THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 8, NO.2, 1995
Everyday Practice73
Principles of drug therapy in heart failureS. K. DEY, V. W. POFLEE
DEFINITIONSCongestive heart failure is a pathophysiological state in
which abnormality of cardiac function leads to inability ofthe heart to pump out blood at a rate commensurate withthe metabolic requirements of the tissues andlor to do sowould require abnormally high filling pressures. It may occurdue to (i) myocardial dysfunction, e.g. cardiomyopathies,(ii) increased load presented suddenly to a normal heart,e.g. acute hypertensive emergencies, and (iii) due toimpaired filling, e.g. chronic constrictive pericarditis,tricuspid stenosis, etc.
Preload indicates ventricular end-diastolic volume.The major determinants of ventricular preload are (i) totalblood volume, (ii) distribution of blood volume, and (iii)atrial contraction
After/oad in the intact heart, can be defined as the stressor tension developed in the wall of the ventricle duringejection. Important determinants of afterload are (i) levelof aortic and peripheral vascular resistance, and (ii) volumeand thickness of the ventricular cavity
PATHOPHYSIOLOGY OF HEART FAILURECardiac performance is maintained by three factors. Theyare preload, myocardial contractility and afterload. In heartfailure there is involvement of one or more factors singlyor in combination, thereby increasing the load on themyocardium resulting in a state of decreased cardiac output.These haemodynamic consequences lead to stimulation ofthe sympathetic nervous system, the renin-angiotensin-aldosterone system and the arginine-vasopressin systemin an attempt to restore arterial pressure and organ per-fusion (Fig. 1).1
In 1969, Meerson proposed that excess mechanical loadingof the left ventricle led to myocardial failure through threephases:"
Phase I. An acute adaptation to the haemodynamic loading,mainly by increasing preload and operation of the Frank-Starling mechanism
Phase II. Compensatory ventricular hypertrophyPhase III. Eventually myocardial failure
Jawaharlal Nehru Medical College, Sawangi (Meghe), Wardha,Maharashtra , India
S. K. DEY Department of PaediatricsV. W. POFLEE Department of Medicine
Correspondence to S. K. DEY, 4/9B, Bijoy Garh, ladavpur,Calcutta 700032, West Bengal
In the early stages of heart failure vasodilator-natriureticsubstances, prostaglandins, atrial natriuretic peptide (ANP),dopamine, calcitonin and calcitonin gene related peptide(CGRP) are released to counter the vasoconstrictor anti-natriuretic effects of these hormones.
Simultaneously, as an adaptive mechanism, redistributionof blood occurs, in an effort to maintain blood flow to vitalorgans. Despite a marked decrease in cardiac function,normal or nearly normal stroke volume is maintained dueto activation of the above adaptive mechanisms. It has beencontended that metabolite abnormalities at cellular level,e.g. abnormality of excitation contraction coupling, mayalso occur.
The physiological basis of heart failure is provided in aschematic diagram (Fig. 2). However, in later stages thereis a marked increase in plasma adrenaline, noradrenaline,aldosterone and renin activity with downgradation of ANPreceptors. These neurohumoral adjustments, though initiallybeneficial, finally lead to an increased haemodynamicburden and exacerbation of myocardial failure.
TREATMENT OF CONGESTIVE HEART FAILURETreatment of congestive heart failure (CHF) is not aimedat curing the disease but providing a better quality of life.All cases of CHF should have a diligent search for anyprecipitating factors such as anaemia, arrhythmias, infectiveendocarditis and dietary factors (increased ingestion ofsodium). Similarly, efforts should be made to remove theunderlying cause of the CHF (e.g. coronary artery disease,valvular disease, systemic hypertension or thyrotoxicosis).Bed rest is important and depends upon the patient's condi-tion. Essential activities are desirable and should bepermitted. After some compensation has been achieved,short periods of rest should be advised (e.g. a nap afterlunch).
