Anti arrhythmic drugs

Key term Arrhythmia: disorder of cardiac conduction. Antiarrhythmic drug: drugs used to restore normal cardiac rhythm. Ectopic focus: area of the heart from which abnormal impulses originate. Supraventricular arrhythmia: arrhythmia that originates in the atrial or atrioventricular ( AV ) nodal area. Bradycardia: heart rates that are too slow < 60 beats/min. Tachycardia: heart rates that are too fast, rate rarely exceeds 200 beats/min in adults..

Background to Arrhythmia – Rhythm of the Heart Human heart is four- chambered Chambers need to contract sequentially (atria, then ventricles) and in synchronicity Also need relaxation between contractions to allow refilling of chambers Above controlled electrically (Purkinje fibers allow rapid, organized spread of activation)

Sequential Discharge of SA and AV nodes

Regulation of Heart Rate Primarily accomplished by sinoatrial node (SA) Located on right atrium Receives autonomic input When stimulated, SA signals atrial contractile fibers  atria depolarization and contraction (primes ventricles with blood) Depolarization picked up by atrioventricular node (AV node)  depolarizes ventricles  blood discharged to pulmonary artery and dorsal aorta  eventually rest of body

Spread of Excitation in the Heart

Classification of arrhythmias A. Their site of origin (atrial or ventricular) B. Whether they cause bradycardia or tachycardia

Mechanisms of Arrhythmias Bradycardia ( bradyarrhythmias ) result from the failure of impulse generation within the sinoatrial node or failure of the excitatory wavefront to conduct from the atrium to the ventricle through the atrioventricular node. In general, bradyarrhythmias are not amenable to longterm pharmacological therapy and may require permanent cardiac pacing.

Mechanisms of Arrhythmias Tachycardia( tachyarrhythmias ), conversely , frequently may be palliated with long-term medical therapy. The mechanisms supporting tachycardias may be classified broadly into three groups: Abnormal automaticity. Triggered activity. Reentry.

Normal ECG Ventricular Fibrillation Atrial Fibrillation

Ion Fluxes During Cardiac Action Potentials and Effects of Antiarrhythmic Drugs (A) Graph of action potential (fast AP) Diff drugs acting at diff phases Quinidine => on Na entry

Ion Fluxes During Cardiac Action Potentials and Effects of Antiarrhythmic Drugs (B)

Uses Mechanism Example Class Atrial and ventricular tachycardias Block Na+ channels (intermediate dissociation) Disopyramide Quinidine Procainamide Ia Ventricular arrhythmias (following infarct) Block Na+ channels (fast dissociation) Lignocaine Ib Ventricular tachycardia Block Na+ channels (slow Flecainide Ic Stress induced tachycardia β antagonist Propranolol II arrhythmias Unknown, ? increase refractory period Amiodarone Sotalol III Atrial tachycardia Calcium channel antagonist Verapamil IV

Class I drugs ( Sodium Channel-Blocking Drugs ) Class 1 action is sodium channel blockade. Subclasses of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade. Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics; Drugs with class 1B action have no significant effects on the APD and dissociate from the channel with rapid kinetics; and drugs with class 1C action have minimal effects on the APD and dissociate from the channel with slow kinetics.

Class I a Agents--- Quinidine Quinidine is an alkaloid obtained from various species of Cinchona or its hybrids, from Remijia pedunculata, or from quinine Sodium Channel Blockers Slows conduction in whole heart Cholinergic => PS effect, slow hr Anti-chol => increase hr

Pharmacokinetics Almost complete absorption Oral bioavailability 1–3 hours Onset of action 1–2 hours Peak response 6–8 hours Duration of action 6 hours Plasma half-life Hepatic; active metabolite Primary route of metabolism 10–50% renal (unchanged) Primary route of excretion 2–4 g /mL Therapeutic serum concentration

Therapeutic Use Maintenance of normal sinus rhythm in patients with atrial flutter or fibrillation. Used occasionally to treat patients with ventricular tachycardia.

side effects Gastrointestinal : diarrhea (35%). nausea, and vomiting (25%). Cinchonism: a syndrome of headache, dizziness, and tinnitus is observed at toxic drug concentrations. Idiosyncratic reactions including thrombocytopenia, hepatitis, angioneurotic edema,and fever are observed rarely. cardiac toxicity: includes A-V and intraventricular block, ventricular tachyarrhythmias, and depression of myocardial contractility. induction of torsade de pointes arrhythmia, and syncope has been referred to as quinidine syncope

Drug Interactions Quinidine can increase the plasma concentrations of digoxin, which may in turn lead to signs and symptoms of digitalis toxicity. Cimetidine inhibits the hepatic metabolism of quinidine. Phenytoin, rifampin, and barbiturates increase the hepatic metabolism of quinidine and reduce its plasma concentrations.

