Chapter 38
Antiarrhythmic Drugs
These are drugs used to prevent or treat irregularities of cardiac rhythm.
Nearly 3 out of 4 patients of acute myocardial infarction (MI) and about half of those given a general anesthetic exhibit at least some irregularity of cardiac rhythm. Arrhythmias are the most important cause of sudden cardiac death. However, only few arrhythmias need to be treated with antiarrhythmic drugs.
Abnormal automaticity or impaired conduction or both underlie cardiac arrhythmias. The generation and propagation of cardiac impulse and properties of excitability and refractoriness are described on p. 476 to 478. Ischemia, electrolyte and pH imbalance, mechanical injury, stretching, neurogenic and drug influences, including antiarrhythmics themselves, can cause arrhythmias by altering electrophysiological properties of cardiac fibres.
Important mechanisms of cardiac arrhythmias are:
A. Enhanced/ectopic pacemaker activity The slope of phase-4 depolarization may be increased pathologically in the automatic fibres or such activity may appear in ordinary fibres. Ectopic impulse may result from current of injury. Myocardial cells damaged by ischaemia become partially depolarized: a current may flow between these and normally polarized fibres (injury current) and initiate an impulse.
B. After-depolarizations These are secondary depolarizations accompanying a normal or premature action potential (AP),
Early after-depolarization (EAD) Repolarization during phase-3 is interrupted and membrane potential oscillates. If the amplitude of oscillations is sufficiently large, neighbouring tissue is activated and a series of impulses are propagated. EADs are frequently associated with long Q-T interval due to slow repolarization and prolonged APs. They result from depression of delayed rectifier K+ current.
Delayed after-depolarization (DAD) After attaining resting membrane potential (RMP) a secondary deflection occurs which may reach threshold potential and initiate a single premature AP. Generally result from Ca2+ overload (digitalis toxicity, ischaemia-reperfusion). Because an AP is needed to trigger after-depolarizations, arrhythmias based on these have been called triggered arrhythmias.
C. Reentry Due primarily to abnormality of conduction, an impulse may recirculate in the heart and cause repetitive activation without the need for any new impulse to be generated. These are called reentrant arrhythmias.
(i) Circus movement type It occurs in an anatomically defined circuit. A premature impulse, temporarily blocked in one direction by refractory tissue, makes a one-way transit around an obstacle (natural orifices in heart, infarcted or refractory myocardium), finds the original spot in an advanced state of recovery and reexcites it, setting up recurrent activation of adjacent myocardium (Fig. 38.2)
Reentry occurring in an anatomically fixed circuit can be permanently cured by high radiofrequency catheter ablation of the defined pathway.
(ii) Micro reentry circuit It may form at the junction of a Purkinje fibre (PF) with ordinary ventricular fibre (gate region). One of the branches of the PF may get sufficiently depolarized to cause unidirectional block (Fig. 38.3). Extremely slow conduction at this site due to slow channel depolarization and markedly abbreviated action potential duration (APD) and effective refractory period (ERP) makes reentry possible in a short loop of tissue.
For reentry to occur, the path length of the circuit should be greater than the wave length (ERP × conduction velocity) of the impulse. Slow conduction in the reentrant circuit may be caused by:
(a) Partial depolarization of the membrane—decreased slope of phase 0 depolarization, i.e. depressed fast channel response.
(b) Cells changing over from fast channel to slow channel depolarization which conducts extremely slowly. When a fibre is depolarized to a RMP of about –60 mv, the Na+ (fast) channels are inactivated, but it can still develop Ca2+ (slow) channel response. Reentry can be abolished both by marked slowing of conduction (converting unidirectional block to bidirectional block) as well as by acceleration of impulse (retrograde impulse reaches so early as to meet refractory tissue).
D. Fractionation of impulse When atrial ERP is brief and inhomogeneous (under vagal overactivity), an impulse generated early in diastole gets conducted irregularly over the atrium, i.e. it moves rapidly through fibres with short ERP (which have completely recovered) slowly through fibres with longer ERP (partially recovered) and not at all through those still refractory. Thus, asynchronous activation of atrial fibres occurs → atrial fibrillation (AF). This arrhythmia must be initiated by a premature depolarization, but is self sustaining, because passage of an irregular impulse leaves a more irregular refractory trace and perpetuates the inhomogeneity of ERPs.