A wholesome diet in small frequent meals should be
Lowoutput syrnpto
t myocardial load Congestive
sympr~
• contractility I I t preload I
~ cardiac output t aIIerload I
Sympathetic nervous system
Renin-angiotensin-aldosterone
Arginine-vasopressin
Sodium-water retention
FIG 1. Haemodynamic consequences of CHF
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Symptomsrelieved
Affect on heart Drugs
Venodilatersand diuretics
Preload .J.I Congestive4rsymptoms
.~.eart.zeontractilityt
lonotropicagents
1Low outputsymptoms
FIG 2. Physiologic basis for the management of CHF
Newer inotropes
Vasodilators
Digitalis
ACE inhibitors
Diuretics
Rest, salt restriction IFIG 3. Step-care approach in CHF
allowed. Salt intake should be kept to a minimum. In obesepatients, caloric intake should be restricted. Oxygenadministration may be necessary for some patients whoshould be placed in a propped up position especially ifthey are severely dyspnoeic.
DRUG THERAPYDrugs are the mainstay of therapy. The various drugsavailable can be grouped separately and are used in a step-wise manner (Fig. 3). They are diuretics, inotropic agents,vasodilators and digitalis. The selection of drugs, however,is mostly individualized and depends upon the severity ofdisease, its cause and haemodynamic and clinical features.
DIURETICSThese remain the first line of drug treatment in CHF andare widely used. They act by decreasing reabsorption ofsodium and other electrolytes at various sites (Fig. 4) of
THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 8, NO.2, 1995
the nephron resulting in diuresis, leading to a decrease inpreload. Diuretics should be used alone or in combinationdepending upon the severity of heart failure. In severe cases,a combination of a thiazide, a loop diuretic and a potassiumsparing diuretic may be required (Fig. 4). In less severecases, loop diuretics alone or in combination with spirono-lactone or triamterene can be used.
Thiazides are used in addition to loop diuretics in thetreatment of resistant CHF and metolazone with loop diureticsin cases of CHF which are thiazide resistant. Diuretics losetheir effectiveness in the face of impaired renal function.
The side-effects of thiazide diuretics include hypokalaemia,hyperglycaemia, hyperuricaemia, skin rashes and thrombo-cytopenia. It is worth remembering that hypokalaemia mayenhance digitalis toxicity. Loop diuretics also producehyponatraemia, hyperglycaemia, hyperuricaemia andmetabolic alkalosis.
INOTROPIC AGENTSThe inotropic agents used in heart failure are shown inFig. 5. Drugs under this group are:
Beta 1 specific drugs (prenalterol, xamoterol, butopamin)These are potent inotropic agents and are useful for shortterm therapy since tolerance develops to these drugs (downregulation). Xamoterol activates beta 1 receptors whenadrenergic activity is low and acts as a beta receptor anta-gonist during high sympathetic activity. Its main indicationis in the treatment of patients who have mild heart failurewith angina because of its anti-ischaemic properties.
Bipyridines (amrinone, milrinone, enoximone)These recently introduced drugs exert a vasodilator action by
DEY, POFLEE : DRUG THERAPY IN HEART FAILURE
Directstimulants(Forskolin)
Non-adrenergicstimulation
Adenylalecyclase
~ b-receptoragonist[NE,E,DA,DBA,ISP)
ATP ---:~-:::::~~A~M~P~=-:;-...,~~ AMPPKa.... ~PKIt
SlowCa-channelsi r
adrenergic directslowagonist channel stimulant
BayK8644
Phosphodiesterase
Ca++
e e
Na-KATPaseinhibition(digitalis)
PDEPIIIBipyridine
Weaktheophylline
FIG 5. Inotropic agents in CHF
inhibiting phosphodiesterase; hence they are sometimescalled 'ionodilators'. Their action on the cardiac and vascularsmooth muscle is depicted in Fig. 5. These drugs are usedvia the intravenous route only. Milrinone is five times morepotent than amrinone. Unlike other sympathomimetics theireffects last and they can be used for long term treatment.Adverse drug reactions include fever and thrombocytopenia.
Enoximone has effects on exercise tolerance similar tocaptopril and is useful in patients with moderate 10 severeCHF.
The present data on these phosphodiesterase inhibitors,however, suggests that they are not better than angiotensinconverting enzyme (ACE) inhibitors or digoxin in relievingsymptoms and exercise tolerance in patients with CHF.
