAPA behaves like a class III drug.
Class 1A Clinical Applications
Atrial fibrillation; supraventricular and ventricular tachyarrhythmias (class IA drugs have largely been replaced by safer antiarrhythmics due to primarily their proarrhythmic risk). Procainamide still maintains a specific niche as the drug of choice for the management of stable preexcited atrial fibrillation.
Class IA Adverse Effects and Contraindications
The anticholinergic effects of IA drugs produce the typical side effects of tachycardia, dry mouth, urinary retention, blurred vision and constipation. Diarrhea, nausea, headache and dizziness are also common side effects of many Class I drugs. They cause a prolongued QRS signal and a prolongued QT segment!!
Quinidine
By increasing the refractory period quinidine can precipitate arrhythmias such as torsades de pointes. It can also enhance digoxin toxicity by decreasing its renal clearance. Other side effects of quinidine include CINCHONISM (blurred vision, tinnitus, headache, psychosis); nausea, vomiting, diarrhea and abdominal cramps, thrombocytopenic purpura and hemolytic anemia. Inhibits CYP 2D6, 3A4 & P-glycoprotein.
Procainamide
The chronic use of procainamide is associated with a high incidence of adverse effects including a reversible lupus-like syndrome, GI intolerance, aggravation of underlying HF, induction of ventricular arrhythmias and CNS effects such as depression, hallucinations and psychosis. It is contraindicated by the presence of QT prolongation or congestive heart failure.
Disopyramide
Disopyramide has pronounced negative inotropic effects and may induce hypotension & cardiac failure without pre- existing myocardial dysfunction. It is also associated with severe antimuscarinic effects. It can be proarrhythmic by causing lengthening of the QT interval.
Class IA Contraindications
Quinidine
Quinidine is contraindicated in patients with complete heart block and advised to be used with caution in patients with the following conditions: prolonged QT interval, history of torsades de pointes, incomplete heart block, uncompensated heart failure, myocarditis, and severe myocardial damage.
Procainamide
Procainamide is contraindicated in patients with: hypersensitivity, complete heart block, 2nd degree AV block, SLE, torsades de pointes, and advised to be used with caution in patients with heart failure and hypertension.
Disopyramide
Disopyramide is contraindicated for patients with uncompensated heart failure due to its negative inotropic actions.
Name the 2 Class IB Drugs and their General Clinical Applications
(Lidocaine & Mexiletine)
Class IB drugs suppress automaticity of conduction tissue by increasing the electrical stimulation threshold of the ventricle and His-Purkinje system. They are less prominent blockers of the Na+ channels at rest but effectively block the channels in depolarized tissues. In ischemic tissue, cells are partly depolarized because they lack sufficient ATP to operate the sodium pump. As a result, sodium channels in ischemic tissue spend more time in the inactivated state than do channels in nonischemic tissue. Because Class IB antiarrhythmics have a greater affinity for inactivated channels, they suppress conduction more in ischemic tissue than in normal tissue. Class IB drugs also dissociate from the sodium channel more rapidly than other Class I drugs. Class IB drugs have little effect on normal cardiac tissue and EKG findings at therapeutic levels. Hence, they are not very effective in the treatment of supraventricular arrhythmias because these arrhythmias usually arise in nonischemic tissue. Mexiletine has a slightly greater effect on normal cardiac tissue than does lidocaine.
Class 1B Clinical Applications
Ventricular tachyarrhythmias. Lidocaine is the drug of choice for the termination of ventricular tachycardia and the prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. Lidocaine’s use for VT has declined as a consequence of trials showing IV amiodarone to be superior. Mexiletine is occasionally used in patients with ventricular tachycardia who respond to IV lidocaine. Lidocaine is also used in the treatment of digitalis-induced arrhythmias. Lidocaine is used as a local anesthetic.
They prolongue QRS but decrease QT segment. Lidocaine shows no difference in EKG.
Slow Phase 0 & decrease slope of Phase 4
Shorten Phase 3 repolarization
Little effect on depolarization phase of action potential in normal cells
Class IB Adverse Effects
Lidocaine (IV only-extensive first pass metabolism)
Lidocaine has a wide toxic-therapeutic ratio so at therapeutic doses there is little risk of toxic effects. Adverse effects of lidocaine include dizziness, sedation, slurred speech, blurred vision, paresthesia, muscle twitching, confusion, nausea, vomiting, seizures, psychosis, sinus arrest, and aggravation of underlying conduction disturbances. Toxic doses of lidocaine result in convulsions/seizures and coma.
