Sodium channel blockers

Sympathetic cascade blockers

Potassium channel blockers

Calcium channel blockers

Selectively target ectopic pacemakers and decrease their automaticity (more than the SA node)

Reduce conduction/excitability

Increase refractory period

Steady state reduction in the number of available unblocked channels

Prolongation of the recovery time of sodium channels

Sodium channel blockade

3 subclasses

Class IA antiarrhythmics

Mechanism of Action

Prolong the action potential duration by slowing upstroke

Prolong QT interval by blockade of K channels

Increased QRS duration by slowing conduction in conduction system

Dissociate from channel with intermediate kinetics

Examples = procainamide, quinidine, disopyramide

Class IA antiarrhythmics

Extracardiac Effects

Peripheral vascular resistance

Hypotension

Class IA antiarrhythmics

Toxicity

Action potential prolongation
QT prolongation

Induction of torsade de pointes

Arrythmia

Syncope

Excessive slowing of conduction sys -> new arrhythmias

Class IA antiarrythmic

Can cause SLE like symptoms in 1/3 of patients

Eliminated by hepatic metabolism to NAPA (t1/2: 3-4 hrs)

NAPA eliminated by kidney (can cause torsade)

Class IA antiarrhythmic

Can cause anti-muscarinic effects (dry)

More pronounced effects

Need to be given with a drug that slows AV conduction when used for atrial fibrillation

Half life = 7-8 hours

Type IA antiarrythmic

Some antimuscarinic effects (dry)

Half life = 6-8 hours

Effective against atrial and ventricular arrhythmias

Requires frequent dosing, not good for long term

Therapeutic use for quinidine

Rarely used

Maintain normal sinus rhythm in patients with normal hearts but with atrial flutter or fibrillation

Patients treated with quinidine more likely to have normal sinus rhythm, but 2-3x increase in death

Therapeutic use for disopyramide

Rarely used

Only approved for treatment of ventricular arrhythmias in the US

Class IB Antiarrythmics

Mechanism of action

Shorten the action potential duration

Dissociate from channel with rapid kinetics

Preferentially affect more depolarized tissues

No effect on conduction

Increased inactivation and slow unbinding kinetics -> selective depression of conduction in depolarized cells, little effect on normal cardiac cells

Examples: lidocaine, mexiletine

Lidocaine

Cardiac Toxicity

Lowest cardiotoxicity of all sodium  blockers

Proarrhythmic effects: SA node arrest, worsening of impaired conduction, ventricular arrhythmia

In large doses, may decrease contractility, causing hypotension in patients with preexisting heart failure

Lidocaine

Extracardiac toxicity

Dose related

Local anesthetic .: neurologic effects

Paresthesia, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions.

Lidocaine

Pharmacokinetics

Extensive first pass hepatic metabolism

Only 3% of orally administered drug makes it to plasma

Usually given parenterally

T 1/2: 1-2 hours

Lidocaine

Therapeutic Uses

Highly effective for arrhythmias from acute MI (metabolic injury)

Agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion during acute ischemia

Class IB Antiarrhythmic

Orally active cogener of lidocaine

Similar function

T 1/2: 8-20 hours

Used for chronic pain due to diabetic neuropathy and/or nerve injury

Minimal effects of action potenial duration

Dissociate from channel with slow kinetics

Used for patients with otherwise normal hearts with supraventricular rhythms

Examples: flecainide, moricizine, propafenone

Class IC Antiarrhythmics

Toxicity

Provocation or exacerbation of arrhythmia

Can accelerate ventricular rate in patients with atrial flutter

Can increase frequency of episodes of re-entrant ventricular tachycardia

Flecainide

Pharmacokinetics

Elimination by renal excretion of unchanged drug AND

hepatic metabolism to inactive metabolites

T 1/2 = 10-17 hours (depends on urinary pH)