The important cardiac arrhythmias are:
1. Extrasystoles (ES) are premature beats due to abnormal automaticity or after-depolarization arising from an ectopic focus in the atrium (AES), A-V node (nodal ES) or ventricle (VES). The QRS complex in VES is broader and abnormal in shape
2. Paroxysmal supraventricular tachycardia (PSVT) is sudden onset episodes of atrial tachycardia (rate 150–200/min) with 1:1atrioventricular conduction: mostly due to circus movement type of re-entry occurring within or around the A-V node or using an accessory pathway between atria and ventricle (Wolff-Parkinson-White syndrome).
3. Atrial flutter (AFI) Atria beat at a rate of 200– 350/min and there is a physiological 2:1 to 4:1 or higher A-V block (because A-V node cannot transmit impulses faster than 200/ min). This is mostly due to a stable re-entrant circuit in the right atrium, but some cases may be due to rapid discharge of an atrial focus.
4. Atrial fibrillation (AF) Atrial fibres are activated asynchronously at a rate of 350–550/min (due to electrophysiological inhomogeneity of atrial fibres), associated with grossly irregular and often fast (100–160/min) ventricular response. Atria remain dilated and quiver like a bag of worms.
5. Ventricular tachycardia is a run of 4 or more consecutive ventricular extrasystoles. It may be a sustained or nonsustained arrhythmia and is due either to discharges from an ectopic focus, after-depolarizations or single site (monomorphic) or multiple site (polymorphic) reentry circuits.
6. Torsades de pointes (French: twisting of points) is a life-threatening form of polymorphic ventricular tachycardia with rapid asynchronous complexes and an undulating baseline on ECG. It is generally associated with long Q-T interval.
7. Ventricular fibrillation (VF) is grossly irregular, rapid and fractionated activation of ventricles resulting in incoordinated contraction of its fibres with loss of pumping function. It is fatal unless reverted within 2–5 min; is the most common cause of sudden cardiac death.
8. Atrio-ventricular (A-V) block is due to depression of impulse conduction through the A-V node and bundle of His, mostly due to vagal influence or ischaemia. First degree A-V block: Slowed conduction resulting in prolonged P-R interval. Second degree A-V block: Some supraventricular complexes are not conducted: drop beats.
Third degree A-V block: No supraventricular complexes are conducted; ventricle generates its own impulse; complete heart block.
Arrhythmogenic potential of antiarrhythmics Most antiarrhythmics can themselves precipitate serious arrhythmias, especially during long-term prophylactic use. Two multicentric trials ‘Cardiac Arrhythmia Suppression Trial I and II’ (CAST I, II, 1991, 1992) have shown that post-MI patients randomized to receive on a long-term basis encainide, flecainide, moricizine had higher incidence of sudden death, though initially the same drugs had suppressed VES in these patients. It is possible that during transient episodes of ischaemia, the intraventricular conduction slowing action of these drugs gets markedly accentuated resulting in VT and VF. It is therefore not prudent to try and suppress all extrasystoles/arrhythmias with drugs.
CLASSIFICATION
CLASS I
reduce rate of phase-4 depolarization in automatic cells.
SUBCLASS IA
arrhythmic drugs quinidine and procainamide are open state Na+ channel blockers which also moderately delay channel recovery (1–10s), suppress A-V conduction and prolong refractoriness. The Na+ channel blockade is greater at higher frequency (premature depolarization is affected more). These actions serve to extinguish ectopic pacemakers that are often responsible for triggered arrhythmias and abolish re-entry by converting unidirectional block into bidirectional block.
It is the dextro isomer of the antimalarial alkaloid quinine found in cinchona bark. In addition to Na+ channel blockade, quinidine has cardiac antivagal action which augments prolongation of atrial ERP and minimizes RP disparity of atrial fibres. A-V node ERP is increased by direct action of quinidine, but decreased by its antivagal action; overall effect is inconsistent. Quinidine depresses myocardial contractility; failure may be precipitated in damaged hearts.
ECG: It increases P-R and Q-T intervals and tends to broaden QRS complex. Changes in the shape of T wave may be seen reflecting effect on repolarization.
