Healthcare in India

Cardiac Glycosides and Drugs for Heart Failure

CARDIAC GLYCOSIDES

These are glycosidic drugs having cardiac inotropic property. They increase myocardial contractility and output in a hypodynamic heart without a proportionate increase in O2 consumption. Thus, efficiency of failing heart is increased. In contrast, ‘cardiac stimulants’ (Adr, theophylline) increased O2 consumption rather disproportionately and tend to decrease myocardial efficiency, i.e. increase in O2 consumption is more than increase in contractility. Further, cardiac stimulants also increase heart rate and have a shortlived action, while-cardiac glycosides do not increase heart rate and have a prolonged action.
William Withering, a Birmingham physician, learnt that a decoction containing ‘foxglove’ (Digitalis) with other herbals, prepared by an old lady, relieved dropsy. He tried extract of foxglove alone and found it to be remarkably effective in some cases. He published his classic monograph ‘An account of the Foxglove and some of its medicinal uses: with practical remarks on dropsy and other diseases’ in 1785 and ascribed the beneficial effect to an action on the kidney. Later Digitalis was used indiscriminately, disregarding the precautions mentioned by Withering; was found to be toxic and fell into disrepute. Cushney and Mackenzie, in the beginning of 20th century, established its action on the heart and its use in congestive heart failure (CHF). Strophanthus was used as an arrow poison in Africa. Fraser discovered its digitalis like action in 1980. The use of squill has come from Egyptian medicine, Toad skin from Chinese medicine and Thevetin from Unani medicine. Cases of poisoning with Thevetia and Convallaria are occasionally seen.

* used clinically
By convention, ‘Digitalis’ is applied as a collective term for the whole group and has come to mean ‘a cardiac glycoside’.
CHEMISTRY
All are glycosides; consist of an aglycone (genin) to which are attached on or more sugar (glucose or digitoxose) moieties. The pharmacological activity resides in the aglycone, but attached sugars modify solubility and cell permeability. In general, aglycones have shortlived and less potent action.
The aglycone consists of a cyclopentanoper­hydrophenanthrene (steroid) ring to which is attached a 5 or 6 membered unsaturated lactone ring. One or more hydroxyl and other substitutions are present on the aglycone and determine its polarity, e.g. digoxigenin has an additional OH group than digitoxigenin and is more polar.

PHARMACOLOGICAL ACTIONS
All digitalis glycosides have qualitatively similar action; there are only quantitative and pharma­cokinetic differences. Digoxin is described as prototype.
1. Heart Digitalis has direct effects on myo­cardial contractility and electrophysiological pro­perties. In addition, it has vagomimetic action, reflex effects due to alteration in haemodynamics and direct CNS effects altering sympathetic activity.
Force of contraction Digitalis causes a dose dependent increase in force of contraction of heart-a positive inotropic action. This is especially seen in the failing heart which is exquisitely sensitive. There is increased velocity of tension development and higher peak tension can be generated. Systole is shortened, diastole is prolonged. When a normal heart is subjected to increased impedance to outflow, it generates increased tension so that stroke volume is maintained upto considerably higher values of impedance (Fig. 37.1), while the failing heart is not able to do so and the stroke volume progres­sively decreases. The digitalized failing heart regains some of its capacity to contract more forcefully when subjected to increas.ed resistance to ejection. There is more complete emptying of failing and dilated ventricles-cardiac output is increased.
Digitalis increases force of contraction in normal heart as well, but this is not translated into increased output, because the normal heart empties nearly completely even otherwise and reduction of end diastolic volume is counter­productive.
Tone It is defined by the maximum length of the fibre at a given filling pressure, or the resting tension in the muscle fibre. This is not affected by therapeutic doses of digitalis. However, digitalis does decrease end diastolic size of a failing ventricle, but this is a consequence of better venm.­cular emptying and a reduction in filling pressure.
Rate Hear_ate is decreased by digitalis. Bradycardia is more marked in CHF patients: improved circulation (due to positive inotropic action) restores the diminished vagal tone and abolishes sympathetic overactivity. In addition, digitalis slows the heart by vagal and extravagal actions.
Vagal tone is increased:
(a) Reflexly through nodose ganglion and sensi­tization ofbaroreceptors.
(b) Direct stimulation of vagal centre.
(c) Sensitization of SA node to ACh.
Extravagal: A direct depressant action on SA and A-V nodes.
The vagal action manifests early and can be blocked by atropine, whereas the extravagal action becomes prominent later and cannot be reversed by atropine.
Electrophysiological properties The electrophy­siological effects of digitalis on different types of cardiac fibres differ quantitatively and quali­tatively. The Purkinje fibres, automatic and conducting tissues are more sensitive. In addition to direct effects, the indirect autonomic influences are important in the in situ heart. .
(a) Action potential (AP): The effects are illus­trated diagrammatically in Fig. 37.2. The resting membrane potential (RMP), is progressively decreased (shifted towards isoelectric level) with increasing doses--excitability is enhanced at low doses (due to reduction of gap between RMP and threshold potential) but depressed at toxic doses (depolarization to below the level of critical potential which inactivates the fast channels).
The rate of 0 phase depolarization is reduced. This action is most marked in A-V node and bundle of His.
The slope of phase-4 depolarization is increased in the PFs--ectopic automaticity is enhanced-latent pacemakers become overt at high doses -7 extrasystoles. High doses of digitalis produce coupled beats by another mechanism: the RMP shows oscillations during phase-4; when their magnitude is sufficient enough, delayed after-depolarizations result (see Fig. 38.1). The SA and A-V node automaticity is reduced at therapeutic concentrations by vagal action which hyperpolarizes these cells and reduces their phase-4 slope. Toxic doses markedly reduce RMP of SA nodal cells by direct action and stop impulse generation.
The action potential duration (APD) is reduced (primarily at phase-2) and amplitude of AP is diminished.
(b) Effective refractory period (ERP):