Dopamine, dobutamine and ibopamineDopamine. This is a naturally occurring precursor of
norepinephrine. In doses of 0.5-2 J.lg/kg/minute it directlystimulates specific dopaminergic receptors in the renal andsplanchnic circulations resulting in vasodilation. In doses of2-5 ltg/kg/minute, it stimulates myocardial beta receptorsbut induces little tachycardia. At higher doses of 5-20 ltg/kg/minute, it also stimulates alpha adrenergic receptors andraises arterial blood pressure.
Dobutamine. This acts on beta 1, beta 2 and alphareceptors. It exerts a potent inotropic action withoutincreasing the heart rate. It also lowers peripheral vascularresistance and increases cardiac output and this has littleeffect on arterial pressure. It is used in a dose of 2.5-10Itg/kg/minute as an infusion. It is useful when inotropicsupport to the heart is required for a short period. Recently,it has been found to be effective in idiopathic or ischaemiccardiomyopathy. Occasionally, it causes cardiac arrhythmiasand hypertension.
lbopamine. This is a dopaminergic agent and hasvasodilator, inotropic and natriuretic effects in CHF. 3
In combination with diuretics and digoxin, it is useful in
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Frank Starling's lawLaplace's law Normal
FIG 6. Diagrammatic representation of Frank-Starling andLaplace laws
moderately severe heart failure. It can be used as an alter-native to ACE inhibitors and may be used as a diureticsparing agent in mild CHF.
VASODILATORSVasodilator therapy has now become the mainstay of thetreatment of CHF. It has been commonly observed that leftventricular afterload is increased in most patients with CHF.as a result of vasoconstrictive neural and humoral factors.A normally functioning heart tolerates this well. However,in the failing heart, the ventricles are already functioningat the flat portion of the Frank-Starling curve (Fig. 6) andany additional increase in afterload impedes stroke volume.Vasodilators act by decreasing the afterload and preload,thus improving the stroke volume.
In CHF due to coronary artery disease, cardiomyopathyand multivalvular disease, vasodilator therapy results in anincrease in cardiac output, decrease in pulmonary wedgepressure and improvement in the symptoms.
3. Balance vasodilators: prazosin, nitroprusside and ACEinhibitors. These drugs act on both arteries and veins,and are useful in decreasing the preload and afterIoad.
HydralazineThis is an arterial dilator which, when used alone, is lesseffective than an ACE inhibitor. However, along with adiuretic, venodilator, ACE inhibitors or digoxin, it may bea useful adjunct to conventional therapy in patients withresistant CHF. It is given in a dose of 300-600 mg daily.Its common side-effects are headache, dizziness and nausea.A lupus-like syndrome may also occur.
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NitratesThese are venodilators and act by reducing ventricular fillingpressure. They may be used when optimal doses of diuretics,digoxin and ACE inhibitors fail to relieve the patient'ssymptoms. Nitrates can be combined with arteriodilators,thus acting as 'balanced vasodilators'. This combinationtherapy has been observed to be superior to enalapril inimproving exercise tolerance and the left ventricular ejectionfraction." However, presently, these drugs should be usedonly in patients who cannot tolerate ACE inhibitors.Isosorbide dinitrate is given in a dose of 20-40 mg threetimes daily. Adverse reactions include headache andhypotension.
Sodium nitroprussideThis agent acts on both the arterial and venous circulation.Since its onset of action is rapid, and brief, it is the vasodilatorof choice for treating acute heart failure. However, intensivehaemodynamic monitoring is required as it can producesevere hypotension. Less commonly, toxicity may resultfrom conversion of nitroprusside to cyanide and thiocyanate,especially if it is infused for more than 24-48 hours and ifrenal function is impaired.
ACE inhibitorsThe discovery of this group of drugs has revolutionized thetreatment of CHF. These are balanced vasodilators whichcause both arterial and venous dilatation (Fig. 7). Theimportant ACE inhibitors and their properties are enumeratedin Table I.
The acute haemodynamic effects of ACE inhibitors arereduction of the pulmonary wedge pressure (left ventricularfilling pressure), systemic vascular resistance, blood pressureand right atrial pressure, and an increase in stroke volumeand cardiac index.
Randomized trials>" have clearly indicated that enalaprilis an alternative to digitalis in mild to severe heart failureand reduces the number of deaths due to pump failure. Inanother trial lisinopril was found to be more effective inreducing symptoms in patients with severe heart failure."