Mechanism of action: Quinidine blocks myocardial Na+ channels in the open state—reduces automaticity and maximal rate of 0 phase depolarization in a frequency dependent manner. Prolongation of APD is due to K+ channel block, while lengthening of ERP is caused by its moderate effect on recovery of Na+ and K+ channels. At high concentrations it also inhibits L type Ca2+ channels. Quinidine decreases the availability of Na+ channels as well as delays their reactivation. The other actions of quinidine are fall in BP (weak α adrenergic blockade and cardiac depression), decreased skeletal muscle contractility, uterine contractions, vomiting, diarrhoea and neurological effects like ringing in ears, vertigo, deafness, visual disturbances and mental changes (Cinchonism). Like its levo isomer, it has antimalarial action, and has been used as a parenteral alternative to quinine for falciparum malaria. The important drug interactions of quinidine are:
Rise in blood levels and toxicity of digoxin due to displacement from tissue binding and inhibition of Pglycoprotein mediated renal and biliary clearance of digoxin.
Marked fall in BP in patients receiving vasodilators.
Risk of torsades de pointes is increased by hypokalaemia caused by diuretics.
Synergistic cardiac depression with β-blockers, verapamil, K+ salts.
Quinidine inhibits CYP2D6: prolongs t½ of propafenone and inhibits conversion of codeine to morphine.
Use: Though quinidine is effective in many atrial and ventricular arrhythmias, it is not used to terminate them because of risk of adverse effects, including that of torsades de pointes, sudden cardiac arrest or VF; idiosyncratic angioedema, vascular collapse, thrombocytopenia. It is occasionally used in a dose of 100–200 mg TDS to maintain sinus rhythm after termination of AF or AFI, and rarely in ventricular arrhythmias.
QUINIDINE SULPHATE 200 mg tab; QUININGA 300 mg tab, 600 mg/2 ml inj; NATCARDINE 100 mg tab.
Procainamide
It is the orally active amide derivative of the local anesthetic procaine, with cardiac electrophysiological actions almost identical to those of quinidine, viz. slowing of 0 phase and impulse conduction, prolongation of APD, ERP, QRS complex and Q-T interval. Significant differences between the two are:
It is less effective in suppressing ectopic automaticity.
It causes somewhat less marked depression of contractility and A-V conduction.
Antivagal action is minimal.
It is not an α blocker: causes less fall in BP; at high doses, fall in BP is due to ganglionic blockade.
Pharmacokinetics Oral bioavailability of procainamide is about 75%, peak plasma concentration occurs in 1 hour. It is metabolized in liver, primarily by acetylation to N-acetyl-procainamide (NAPA) which has no Na+ channel blocking property but blocks K+ channels and prolongs repolarization: APD is lengthened. There are fast and slow acetylators of procainamide (as there are for isoniazid). More than half of procainamide is excreted unchanged in urine; plasma t½ is relatively short (3–4 hours). Thus, more frequent dosing than quinidine is required.
Dose: For abolition of arrhythmia—0.5–1 g oral or i.m. followed by 0.25–0.5 g every 2 hours; or 500 mg i.v. loading dose (25 mg/min injection) followed by 2 mg/kg/hour. Maintenance dose—0.5 g every 4–6 hours.
PRONESTYL 250 mg tab., 1 g/10 ml inj.
Adverse effects
Gastrointestinal tolerance of procainamide is better than quinidine, but nausea and vomiting do occur. CNS: weakness, mental confusion and hallucinations are noted at higher doses. Flushing and hypotension are seen on rapid i.v. injection. Cardiac toxicity, ability to cause torsades de pointes are similar to quinidine. Hypersensitivity reactions are rashes, fever, angioedema. Agranulocytosis and aplastic anaemia is rare. More than half of patients given chronic high dose procainamide therapy develop antinuclear antibodies and about 1/5 develop systemic lupus erythematosus (SLE). It is more common in slow acetylators.
Use Procainamide (i.v.) can terminate monomorphic VT in upto 80–90% patients, but is less effective in preventing recurrences. Many WPW reciprocal VTs respond and it has been used to prevent recurrences of VF. However, procainamide is not suitable for prolonged oral therapy because of inconveniently frequent dosing and high risk of lupus.
Disopyramide It is a quinidine like Class IA drug that has prominent cardiac depressant and anticholinergic actions, but no α adrenergic blocking property. Disopyramide usually has no effect on sinus rate because of opposing direct depressant and antivagal actions. Prolongation of P-R interval and QRS broadening are less marked.
