Antiarrhythmic Drugs PDF

Antiarrhythmic Drugs 1 Electrical activity of different kinds of cardiac cells 2  Action potential of SA pacemaker cell Phase 0 Pha se 3 se4 4...

Antiarrhythmic Drugs 1 Electrical activity of different kinds of cardiac cells 2  Action potential of SA pacemaker cell Phase 0 Pha se 3 se4 4 a e Ph has P 3 www.cvphysiology.com/ A nodal action potentials are divided into three phases: Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the action potential once the membrane potential reaches threshold between -40 and -30 mV). Phase 0 is the depolarization phase of the action potential. This is followed by phase 3. Phase 3 is the repolarization phase. Once the cell is completely repolarized at about -60 mV, the cycle is spontaneously repeated. 4 www.cvphysiology.com/  Action potential of cardiomyocyte Effective refractory period (ERP) 5  Effective refractory period (ERP) During the ERP, stimulation of the cell does not produce new, propagated action potentials, because the fast sodium channels are not fully reactivated. The ERP acts as a protective mechanism in the heart by preventing multiple, compounded action potentials from occurring. The length of the refractory period limits the frequency of action potentials (and therefore contractions) that can be generated by the heart. Many antiarrhythmic drugs alter the ERP, thereby altering cellular excitability. 6 Arrhythmias can be: A. Bradyarrhythmias (slow heart rhythms) B. Tachyarrhythmias (fast heart rhythms) 1. Supraventricular (arising from above the ventricles, that is the atria), or 2. Ventricular (arising from either of the bottom ventricles) 7  Arrhythmias are caused by abnormalities in: – Generation of the electrical impulses or – Conduction of the electrical impulses or – Both 8  Your physician will assess your symptoms and attempt to capture this arrhythmia with an electrocardiogram (EKG) monitoring modality, including a Holter or Event monitor and a 12-lead EKG. 9 10  Treatment of tachyarrhythmias Class I drugs (Membrane stabilizing drugs) Ø Mechanism: – Class I drugs block fast Na+ channels, thereby – Reducing the rate of phase 0 depolarization of cardiomyocytes – Prolonging the effective refractory period – Increasing the threshold of excitability – Reducing phase 4 depolarization of SA node 11  Treatment of tachyarrhythmias Class I drugs (Membrane stabilizing drugs) – Sodium-channel blockers (particularly Class IA) increase the ERP by prolonging the inactivation state of fast- Na+ channels, – Can be particularly effective in abolishing reentry currents that lead to tachyarrhythmias. – These drugs also have local anesthetic properties. 12  Class IA 1. Quinidine Alkaloid – cinchona , dextro isomer of quinine Adverse effects - GIT : Diarrhea, nausea, vomiting - Cinchonism (tinnitus, headache, deafness, and occasionally, anaphylactoid shock) - Thrombocytopenia - Precipitate torsade de pointes by prolonging QT interval 13 2. Procainamide Like quinidine, but safer to use intravenously produces fewer adverse GI effects. Acetylated in the liver and Eliminated by the kidney High incidence of adverse effects with long-term use: – It is more likely than quinidine to produce severe or irreversible heart failure. q Adverse effects – SLE like syndrome consisting of arthralgia and arthritis specially in slow acetylators. 14 3. Disopyramide Has prominent anti-cholinergic activity Approved only for ventricular arrhythmia (not a first line). 15  Class IB 1. Lidocaine: Least cardiotoxic Blocks inactivated Na channels: preference for partially depolarized cells in ischemic area High first pass metabolism – not given orally 16  Class IB 1. Lidocaine: Used in: – Ventricular arrhythmia – Digoxin induced arrhythmia Main toxicity is neurological – drowsiness, nystagmus, and seizures. 17  2. Mexiletine and Tocainide – Similar in action to Lidocaine – Can be administered orally. – Mexiletine is used primarily for long-term treatment of ventricular arrhythmias associated with previous MI. 3. Moricizine – Moricizine, a phenothiazine, has properties of class IB, IA, and IC antiarrhythmics, and its use should be limited to life-threatening ventricular arrhythmias 18  Class IC Potent Na+ channel blocker Have negative inotropic effect High pro-arrhythmogenic potential – sudden death 19  1. Flecainide – Orally active – Used for ventricular tachyarrhythmias and maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter 2. Propafenone – Has a spectrum of action similar to that of Quinidine. – Possesses β-adrenoceptor antagonist activity. – Approved for the treatment of supraventricular arrhythmias and suppression of life-threatening ventricular arrhythmias. 20  Treatment of tachyarrhythmias Class II drugs (beta-blockers) Mechanism: – β-adrenoceptor antagonists, including propranolol, which act by reducing sympathetic stimulation. They inhibit phase 4 depolarization of SA node Depress automaticity Prolong AV conduction Decrease – Heart rate (except for agents that have interinsic sympathomimetic activity) – Contractility. 21  Treatment of tachyarrhythmias Class II drugs (beta-blockers) Major drugs - Propranolol, a nonselective β-adrenoceptor antagonist - Acebutolol & esmolol, more selective β1-adrenoceptor antagonists - are used to treat ventricular arrhythmias. - Propranolol, metoprolol, nadolol, and timolol are frequently used to prevent recurrent MI. 22  Treatment of tachyarrhythmias Class II drugs (beta-blockers) - Therapeutic uses - Class II drugs are used to treat tachyarrhythmias caused by increased sympathetic activity. - They also are used for a variety of other arrhythmias, including atrial flutter and atrial fibrillation. 