Comprehensive Overview of Anti-Arrhythmic Drugs and Cardiac Action Potentials

Comprehensive Overview of Anti-Arrhythmic Drugs and Cardiac Action Potentials

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  Anti- Arrhythmic Drugs
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  Overview: Cardiac cells undergodepolarization and repolarization to form cardiac action potentials about 60s times/min.  activity of ion channel protein complexes determines the shape and duration of each action potential . Ion channel function can be perturbed by acute ischemia, sympathetic stimulation, or myocardial scarring to create abnormalities of cardiac rhythm, or arrhythmias.
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  • antiarrhythmic drugssuppress arrhythmias by blocking flow through specific ion channels or by altering autonomic function. • Arrhythmias can range from incidental, asymptomatic clinical findings to life- threatening abnormalities.
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  • Antiarrhythmic drugtherapy can have two goals: • termination of an ongoing arrhythmia • or prevention of an arrhythmia. • Unfortunately, antiarrhythmic drugs not only help to control arrhythmias but also can cause them, especially during long- term therapy.
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  • Most antiarrhythmic drugs affect more than one current; such as modification of cardiac contractility or autonomic nervous system function. • Thus antiarrhythmic drugs usually exert multiple actions and can be of beneficial or harmful in individual patients.
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  Antiarrhythmic Drugs • Theaim of therapy is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. • Most of anti-arrhythmic drugs suppress automaticity by raising the threshold of discharge to a less negative voltage • They also prevent reentry by slowing conduction or increasing the refractory period required to convert a unidirectional block to a bidirectional block
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  • In emergencytreatment, drugs are not used, but rather done by physical means, like pacing, direct current shock… • Four classes of drugs are identified, I, II, III and IV.
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  Cardiac Action Potential
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  • The majormechanisms to accomplish these aims are: 1. Na + channel blockade 2. Blockade of sympathetic effects in the heart 3. Prolongation of effective refractory period 4. Ca ++ channel blockade
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  Classification of Anti-ArrhythmicDrugs (Vaughn-Williams Classification) • Classified according to effect on action potential: 1. Class I – Na+ channel blockers 2. Class II – b-adrenoreceptor blockers 3. Class III – drugs that prolong repolarisation 4. Class IV – Ca2+ channel blockers • Other antiarrythmic drugs e.g. digoxin and adenosine, Mg, K.
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  Class I: Na+ ChannelBlockers • Binds to the α-subunit of the Na+ channels and prevent conduction of ions. • They act by reducing the maximum rate of depolarisation during phase 0. • They show “use dependence” i.e. the more frequently the channels are activated, the greater the degree of block produced.
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  • The morethe channel is used, the more drug is bound. • Useful in conditions where channels open frequently. • Sub-classified according to effect on duration of action potential into 3 groups: IA, IB and IC.
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  Class IA: Quinidine,Procainamide, Disopyramide • Slow phase 0 of the cardiac AP, slow conduction, prolong phase 3 repolarisation but less than class III. • Increase fibrillation threshold in atria and ventricles. • These drugs associate and dissociate at intermediate rate.
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  Quinidine: – The prototype –Treat a wide variety of arrythmias, including atrial, AV junctional and ventricular – Has potential adverse effects.* – Cinchonism.
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  Procainamide: – Shows actionssimilar to quinidine – Chronic use leads to lupus erythematosus-like syndrome in 25% of patients.
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  Disopyramide: – Shows actionssimilar to quinidine – Produces a negative inotropic effect – Used for ventricular arrythmias. – Shows anticholinergic side effects; i.e. has atropine- like actions, blurred vision, dry mouth, constipation, glaucoma and urinary retention. It can precipitate heart failure and can cause torsades de pointes. – Dose has to be reduced in patients with renal dysfunction. Higher doses are needed in patients taking phenytoin.
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  Class IB –Lidocaine, Mexiletine, Tocainide • Minimal phase 0 depression and slows conduction (less than Ia). • Shortens repolarisation. • associate and dissociate rapidly. It binds to the open channels during phase 0 (rapid depolarisation). They can also bind selectively to refractory channels, thus block cells when they are depolarised.
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  Lidocaine: (Xylocaine ) •Is the drug of choice for emergency treatment of cardiac arrhythmias. • is used (i.v.) to treat ventricular tachycardia and to prevent ventricular fibrillation after myocardial infarction. • Can cause heart failure or heart block. • It blocks both open and inactivated cardiac sodium channels. Recovery is very rapid. • Not useful in Atrial arrhythmias because Atrial action potentials are so short that the sodium channel is in the inactivated state only briefly.