Pharmacokinetics Bioavailability of oral disopyramide is about 80%. It is partly metabolized in liver by dealkylation, nearly half is excreted unchanged in urine; plasma t½ is 6–8 hrs. The t½ is increased in patients of MI and in renal insufficiency.
Dose: 100–150 mg 6–8 hourly oral.
NORPACE 100, 150 mg cap, REGUBEAT 100 mg tab.
Adverse effects Disopyramide is better tolerated than quinidine, less g.i. effects. Anticholinergic side effects are the most prominent: dry mouth, constipation, urinary retention (especially in elderly males) and blurred vision. It can cause greater depression of cardiac contractility. Cardiac decompensation and hypotension may occur in patients with damaged hearts because it also increases peripheral resistance, so that cardiac output may be markedly decreased. Contraindications are—sick sinus, cardiac failure and prostate hypertrophy.
Use The primary indication of disopyramide is as a second line drug for prevention of recurrences of ventricular arrhythmia. It may also be used for maintenance therapy after cardioversion of AF or AFl .
Moricizine This Class IA drug delays Na+ channel recovery to a greater extent (also classified as Class IC), but cardio depressant and CNS effects are less marked. It has been used to suppress VES and WPW arrhythmias, but the CAST II study has found it to increase mortality in post-MI patients.
SUBCLASS IB
Lidocaine (Lignocaine)
It is the most commonly used local anaesthetic. In addition, it is a popular antiarrhythmic in intensive care units.
The most prominent cardiac action of lidocaine is suppression of automaticity in ectopic foci. Enhanced phase-4 depolarization in partially depolarized or stretched PFs, and afterdepolarizations are antagonized, but SA node automaticity is not depressed.
The rate of 0 phase depolarization and conduction velocity in A-V bundle or ventricles is not decreased. Lidocaine decreases APD in PF and ventricular muscle, but has practically no effect on APD and ERP of atrial fibres. Atrial reentry is not affected. However, it can suppress reentrant ventricular arrhythmias either by abolishing one-way block or by producing two way block.
Lidocaine is a blocker of inactivated Na+ channels more than that of open state. As such, it is relatively selective for partially depolarized cells and those with longer APD (whose Na+ channels remain inactivated for longer period). While normal ventricular and conducting fibres are minimally affected, depolarized/damaged fibres are significantly depressed. Brevity of atrial AP and lack of lidocaine effect on channel recovery might explain its inefficacy in atrial arrhythmias.
Lidocaine has minimal effect on normal ECG; QT interval may decrease. It causes little depression of cardiac contractility or arterial BP. There are no significant autonomic actions: all cardiac effects are direct actions.
Pharmacokinetics Lidocaine is inactive orally due to high first pass metabolism in liver. Action of an i.v. bolus lasts only 10–20 min because of rapid redistribution. It is hydrolysed, deethylated and conjugated; metabolites are excreted in urine. Metabolism of lidocaine is hepatic blood flow dependent.
The t½ of early distribution phase is 8 min while that of later elimination phase is nearly 2 hours. Its t½ is prolonged in CHF, because of decrease in volume of distribution and hepatic blood flow.
Dose and preparations Lidocaine is given only by i.v. route: 50–100 mg bolus followed by 20–40 mg every 10– 20 min or 1–3 mg/min infusion.
XYLOCARD, GESICARD 20 mg/ml inj. (5, 50 ml vials).
These preparations for cardiac use contain no preservative. The local anaesthetic preparations should not be used for this purpose. Ventricular ectopic activity can be titrated with the rate of administration. Propranolol prolongs t½ of lidocaine by reducing hepatic blood flow. Cimetidine also increases plasma levels of lidocaine.
Adverse effects The main toxicity is dose related neurological effects: Drowsiness, nausea, paresthesias, blurred vision, disorientation, nystagmus, twitchings and fits. Lidocaine has practically no proarrhythmic potential and is the least cardiotoxic antiarrhythmic. Only excessive doses cause cardiac depression and hypotension.
Use Lidocaine is used only in ventricular tachyarrhythmias. It is ineffective in atrial arrhythmias. Because of rapidly developing and titratable action it is a good drug in the emergency setting, e.g. arrhythmias following acute MI, during cardiac surgery, etc. Given prophylactically by infusion in acute MI, it reduces occurrence of VF. However, metaanalysis has shown that lidocaine fails to improve survival; may even increase short term mortality. Therefore, it is no longer administered routinely to all MI patients.
