ANTI ARRHYTHMIC DRUGS

Antiarrhythmic drugs:

Antiarrhythmic drugs Dr Kiran Kumar C

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The cardiac action potential has five phases. The standard model used to understand the cardiac action potential is the action potential of the

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Arrhythmias result from (1) Disturbances in impulse formation, (2) Disturbances in impulse conduction, or (3) Both. Factors can precipitate or exacerbate arrhythmias: Ischemia, hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine exposure, autonomic influences, drug toxicity (eg, digitalis or antiarrhythmic drugs), overstretching of cardiac fibers, and the presence of scarred or otherwise diseased tissue

Types::

Types: Tachyarrythmias Bradyarrhythmia Tachyarrythmias Atrial Nodal ventricular -Af,Afib -A-V nodal -VT, -SVT -tachycardia -Vf -Sinus tachycardia -VF

classification:

classification CLASSIFICATION OF ANTI-ARRHYTHMIC DRUGS ACCORDING TO THEIR EFFECT ON THE INTRACELLULAR ACTION POTENTIAL Class I -membrane- stabilising agents (sodium channel blockers) ( a ) Block Na + channel and prolong action potential Quinidine , disopyramide , procainamide ( b ) Block Na + channel and shorten action potential Lidocaine , mexiletine ( c ) Block Na + channel with no effect on action potential Flecanide , propafenone Class II - β- adrenoceptor antagonists ( β- blockers) Atenolol , bisoprolol , metoprolol , I- sotalol Class III -drugs whose main effect is to prolong the action potential Amiodarone , d- sotalol Class IV -slow calcium channel blockers Verapamil , diltiazem

Sodium Channel-Blocking Drugs (Class 1) :

Sodium Channel-Blocking Drugs (Class 1) -1A: Block Na + channel and prolong action potential -Drugs with local anesthetic action block sodium channels and reduce the sodium current, I Na . - They are the oldest group of antiarrhythmic drugs and are still widely used.

Procainamide (Subgroup 1A) :

Procainamide (Subgroup 1A) Cardiac Effects By blocking sodium channels slows the upstroke of the action potential, slows conduction, prolongs the QRS duration of the ECG. The drug also prolongs the action potential duration by nonspecific blockade of potassium channels. Procainamide has direct depressant actions on sinoatrial and atrioventricular nodes( α blocking)

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Extracardiac Effects Procainamide has ganglion-blocking properties. This action reduces peripheral vascular resistance and can cause hypotension, particularly with intravenous use.

Pharmacokinetics:

Pharmacokinetics Absorbed well orally Metabolised in liver and excreted by kidney N-acetylprocainamide (class 3 ) Torsade de pointes .

Toxicity :

Toxicity Cardiotoxic Excessive action potential prolongation, QT interval prolongation, and induction of torsade de pointes arrhythmia and syncope. New arrhythmias can be precipitated. Lupus erythematosus Pleuritis , pericarditis, or parenchymal pulmonary disease. Renal lupus is rarely induced by procainamide Nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (< 5%), and agranulocytosis (approximately 0.2%).

Therapeutic Use :

Therapeutic Use Atrial and ventricular arrhythmias

Quinidine:

Quinidine Similar to procainamide Also blockes K+ channels Anticholinergic, blocking α receptors. Extracardiac Effects Diarrhea , nausea, and A syndrome of headache, dizziness, and tinnitus ( cinchonism ) is observed at toxic drug concentrations. Idiosyncratic or immunologic reactions, including thrombocytopenia, hepatitis, angioneurotic edema, and fever, are observed rarely.

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Excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart.

Disopyramide: :

Disopyramide : Similar Marked anticholinergic actions

Lidocaine (Subgroup 1B) :

Lidocaine (Subgroup 1B) 1B: Block Na + channel and shorten action potential Lidocaine has a low incidence of toxicity A high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route.

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Cardiac Effects Lidocaine blocks activated and inactivated sodium channels with rapid kinetics Toxicity Lidocaine is one of the least cardiotoxic of the currently used sodium channel blockers Paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions. preexisting heart failure, lidocaine may cause hypotension

Pharmacokinetics:

Pharmacokinetics Extensive first-pass hepatic metabolism Lidocaine must be given parenterally Lidocaine has a half-life of 1–2 hours. Heart failure , liver failure Therapeutic Use: Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia

Mexiletine (Subgroup 1B) :

Mexiletine (Subgroup 1B) Mexiletine is an orally active congener of lidocaine. Its electrophysiologic and antiarrhythmic actions are similar to those of lidocaine Mexiletine is used in the treatment of ventricular arrhythmias. Pain due to diabetic neuropathy and nerve injury Tremor , blurred vision, and lethargy. Nausea

Flecainide (Subgroup 1C):