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  • Adverse effects:I.V. can cause seizures, tremor and nystagmas • Undergoes extensive first pass effect and plasma levels are affected by rapid distribution into tissues and reduced hepatic blood flow by reduced cardiac output.
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  Class IC: flecainide,encainide, and Propafenone. • associate and dissociate much more slowly. • Markedly slow phase 0 depolarization. • No effect on repolarisation. • Refractory period of AV node increased. • There are doubts on the safety of the class 1C drugs
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  Flecainide: • Approved onlyfor refractory ventricular arrythmias • used mainly in patients with supraventricular arrhythmias to maintain sinus rhythm and also for atrial fibrillation. • Can aggrevate preexisting arrythmias. • Adverse effects: blurred vision. Can exacerbate congestive heart failure in patients with depressed left ventricular performance. • Serious AD include exacerbation of potentially lethal arrhythmias in patients with atrial flutter. • Can also cause heart block in patients with conduction system disease.
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  Propafenone: – similar toflecainide, but with broad spectrum of antiarrythmic activity.
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  Class II –b-adrenoreceptor blockade • There are b1 receptors in the heart which increase heart rate when stimulated by sympathetic nerves. • Adrenaline may cause arrhythmias by increasing spontaneous firing of the SA node. AV node conduction also requires sympathetic activity. e.g. ventricular dysrhythmias after myocardial infarction is due to increased sympathetic activity. SVT and paroxysmal attacks of atrial fibrillation . • b-blockers prevent these events. • Propanolol, metoprolol and esmolol decrease heart rate.
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  • Propranolol: – Themost widely used for cardiac arrythmias – Reduces the incidence of sudden arrythmic death after myocardial infarction • Metoprolol: – Β1 adrenergic blocker – Reduces the risk of bronchospasm • Esmolol: – Short acting – For acute arrythmias (emergency, i.v.)
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  Class III -Drugs that prolong repolarisation • Examples are sotalol, bretyllium and amiodarone. • Full mechanism is not understood, but they block some of the potassium channels involved in cardiac repolarisation. • Prolong phase 3 repolarization and refractory period
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  • Action potentialprolongation increases the refractory period, causing powerful & varied antidysrhythmic activity. • Be careful in patients taking other drugs that may cause prolonged Q-T interval on ECG (torsades de pointes). • Antipsychotic drugs, hypokalaemia, hypercalcaemia or in individuals with hereditary prolonged Q-T mainly “Ward- Romano syndrome”.
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  Amiodarone (Cordarone) • Pharmacologicaleffects: • Blocks inactivated potassium channels with rapid rate of recovery • Decreases calcium current • Decreases transient outward delayed rectifier and inward rectifier potassium currents • Exerts a non-competitive adrenergic blocking effect. • Blocks abnormal automaticity and prolongs action potential duration.
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  • Decreases conductionvelocity • Prolongs PR, QRA and QT intervals • Ad. Effects: Hypotension with intravenous injections • Depressed contractility during long term treatment via the oral route. • During chronic amiodarone therapy is pulmonary fibrosis which can be rapidly progressive and fatal • Risk factors for pulmonary fibrosis include underlying lung disease, doses of 400mg/day or more, and pneumonia. • Corneal deposits, hepatic dysfunction, perpheral neuropathy, muscular weakness, photosensitivity and hypo- or hyperthyroidism.
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  • Treatment consistsof withdrawal of the drug and administration of corticosteroids and other supportive measures. • Poor absorption, 30% bioavailability. Distributes into fat (300:1) • Undergoes hepatic metabolism (CYP3A4) to active metabolite, desethylamiodarone. • Dosages of digoxin, warfarin, flecainide usually require reduction during amiodarone therapy.
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  • Sotalol: forlong therapy after acute MI • Bretyllium only used for life-threatening ventricular arrhythmias, amiodarone for recurrent ventricular fibrillation.
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  Class IV:Ca2+ -channel blockers •Verapamil, diltiazem, nifedipine • Block Ca2+ channels (especially L-type channels). • Slow conduction in the SA and AV nodes where action propagation depends on slow inward Ca2+ CURRENT.
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  • They shortenthe plateau of the action potential and reduce the force of contraction. • Reduced calcium entry reduces after- depolarisation and thus suppresses premature ectopic beats.
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  • Verapamil anddiltiazem: – are more effective against atrial than ventricular dysrythmias – Have negative inotropic effects and may be contraindicated in patients with depressed cardiac function