TABLEI. Major kinetic and other properties of ACE inhibitors
THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 8, NO.2, 1995
r----------t t PreloadtAfterload
PVR Na+.H20
o 1 tRenin ]. Vasoconstrict Aldosterone
G t--rAngiotensinogen Angio Angio II
ACE inihibitors
Kininogen -----"'I.•~Bradykinin* t
Inactive forms
Prostaglandins ) Vasodilation
l.t.pre7oad IFIG 7. Renin-angiotensin system
Patients with left ventricular failure who are symptomaticeven after therapy with diuretics and digoxin also improveafter ACE inhibitor therapy.
There is growing evidence that ACE inhibitors preventprogressive pump failure, if given in the early stages of CHF.Similarly, these drugs retard development of overt heartfailure when administered to patients with left ventriculardysfunction without CHF. There is a reduction in the sizeof the ventricular cavity and true remodelling occurs" dueto the haemodynamic changes which prevent detrimentaleffects on the heart. The effect of ACE inhibitors on diastolicfunction is not clear. ACE inhibitors, thus, are extremelyuseful agents for the long term oral therapy of CHF.
They should be started in small doses to avoid their 'firstdose hypotensive effect'. This is especially pronouncedin patients with hypovolaemia and a 'high renin state' asindicated by persistent hyponatraemia. Diuretics should be
stopped or their dose decreased in the beginning of treat-ment. Subsequently, they may be reintroduced gradually.
Cough and angio-oedema can occur during therapy withACE inhibitors. A sudden and spasmodic cough occursin approximately 10% to 15% of patients and can be sodistressing that treatment may need to be stopped. Renalinsufficiency can occur in patients with bilateral renal arterystenosis, or stenosis of the artery in a single remainingkidney. This is caused by reduction in the concentration ofangiotensin II which is needed to constrict efferent arteriolesand maintain glomerular blood flow. Serum potassium levelsshould be monitored, since hyperkalaemia may sometimesdevelop.
Bilateral renal artery stenosis, aortic stenosis and severeobstructive cardiomyopathy are the few contraindicationsto ACE inhibitors.
PrazosinThis is a receptor blocker and, like ACE inhibitors, actson both veins and arteries. It can also produce hypotensionafter the first dose and this reaction should be lookedfor. Added beneficial effects include relief in symptoms inpatients with benign prostatic hypertrophy. Neutropenia andproteinuria are seen with high doses.
DIGITALISThis drug was the frontline therapy of CHF till the adventof vasodilators. The inotropic effects of digitalis areexhibited in normal and non-failing hearts as well as thosethat are hypertrophied and have myocardial dysfunction.This effect is produced through its action on excitation-contraction coupling. It also alters the properties ofcontractile muscle cells and electrical pathways. A negativechronotropic action is exerted in the setting of CHF.
In CHF, digitalis improves emptying of the ventricles,decreases end diastolic pressure and ameliorates pulmonaryvascular congestion. The beneficial effects have beenobserved in CHF due to coronary artery disease, multi-valvular disease, hypertensive heart disease and congenitalheart disease. When heart failure is associated with a rapidventricular rate, as in atrial flutter or fibrillation, digitalisis clearly indicated. It is of doubtful efficacy, however, inheart failure associated with myocarditis, beri-beri, theadvanced cardiomyopathies, thyrotoxicosis, cor pulmonaleand chronic constrictive pericarditis.
With the advent of vasodilators, the role of digoxin in thetherapy of CHF has been re-explored and several studieshave compared it with ACE inhibitors. In mild to moderateheart failure, the efficacy of digoxin is comparable to ACEinhibitors." However, ACE inhibitors seem to improvesymptoms in patients already receiving digoxin. The use ofa combined regimen of digoxin and ACE inhibitors in CHFis theoretically sound since the effects of both drugs areadditive and preliminary studies indicate that this notionmay be true. However, evidence of long term symptomatic,haemodynamic and survival benefit of such a treatmentstrategy is not yet available.
Digoxin has a half-life of 1.6 days and 85% of the drugis excreted unchanged in the urine. Therefore, its dose needsto be altered in the presence of renal failure. A loading doseof 0.375-0.75 mg and a maintenance dose of 0.175-0.25 mgis recommended for adults and 0.04 mg/kg and 0.01 mg/kgfor children.