Flecainide (Subgroup 1C) 1C: Block Na + channel with no effect on action potential Flecainide is a potent blocker of sodium and potassium channels. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval) It has no antimuscarinic effects.

pharmacokinetics:

pharmacokinetics Flecainide is well absorbed and has a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney USES: Premature ventricular contractions AF, WPW syndome Toxicity : Arrhythmia

Propafenone (Subgroup 1C) :

Propafenone (Subgroup 1C) Blocks Na+ channel 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 THERAPEUTIC USE: Supraventricular arrhythmias. TOXICITY: metallic taste and constipation; arrhythmia exacerbation

Beta-Adrenoceptor–Blocking Drugs (Class 2) :

Beta- Adrenoceptor –Blocking Drugs (Class 2) PROPRANOLOL: Supress adrenergically mediated ectopic activity Drugs have antiarrhythmic properties by virtue of their β -receptor–blocking action and direct membrane effects Some of these drugs have selectivity for cardiac β 1 receptors, Some have intrinsic sympathomimetic activity, Some have marked direct membrane effects, and some prolong the cardiac action potential

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These agents can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction. THERAPEUTIC USES: Sinus tachycardia, Atrial/ nodal extrasystole Pheochromacytoma Arryhthmia due to halothane /digitalis. WPW syndrome

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Esmolol is a short-acting β blocker used primarily as an antiarrhythmic drug for intraoperative and other acute arrhythmias Sotalol is a nonselective β -blocking drug that prolongs the action potential (class 3 action).

Drugs that Prolong Effective Refractory Period by Prolonging the Action Potential (Class 3):

Drugs that Prolong Effective Refractory Period by Prolonging the Action Potential (Class 3) These drugs prolong action potentials, usually by blocking potassium channels in cardiac muscle or by enhancing inward current Amiodarone Cardiac Effects Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) Amiodarone also significantly blocks inactivated sodium channels

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Amiodarone also has weak adrenergic and calcium channel blocking actions Extracardiac Effects Amiodarone causes peripheral vasodilation. Toxicity Bradycardia and heart block The drug accumulates in many tissues, including the heart (10–50 times more so than in plasma), lung, liver, and skin, and is concentrated in tears

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Fatal pulmonary fibrosis Abnormal liver function tests and hepatitis Photodermatitis and a gray-blue skin discoloration in sun-exposed areas Corneal microdeposits Halos develop in the peripheral visual fields Optic neuritis may progress to blindness Hypothyroidism or hyperthyroidism

Pharmacokinetics :

Pharmacokinetics Incompletely and slowly absorbed orally It undergoes hepatic metabolism, and the major metabolite, desethylamiodarone, is bioactive. The elimination half-life is complex Therapeutic Use Recurrent ventricular tachycardia Atrial fibrillation. Rapid termination of SVT, VT WPW syndrome

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Ibutilide Dofetilide Sotalol Vernakalant Dronedarone

Calcium Channel-Blocking Drugs (Class 4) Verapamil :

Calcium Channel-Blocking Drugs (Class 4) Verapamil Cardiac Effects Verapamil blocks both activated and inactivated L-type calcium channels AVnodal conduction time and effective refractory period are prolonged Slows the SA node by its direct action Extracardiac Effects Peripheral vasodilation ????

Pharmacokinetics:

Pharmacokinetics Absorbed orally It is extensively metabolized by the liver Therapeutic Use Supraventricular tachycardia Atrial fibrillation and flutter Toxicity

Miscellaneous Antiarrhythmic Agents:

Miscellaneous Antiarrhythmic Agents These include digitalis, adenosine, magnesium, and potassium Adenosine Mechanism: Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Activation of an inward rectifier K + current and inhibition of calcium current

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Marked hyperpolarization and suppression of calcium-dependent action potentials. -Atrioventricular nodal conduction and the atrioventricular nodal refractory period DOC conversion of paroxysmal supraventricular tachycardia to sinus rhythm High efficacy (90–95%) and very short duration of action.

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Toxicity Adenosine causes flushing Shortness of breath or chest burning Induction of high-grade atrioventricular block Atrial fibrillation may occur. Less common headache, hypotension, nausea, and paresthesias

Magnesium :

Magnesium Digitalis-induced arrhythmias. Mechanisms Na + ,K + ATPase, sodium channels, certain potassium channels, and calcium channels. USES: Digitalis -induced arrhythmias Torsade de pointes even if serum magnesium is normal.

Potassium :

Potassium (1) a resting potential depolarizing action (2) a membrane potential stabilizing action, Hypokalemia :delayed afterdepolarizations, and ectopic pacemaker activity, (digitalis). Hyperkalemia depresses ectopic pacemakers (severe hyperkalemia is required to suppress the sinoatrial node) and slows conduction. Because both insufficient and excess potassium is potentially arrhythmogenic,

Drugs in av block Choice of anti arrhythmic :

Drugs in av block Choice of anti arrhythmic