Mexiletine (derivative of Lidocaine, orally active)
Mainly CNS and GI side effects.
Name the 2 Class IC Drugs and their General Clinical Applications
Class IC (Flecainide & Propafenone)
Class IC drugs primarily block open Na+ channel and slow conduction. Due to their slow kinetics they are the most potent of all the class I drugs (reflected as a substantial increase in QRS). They produce a dose-related decrease in intracardiac conduction in all parts of the heart, with the greatest effect on the His-Purkinje system (HV conduction). The effects of Class IC drugs on atrioventricular (AV) nodal conduction time and intra-atrial conduction times, though present, are less pronounced than are the drug’s effects on ventricular conduction velocity.
Propafenone also has beta-blocking activity.
Class 1C Clinical Applications
Life-threatening supraventricular tachyarrhythmias and ventricular tachyarrhythmias. Prevention of paroxysmal atrial fibrillation and the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation. Both flecainide and propafenone are used almost exclusively for suppression of atrial arrhythmias in the structurally normal heart.
Marked increase in QRS but lenght of action potential is the same because it has no effect in the repolarization phase.
Class IC Adverse Effects
Class IC Adverse Effects
Flecainide
Common side effects with flecainide include blurred vision, dizziness, dyspnea, headache, tremor, nausea, aggravation of existing heart failure (due to negative inotropic effect) and conduction disturbances. Flecainide is associated with proarrhythmia and the potential for fatal ventricular arrhythmias in persons with structural heart disease. Conversely, flecainide does not appear to increase mortality when used for the treatment of supraventricular arrhythmias in persons with structurally normal hearts.
Propafenone
Approx. 15-20% of patients taking propafenone will have side effects that require drug discontinuation. Dizziness, fatigue, bronchospasm (due to a slight -blocking effect), headache, taste disturbances, GI upset, AV block, aggravation of underlying heart failure (due to -blocking and slight Ca2+ channel blocking activity), conduction disturbances, or arrhythmias can all occur with the use of propafenone. Propafenone intoxication, often due to overdose, is a life-threatening condition marked by heart failure, hemodynamically-unstable ventricular tachyarrhythmias and/or bradyarrhythmias, and seizures.
Class II Antiarrhythmics
What 3 drugs are Class II Antiarrhythmics?
(B-adrenergic Blockers)
Class II drugs are B-blockers (Esmolol, Metoprolol & Propranolol) and act by inhibiting sympathetic tone which affects predominantly slow-response tissues (SA and AV nodes).
Sympathetic stimulation is mediated primarily through β1-adrenoceptors and has the following proarrhythmic actions:
- An increase in automaticity due to enhancement of phase 4 spontaneous depolarization
- An increase in membrane excitability due to shortening in refractoriness (phases 2 and 3 of the AP)
- An increase in the rate of impulse conduction through the myocardial membrane resulting from acceleration of Phase 0 upstroke velocity or the rate of membrane depolarization
- An increase in delayed afterpotentials
Through these actions B-blockers slow the rate of discharge of the sinus and ectopic pacemakers and increase the effective refractory period of the AV node. Thus, heart rate is slowed, PR interval is lengthened, and repolarization is prolonged at the AV node.
Propranolol is a non-selective -blocker, whilst metoprolol and esmolol are B1- selective.
Prolonged repolarization at AV node = increased PR
Dominant effect is at the AV node, you slow impulses at AV node, you don’t want to dampen too much at SA node because it stops heart leading to a prolongued Phase 4. Useful in atrial fibrillation because it slows impulses through the AV node.
Class II Clinical Applications, Adverse Effects, and Contraindications
Clinical Applications
Class II drugs are primarily used to treat supraventricular arrhythmias (such as atrial flutter & fibrillation & AV-nodal re-entrant tachycardia). They are also used to treat ventricular tachyarrhythmias.
The use of B-blockers has been shown to reduce incidence of sudden arrhythmic death after MI. Useful in catecholamine-induced arrhythmias.
Pharmacokinetics
Esmolol is a short-acting 1-selective antagonist (t1/2 = ~9 min) and is useful in the treatment of acute arrhythmias occurring during surgery or in emergency situations.
Adverse Effects
B-blockers are usually well tolerated; adverse effects include sleep disturbance, GI upset, bradycardia, hypotension and CNS effects.
Contraindications
B-blockers are contraindicated in acute CHF, severe bradycardia or heart block (due to their negative inotropic effect) and severe hyperactive airway disease (due to the blockade of B2 receptors).
Class III Antiarrhythmics
Which 3 drugs are Class III Antiarrhythmics?