Efficacy of lidocaine in chronic ventricular arrhythmia is low, but it is useful in digitalis toxicity because it does not worsen A-V block.
Mexiletine
It is a local anaesthetic and an active antiarrhythmic by the oral route; chemically and pharmacologically similar to lidocaine. It reduces automaticity in PF, both by decreasing phase-4 slope and by increasing threshold voltage. By reducing the rate of 0 phase depolarization in ischaemic PF it may convert one-way block to twoway block.
Mexiletine is almost completely absorbed orally, 90% metabolized in liver and excreted in urine; plasma t½ 9–12 hours.
Bradycardia, hypotension and accentuation of A-V block may attend i.v. injection of mexiletine. Neurological—tremor, nausea and vomiting are common; dizziness, confusion, blurred vision, ataxia can occur.
Dose: 100–200 mg i.v. over 10 min., 1 mg/min infusion. Oral: 150–200 mg TDS with meals.
MEXITIL 50, 150 mg caps, 250 mg/10 ml. inj.
Use Parenteral mexiletine is effective in postinfarction ventricular arrhythmias as alternative to lidocaine in resistant cases. Orally it is used to keep VES and VT suppressed over long-term.
SUBCLASS IC
Propafenone By blocking Na+ channels propafenone markedly depresses conduction and has β adrenergic blocking property—can precipitate CHF and bronchospasm. Sino-atrial block has occurred occasionally. Propafenone is absorbed orally and undergoes variable first pass metabolism; there being extensive or poor metabolizers. Bioavailability and t½ differs considerably among individuals. Some metabolites are active. Side effects are nausea, vomiting, bitter taste, constipation and blurred vision.
Propafenone is a reserve drug for ventricular arrhythmias, reentrant tachycardias involving AV node/accessory pathway and to maintain sinus rhythm in AF.
Dose: 150 mg BD–300 mg TDS;
RHYTHMONORM 150 mg tab
Flecainide
It suppresses VES, VT, WPW tachycardia and prevents recurrences of AF and PSVT. But in the CAST study it was found to increase mortality in patients recovering from MI; can itself provoke arrhythmias during chronic therapy. It is reserved for resistant cases of recurrent AF, and WPW rhythms in patients not having associated CHF.
CLASS II
The primary action of drugs in this class is to suppress adrenergically mediated ectopic activity.
Propranolol (see Ch. 10) Some β blockers, e.g. propranolol have quinidine like direct membrane stabilizing action at high doses, but in the clinically used dose range—antiarrhythmic action is exerted primarily because of cardiac adrenergic blockade. Propranolol decreases the slope of phase-4 depolarization and automaticity in SA node, PF and other ectopic foci when this has been increased under adrenergic influence; little action otherwise. The other most important action is to prolong the ERP of A-V node (an antiadrenergic action). This impedes A-V conduction (no paradoxical tachycardia can occur when atrial rate in AF or AFl is reduced).
Slow channel responses and after-depolarizations that have been induced by catecholamines (CAs) are suppressed. Reentrant arrhythmias that involve A-V node (many PSVTs) or that are dependent on slow channel/depressed fast channel response may be abolished by its marked depressant action on these modalities.
The most prominent ECG change is prolongation of PR interval. Depression of cardiac contractility and BP are less marked than with quinidine.
Administration For rapid action, propranolol may be injected i.v. 1 mg/min (max. 5 mg) under close monitoring. The usual oral antiarrhythmic dose is 40–80 mg 2–4 times a day.
Use Propranolol is very useful in treating inappropriate sinus tachycardia, atrial and nodal ESs provoked by emotion or exercise. It is less effective than adenosine and verapamil for PSVT—conversion rate is about 60%.
Propranolol rarely abolishes AF or AFl, but can be used to control ventricular rate. It is highly effective in sympathetically mediated arrhythmias seen in pheochromocytoma and during anaesthesia with halothane. Digitalis induced tachyarrhythmias may be suppressed.
Efficacy in chronic ventricular arrhythmias is low, but its antiischaemic action may be protective. Prophylactic treatment with β blockers reduces mortality in post-MI patients. Propranolol has also been used for WPW, but in some cases severe bradycardia may be precipitated.