A-V node and
bundle of his

Ventricle-ERP is abbreviated by direct action.
(c) Excitability._ Enhanced at low doses but depressed at high doses as explained above.
(d) Conduction: A-V conduction is demonstrably slowed by therapeutic doses due to a reduction in the rate of 0 phase depolarization.,. At high doses, intraventricular conduction in PFs is also depressed by uncoupling of gap junctions.
(e) ECG: Therapeutic doses of digitalis produce changes in the ECG. These are accentuated at high doses-may also produce arrhythmias.. The changes are:

• Decreased amplitude or inversion of T wave.
• Increased P-R interval (slowing of A-V conduction), A-V block at toxic doses.
• Shortening of Q-T interval (reflecting shor­tening of systole).
• Depression of ST segment (at high doses-due to interference with repolarization).

The abnormal QRS of Wolff-Parkinson-White (WPW) syndrome is widened because conduction through the normal A-V bundle is slowed but not that through the aberrant pathway.
Mechanism of action : Digitalis increases force of cardiac contraction by a direct action independent of innervation. It selectively binds to extracellular face of the membrane associated Na+K+ ATPase of myocardial fibres and inhibitis this enzyme. Inhibition of this caution pump results in progressive accumulation of Na+ intracellularly. This indirectly results in intracellular Ca2+ accumulation.
During depolarization Ca2+ ions enter the cell driven by the steep Ca2+ gradient (>1 mM extra cellular to < 100 nM cytosolic during diastole) through voltage sensitive Ca2+ channels. This triggers release of Ca2+ stored in sarcoplasmic reticulum (SR) ® cytosolic Ca2+ increases transiently to about 500 nM (calcium transients) ® triggers contraction. Ca2+ is then actively taken up by SR and a fraction (equal to that which entered from outside during depolarization) is extruded mainly by 3Na+/1Ca2+ exchange tranporter (NCX-antiporter) as well as by sarcolemmal Ca2+ pump (Ca2+ ATPase). During phase 3 of AP membrane Na+K+ ATPase moves 3 intracellular Na+ ions for 2 extracellular K+ ions. The slight (1-1.5 mM) increase in cytosolic Na+ over normal (8-10 nM) due to partial inhibition of Na+K+ATPase by digitalis reduces transmembrane gradient of Na+ which drives the extrusion of Ca2+. The excess Ca2+ remaining in cytosol is taken up into SR which progressively get loaded with more Ca2+ ® subsequent calcium transients are augmented.
The relationship of cytosolic [Na+] and [Ca2+] is such that a small percentage increase in Na+ concentration leads to a large percentage increase in Ca2+ concentration.
Moreover, raised cytosolic Ca2+ induces greater entry of Ca2+ through voltage sensitive Ca2+ channels during the plateau phase. It has been shown that 1 mM rise in cytosolic [Na+] results in 20-30% increase in the tension developed by ventricular fibres.
Binding of glycoside to Na+K+ ATPase is slow. Moreover, after Na+K+ATPase inhibition, Ca2+ loading occurs gradually. As such, inotropic effect of digitalis takes hours to develop, even after i.v. administration.
Inhibition of Na+K+ ATPase is clearly invol­ved in the toxic actions of digitalis. At high doses, there is depletion of intracellular K+; toxicity is partially reversed by infusing K+. Excessive Ca2+ loading of SR results in spontaneous cycles of Ca2+ release and uptake producing oscillatory after-depolarizations and after-contractions. Since both therapeutic and toxic effects of digi­talis are due to myocardial Ca2+ loading, these are inseparable and therapeutic index is low.
2. Blood vessels Digitalis has mild direct vasoconstrictor action-peripheral resistance is increased in normal individuals. However, in CHF patients this is more than compensated by the indirect effect of improvement in circulation, i.e. reflex sympathetic overactivity is withdrawn and a net decrease in peripheral resistance occurs. Venous tone is improved in normal individuals as well as in CHF patients.
Digitalis has no prominent effect on BP: systolic BP may increase and diastolic may fall in CHF patients-pulse pressure increases. Hypertension is no contraindication to the use of digitalis.
Despite a weak direct coronary constrictor action, therapeutic doses of digitalis have no significant effect on coronary circulation­coronary insufficiency is no contraindication to its use. Coronary debt may even decrease if ventricles were in a dilated state.
3. Kidney Diuresis is seen promptly in CHF patients, secondary to improvement in circulation and renal perfusion. The retained salt and water is gradually excreted. No diuresis occurs in normal individuals or in patients with edema due to other causes.
4. CNS Digitalis has little apparent CNS effect in therapeutic dose. Higher doses cause CTZ activation _ nausea and vomiting. Still higher doses produce hyperapnoea, central sympathetic stimulation, mental confusion, disorientation and visual disturbances.