Procainamide (class 1a) is a derivative of the local anesthetic agent procaine. The electrophysiologic effects of procainamide are similar to those of quinidine with less prominent antimuscarinic action. It is effective orally. Administered safely by the intravenous and intramuscular routes It has a longer half-life ( N-acetylprocainamide (NAPA), which has class III activity)

Procainamide (class 1a) Therapeutic Use It is effective against most atrial and ventricular arrhythmias. Procainamide is the drug of second choice (after lidocaine) in most coronary care units for the treatment of sustained ventricular arrhythmias associated with acute myocardial infarction. does not cause CNS toxicity at therapeutic plasma concentrations.

Procainamide (class 1a) Toxicity Cardiac Procainamide's cardiotoxic effects are similar to those of quinidine. New arrhythmias may be precipitated. Extracardiac Approximately one third of patients receiving long-term therapy develop reversible lupus-related symptoms, consisting of arthralgia and arthritis. serologic abnormalities (eg, increased antinuclear antibody titer) occur in nearly all patients. Other adverse effects include nausea and diarrhea (about 10% of cases), rash, fever, hepatitis (< 5%), and agranulocytosis (approximately 0.2%).

Disopyramide. (class 1a) The effects of disopyramide are very similar to those of quinidine. Its cardiac antimuscarinic effects are even more marked than those of quinidine. Therapeutic Use can suppress ventricular arrhythmias and is longer acting than other drugs in its class. Disopyramide's atropine-like activity accounts for most of its symptomatic adverse effects.

Disopyramide. (class 1a) Toxicity Cardiac It can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. It should not be used in patients with heart failure. Extracardiac atropine-like activity accounts for most of its symptomatic adverse effects: urinary retention ,dry mouth,blurred vision, constipation, and worsening of preexisting glaucoma.

Lidocaine (Subgroup 1b) It is alocal anesthetic. It is used only by the intravenous route. Lidocaine blocks activated and inactivated sodium channels with rapid kinetics. Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction.

Lidocaine Toxicity Cardiac It is one of the least cardiotoxic. Proarrhythmic effects, including sinoatrial node arrest, worsening of impaired conduction.

Lidocaine Toxicity Extracardiac neurologic: paresthesias, tremor, nausea of central origin, light headedness, hearing disturbances, slurred speech, and convulsions. The effects are dose-related and usually short-lived; seizures respond to intravenous diazepam.

Flecainide (Subgroup 1c) Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects. it may cause severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with a previous myocardial infarction and ventricular ectopy The drug is well absorbed and has a half-life of approximately 20 hours

Class IC Agents--- Propafenone Propafenone has some structural similarities to propranolol and possesses weak β-blocking activity. Its spectrum of action is very similar to that of quinidine. Its sodium channel blocking kinetics are similar to that of flecainide. Propafenone is metabolized in the liver, with an average elimination of 5–7 hours except in poor metabolizers (7% of whites), in whom it is as much as 17 hours. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation; arrhythmia exacerbation can occur.

Class II drugs Class 2 action is sympatholytic. Drugs with this action reduce β-adrenergic activity in the heart.

Class II. Beta Blocker --- Propranolol (β1 & β 2 -blocker Propranolol and similar drugs have antiarrhythmic properties by virtue of their -receptor–blocking action and direct membrane effects. Therapeutic Use Supraventricular tachycardia (above the AV node), Contraindication: asthma b/c it blocks β 2 receptors => airways constriction)

Class II. Beta Blocker Esmolol is a short β1 -acting blocker used primarily as an antiarrhythmic drug for intraoperative and other acute arrhythmias.

Class III drugs Class 3 action is manifest by prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectifier potassium current,

Class III drugs Amiodarone Amiodarone has a broad spectrum of cardiac actions. The drug is effective in the prevention of recurrent ventricular tachycardia. Its use is not associated with an increase in mortality in patients with coronary artery disease or heart failure.