Sotalol (see p. 140) It is a nonselective β blocker having prominent Class III action of prolonging repolarization by blocking cardiac K+ channels. It is not a Na+ channel blocker—does not depress conduction in fast response tissue, but delays A-V conduction and prolongs its ERP. Sotalol is effective in polymorphic VT and for maintaining sinus rhythm in AF/AFl. Due to prolongation of APD and Q-T, risk of dose-dependent torsades de pointes is the major limitation. It is contraindicated in patients with long Q-T interval.
Esmolol (see p. 141) This quick and short acting β1 blocker administered i.v. is very useful for emergency control of ventricular rate in AF/AFl. It can terminate supraventricular tachycardia, and is mainly used for arrhythmias associated with anaesthesia.
MINIBLOCK 100 mg/10 ml, 250 mg/10 ml inj.; 0.5 mg/ kg in 1 min followed by 0.05–0.2 mg/kg/min i.v. infusion.
CLASS III
The characteristic action of this class is prolongation of repolarization; AP is widened and ERP is increased. The tissue remains refractory even after full repolarization: reentrant arrhythmias are terminated.
Amiodarone
This unusual iodine containing highly lipophilic long-acting antiarrhythmic exerts multiple actions:
Prolongs APD and Q-T interval attributable to block of myocardial delayed rectifier K+ channels. This also appears to reduce nonuniformity of refractoriness among different fibres.
Preferentially blocks inactivated Na+ channels (like lidocaine) with relatively rapid rate of channel recovery: more effective in depressing conduction in cells that are partially depolarized or have longer APD.
Inhibits myocardial Ca2+ channels and has noncompetitive β adrenergic blocking property.
Conduction is slowed and ectopic automaticity is markedly depressed, but that of SA node is affected only slightly. Effect of oral doses on cardiac contractility and BP are minimal, but i.v. injection frequently causes myocardial depression and hypotension.
Despite prolongation of APD, the arrhythmia (torsades de pointes) provoking potential of amiodarone is low, probably because it does not exhibit ‘reverse usedependence’ of APD prolongation or because of its multiple antiarrhythmic mechanisms. The prolongation of APD by most class III drugs is more marked at slower rates of activation (encouraging EAD) than at higher rates (reverse use-dependence), while with amiodarone it is independent of rate of activation.
Pharmacokinetics Amiodarone is incompletely and slowly absorbed from the g.i.t. On daily oral ingestion the action develops over several days, even weeks. However, on i.v. injection, action develops rapidly. It accumulates in muscle and fat from which it is slowly released and then metabolized in liver mainly by CYP3A4. One metabolite is active. The duration of action is exceptionally long; t½ 3–8 weeks.
Dose: Amiodarone is mainly used orally 400–600 mg/ day for few weeks, followed by 100–200 mg OD for maintenance therapy. 100–300 mg (5 mg/kg) slow i.v. injection over 30–60 min.
CORDARONE, ALDARONE, EURYTHMIC 100, 200 mg tabs, 150 mg/3 ml inj.
Use Amiodarone has been found effective in a wide range of ventricular and supraventricular arrhythmias. Resistant VT and recurrent VF are the most important indications. It is also used to maintain sinus rhythm in AF when other drugs have failed. Rapid termination of ventricular and supraventricular arrhythmias can be obtained by i.v. injection. WPW tachyarrhythmia is terminated by suppression of both normal and aberrant pathways.
Its long duration of action makes it suitable for long-term prophylactic therapy; has been found to reduce sudden cardiac death. Because of high and broad-spectrum efficacy and relatively low proarrhythmic potential, amiodarone is a commonly used antiarrhythmic, despite its organ toxicity in the long-term.
Adverse effects These are dose-related and increase with duration of therapy. Fall in BP, bradycardia and myocardial depression occurs on i.v. injection and on drug cumulation. Nausea, gastrointestinal upset may attend oral medication, especially during the loading phase. Photosensitization and skin pigmentation occurs in about 10% patients. Corneal microdeposits are common with long-term use, but are reversible on discontinuation.
Pulmonary alveolitis and fibrosis is the most serious toxicity of prolonged use, but is rare if daily dose is kept below 200 mg. Peripheral neuropathy generally manifests as weakness of shoulder and pelvic muscles. Liver damage is rare. Amiodarone interferes with thyroid function in many ways including inhibition of peripheral conversion of T4 to T3: goiter, hypothyroidism and rarely hyperthyroidism may develop on chronic use.
