Cardiac Electrophysiology And Drugs

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Subclasses of Class I Na Channel Blockers

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IA: Na channel blockade with intermediate dissociation time (1-3 sec) from resting channel plus increase in action potential duration (APD) (Also has K+ channel block--Class III activity).(quinidine, procainamide, disopyramide,)

IB: Na channel blockade with rapid dissociation time (0.1-0.4 sec) APD shortening (block of window Na current) (lidocaine, mexiletine)

IC: Na channel blockade with long dissociation time (10 sec) "no change in APD" (but this varies with region and action potential frequency) (flecainide, propafenone)

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Class II drugs

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Beta Blockers

1. Mechanisms: Decrease sympathetic tone to heart, thus decreasing automaticity and increasing refractoriness at the AV node and decreasing sympathetic-induced DADs. (propranolol, acebutalol, esmolol, sotalol(also has class III activity), carvedilol (also blocks ryanodine (RyR2) receptor decreasing intracellular Ca release)

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Class III drugs

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Action potential lengtheners—most are K channel blockers

1. Mechanisms by which K channel blockers can be antiarrhythmic: Increase refractoriness by increasing the action potential duration. (dofetilide, sotalol, amiodarone and dronedarone (both also class I, II and IV actions))

2. Another mechanism for increasing APD is to enhance the “window” (or persistent) Na current--ibutilide does this (as well as some K blocking action)

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Class IV drugs

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Calcium channel blockers (nondihydropyridine)

1. Mechanisms by which Ca channel block can be antiarrhythmic. Decreases conduction velocity and increases threshold and refractoriness in nodal cells and decreases the terminal portion of phase 4 depolarizations via block of Ca component which also decreases excitability. (verapamil, diltiazem)

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quinidine

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IA Na channel blocker

Has vagolytic properties (common to all IA antiarrhythmics but to varying degrees) in addition to IA, so effects on SA and AV node are a combination of direct actions (Na block in AV transitional cells) and vagal block. If given alone with atrial flutter or fibrillation can produce "paradoxical" ventricular tachycardia

Arrhythmogenic--torsades de pointes (classic "quinidine syncope")—secondary to prolongation of ventricular action potentials (QT). The incidence of torsades with quinidine is reduced if verapamil is also given

Negative inotropic effects.

Most common non-cardiac effects are GI--diarrhea, nausea/vomiting; and cinchonism
(headache, dizziness, tinnitus)

Inhibitor of CYP2D6 (It is marketed with dextromethorphan for treatment of pseudobulbar affect, to increase the bioavailability and decrease the clearance of dextromethorphan. Quinidine levels are well below those necessary for antiarrhythmic action.)

Inhibitor of P-glycoprotein, reduces renal clearance of digoxin.

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procainamide

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IA Na channel blocker

Similar to quinidine, but much less vagolytic action, less toxicity

Only available for IV administration—approved for treatment of monomorphic ventricular tachycardia

Classic non-cardiac effect (when drug was used chronically) is drug-induced lupus erythematosis-like syndrome. (Like many other drugs that can causes ANA and lupus, procainamide is metabolized by N-acetyltransferase )

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lidocaine

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IB Na channel blocker


The prototype IB antiarrhythmic, lidocaine primarily blocks inactivated channels, but has rapid dissociation so that with normal diastolic intervals most channels become unblocked and the normal EKG is unaffected.

Lidocaine is particularly effective in depolarized tissue and except for digoxin toxicity, use is restricted to ventricular arrhythmias.

Lidocaine can only be given parenterally because there is extensive first pass metabolism and the metabolites contribute to toxicity, but not to the therapeutic effect.

Most important non-cardiac effects are neurological--dizziness--lightheadedness to seizures (see local anesthetic syllabus)

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flecainide

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IC Na channel blocker

The prototype IC antiarrhythmic, flecainide has a very slow off-rate from the sodium channel so that conduction is depressed even at slow rates. It was originally described as a sodium blocker that did not change the APD. However, it can block K channels, but unlike quinidine which has optimal K blocking activity at low heart rates, flecainide has significant K blocking activity only at faster rates.

Eliminated both by metabolism (some via CYP2D6), and unchanged in urine (<50%)

Arrhythmogenic

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propafenone(just class identification)

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IC Na Channel Blocker

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propranolol

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Bblocker

Primary action is to block sympathetic tone, thus decreasing conduction and increasing AV refractoriness.

This can be used for "rate control" in patients with atrial fibrillation and to block AV re-entrant tachycardias(PSVT). Beta blockade will also reduce DADs evoked by high sympathetic tone in patients with no myocardial damage who have ventricular tachycardia triggered by the DADs

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esmolol

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Bblocker

A beta blocker with a half-life of about 10 minutes due to metabolism by blood esterases. It is well suited for rapid titration of appropriate plasma levels by IV infusion.