PHARMACOKINETICS

The pharmacokinetic properties of digoxin and digitoxin are presented in Table 37.1.
Digitoxin is the most lipid soluble, digoxin is relatively polar, while ouabain has the highest polar character. Bioavailability of digoxin tablets from different manufacturers may differ. Presence of food in stomach delays absorption of digoxin as well as digitoxin.
The volume of distribution of cardiac glyco­sides is large, e.g. 6-8 L/Kg in case of digoxin. All are concentrated in the heart (_20 times than plasma), skeletal muscle, liver and kidney.

Table 37.1:    Pharmacokinetic properties of digoxin and digitoxin and digitoxin

* Of full digitalizing dose given i.v.; ** fraction of total amount present in the body.
Digitoxin is primarily metabolized in liver, partly to digoxin, and undergoes some entero­hepatic circulation. Digoxin is primarily excreted unchanged by the kidney: mainly by glomerular filtration; rate of excretion is altered parallel to creatinine clearance. Its tlh is prolonged in elderly patients and in those with renal insufficiency: dose has to be reduced. Dose of digitoxin is not greatly altered in renal failure.
Cardiac glycosides are cumulative drugs. When maintenance doses are given from the beginning, steady state levels and full therapeutic effect are attained after 4 x tlh, i.e. 6--7 days for digoxin and 4 weeks for digitoxin.
Preparations
1. Digoxin: DIGOXIN 0.25 mg tab., 0.05 mg/ml pediatric elixir, 0.5 mg/2 ml inj. LANOXIN 0.25 mg tab, CARDIOXIN, DIXIN 0.25 mg tab, 0.5 mg/2 ml inj.
2. Digitoxin: DIGITOXIN 0.1 mg tab.
All glycosides have the same safety margin; choice of preparation depends on kinetic properties. Digoxin is well absorbed orally, has reasonably quick action, intermediate tV2, dose adjustments are possible in 2-3 days, can be used for routine treatment as well as emergency; in case of toxicity-discontinuation of the drug produces reasonably rapid disappearance of manifestations. Thus, it is an all purpose and most commonly used glycoside.
Digitoxin may be used for maintenance; because of its long tV2, diurnal fluctuations in blood level are low. However, any dose adjustment takes weeks and toxic effects are more persistent. Therefore, most physicians prefer digoxin for maintenance therapy also.

ADVERSE EFFECTS
Toxicity of digitalis is high, margin of safety is low (therapeutic index 1.5-3). Higher cardiac mortality has been reported among patients with steady-state plasma digoxin levels> 1.1 ng/ml during maintenance therapy. About 25% patients develop one or other toxic symptom. The manifes­tations are:
Extracardiac Anorexia, nausea, vomiting and abdominal pain are usually reported first: are due to gastric irritation, mesenteric vasoconstriction and CTZ stimulation. Fatigue, no desire to walk or lift an arm, malaise, headache, mental confusion, restlessness, hyperapnoea, disorienta­tion, psychosis and visual disturbances are the other complaints. Diarrhoea occurs occasionally. Skin rashes and gynaecomastia are rare.
Cardiac Almost every type of arrhythmia can be produced by digitalis: pulsus bigeminus, nodal and ventricular extrasystoles, ventricular tachycardia and terminally fibrillation. Partial to complete A-V block may be the sole cardiac toxicity or it may accompany other arrhythmias. Severe bradycardia, atrial extrasystoles, AF or API have also been noted. In about 2/3 patients showing toxicity, extra cardiac symptoms precede cardiac; in the rest serious cardiac arrhythmias are the first manifestation. The central actions of digitalis appear to contribute to the development of arrhythmias by inducing fast and irregular activity in the cardiac sympathetic and vagus nerves.
Treatment Further doses of digitalis must be stopped at the earliest sign of toxicity; nothing more needs to be done in many patients, especially if the manifestations are only extracardiac.
(a) For tachyarrhythmias When they are caused by chronic use of digitalis and diuretics (both induce K+ depletion)-infuse KC120 m.mol/hour (max. 100 m. mol) i.v. or give orally in milder cases. K+ tends to antagonize digitalis induced enhanced automaticity and decreases binding of the glycosides to Na+K+ATPase by favouring a conformation of the enzyme that has lower affinity for cardiac glycosides. When toxicity is due to acute ingestion of large doses of digitalis, plasma K+ may be high; it should not be given from outside. In any case, it is desirable to measure serum K+ to guide KCl therapy. K+ is contra­indicated if higher degree of A-V block is present: complete A-V block and ventricular asystole can be precipitated.
(b) For ventricular arrhythmias Lidocaine i.v. repeated as required is the drug of choice. It suppresses the excessive automaticity, but does not accentuate A-V block. Phenytoin is also effective but seldom used now, because sudden deaths have occurred when it was injected i.v. in digitalis intoxicated patients. Quinidine and procainamide are contraindicated.
(c) For supraventricular arrhythmias Propranolol may be given i.v. or orally depending on the urgency.
(d) For A-V block and bradycardia Atropine 0.6-1.2 mg i.m. may help; otherwise cardiac pacing is recommended.
Cardioversion by DC shock is contraindicated because severe conduction defects may be unmasked in the digitalis intoxicated heart. Attempts to enhance the elimination of digitalis by diuretics or haemodialysis are not very effective.
Digoxin antibody Developed for measuring plasma concentration of digoxin by radioimmunoassay, it has been found effective in treating toxicity as well. Digoxin specific antibody crossreacts with digitoxin also. The Fab fragment has been marketed in Europe as DIGlBIND (38 mg vial). It is nonimmunogenic because it lacks the Fc fragment. Given by i.v. infusion it has markedly improved the survival of seriously digitalis intoxicated patients. The digoxin-Fab complex is rapidly excreted by kidney.
PRECAUTIONS AND CONTRAINDICA TIONS
(a) Hypokalemia: enhances digitalis toxicity by increasing its binding to Na+K+ ATPase.
(b) Elderly, renal or severe hepatic disease: patients are more sensitive.
(c) Myocardial infarction: severe arrhythmias are more likely. Digitalis should be used after MI only wh_n heart failure is accompanied with AF and rapid ventricular rate.
(d) Thyrotoxicosis: reduces responsiveness to digi­talis, but these patients are more prone to develop digitalis arrhythmias.
(e) Myxoedema: these patients eliminate digoxin more slowly; cumulative toxicity can occur.
(f) Ventricular tachycardia: digitalis is contraindi­cated-may precipitate ventricular fibrillation. (g) Partial A- V block: may be converted to comp­lete A-V block.
(h) Acute myocarditis: Diphtheria, acute rheumatic carditis, toxic carditis-inotropic response is poor, more prone to arrhythmias.
(i) Wolff-Parkinson- White syndrome: Digitalis is contraindicated-decreases the ERP of bypass tract in 1/3 patients. In them rapid atrial impulses may be transmitted to ventricles ® VF may occur. Digitalis can increase the chances of reentry by slowing conduction in the normal A-V bundle and accelerating it in the aberrant pathway.
INTERACTIONS
1. Diuretics: cause hypokalemia which can preci­pitate digitalis arrhythmias; potassium supple­ments may be given prophylactically.
2. Calcium: synergises with digitalis ® precipi­tates toxicity.
3. Quinidine: reduces binding of digoxin to tissue proteins as well as its renal and biliary clearance by inhibiting efflux transporter P-glycoprotein ® plasma concentration is doubled ® toxicity can occur. Verapamil, diltiazem, captopril and amio­darone: increase plasma concentration of digoxin to variable extents.
4. Adrenergic drugs: can induce arrhythmias in digitalized patients; both increase ectopic automaticity.
5. Digoxin absorption can be reduced by metoclopramide (gastrointestinal hurrying) and sucralfate which adsorbs digoxin. Antacids, neomycin, sulfasalazine also can reduce digoxin absorption; stagger their administration. Absorption is increased by atropinic drugs, including tricyclic antidepressants, by delaying gastric emptying. Erythromycin, omeprazole and tetracycline increase bioavailability of digoxin.
6. Propranolol, verapamil, diltiazem and disopyra­mide: may additively depress A-V conduction and oppose positive inotropic action.
7. Phenobarbitone and other enzyme inducers expedite digitoxin metabolism and decrease its tlh; no effect on digoxin tlh as it is not metabolized significantly.
8. Succinylcholine: causes arrhythmias in digi­talized patients.