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Digitalis intoxication is a life-threatening complication.The majority of patients in hospital taking digitalis showsome sign of toxicity which is usually preceded by thedevelopment of hypokalaemia due to diuretic therapy. Theearliest toxic manifestations are nausea and vomiting.Cardiac rhythm and conduction defects occur in the formof premature ventricular beats, bigemini, atrio-ventricularblock, non-paroxysmal atrial tachycardia, sino-atrial block,sinus arrest and multifocal ventricular tachycardia. Otherside-effects include headache, fatigue, exacerbation of CHF,disturbance of colour vision and gynaecomastia.
REFRACTORY HEART FAILUREHeart failure is considered to be refractory when the heartdoes not respond to conventional therapy. The diagnosisshould be re-assessed and contributing factors treated(Fig. 8).
Managing a patient with refractory CHF is often notdifficult and a four-step approach for managing such casesis detailed in Fig. 9. In the first step, a high dose aggressivediuretic combination therapy should be tried with carefulmonitoring of fluid volume status and blood chemistry. Ifthe patient does not respond to oral therapy, intravenousdiuretics should be given. In the second step ACE inhibitorswith spironolactone or inotropes should be given especiallyif the patient is uraemic. If the patient still remains diureticresistant then an invasive balloon flotation cathetershould be introduced and a trial with sodium nitroprusside,milrinone, amrinone or enoximone may improve thehaemodynamic status. However, vasodilators should beused only in patients with raised filling pressures and asystolic arterial pressure greater than 80 mmHg.
When all these measures fail, the patient is labelled ashaving 'intractable' CHF. This is best defined as CHF dueto irreversible cardiac disease associated with an unaccept-able quality of life and/or a very high risk of early mortality.
These cases need aggressive inotropic and vasodilatortherapy under intensive haemodynamic monitoring. Ifthey do not respond they should be referred for cardiactransplantation.
A rrythmia
B lood pressure
C HF due to renal shutdown
D rug toxicity (digitalis, electrolyte imbalance)
E ndocarditis, embolism
F ever
G oiter thyrotoxicosis
H aemoglobin, hyponatremia, hypokalemia
I nfection (pulmoary or urinary)
FIG8. Re-assessment of contributory factors in refractory CHF
78 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 8, NO.2, 1995
FIG 9. Four step approach to the treatment of refractory congestive heart failure (CHF)
CONCLUSIONWith the advent of newer drugs and the availability ofhaemodynamic monitoring, the management of a patientwith CHF has changed dramatically. A precise diagnosis,elimination of precipitating factors, correction of treatablecauses and drug therapy can not only control CHF quicklybut also give the patient a better quality of life.
Treatment should be initiated with a diuretic and ACEinhibitor. Most patients will respond to this therapy.Those who do not should have their diuretic dose doubled,provided their renal function is normal. Digitalis, newerinotropes and nitrates can be added whenever required. Inpatients with atrial fibrillation, digitalis should be addedearly in the course of treatment and those who have anginawith mild to moderate CHF benefit from the addition ofxameterol. ACE inhibitors are the drugs of choice in patientswith hypertension and CHF.
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2 Meerson FZ. The myocardium in hyperfunction, hypertrophy and heart failure.Circ Res 1969;25 (Suppl 2):1-163.
3 Condorelli M, Bonaduce A, Montemurro A, Mattioli G, Cappello C,Caponnetto S, et al. The long-term efficacy of ibopamine in treating patientswith severe heart failure: A multicentre investigation. J Cardiovasc Pharmacol1989;14 (Suppl 8):S83-S92.
4 Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et at. Acomparison of enalapril with hydralazine-isosorbide dinitrate in the treatmentof chronic congestive heart failure. N Engl J Med 1991;325:303-10.
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7 Giles TO, Katz R, Sullivan JM, Wolfson P, Haugland M, Kirlin P, etal. Short-and long-acting angiotensin converting enzyme inhibitors: A randomized trialof lisinopril versus captopril in the treatment of congestive heart failure. JAmColi CardioI1989;13:124G-7.
8 Baur LHB, Schipperheyn JJ, Bann J, van der Laarse A, van der Wall EE.van Dijk AD, et al. Influence of angiotensin converting enzyme inhibition onpump function and cardiac contractility in patients with congestive heart failure.Br Heart J 1991;65:137-42.
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