Chapter 8  Medical Pharmacology:   Antiarrhythmic Agents

Antiarrhythmic Drug Classes

• ß-adrenoceptor blockers:

  • Decrease the slope of phase IV depolarization slowing the heart

  • Depressing automaticity.

  • Conduction time through AV node is increased while contractility is diminished.

• Class II Antiarrhythmic drugs

  • Propranolol (Inderal)

  • Metoprolol (Lopressor) (beta-1 "specific")

  • Pindolol (Visken) (partial agonist)

  • Esmolol (Brevibloc)(very short acting)

• Propranolol

  • Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally, sympathetic drive results in increased in Ca²⁺ ,K⁺ ,and Cl^- currents.

  • Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias. These effects are blocked by beta-adrenergic receptor blockers.

  • β-adrenergic receptor blockers increase AV conduction time and increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

  • β-adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and fibrillation, again by acting at the AV node.

  • Adverse effects of beta blocker therapy can lead to fatigue, bronchospasm, depression, impotence, and attenuation of hypoglycemic symptoms in diabetic patients and worsening of congestive heart failure.

  Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241

• Esmolol (Brevibloc)

  • Esmolol (Brevibloc) is a very short acting, cardioselective beta-adrenergic receptor antagonist.

  • I.V. administration is used for rapid beta-receptor blockade in treatment of atrial fibrillation with high ventricular following rates.

  • Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally, sympathetic drive results in increased in Ca²⁺ ,K⁺and Cl^- currents.

  • Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias. These effects are blocked by beta-adrenergic receptor blockers.

  • β-adrenergic receptor blockers

    • Increase in AV conduction time

    • Increase in AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241; Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Class III: Potassium Channel Blockers

• Blockade of potassium channels delay repolarization and prolong the action potential. As a result, the effective refractory period is increased.

  • Bretylium (Bretylol)

    • Overview:

      • Initially released as an antihypertensive agent.

        •  Orthostatic hypotension may occur following chronic use

      • Inhibits neuronal catecholamine release, following an initial direct early release of norepinephrine from adrenergic nerve terminals (transient hypertension)

      • Direct antiarrhythmic properties

    • Pharmacokinetics:

      • IV or IM Route of Administration

      • Following rapid IV administration: nausea and hypotension

      • After the first doses: bretylium-mediated norepinephrine release causes:

        • Transient hypertension

        • Increased ventricular irritability (particularly in patients also receiving digitalis)

      • Renal elimination: 8-12 hour halftime

      • Dosage reduction required in patients with renal dysfunction

      • Hepatic metabolism: not demonstrated

    • Cardiac Actions:

      • Antiarrhythmic effect due to prolongation of the cardiac action potential and inhibition of norepinephrine reuptake by sympthetic nerves

      • Increased ventricular (not atrial) action potential duration and effective refractory period

      • Somewhat selective for ischemic cells which have shortened action potential durations

        • Bretylium may reverse shortening of action potential duration due to ischemia

      • Possesses anti-fibrillatory activity; independent of sympatholytic action

      • Initial catecholamine release (prior to inhibition of release), results in some positive inotropic effect; however, this action may induce ventricular arrhythmias (catecholamines generally are pro-arrhythmogenic).

      • Inhibition of catecholamine release may result in bradycardia.

    • Clinical Use:

      • Management of serious ventricular arrhythmias refractory to lidocaine or procainamide

      • Possible initial drug for treatment of ventricular fibrillation--Rationale:

        • Increases ventricular fibrillation threshold;

        • Prolongs action potential duration;

        • Prolongs effective refractory period

  • Amiodarone (Cordarone)

    • Overview:

      • A benzofurane derivative, 37% iodine by weight, structurally similar to thyroxine

        • May cause hypothyroidism or hyperthyroidism (frequency: 2%-4%)

          • Insidious development

          • Patients with previous thyroid dysfunction: more likely to develop amiodarone-mediated thyroid effects

          • Hyperthyroidism: most readily evidenced by increased plasma level of triiodothyronine

            • Secondary to iodine release from parent drugs;

            • Often refractory to conventional treatment

              • Intolerant of β-adrenergic receptor blockade (because of underlying cardiac disease)

            • Following failed medical management: surgical thyroidectomy is appropriate

              •  bilateral superficial cervical plexus block has been used for anesthetic management of subtotal thyroidectomy in this patient group

          • Hypothyroidism: most readily evidenced by increased plasma level of thyroid-stimulating hormone (TSH)

        • May interfere with certain radiologic procedures (Iodine accumulation)

      •  Approved for use only in treatment of serious ventricular arrhythmias (USA)

        • Also used for refractory supraventricular arrhythmias

      •  Numerous adverse effects.