Interactions Amiodarone can increase digoxin and warfarin levels by reducing their renal clearance. Additive A-V block can occur in patients receiving β blockers or calcium channel blockers. Inducers and inhibitors of CYP3A4 respectively decrease and increase amiodarone levels.
Bretylium It is an adrenergic neurine blocking drug (see Ch. 10) introduced in 1960 as antihypertensive but was soon withdrawn. It was reintroduced for parenteral use to facilitate reversal of VF, but is not available in India or the USA, and is rarely used elsewhere. Bretylium has complex electrophysiological effects which are partly a result of initial NA release from adrenergic terminals in heart, and later blockade of NA release, but major direct action is prolongation of APD and ERP, due to K+ channel blockade.
Dofetilide This newer antiarrhythmic prolongs APD and ERP by selectively blocking rapid component of delayed rectifier K+ current without affecting other channels or receptors; has no autonomic or peripheral actions. It is therefore labelled as pure class III antiarrhythmic.
Oral dofetilide can convert AF or AFl to sinus rhythm in ~30% cases, but is more effective in maintaining sinus rhythm in converted patients—its primary indication. Significantly, chronic therapy with dofetilide in patients with high risk of sudden cardiac death/post MI cases has not increased mortality, despite provoking torsades de pointes in some recipients. It is mainly excreted unchanged in urine and produces few side effects.
Ibutilide is another new class III antiarrhythmic used i.v. for pharmacological conversion of AFl and AF to sinus rhythm.
CLASS IV
Verapamil
Of the many Ca2+ channel blockers, verapamil has the most prominent cardiac electrophysiological action (Table 38.1). It blocks L type Ca2+ channels and delays their recovery. Its antiarrhythmic aspects are described here, while other aspects are covered in Ch. 39 and 40.
The basic action of verapamil is to depress Ca2+ mediated depolarization. This suppresses automaticity or reentry dependent on slow response. Phase-4 depolarization in SA node and PFs is reduced resulting in bradycardia and extinction of latent pacemakers. Reflex sympathetic stimulation due to vasodilatation partly counteracts the direct bradycardia producing action. Delayed after-depolarizations in PFs are dampened.
The most consistent action of verapamil is prolongation of A-V nodal ERP. As a result A-V conduction is markedly slowed and reentry involving A-V node is terminated. Intraventricular conduction, however, is not affected. Verapamil has negative inotropic action due to interference with Ca2+ mediated excitation-contraction coupling in myocardium.
Uses and precautions
1. PSVT—Verapamil can terminate attacks of PSVT; 5 mg i.v. over 2–3 min is effective in 80% cases, but marked bradycardia, A-V block, cardiac arrest and hypotension can occur. Verapamil should not be used if PSVT is accompanied with hypotension or CHF. It is also useful for preventing recurrences: 60 to 120 mg TDS orally.
2. To control ventricular rate in AF or AFl; it may be used as an alternative to, or in addition to digitalis: 40–80 mg TDS oral. In few cases the AF or AFl may revert to sinus rhythm, but this is an unusual happening.
Reentrant supraventricular and nodal arrhythmias (WPW) are susceptible to verapamil, but it should not be used because of risk of increased ventricular rate due to reflex sympathetic stimulation and reduction of ERP of the bypass tract in some cases.
Verapamil has poor efficacy in ventricular arrhythmias. In contrast to β blockers, verapamil prophylaxis does not reduce mortality in post-MI patients. In some patients of VT, i.v. injection of verapamil has precipitated VF: therefore contraindicated. It is also not recommended for digitalis toxicity, because additive A-V block may occur. It is contraindicated in partial heart block and sick sinus.
CALAPTIN 40, 80 mg tab; 120, 240 mg SR tab, 5 mg/2 ml inj
Diltiazem The direct cardiac actions of diltiazem are similar to those of verapamil. However, they are less marked. It is an alternative to verapamil for PSVT.
For rapid control of ventricular rate in AF or AFl, i.v. diltiazem is preferred over verapamil, because it can be more easily titrated to the target heart rate, causes less hypotension and myocardial depression—can be used even in the presence of mild-to-moderate CHF.
DILZEM 30, 60, 90 mg tabs, 25 mg/5 ml inj
Drugs for PSVT
An attack of PSVT can be terminated by i.v. injection of verapamil, diltiazem, esmolol or digoxin; but most cardiologists now prefer adenosine. Maintenance therapy with oral digoxin/ verapamil/β blockers can prevent recurrences.
