Pharmacology
ا.م.د.شامل هاشم ألنعيمي ثالث/ أدويةAntiarrhythmic drugs
Overview:The pathophysiology of cardiac arrhythmias is complex and the actions of drugs that are useful in stopping or controlling them may seem equally so. Drug therapy for arrhythmias has a place beside radiofrequency ablation or the use of implanted devices, e.g. pacemakers or implantable defibrillators , which often provide the best treatment option.
DRUGS FOR CARDIAC ARRHYTHMIAS
OBJECTIVES OF TREATMENT
In almost no other set of conditions is it so clearly obvious to remember the dual objectives, which are to reduce morbidity and mortality.
SOME PHYSIOLOGY AND PATHOPHYSIOLOGY
The first type is ordinary myocardial (atrial and ventricular) muscle, responsible for the pumping action of the heart.
The second type is specialised conducting tissue that initiates the cardiac electrical impulse and determines the order in which the muscle cells contract e.g. the sinoatrial (SA) and atrioventricular (AV) nodes
CLASSIFICATION OF ANTIARRHYTHMIC DRUGS
This partially relates to the phases of the cardiac cycle:
Phase 0 is the rapid depolarisation of the cell membrane that is associated with a fast inflow of sodium ions through channels that are selectively permeable to these ions.
Phase 1 is short initial period of rapid repolarisation brought about mainly by an outflow of potassium ions.
Phase 2 is a period when there is a delay in repolarisation caused mainly by a slow movement of calcium ions from the exterior into the cell through channels that are selectively permeable to these ions ('long-opening' or L-channels).
Phase 3 is a second period of rapid repolarisation during which potassium ions move out of the cell.
Phase 4 begins with the fully repolarised state. For cells that discharge automatically, potassium ions then progressively move back into, and sodium and calcium ions move out of, the cell. The result is that the interior becomes gradually less negative until a (threshold) potential is reached, which allows rapid depolarisation (phase 0) to occur, and the cycle is repeated.
CLASSIFICATION OF DRUGS
Class I: sodium channel blockade
These drugs restrict the rapid inflow of sodium during phase 0 and thus slow the maximum rate of depolarization (membrane stabilising activity)
The class subdivides into drugs that:
A. lengthen action potential duration and refractoriness (adjunctive class III action), e.g. quinidine, disopyramide, procainamide
B. shorten action potential duration and refractoriness, e.g. lidocaine and mexiletine
C. have negligible effect on action potential duration and refractoriness, e.g. flecainide, propafenone.
Class II: catecholamine blockade
Propranolol and other β-adrenoceptor antagonists reduce background sympathetic tone in the heart, reduce automatic discharge (phase 4) and protect against adrenergically stimulated ectopic pacemakers
Class III: lengthening of refractoriness
(without effect on sodium inflow in phase 0). Prolongation of the cardiac action potential and increased cellular refractoriness beyond a critical point e.g. amiodarone, sotalol.Class IV: calcium channel blockade
These drugs depress the slow inward calcium current (phase 2) and prolong conduction and refractoriness particularly in the SA and AV nodes, which helps to explain their effectiveness in terminating paroxysmal supraventricular tachycardia, e.g. verapamil.
PRINCIPAL DRUGS BY CLASS
Quinidine
Quinidine is considered the prototype class I drug. In addition to its class IA activity, quinidine slightly enhances contractility of the myocardium (positive inotropic effect) and reduces vagus nerve activity on the heart (antimuscarinic effect).
Adverse reactions:
1. Antimuscarinic effect
2. Serious ventricular tachyarrhythmias
3. Non-cardiac effects, called 'cinchonism', include diarrhoea and other gastrointestinal symptoms, rashes, thromobocytopenia and fever.
CLASS II (CATECHOLAMINE BLOCKADE):
β-Adrenoceptor blockers are effective probably because they counteract the arrhythmogenic effect of catecholamines. The following actions appear to be relevant:
1.The rate of automatic firing of the SA node is accelerated by β-adrenoceptor activation and this effect is abolished by β-blockers.
2.β-Blockers prolong the refractoriness of the AV node, which may prevent re-entrant tachycardia at this site.
3.Many β-blocking drugs (propranolol, oxprenolol, alprenolol, acebutolol, labetalol) also possess membrane stabilising (class I) properties.
4.β-Adrenoceptor antagonists are effective for a range of supraventricular arrhythmias, in particular those associated with exercise, emotion or hyperthyroidism.
Interactions
In patients with depressed myocardial contractility, the combination of oral or intravenous β-blockade and calcium channel blockade (nifedipine, verapamil) may cause hypotension or heart failure
CLASS III (LENGTHENING OF REFRACTORINESS DUE TO POTASSIUM CHANNEL BLOCKADE)
Amiodarone:
Amiodarone is the most powerful antiarrhythmic drug available for the treatment and prevention of both atrial and ventricular arrhythmias
USES:
1. Chronic ventricular arrhythmias
2. To maintain sinus rhythm after cardioversion for atrial fibrillation or flutter.
3.Amiodarone was used for the management of re-entrant supraventricular tachycardias.
Adverse reactions:
1.Cardiovascular effects include bradycardia, heart block and induction of ventricular arrhythmia.
2.Other effects include nausea, vomiting, taste disturbances and the development of corneal microdeposits, which may rarely cause visual haloes, night glare and photophobia.
3.Plasma transaminase levels may rise.
4. Amiodarone contains iodine, and both hyperthyroidism and hypothyroidism are quite common.
5.Photosensitivity reactions are common.
6.Amiodarone may also cause a bluish discoloration on exposed areas of the skin.
7. Less commonly, pneumonitis and pulmonary fibrosis occur.
8.Peripheral neuropathy and myopathy occur.
Interaction
1.With digoxin (by displacement from tissue binding sites and interference with its elimination) and with warfarin (by inhibiting its metabolism) increases the effect of both these drugs.
2.β-Blockers and calcium channel antagonists augment the depressant effect of amiodarone on SA and AV node function.
CLASS IV (CALCIUM CHANNEL BLOCKADE
Calcium channel blockers inhibit the passage of calcium through the membrane channels; the result in myocardial cells is to depress contractility, and in pacemaker cells to suppress their automatic activity. Members of the group therefore may have negative cardiac inotropic and chronotropic actions, which can be separated: nifedipine, at therapeutic concentrations, acts almost exclusively on non-cardiac ion channels and has no clinically useful antiarrhythmic activity, whereas verapamil is an effective rate control agent.