(K+ Channel Blockers)
Class III drugs (Amiodarone, Dofetilide and Sotalol) are primarily K+ channel blockers. By blocking the K+ channels responsible for phase 3 repolarization, class III drugs are able to prolong action potential duration and increase the effective refractory period in both fast- and slow-response tissues. The electrophysiological changes prolong the period of time that the cell is unexcitable (refractory) and therefore make the cell less excitable. The predominant effect on the ECG is QT-interval prolongation. Amiodarone however, is associated with a low risk of Torsades de Pointes (due to its multi-class effects).
Amiodarone shows class I (Na+ channel blocking), II (-blocking), III (K+ channel blocking) and IV (Ca2+ channel blocking) activity and therefore decreases the slope of phase 4 and conduction velocity in addition to its effect on phase 3. Its dominant effect is its ability to block K+ channels. Due to its wide range of effects, amiodarone is one of the most commonly employed antiarrhythmic drugs.
Dofetilide is a very potent K+ channel blocker and has virtually no extracardiac pharmacological effects. Potent and pure K+ channel blocker.
Sotalol is a class III antiarrhythmic that is primarily a potassium channel-blocking drug with a weak beta-blocking effect. Potent non-selective -blocker. Inhibits rapid outward K+ current.
Class III Clinical Applications
Clinical Applications
Amiodarone – severe supraventricular and ventricular arrhythmias. Amiodarone is the drug of choice for acute VT refractory to cardioversion shock or other antiarrhythmic agents. Amiodarone can also be used to maintain ventricular rate in patients with atrial fibrillation.
Dofetilide – maintenance of normal sinus rhythm in patients with chronic atrial fibrillation / flutter of longer than 1-week duration who have been converted to normal sinus rhythm. Conversion of atrial fibrillation / flutter to normal sinus rhythm.
Sotalol – treatment of life-threatening ventricular arrhythmias. Maintenance of sinus rhythm in patients with atrial fibrillation & flutter who are currently in sinus rhythm. Due to its pro-arrhythmic effects, sotalol is not used for asymptomatic arrhythmias.
Class III Adverse Effects and Contraindications
Pharmacokinetics
Amiodarone can be taken IV or orally. It has a very long t 1⁄2 (25-60 days) so requires a loading dose. The full clinical (and adverse) effects of the drug may take 6 weeks to be achieved.
Adverse Effects
Amiodarone- With long term use more than 50% of patients experience adverse effects severe enough for discontinuation. Most effects are dose-related and can be resolved by decreasing the dose. Common effects include tremor, ataxia, paresthesia, GI disturbances, bradycardia, AV block, hyper- or hypo-thyroidism (patients serum TSH should be tested before initiation of therapy), interstitial pulmonary fibrosis, arrhythmias, liver toxicity, photosensitivity, corneal deposits, blue-gray skin discoloration and hypotension (IV only).
Related structurally to thyroxine (contains iodine). It causes skin discoloration, change in skin tone (Blue skin discoloration)
Dofetilide- Common effects include headache and dizziness. Ventricular tachycardia and torsade de pointes can also occur.
Sotalol- has the lowest rate of long-term or acute adverse effects. It has similar effects to all B-blockers as well as dizziness, weakness and fatigue. Torsades de Pointes.
Contraindications
Amiodarone
Due to its class IV and class II effects amiodarone is contraindicated in patients with the following conditions:
- bradycardia
- SA or AV block
- severe hypotension
- severe respiratory failure
Amiodarone is also able to alter the concentrations of the following drugs digoxin, theophylline, warfarin and quinidine and dosage adjustments may be necessary.
Class IV Antiarrhythmics
Which 2 drugs are Class IV Antiarrhythmics?
Diltiazem & Verapamil
(Ca2+ Channel Blockers)
Class IV drugs (Diltiazem & Verapamil) are the ‘cardiac-selective’ Ca2+ channel blockers. They decrease Ca2+-dependent action potentials in slow-response tissues (decreased rate of phase 4 spontaneous depolarization) and thus decrease the rate of automaticity, slow conduction velocity, and prolong the effective refractory period. Heart rate is thus slowed and PR interval lengthened together with prolonged repolarization at the AV node.
Verapamil has slightly higher selectivity for the myocardium than diltiazem.
Decrease inward Ca2+ current leads to decreased rate of Phase 0 spontaneous depolarization
Slow conduction in tissues dependent on Ca2+ current (SA & AV nodes)
Major effects on both vascular & cardiac smooth muscle
Same effects as B-blockers, prolongued PR interval.