Type IC Antiarrhythmic

Many metabolites, some which can remain active and have long half-lives

Beta-adrenoceptor blocking drugs, examples: propanolol, esmolol

Reduce cAMP -> reduction in sodium, calcium current -> suppression of abnormal pacemakers

AV node particularly sensitive, prolong the PR interval

Safer than class I, used to control ventricular contraction in a-fib/flutter

Contraindicated for patients with Wolff-Parkinson-White

Class II Antiarrhythmic

Non-selective beta adrenoceptor antagonist

T 1/2 = 3-6 hours

Type II antiarrhythmic

IV cardioselective/beta-1 selective agent

T 1/2 = 9 minutes

Effects disappear within 30 mins after stopping the infusion

Effective in controlling the ventricular response to atrial flutter/fibrillation, especially after cardiac surgery

Esmolol

Adverse Effects

Hypotension

Bradycardia

Usually stop within 30 minutes after infusion terminated

Prolong effective refractory period by prolonging action potential, examples: sotalol, ibutilide

Blockade of Ik potassium channels OR enhance inward current

Reduces ability for heart to respond to tachycardia

Increase QT interval

Reverse use dependent: most reduction at lower heart rates

Can induce torsade de pointes at lower heart rates

Class III antiarrhythmic, nonselective beta-blocking drug

More effective for arrhythmias than beta blockers because of Ik inhibition

T1/2 = 12 hours

Approved for treatment of life-threatening ventricular arrhythmias and maintenance of sinus rhythm in patients with atrial fibrillation

Approved for supraventricular and ventricular arrhythmias in pediatric population

Sotalol

Adverse effects

Dose related torsade de pointes

Excessive beta blockade -> sinus bradycardia, asthma

Class III Antiarrhythmic, most efficacious of all antiarrhythmics

Can block sodium, calcium, potassium channels and beta aderenoceptors

Only used for arrhythmias that are resistant to other drugs

Rapid elimination (3-10 days), slower component (weeks)

Effects for 1 to 3 months

Amiodarone

Toxic effects

Many toxic effects

Microcrystalline deposits in cornea and skin

Thyroid dysfunction

Parasthesias

Tremor

Pulmonary Fibrosis

Amiodarone

Therapeutic Uses

Most effective in preventing recurrences of a-fib, VT, v-fib

Increase in mortality in patients with CAD, CHF

Slows cardiac repolarization of Ik

May induce expression of slow inward Na current

Adverse effect: excessive QT interval, torsades de pointes

IV used for acute a flutter, a-fib

Class III Antiarrhythmic

Slows cardiac repolarization by blockade of Ikr

Torsades de pointes

Approved for maintenance of normal sinus rhythm in patients with a-fib

Class III Antiarrhythmic

Structural analog of amiodarone

First antiarrhythmic to demonstrate a reduction in mortality or hospitalization of patients with a-fib

Type III antiarrhythmic

Investigational mulit channel blocker

Developed for treatment a-fib

Calcium channel blockers, prototype: verapamil, dilitazem

Extensively metabolized by liver

T 1/2: 7 hrs (V), 4 hrs (dil)

Block activated and inactivated L-type calcium channels

Increase refractory period (PR interval increased)

Cause peripheral vasoconstriction

Dose related, usually avoidable

AV block with large doses or AV node disease

Constipation, lassitude, nervousness, peripheral edema

Contraindicated in Wolff-Parkinson-White syndrome

Therapeutic use

Verapamil/dilitazem

Adults with heart failure, SA/AV nodal disease

To terminate supraventricular tachycardia (adenosine preferred)

Used in patients to prevent recurrence

Activate inward rectifier K+ current, inhibit Ca current

Hyperpolarization and suppression of calcium dependent action potentials

Directly inhibits AV nodal conduction

Increases AV nodal refractory period (smaller effect on SA) High efficacy, short duration of action

Drug of choice for conversion of paroxysmal supraventricular tachycardia to sinus rhythm

Antiarrhythmic effects even with normal Mg levels

Indicated for digitalis-induced arrhythmias