    • Metabolism and Excretion

      • Long elimination halftime: 29 days

      • Minimal renal excretion

      • Principal metabolite (desmethylamiodarone) -- longer elimination halftime compared to amiodarone

      • Extensive protein binding

      • Amiodarone concentrated in the myocardium (10-50 times plasma concentration)

    • Cardiovascular Properties and Uses:

      • Used in patients with ventricular tachycardia or fibrillation resistant to treatment with other drugs.

      • Effective inhibitor of abnormal automaticity.

      • Oral administration, preoperatively, reduces likelihood of atrial fibrillation following cardiac surgery.

      •  Suppresses tachyarrhythmias associate with Wolff-Parkinson-White syndrome

        • secondary to depression of conduction in the AV node and accessory bypass tracts.

      • Similar to beta-blockers (unlike most class I antiarrhythmics), amiodarone decreases mortality after myocardial infarction

      • Antiarrhythmic effectiveness begins within 72 hours following initiation of oral treatment; nearly immediate effect following IV administration

        • Following discontinuation of chronic oral therapy: pharmacological effects may last up to two months (long elimination half-time)

    • Mechanism of Action

      • Blocks sodium and potassium channels and prolongs action potential duration.

      • Prolongs effective refractory period in

      1. SA node

      2. AV node

      3. Ventricles

      4. Atrium

      5. His-Purkinje system

      6. Accessory bypass tracts (Wolff-Parkinson-White syndrome)

    • Vascular Effects

      • Noncompetitive α- and β-adrenergic receptor blocker

      • Systemic vasodilation

      • Antianginal properties, secondary to coronary vasodilation

    • Side Effects

      • Pulmonary:

        • Most serious adverse effect seen in long-term therapy is a rapidly progressive pulmonary fibrosis which may be fatal

          • Frequency: 5%-15% treated patients

          • Mortality rate: 5% to 10%

          • Cause: unknown (possibly related to amiodarone-mediated generation of free oxygen radicals in the lung)

          • Two types of amiodarone-pulmonary toxicity clinical presentations:

            1.  More common: Slow, insidious, progressive dyspnea, cough, weight loss, pulmonary infiltration (chest x-ray)

            2.  Acute onset: dyspnea, cough, arterial hypoxemia.

      •  Anesthetic Implications: pulmonary

        •  Suggested restriction of inspired oxygen concentration in patients receiving amiodarone (Cordarone) and undergoing general anesthesia to as low a level as while retaining adequate systemic oxygenation

        •  Postoperative pulmonary edema has been reported in patients treated with amiodarone (Cordarone) chronically-- resembles acute onset form of amiodarone toxicity.

        •   In patients with preexisting amiodarone-caused pulmonary damage are at increased risk for adult respiratory distress syndrome following surgery requiring cardiopulmonary bypass.

      • Cardiovascular:

        • Prolongation of QT interval (ECG); increased incidence of ventricular tachyarrhythmias (including torsades de pointes)

        • Bradycardia (atropine-resistant)

        • Catecholamine responsiveness: diminished due to α- and β-receptor blocking activity

        • Hypotension; A-V block (following IV administration)

      • Anesthetic Implications: cardiovascular

        • With general anesthesia -- enhanced antiadrenergic action, presentation as:

          • A-V block, sinus arrest, decrease cardiac output, hypotension

          • Sinus arrest more likely in the presence of anesthetics that inhibit SA nodal automaticity (e.g. lidocaine, halothane)

          • Consideration should be given for temporary ventricular pacemaker and sympathomimetic administration (e.g. isoproterenol) for patients taking amiodarone and scheduled undergo surgery.

      • Ocular and other Side Effects and Drug-drug interaction:  As above

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241; Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Class IV: Calcium Channel Blockers

• These drugs block the inward calcium current and therefore slow conduction through the AV node and decrease the slow of phase 4 depolarization.

  • Calcium channel blockers are especially active at vascular smooth muscle and at the heart.

    • Verapamil (Isoptin, Calan) (main action on the heart)

    • Nifedipine (Procardia, Adalat) (main action on vascular smooth muscle (anti-hypertensive effect))

    • Diltiazem (Cardiazem) (action on both the heart and vascular smooth muscle)

• Adenosine (Adenocard)   

  • Effects mediated through G protein-coupled adenosine receptor.

  • Activates acetylcholine-sensitive K+ current in the atrium and sinus and A-V node.

  • Decreases action potential duration, reduces automaticity

  • Increases A-V nodal refractoriness

  • Rapidly terminates re-entrant supraventricular arrhythmias (I.V)