USES

The two main indications of digitalis are CHF and control of ventricular rate in atrial fibrilla­tion/flutter.
1. Congestive heart failure
CHF occurs when cardiac output is insufficient to meet the demands of tissue perfusion. Heart failure may primarily be due to systolic dysfunction or diastolic dysfunction.
Systolic dysfunction The ventricles are dilated and unable to develop sufficient wall tension to eject adequate quantity of blood. This occurs in ischaemic heart disease, valvular incompetence, dilated cardiomyopathy, myocarditis, tachy­arrhythmias.
Diastolic dysfunction The ventricular wall is thickened and unable to relax properly during diastole; ventricular filling is impaired because of which output is low. It occurs in sustained hypertension, aortic stenosis, congenital heart disease, A-V shunts, hypertrophic cardiomyo­pathy.
However, most patients, especially long­standing CHF, have both systolic and diastolic dysfunction. Cardiac glycosides primarily miti­gate systolic dysfunction. Best results are obtained when myocardium is not primarily deranged, e.g. in hypertension, valvular defects or that due to rapid heart rate in atrial fibrillation. Poor response and more toxicity is likely when the myocardium has been damaged by ischaemia, inflammation or degenerative changes and in thiamine deficiency, as well as in high output failure (in anaemia).
Cardiac glycosides are incapable of reversing the pathological changes of CHF or even arresting their progress. Associated with hypertrophy, cardiac muscle undergoes remodeling which may involve shift of isoforms of various functional proteins such as myosin, creatine kinase, Na+K+ATPase, etc. Cardiac glycosides do not affect remodeling. .
Because of lower inotropic state, the failing heart is able to pump much less blood at the
normal filling pressure, more blood remains in the ventricles at the end of systole. The normal venous return is added to it and Frank­Starling compensation is utilized to increase filling pressure: the heart may be able to achieve normal stroke volume, but at a filling pressure which produces congestive symptoms (venous engorgement, edema, enlargement of liver, pulmonary congestion ® dyspnoea, renal congestion ® oliguria).

