Anti Arrhythmic Drugs

Anti arrhythmic drugs • • • Under some conditions ectopic rhythms may arise when the heart is activated from a pacemaker other than the SA node leading to arrhythmias Regions other than the SA node which initiate beats are described as an ectopic foci/ectopic pacemaker Ectopic foci may initiate abnormal beats when: o Their own rhythmicity becomes enhanced o The rhythmicity of the SA node is depressed, o Conduction pathways are blocked between ectopic focus/regions with greater rhythmicity. The aim of anti-arrhythmic drugs is to suppress the ectopic beats thus allowing the heart to return to the normal rhythm instigated by the SA node. Vaughan Williams classification (1970): classifies based on primary mechanism (many drugs have multiple) • Class I: Block voltage-sensitive sodium channels • Class II: β-adrenoceptor antagonists • Class III: Prolong the cardiac action potential by affecting potassium (K+) efflux • Class IV: Calcium channel antagonists • Class V: Work by other or unknown mechanisms Class I drugs (voltage-sensitive sodium channels blockers) • E.g. lignocaine • Block sodium channels by binding to sites in the α-subunit • Their characteristic effect on action potential is to slow down depolarisation – during phase 0. This inhibits action potential propagation and thus the class I drugs blocks the high-frequency excitation of the myocardium that occurs in tachyarrhythmias (usedependent channel block). • Class I drugs bind to Na+ channels most strongly in open or the refractory state, less strongly to channels in resting state – therefore 'use dependence' (more frequent channels activation = greater degree of block produced). Class II drugs (β-adrenoceptor antagonists) • E.g. propranolol • Functions to decrease heart rate, contractility, conduction velocity, and relaxation rate • Beta-adrenoceptors are coupled to a G-protein, which activate adenylyl cyclase to form cAMP from ATP o Decreased cAMP reduces activation of cAMP-dependent protein kinase (PK-A) that phosphorylates the L-type calcium channels, which causes decreased calcium entry into the cells. Increased calcium entry during action potentials leads to less release of calcium by sarcoplasmic reticulum in the heart; these actions decrease inotropy (contractility). o G-protein activation also decreases heart rate by reducing the opening ion channels responsible for pacemaker currents in the sinoatrial node (PK-A phosphorylates sites on the sarcoplasmic reticulum, which release calcium for binding troponin-C → decrease inotropy). o Increased refractory period of AV node • Used to reduce mortality following myocardial infarction and to prevent recurrence of tachyarrhythmia’s caused by increased sympathetic activity Class III drugs (prolonging cardiac action potential by K+ efflux) • E.g. amiodarone, sotalol • Blocks some of the potassium channels involved in cardiac repolarisation and substantially prolong the cardiac action potential • Action potential prolongation increases the QT interval, increasing refractory period, accounting for the varied antidysrhythmic activity (interrupts re-entrant tachycardia & suppressing ectopic activity) • Used in supraventricular and ventricular tachycardia such as Wolff-Parkinson-White syndrome which is a syndrome of pre excitation of the ventricles of the heart due to an abnormal accessory pathway known as the bundle of Kent Class IV drugs (voltage operated calcium channels blockers) • E.g. verapamil • Bind to L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue that is responsible for smooth muscle contraction and cardiac myocyte contraction • By blocking Ca2+ entry into the cell (phase 0) → vascular smooth muscle relaxation, decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), and a decreased conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular node. Drugs that increase myocardial contraction • Cardiac glycosides (example digoxin) historically used as the main drugs in congestive heart failure • May lead to severe adverse effects due to a low therapeutic index (ratio of toxic to therapeutic dose) o Increased risk for cardiac arrhythmia (e.g. ectopic beats, ventricular tachycardia) o Nausea and vomiting (stimulation of the vomiting centre) o Diarrhoea (direct GIT irritation) o Toxic doses → disorientation, hallucinations and altered perception of colour (CNS effects) o Diuretics → hypokalemia → increase digoxin’s toxicity • Function by inhibiting the pumps • Clinical use: o Slow ventricular rate in rapid persistent atrial fibrillation