Amiodarone Toxicity Cardiac: Amiodarone may produce symptomatic bradycardia and heart block in patients with preexisting sinus or atrioventricular node disease.

Amiodarone Toxicity Extracardiac: Dose-related pulmonary toxicity. Fatal pulmonary fibrosis may be observed in 1% of patients. Abnormal liver function tests and hepatitis may develop. The skin deposits result in aphotodermatitis and a gray-blue skin discoloration in sun-exposed areas Amiodarone may result in hypothyroidism or hyperthyroidism. Amiodarone blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3). It is also a potential source of large amounts of inorganic iodine

Class III drugs Bretylium Bretylium was first introduced as an antihypertensive agent. It interferes with the neuronal release of catecholamines but also has direct antiarrhythmic properties. Therapeutic Use Bretylium is usually used in an emergency setting, often during attempted resuscitation from ventricular fibrillation when lidocaine and cardioversion have failed. Bretylium is available only for intravenous use.

Bretylium Toxicity Cardiac Effects Since bretylium causes an initial release of catecholamines, it has some positive inotropic actions when first administered. This action may also precipitate ventricular arrhythmias and must be watched for at the onset of therapy with the drug. Extracardiac Effects The major adverse effect is postural hypotension. This effect can be almost totally prevented by concomitant administration of a tricyclic antidepressant agent such as protriptyline. Nausea and vomiting may occur after the intravenous administration of a bolus of bretylium.

Class III drugs Sotalol A class III drug and also a β antagonist Less adverse effects than amiodorone. Therapeutic Use Treatment of life-threatening ventricular arrhythmias and the maintenance of sinus rhythm in patients with atrial fibrillation. Treatment of supraventricular and ventricular arrhythmias in the pediatric age group. The adverse effects which do occur are the result of its β blocking effects (e.g. bronchoconstriction, decreased cardiac activity)

Class IV drugs Class 4 action is blockade of the cardiac calcium current. This action slows conduction in regions where the action potential upstroke is calcium dependent, eg, the sinoatrial and atrioventricular nodes.

Class IV: Calcium Channel Blockers Verapamil Blocks voltage sensitive Ca2+ channels More selective for cardiac tissue than Ca2+ channels present elsewhere (e.g. in vascular smooth muscle) Shortens phase 2 (plateau phase) of the action potential by reducing the influx of Ca2+. This causes Suppression of premature ectopic beats by preventing phase 4 depolarisation Reduces cardiac contractility Must not use verapamil in conjunction with β blockers because they both have an additive effect in causing cardiac depression Effective for use in atrial tachycardia (but not ventricular tachycardia) Do not use if there is underlying impairment of cardiac contractility

Class IV: Calcium Channel Blockers DILTIAZEM: Diltiazem appears to be similar in efficacy to verapamil in the management of supraventricular arrhythmias, including rate control in atrial fibrillation. An intravenous form of diltiazem is available for the latter indication and causes hypotension or bradyarrhythmias relatively infrequently.

Other miscellaneous drugs Digoxin: It is a cardiac glycoside A positive ionotropic agent (increases the force of contraction) It delays AV conduction. Also sensitises the AV node to vagal input (it enhances parasympathetic activity on the heart). Increased cardiac output as a result of increased force, decreases sympathetic activity. Therefore, by preventing sympathetic activity, the possibility of arrhythmias is reduced.

Other miscellaneous drugs Digoxin: It is used to slow ventricular rate in atrial fibrillation i.e. It does not stop the atrial fibrillaton. Instead, it slows the AV conduction, so that the impulses reaching the ventricles is slowed, rather than at the abnormal rate present in the atrium.

Other miscellaneous drugs Adenosine Adenosine is a nucleoside that occurs naturally throughout the body Acts at A1 adenosine receptors to slow AV conduction Used acutely (intravenous) to reverse supraventricular tachycardias Adverse effects: Flushing (vasodilator effect) Bronchospasm Chest pain (due to bronchospasm) These adverse effects are due to the action of A1 receptors located at other sites

Other miscellaneous drugs Atropine M antagonist Blocks parasympathetic activity to the heart Used to treat sinus bradycardia.