Adenosine
Administered by rapid i.v. injection (over 1–3 sec) either as the free base (6–12 mg) or as ATP (10–20 mg), adenosine terminates within 30 sec. more than 90% episodes of PSVT involving the A-V node. It activates ACh sensitive K+ channels and causes membrane hyperpolarization through interaction with A1 type of G protein coupled adenosine receptors on SA node (pacemaker depression → bradycardia), A-V node (prolongation of ERP → slowing of conduction) and atrium (shortening of AP, reduced excitability). It indirectly reduces Ca2+ current in A-V node; depression of the reentrant circuit through A-V node is responsible for termination of PSVT. Adrenergically induced DADs in ventricle are also suppressed. Coronary dilatation occurs transiently.
ADENOJECT, ADENOCOR 3 mg adenosine (base) per ml in 2 ml and 10 ml amp.
Adenosine has a very short t½ in blood (~10 sec) due to uptake into RBCs and endothelial cells where it is converted to 5-AMP and inosine. Almost complete elimination occurs in a single passage through coronary circulation. Injected ATP is rapidly converted to adenosine.
Dipyridamole potentiates its action by inhibiting uptake, while theophylline/ caffeine antagonize its action by blocking adenosine receptors. Higher doses may be required in heavy tea/coffee drinkers. Patients on carbamazepine are at greater risk of developing heart block. Advantages of adenosine for termination of PSVT are:
Efficacy equivalent to or better than verapamil.
Action lasts < 1 min; adverse effects (even cardiac arrest, if it occurs) are transient.
No hemodynamics deterioration; can be given to patients with hypotension, CHF or those receiving β blockers. Verapamil is contraindicated in these situations.
Safe in wide QRS tachycardia (verapamil is unsafe).
Effective in patients not responding to verapamil.
However, adenosine produces transient dyspnoea, chest pain, fall in BP and flushing in 30–60% patients; ventricular standstill for few sec or VF occurs in some patients. Bronchospasm may be precipitated in asthmatics. Adenosine has to be rapidly injected in a large vein and has brief action, not suitable for recurrent cases. It is expensive and cannot be used to prevent recurrences.
Other uses of adenosine
(a) Diagnosis of tachycardias dependent on A-V node.
(b) To induce brief coronary vasodilatation during certain diagnostic/interventional procedures.
(c) To produce controlled hypotension during surgery.
Drugs for A-V Block
Atropine: When A-V block is due to vagal overactivity, e.g. digitalis toxicity, some cases of MI; it can be improved by atropine 0.6–1.2 mg i.m. Atropine abbreviates A-V node ERP and increases conduction velocity in bundle of His.
Sympathomimetics (Adr, isoprenaline): These drugs may overcome partial heart block by facilitating A-V conduction and shortening ERP of conducting tissues.
They may also be used in complete (3rd degree) heart block to maintain a sufficient idioventricular rate (by increasing automaticity of ventricular pacemakers) till external pacemaker can be implanted.
Choice of antiarrhythmics Asymptomatic arrhythmias and those which do not jeopardize haemodynamics, e.g. most AES and occasional VES, first degree A-V block,
bundle branch block, etc. in an otherwise normal heart, do not require antiarrhythmic treatment. Chronic prophylactic therapy with class I and class IV antiarrhythmics does not appear to afford survival benefit, except in few selected cases. On the other hand, vigorous therapy is indicated when:
Arrhythmia is life-threatening, e.g. sustained VT, torsades de pointes, VF.
Arrhythmia is causing hypotension, breathlessness or cardiac failure.
Palpitation is marked, e.g. in PSVT, sustained VT, AF, torsades de pointes.
When simple arrhythmia may lead to more serious ones, e.g. after MI (warning arrhythmias).
In the above situations antiarrhythmics are mostly needed for short periods. The choice of an antiarrhythmic in a patient depends on:
(a) ECG diagnosis
(b) Possible mechanism underlying the arrhythmia
(c) Mechanism of action and range of antiarrhythmic activity of the drug
(d) Pharmacokinetic profile of the drug
(e) Hemodynamic effects of the drug
The aim is to improve cardiovascular function either by restoring sinus rhythm, or by controlling ventricular rate, or by conversion to a more desirable pattern of electrical and mechanical activity.
Despite extensive investigation, choice of an antiarrhythmic is still largely empirical. Current guidelines are summarized in Table 38.2.
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