23  Treatment of tachyarrhythmias: Class III drugs. Mechanism of action Interfere with outward K+ currents or Slow inward Na+ currents This results in: - Prolonging action potential duration - Prolonging effective refractory period Ø they retard phase 3 repolarization Ø increase the action potential duration, Ø thereby increasing the ERP. 24 1. Amiodarone – Amiodarone is structurally related to thyroxine. – Net effect: It increases refractoriness it depresses sinus node automaticity slows conduction. – The long half-life of amiodarone (14—100 days) increases the risk of toxicity. 25  Amiodarone The plasma concentration of Amiodarone is not well correlated with its effects. After parenteral administration - electrophysiologic effects may be seen within hours - effects on abnormal rhythms may not be seen for several days. The antiarrhythmic effects may last for weeks or months after the drug is discontinued. 26  Amiodarone Amiodarone is used for treatment of: - refractory life-threatening ventricular arrhythmias in preference to Lidocaine - treatment of atrial and/or ventricular arrhythmias Adverse effects – Pulmonary fibrosis – Skin pigmentation – Corneal deposits – Interferes with the thyroid function 27 2. Ibutilide Indicated for atrial fibrillation & atrial flutter administered by intravenous infusion. Ibutilide blocks slow inward Na+ currents and prolongs the action potential duration, thereby causing a slowing of the sinus rate and AV conduction velocity. 28 3. Sotalol – Net Effects: – prolongs the cardiac action potential – increases the duration of the refractory period – has nonselective β-adrenoceptor antagonist activity – Uses include treatment of: – atrial arrhythmias or life-threatening ventricular arrhythmias – treatment of sustained ventricular tachycardia. – Adverse effects: proarrhythmic actions, dyspnea, and dizziness. 29  4. Dofetilide Used in atrial fibrillation or atrial flutter. Dofetilide is a potent inhibitor of K+-channels Adverse effects: » serious arrhythmias 30 5. Bretylium It has properties of class II drugs. Used for Ventricular arrhythmia after Lidocaine has failed. 31  Treatment of tachyarrhythmias: Class IV drugs (CCB) – Mechanism Class IV drugs selectively block L-type calcium channels. These drugs prolong nodal conduction and effective refractory period and have predominate actions in nodal tissues 32 1. Verapamil Verapamil blocks both activated and inactivated slow calcium channels. It has equipotent activity on the AV and SA nodes and in cardiac and vascular muscle tissues. 33  Verapamil is useful in » supraventricular tachycardia » atrial flutter and fibrillation. Adverse effects: Negative inotropic action that limits its use in damaged hearts Can lead to AV block: – when given in large doses or – in patients with partial blockage. It can precipitate sinus arrest in diseased patients it causes peripheral vasodilation. 34  Treatment of tachyarrhythmias: Class V drugs 1. Adenosine Adenosine acts through specific purinergic (P1) receptors Adenosine causes: – an increase in potassium efflux – decreases calcium influx This hyperpolarizes cardiac cells and decreases the calcium- dependent portion of the action potential. Adenosine is the drug of choice for the treatment of paroxysmal supraventricular tachycardia, including those associated with Wolff-Parkinson-White syndrome 35 2. Digoxin Inhibit Na+/K+-ATPase → ↑Intracellular Na+ → ↓Na+ conc. gradient → ability of Na+/Ca2+ exchanger to move Ca2+ out of the cell → ↑ contractility Na+/K+-ATPase inhibition raises resting membrane potential (- 90 to -70 mV) → excitability →risk of arrhythmias Digoxin enhances the Vagal tone, thus decreasing HR and myocardial oxygen demand Digoxin slows conduction velocity through AV node, can control ventricular response in atrial flutter or fibrillation 36  Treatment of bradyarrhythmias 1. Atropine Atropine blocks the effects of acetylcholine. It elevates: – Sinus rate – AV nodal and sinoatrial (SA) conduction velocity It decreases refractory period Atropine is used to treat bradyarrhythmias that accompany MI. Atropine produces adverse effects that include dry mouth, mydriasis, and cycloplegia; it may induce arrhythmias. 37 2. Isoproterenol Stimulates β-adrenoceptors and increases heart rate and contractility. It is used to maintain adequate heart rate and cardiac output in patients with AV block. It may cause tachycardia, anginal attacks, headaches, dizziness, flushing, and tremors. 38  Prototype Group Drug Mechanism Uses Class Ia Quinidine Moderate block of Na+ Suppress ventricular and supraventric- Procainamide channels; ular arrhythmias Disopyramide prolong action potentials Class Ib Lidocaine Weakly block Na+channels; Suppress ventricular arrhythmias Mexiletine shorten action potentials Class Ic Flecainide Strongly blocks Na +and Treat severe ventricular K+channels tachyarrhythmias Class II Propranolol Blocks β-adrenoceptors Suppress some ventricular arrhythmias; Atenolol inhibit AV node Nadolol Class III Amiodarone Prolongs refractory period Suppress ventricular arrhythmias Class IV Verapamil Blocks Ca+channel Treat reentrant supraventricular tachy- cardia; suppress AV node conduction Class V Adenosine P-1receptor antagonist Treat paroxysmal atrial tachycardia Others Atropine Atropine Muscarinic antagonist Increase heart rate in bradycardia and heart blocks Digitalis Digoxin Increases vagal tone Inhibit AV node; treat atrial fibrillation 39