Digitalis induced enhancement of contrac­tility increases ventricular ejection and shifts the curve relating stroke output to filling pressure towards normal, so that adequate output may be obtained at a filling pressure that does not produce congestive symptoms. Improved tissue perfusion results in withdrawal of sympathetic overactivity ® heart rate and central venous pressure (CVP) are reduced. Compensatory mechanisms retain­ing Na+ and water are inactivated ® diuresis ® edema is cleared. Liver regresses, pulmonary con­gestion is reduced ® dyspnoea abates, cyanosis disappears. Low output symptoms like decreased capacity for muscular work are mitigated.
A dilated ventricle automatically becomes inefficient according to Laplace equation.
Wall tension = Intraventricular pressure  x
ventricular radius
i.e. to generate the same ejection pressure a dilated ventricle has to develop higher wall tension. By reducing end diastolic volume (due to better emptying), digitalis restores efficiency of translation of cardiac work into cardiac output. That is why O2 consumption does not increase proportionately.
Dosage The dosing schedule and route depend on the desired speed of action and the factors which govern individual susceptibility. Gene­rally, higher dose is needed for more severe CHF.
There is some recent evidence that maintenance therapy with sub-maximal inoh"opic doses (producing steady-stage digoxin levels < 1 ng/ml) may benefit by counteracting neurohumoral activation of CHF without risk of toxicity.
(a) Slow digitalization In most mild to moderate cases, maintenance dose of digoxin (0.125-0.25 mg/day) is given from the beginning. Full response takes 5-7 days to develop, but the procedure is much safer. In case adequate response is not seen after 1 week, increase the dose to 0.375 and then to 0.5 mg after another week. Evaluation of adequate response is primarily clinical. Relief of signs and symptoms of failure, reduction of heart rate and body weight to normal are the best guide. Bradycardia (HR < 60/min) is an indication for stopping further medication. ECG changes are not valuable in quanlitation of doses unless arrhythmias occur.
(b) Rapid oral digitalization Digoxin 0.5-1.0 mg stat followed by 0.25 mg every 6 hours with careful monitoring and watch for toxicity till response occurs-generally takes 6-24 hours (total dose 0.75-1.5 mg). This is seldom practised now.
(c) Emergent i.v. digitalization It is practised rarely now, only as a desperate measure in CHF or in atrial fibrillation. Digoxin 0.25 mg followed by 0.1 mg hourly is given by slow Lv. injection with close ECG, BP and CVP monitoring till response occurs (2-6 hours, total dose 0.5-1.0 mg).
Current status of digitalis Before the intro­duction of high ceiling diuretics and ACE inhibitors, digitalis was considered an indispensible part of anti-CHF treatment. It is not so now. Many mild-to-moderate cases can be managed without digitalis, i.e. with diuretics and vasodilators, especially an ACE inhibitor. Lately, _ blockers have got added to the standard therapy. Emergency i. v. use of digoxin for CHF is practically extinct. However, digitalis is still the most effective drug capable of restoring cardiac compensation, especially in patients with dilated heart and low ejection fraction; all patients not controlled by ACE inhibitor/ ATl receptor blocker, b blocker and diuretic should be treated with digitalis. Uncertainty exists in the area of maintenance therapy, i.e. after decompensation has been corrected in patients not having atrial fibrillation (AF). There has been a trend to discontinue digitalis once compensation has been restored, especially in mild-to-moderate cases.
Two large randomized trials-Randomized assessment of digoxin on inhibition of angiotensin converting enzyme (RADIANCE, 1993) and Prospective randomized study of ventricular failure and efficacy of digoxin (PROVED, 1993) on CHF patients in sinus rhythm showed that discontinuation of digitalis resulted in reduced exercise capacity and haemodynamic deterioration in a significant number of cases despite continued use of diuretic with or without ACE inhibitor. A trend has emerged in favour of maintenance ACE inhibitor and digitalis therapy with intermittent symptom based use of diuretics. However, the trials referred above also showed that digitalis can be withdrawn without haemodynamic deterioration in 60% (not receiving ACE inhibitor) and in 72% (receiving ACE inhibitor) patients:
If stable clinical state has been maintained for 2-3 months, withdrawal of digitalis may be attempted. Early reinstitution of digitalis is recommended if cardiac status declines. Continued digitalis therapy is the best course in CHF patients with atrial fibrillation.
Large studies including those by Digoxin Investigation Group (DIG) have found no evidence that digitalis decreases overall mortality in CHF patients, though episodes of decom­pensation and heart failure deaths are reduced. The two major limitations in the use of cardiac glycosides are low margin of s_fety and inability to reverse/retard the processes which cause the heart to fail.
2. Cardiac arrhythmias
Atrial fibrillation (AF) Digitalis is the drug of choice for controlling ventricular rate in AF, whether associated with CHF or not. However, it is incapable of curing AP, i.e. does not revert it to sinus rhythm, even perpetuates it.
Digitalis reduces ventricular rate in AF by decreasing the number of impulses that are able to pass down the A-V node and bundle of His.
(a) It increases ERP of A-V node by direct, vagomimetic and antiadrenergic actions: the minimum interval between consecutive impulses that can successfully traverse the conducting tissue is increased.
(b) A degree of A-V block is naturally established in AF. Because of the relatively long ERP of A-V node, many of the atrial impulses (~500 / min) impinge on it while it is still refractory; others falling early in the relative refractory period get extinguished by decremental conduction. These concealed impulses, nevertheless, leave the upper margin of A -V node refractory for a further period. Thus, any influence which increases rate of AF, by itself reduces ventricular rate. Digitalis decreases average atrial ERP and temporally disperses it (vagal action), thereby increasing fibrillation frequency and indirectly prolonging the interval between any two impulses that are successfully conducted to the ventricle.
When digitalis is given in AP, average ventricular rate decreases in a dose-dependent manner and pulse- deficit is abolished because ventricle does not receive an impulse very early in diastole before it has had time to fill up reasonably. The therapeutic endpoint can be clearly defined: the dose should be adjusted to a ventricular rate of 70-80/ min at rest. If this is not possible with digitalis alone, a b blocker or verapamil may be added.
Atrial flutter (AFI) The atrial rate is 200-350/ min (less than that in AF), but atrial contractions are regular and synchronous. A variable degree of A-V block, depending on the mean ERP of A-V node, is naturally established. Digitalis enhances this A-V block, reduces ventricular rate and prevents sudden shift of A-V block to a lower degree (as may occur during exercise or sympa­thetic stimulation). Digitalis may convert AFl to AF by reducing atrial ERP and making it inhomo­geneous. This is a welcome response because control of ventricular rate is easier in AF (graded response occurs) than in AFl ( A-V block shifts in steps). In nearly ? of the patients when digitalis is stopped, this induced AF reverts to sinus rhythm since the cause of atrial inhomogeneity is gone. Alternatively, AFI may be terminated by cardioversion/ radiofrequency ablation and its recurrence prevented by. subsequent digitalis treatment.
Paroxysmal supraventricular tachycardia (PSVT)
It is a common arrhythmia with a rate 150-200/ min and 1: 1 A-V conduction. It is mostly due to reentry involving the SA or A-V node. Rigidly circumscribed magnitudes of ERP and conduction velocity are required for its persistence. A parenteral glycoside may be injected Lv.­increases vagal tone and depresses the path through the SA/ A-V node, or the ectopic focus, and terminates the arrhythmia (success in 1/3 cases). Verapamil/ adenosine are more effective, less toxic and act faster. Digitalis is now reserved for preventing recurrences in selected cases.
TREATMENT OF CHF
There are two distinct goals of drug therapy in CHF:

• Relief of congestive/low output symptoms and restoration of cardiac performance: Inotropic drugs-digoxin, dobutamine/ dopamine, amrinone / milrinone Diuretics-furosemide, thiazides Vasodilators-ACE inhibitors/AT! antago­nists, hydralazine, nitrate, nitroprusside

b blocker-Metoprolol, bisoprolol, carvedilol

• Arrest/reversal of disease progression and prolongation of survival:

ACE inhibitors/ATl antagonists (ARBs) b  blockers
Aldosterone antagonist-Spironolactone
Important nonpharmacological measures are rest and salt restriction.
Rest reduces peripheral needs, but should be advised only till compensation is restored, beyond that it may lower myocardial reserve and be counterproductive. Salt restriction limits edema formation and is advised in all grades of CHF. The underlying cause of CHF, if treatable like hypertension, myocardial ischaemia, valvular defects, A-V shunts, arrhythmias, thyrotoxicosis, anaemia, should be corrected.
The pathophysiological mechanisms that perpetuate heart failure and contribute to disesae progression, along with site of drug action are depicted in figure. The current pattern of use of drugs in various stages of heart failure is summarized.

Diuretics

Almost all cases of symptomatic CHF are treated with a diuretic. High ceiling diuretics (furosemide, bumetanide) are the diuretics of choice for mobilizing edema fluid; later they may be continued in low doses. In advanced CHF after chronic use, resistance may develop to even high ceiling diuretics; a thiazide / metolazone / spironolactone may be combined to overcome it. Thiazide alone has very limited role in CHF.
Diuretics:
(a) Decrease preload and improve ventricular efficiency by reducing circulating volume.
(b) Remove peripheral edema and pulmonary congesion.
Intravenous furosemide promptly increases systemic venous capacitance and produces rapid symptomatic relief. It has, in conjunction with vasodilators, virtually obviated the need for i.v. digitalization. Further, most mild cases can be maintained on diuretics without recourse to chronic digitalis therapy. However, diuretics do not influence the primary disease process in CHF, through they may dramatically improve symptoms. Despite decades of experience, no prognostic benefit has been demonstrated for diuretics. On the other hand, they may cause activation of renin-angiotensin system (RAS) which has adverse cardiovascular consequences. Chronic diuretic therapy tends to cause hypokalaemia, alkalosis and carbohydrate intolerance. Current opinion is to treat mild heart failure with ACE inhibitors/ARBs ± b blockers only, because they afford survival benefit, while diuretics may be added intermittently as needed. Chronic diuretic therapy should be reserved for relatively advanced cases with tendency to fluid retention when diuretic is stopped. Dose should be titrated to the lowest that will check fluid retention, but not cause volume depletion to activate RAS.
Vasodilators
Vasodilators are used Lv. to treat acute heart failure that occurs in advanced cases, as well as orally for long-term therapy of chronic CHF, and have become the mainstay of anti-CHF measures. Vasodilators with differing profiles of arteriolar and venodilator action are available (see box).
(i) Preload reduction: Nitrates cause pooling of blood in systemic capacitance vessels and reduce ventricular end-diastolic pressure and volume. With reduction in size of ventricles, effectiveness of myocardial fibre shortening in causing ejection of blood during systole improves (Laplace relationship). Controlled i. v. infusion of glyceryl trinitrate affords rapid relief in acute left ventricular failure. However, a marked lowering of preload (by vasodilators + strong diuretics) may reduce output of a failing heart whose performance is dependent upon elevated filling pressure. Occurrence of nitrate tolerance limits their utility in routine treatment of CHF.
(ii) After/oad reduction Hydralazine dilates resistance vessels and reduces aortic impedance so that even weaker ventricular contraction is able to pump more blood; systolic wall stress is reduced. It is effective in forward failure when cardiac index (CI = min output/body surface area) is low (< 2.5 L/min/m2) without a marked increase in central venous pressure (< 18 mm Hg). Marked tachycardia and fluid retention limit long­term use of hydralazine monotherapy.
Trials of the three prototype calcium channel blockers verapamil, diltiazem and nifedipine in systolic dysfunction have been disappointing, even negative with occasional worsening of symptoms and increase in mortality. This may be due to reflex sympathetic activation (nifedipine) or- negative inotropic property (verapamil, diltiazem).