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sotalol

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Bblocker

A non selective beta blocker with prominent K blocking activity( d isomer).

Torsade de pointes

Primarily excreted unchanged in urine.

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carvedilol

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Bblocker

A beta blocker with alpha blocking activity and antoxidant properties is very effective in reducing ventricular arrhythmias and sudden death in patients with heart failure.

Superior efficacy may be due to direct blockade of calcium release from overloaded sarcoplasmic reticulum (SOICR) which can cause DADs and subsequent ventricular tachycardias.

The block of release is via open channel block of the cardiac ryanodine receptor (the RYR2 Ca channel in the sarcoplasmic reticulum). None of the other beta blockers share this property. Because beta agonism induces Ca overload, carvidilol exerts two favorable actions.

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amiodarone

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A drug that has been variously classified in class III and in Class I, it has activity across all four antiarrhythmic classes, it has Na blocking activity, beta blocking activity, K channel blocking activity and Ca channel blocking activity.

Its class III action is sustained at rapid heart rates so the incidence of Torsade de pointes is very low compared to other class IA and III drugs. These other drugs have what is called “reverse” use-dependence—that is they have their greatest K channel blocking effects at slow heart rates.

The drug is structurally related to thyroid hormone and interactions with thyroid hormone receptors may contribute to its therapeutic effect.

Pharmacokinetics. Amiodarone has an extremely long half-life (weeks to months) because the drug has a very large Vd (66L/kg) (high lipid solubility). For chronic oral use, it takes a long time to build concentration to therapeutic levels so an extended period of higher than maintenance doses is generally used for oral administration.

Metabolized by CYP3A4 and 2C8 to N,desethylamiodarone (active,-Na>Ca block, t1/2=2 months).

There are some differences in the relative magnitude of the various class effects of amiodarone given intravenously vs. those that are seen with chronic oral administration. A reasonable generalization is that the ratio of the class III effects relative to the AV nodal effects are greater with chronic oral administration.

FDA approved for ventricular arrhythmias, it also has shown significant efficacy in preventing recurrent atrial fibrillation, and is used off-label.

Adverse effects:
acute--with IV administration: -hypotension—most likely in patients with left ventricular dysfunction
chronic--related to maintenance dose and cumulative dose--so may involve tissue accumulation: pulmonary fibrosis, corneal microdeposits, hepatic dysfunction, thyroid abnormalities--hypo and hyperthyroidism, peripheral neuropathy and myopathy, photosensitivity

Drug interactions--Amiodarone is an inhibitor of CYP3A4 , 2C9, 1A2, 2D6 as well as the P-glycoprotein drug transporter. Reduced doses of warfarin, digoxin, flecainide, procainamide, quinidine, theophylline are often required.

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dronedarone

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An iodine free analog of amiodarone, with similar actions across the spectrum of antiarrhythmic mechanisms. As with amiodarone there are active metabolites, and caution is warranted with concomitant inhibitors of CYP3A4, as well as substrates for P-gP, CYP2D6 and CYP3A4 all of which can be inhibited by dronedarone.

Lacks the thyroid and pulmonary toxicity associated with amiodarone, but has recently been associated with rare but severe liver toxicity including 2 cases where transplant was necessary.

Contraindicated in class IV heart failure or class II or III, if recent decompensation

Has half-life of only about 1 day.

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dofetilide

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A prototype Class III agent , dofetilide blocks the rapidly activating component of the delayed rectifier (IKr). It exhibits reverse use dependence. It is used in atrial fibrillation and flutter to convert patients (better success with flutter) and to prevent reoccurrence. It is available for oral use.

Torsade de pointes—Because of danger of torsades, it is only available to those with special training and treatment initiation must be done in hospital.

Virtually no important extracardiac effects.

Elimination: 80% renal, 20% CYP3A4.

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verapamil

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. Prototype Class IV antiarrhythmic it can be used for rate control in atrial fibrillation or to control AV nodal reentrant tachycardias (PSVT). There may be some role in ventricular tachycardias that are sympathetically-evoked, but caution, it can be dangerous in patients with ventricular tachycardia secondary to myocardial damage (hypotension and ventricular fibrillation may result), so diagnosis must be accurate.
2. Cardiac side effects include complete AV block, sinus arrest in patients with diseased sinus node, and negative inotropic activity.

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adenosine

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Activation of A1 receptors (Gi/o coupled) increases K permeability, and inhibits adenylyl cyclase, and decreases Ca conductance at the AV node (and in atrial tissue) (action similar to activation of M2 receptors by acetylcholine). The clinical use of adenosine is based on its ability to slow conduction and increase refractoriness at the AV node. AV actions are greater than SA actions.

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digoxin

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Inibits cardiac Na/K ATPase and enhances vagal effects on the heart. Slows heart rate and AV conduction and increases AV refractoriness.