Verapamil, however, is useful in diastolic dysfunction due to hypertrophic cardiomyopathy. Trials with long­acting and more vasoselective dihydropyridines (felodipine, amlodipine) have reported neither increase nor decrease in heart failure mortality; may be used for symptomatic relief in selected patients.
(iii) Pre- and after load reduction ACE inhibitors/ ARBs are orally active medium efficacy non­ selective arterio-venous dilators, while Sod. nitroprusside is high efficacy i. v. dilator with equal action on the two types of vessels. These drugs act by both the above mechanisms. Titrated i.v. infusion of nitroprusside is employed in conjunction with a loop diuretic + Lv. inotropic drug to tideover crisis in severely decompensated patients. Por symptomatic treatment of acute heart failure, choice of i. v. vasodilator (glyceryl trinitrate or hydralazine or nitroprusside) depends on the primary haemodynamic abnormality in indi­vidual patients.
In the long-term, survival benefit has been obtained only with a combination of hydralazine + isosorbide dinitrate or with ACE inhibitors/ ARBs; the latter performing better than the former. Only ACE inhibitors/ARBs alter the course of pathological changes in CHF (see Ch. 36); afford symptomatic as well as disease modifying benefits by retarding / reversing ventricular hypertrophy, myocardial cell apoptosis and remodeling. Prognostic benefits of ACE inhibitors / ARBs have been established in mild to severe (NYHA class I to IV) CHF as well as in patients with asymptomatic systolic dysfunction. They are thus recommended for all grades of CHF, unless contraindicated, or if renal function deteriorates.
Hydralazine causes more marked renal vasodilatation; may be selected for patients with renal insufficiency who cannot tolerate ACE inhibitors. Severe CHF patients already receiving ACE inhibitors + digoxin + diuretic have obtained extra benefit from addition of hydralazine with or without a nitrate.
For reasons not known, the a1 blocker prazosin has not been able to afford prognostic benefit.
b-Adrenergic blockers : Extensive studies over the past 25 years have now established the utility of b1 blockers (mainly metoprolol and bisoprolol) and the nonselective b + selective a1 blocker carvedilol in mild to moderate CHF treated with ACE inhibitor ± diuretic / digitalis.
A large number of randomized trials including Metoprolol in dilated cardiomyopathy trial (1993), US carvedilol trial (1996), MERIT-HF trial (1999), CIBIS-II trial (1999), CAPRICORN trial (2001), COPERNICUS trial (2002) have demonstrated subjective, objective prognostic and mortality benefits of the above 3 b blockers over had above that afforded by ACE inhibitors + diuretic ± digitalis.
Though the immediate hemodynamic action of b blockers is to depress cardiac contractility and ejection fraction, these  parameters gradually improve over weeks. After a couple of months ejection fraction is generally higher than baseline, and slow apward titration of dose  further improves cardiac performance. The hemodynamic benefit is maintained over long term and hospitalization / mortality due to worsening cardiac failure, as well as all cause mortality is reduced. The benefits appear to be due to antagonism of ventricular wall stress enhancing, apoptosis promoting and pathological remodeling effects of excess sympathetic activity in CHF, as well as due to prevention of sinister arrhythmias. b blockers decrease plasma markers of activation of sympathetic, renin,,:angiotensin systems and endothelin-l.
However, b blocker therapy in CHF requires caution, proper patient selection and observance of several guidelines:

• Greatest utility of b blockers has been shown in mild to moderate (NYHA class II, III) cases of dilated cardiomyopathy with systolic dysfunction in which they are now routinely coprescribed unless contraindicated.
• Encouraging results (upto 35% decrease in mortality) have been obtained in class IV cases as well, but use in severe failure could be risky and needs constant monitoring.
• There is no place for b blockers in decompen­sated patients. b blockers should be stopped during an episode of acute heart failure and recommenced at lower doses followed by up titration after compensation is retored. Conventional therapy should be continued along with them.
• Starting dose should be very low-then titrated upward as tolerated to target level (carvedilol 50 mg/ day, bisoprolol 10 mg/ day, metoprolol 200 mg/ day) or near it for maximum protection.
• A long-acting preparation (e.g. sustained release metoprolol) or 2-3 times daily dosing to produce round-the-clock b blockade should be selected.
• There is no evidence of benefit in asymptomatic left ventricular dysfunction.

Aldosterone antagonist (Spironolactone) Over the past 2 decades it has been realized that rise in plasma aldosterone in CHF, in addition to its well known Na+ and water retaining action, is an important contributor to disease progression by direct and indirect effects:
(a) Expansion of e.c.f. volume ® increased cardiac preload.
(b) Fibrotic change in myocardium ® worsening systolic dysfunction and pathological remode­ling.
(c) Hypokalemia and hypomagnesemia ® increased risk of ventricular arrhythmias and sudden cardiac death.
(d) Enhancement of cardiotoxic effect of sympa­thetic overactivity.
The aldosterone antagonist spironolactone is a weak diuretic (see Ch. 41), but can benefit CHF by antagonizing the above effects of aldosterone.
In addition to several small studies, a large Randomised aldactone evaluation study (RALES, 1999) conducted on 1663 NYHA class III and IV patients having left ventricular ejection fraction ? 35% has confirmed the additional. survival benefit (30%) of spironolactone when added to conventional therapy with ACE inhibitors + other drugs. A subsequent trial (EPHESUS, 2003) using another aldosterone antagonist eplerenone in post acute MI heart failure has further substantiated the mortality and anti­remodeling benefit over and above that of ACE inhibitors ± b blockers.
Though ACE inhibitors themselves lower aldosterone levels, this effect is incomplete and short lasting. Current evidence suggests the following regarding spironolactone therapy in CHF:

• It is indicated as add-on therapy to ACE inhibitors + other drugs in moderate-to-severe CHF.
• It can retard disease progression, reduce episodes of decompensation and death due to heart failure as well as sudden cardiac deaths, over and above the protection afforded by ACE inhibitors / ARBs ± b blockers.
• Only low doses (12.5-25 mg/ day) of spirono­lactone should be used to avoid hyperkalaemia; particularly because of concurrent ACE inhibitor / ARB therapy.
• It may help restoration of diuretic response to furosemide when refractoriness has developed.

The onset of benefit of spironolactone in CHF is slow. It is contraindicated in renal insufficiency: carries risk of hyperkalemia-requires serum K+ monitoring. Gynaecomastia occurs in a number of male patients. However, spironolactone is a significant additional therapeutic measure in moderate-severe CHF with prognostic benefits.
Sympathomimetic inotropic drugs (seeCh. 9)
Drugs with j3 adrenergic and dopaminergic D1 agonistic actions have positive inotropic and vasodilator properties through activation of adenylyl cyclase which may be utilized to combat emergency pump failure.
Dobutamine (2-8 mg/kg/min) a relatively selective PI agonist with prominent inotropic action is the preferred drug for i.v. infusion in acute heart failure accompanying myocardial infarction (MI), cardiac surgery as well as to tide over crisis in advanced decompensated CHF.
Dopamine (3-10 mg/kg/min by i.v. infusion) has been used in cardiogenic shock due to MI and other causes. While dobutamine does not raise (may lower) systemic vascular resistance and is preferred in heart failure, dopamine tends to increase afterload, especially at higher rates of infusion (>5 mg/kg/ min) and has limited utility in patients who are not in shock. Low rates of dopamine infusion cause selective renal vaso­dilatation (D1 agonistic action)-improve renal perfusion and g.f.r. This can restore diuretic response to i.v. furosemide in refractory CHF. These drugs afford additional haemodynamic support over and above vasodilators, digitalis and diuretics, but benefits are short-lasting. Due to development of tolerance, these drugs have no role in the long-term management of CHF.

Phosphodiesterase III inhibitors

Theophylline is a phosphodiesterase inhibitor that is non­selective for different isoforrns of this enzyme which degrades intracellular cAMP and cGMP. Intravenous aminophylline had been used in past for acute left ventricular failure with limited benefits, but unacceptable toxicity.
Amrinone (Inamrinone) It is chemically and pharmacologically distinct from digitalis and catecholamines. This bipyridine derivative is a selective phosphodiesterase III (PDE III) inhibitor. The PDE III isoenzyme is specific for intracellular degradation of cAMP in heart, blood vessels and bronchial smooth muscles. Amrinone increases myocardial cAMP and transmembrane influx of Ca2+. It does not inhibit Na+K+ATPase, and its action is independent of tissue catecholamines and adrenergic receptors.
The two most important actions of amrinone are positive inotropy and direct vasodilatation: has been called an 'inodilator'. Compared to dobutamine, proportionately greater decrease in systemic vascular resistance is noted.
In CHF patients i.v. amrinone action starts in 5 min and lasts 2-3 hours; elimination t? is 2-5 hours. It increases cardiac index, left ventricular ejection fraction and decreases peripheral vascular resistance, CVP, left ventricular end diastolic volume and pressure accompanied by mild tachycardia and slight fall in BP.
Adverse effects Thrombocytopenia is the most prominent and dose related side effect, but is mostly transient and asymptomatic.
Nausea, diarrhoea, abdominal pain, liver dam­age, fever and arrhythmias are the other adverse effects.
Use Though amrinone is active orally, its oral use in maintenance therapy of CHF has been abandoned, because efficacy was lost and mor­tality was increased in comparison to placebo.
It is indicated only for short-term i.v. use in severe and refractory CHF, as an additional drug to conventional therapy with digitalis, diuretics and vasodilators.
Dose: 0.5 mg/kg bolus injection followed by 5-10 pg/kg/ min i.v. infusion (max. 10 mg/kg in 24 hours). AMICOR, CARDIOTONE 5 mg/ml (as lactate) 20 ml amp.
Milrinone Related to amrinone; has similar action but is more selective for PDE III, and is at least 10 times more potent. It is shorter-acting with a t ? of 40-80 min.
Thrombocytopenia is not significant. In long term prospective trials, increased mortality has been reported with oral milrinone also. Milrinone is preferred over amrinone for short-term use.
Dose: 50 pg/kg i.v. bolus followed by 0.4-1.0 pg/kg/min infusion.
PRIMA COR IV 10 mg/10 ml inj.
Nisiritide This recombinant brain natriuretic peptide (BNP) has been approved recently for i.v. use to relieve dyspnoea and other symptoms in refractory CHF, especially in patients prone to develop cardiac arrhythmias. It enhances salt and water excretion as well as produces vasodilatation. Additional haemodynamic and sympto­matic improvement can be obtained for short-periods.