failure literally means a condition in The ter Meapth is unable to pump sufficient amount ifthe ~« the metabolic demands of the body whole toreceive it back because every time, wer as) le, Some residual blood remains in its sinwicie- This condition, in the past, has been ferred (0 as congestive heart failure due to Sedematous state produced by the fluid retention ‘cain to pulmonary as well as peripheral congestion. Nowadays. however, the term “heart failure” alone is xed to reflect the clinical syndrome more precisely, because all patients do not necessarily present with fluid overload at the initial stage or on follow-up evaluations (¢.g., patients of high cardiac output type of heart failure associated with hyperthyroidism). LOW OUTPUT VERSUS HIGH OUTPUT HEART FAILURE Heart failure is a syndrome with multiple causes (MI, HT, angina, ventricular tachycardia, diabetes mellitus, hyperthyroidism and anaemia etc. ), that may involve right ventricle, the left ventricle or both. Cardiac output (CO) in heart failure is usually Jow and the most common heart failure (HF) is a “low output cardiac failure” where the metabolic demands of the body are within normal limits, but the heart is unable to meet them, “High output cardiac failure” occurs rarely. In some coexisting conditions (hyperthyroidism, anaemia and arteriovenous shunt), the metabolic demands of the body are excessive that even increased CO is insufficient to meet them. As compared to low output failure it should be treated by correcting the underlying cause. »2. Drug Therapy of Heart Failure LEFT SIDED VERSUS RIGHT SIDED HEART FAILURE (HF) Signs and symptoms of HF usually result from the effects of blood backing up behind the failing ventricles (except in high output form of HF). Left sided and right sided HF do not routinely exist as separate entities because, over time, right sided failure causes left sided failure and vice versa. If the blood cannot be pumped adequately from the left ventricle to the peripheral circulation, a part of it will be retained in left ventricle during systole. Because of this accumulation, the left ventricle will be unable to accept blood from left atrium and the Jungs. Hence, left sided HF is characterised by the presence of pulmonary congestion and oedema (presented as shortness of breath and dyspnoea). ‘On the other hand, when blood cannot be pumped from right ventricle into the lungs a part of it is retained in right ventricle. Because of this accumulation, the right ventricle will be unable to accept blood from the peripheral organs. Hence, right sided HF is characterized by peripheral oedema and/ or juglar venous distension. COMPENSATORY RESPONSES DURING HEART FAILURE ‘The failing heart evokes the following compensatory mechanisms to enhance the CO (CO = stroke volume x HR). If these mechanisms are able to restore the CO, the heart failure is said to be compensated. In Jong-term, however, these compensations rather increase the work load of the heart and cause ‘worsening of cardiac performance (Fig. 22.1). Scanned with CamScanner | PRINCIPLES OF PHARMACOLOGY LB INation of Renin-Angiotensin- terone System (RAAS) in CO decreases blood flow to kidneys. This ots renin release, synthesis of angiotensin II 11) and release of aldosterone (see Ch. 18). This its in an increase in peripheral vascular resistance \VR) with Na* and water retention (Fig. 22.1). Thus sod volume increases and more blood reaches the heart (in preload). Since afterload also increases with rncrease in PVR, the heartis unable to pump this extra volume. The resulting fluid back-up between the left ventricle and the lungs, and up to right ventricle from peripheral circulation, causes pulmonary and peripheral oedema. HF is also associated with increased circulating levels of arginine, vasopressin and endothelin I which also promote vaso- constriction and fluid retention. Although atrial natriuretic peptide is also increased in HF, owing to increased arterial pressure, paradoxically it does not produce natriuretic or vasodilatory effects in patients of HF. Excessive compensatory neurohormonal activity, therefore, ultimately depresses cardiac functions. Ventricular Remodeling The most important intrinsic compensatory mechanism is myocardial hypertrophy with a resultant increase in a more spherical shape of the heart referred to as “cardiac remodeling” which means a type of dilatation other than that due to passive stretch of heart muscle. During remodeling there is proliferation of the connective tissue cells as well as of abnormal myocardial cells under the influence of Ang-Il. Initially the increase in muscle mass helps to maintain cardiac performance. But after the initial beneficial ‘effects, hypertrophy can lead to ischaemic changes ‘and alterations in ventricular geometry. The ventricular ‘yall tension increases, mechanical performance of heart decreases and blood in both the ventricles is retained ‘which ultimately worsens the remodeling process. Over time, the myocytes in the failing heart die through apoptosis leaving the remaining myocytes subject to even greater work load. Hence, remodeling also, ultimately worsens the cardiac performance. © Gaiam 22 oRuG THERAPY OF HEART FaiLURE | 313 PHENOMENON OF DECOMPENSATED HEART FAILURE ‘After certain period, the compensatory mechanisms become exhausted and increasingly ineffective, entering a vicious circle of decompensation in which the compensatory mechanisms become self- defeating. As the strain continues, total peripheral resistance (TPR) and afterload increase, thereby decreasing the ejection fraction per heartbeat. Preload is also increased in HF because of increased blood volume and venous tone. Ultimately, a stage comes when the adaptive mechanisms fail to maintain the CO. The HF now is termed as “decompensated”. ‘As the blood volume expands, the decom- pensated heart is unable to pump and produces signs and symptoms of HF like: a) Pulmonary and peripheral oedema (as discussed above). b) Dyspnoea with cyanosis, due to hypoxia as a re- sult of inadequate oxygenation of blood. ‘c) Hepatomegaly due to hepatic congestion. 4d) Cardiomegaly due to myocardial hypertrophy and cardiac remodeling. e) Reflex tachycardia due to hypoxia and decreased CO induced sympathetic discharge. f) Decreased urine formation due to renal conges- tion 2) Decreased exercise tolerance and muscle fatigue due to diminished CO. DRUGS USED IN HEART FAILURE (HF) ‘The therapeutic goal in the management of HF is to increase cardiac output (CO) anyhow. A better understanding of preload, afterload and myocardial contractility has encouraged the judicious use of the following drugs for the treatment of heart failure: 1. Drugs with positive inotropic effects a) Cardiac Glycosides: DIGOXIN, DIGITOXIN and OUABAIN. b) Bipyridines or Phosphodiesterase Inhibitors: INAMRINONE, MILRINONE, LEVOSIMENDAN and ENOXIMONE ©) B-Adrenergic Agonists: DOPAMINE, DOBUTAMINE and DOPEXAMINE, | PRINCIPLES OF PHARMACOLOGY | &% SS Scanned with CamScanner| PRINCIPLES OF PHARMACOLOGY | 314 | SECTION 4: DRUGS AFFECTING RENAL AND CARDIOVASCULAR SYSTEM, & RELATED AUTACOIBENY TL Drugs without positive inotropic effects Diuretics: BUMETANIDE, FUROSEMIDE, HYDROCHLOROTHIAZIDE, METOLAZONE, and SPIRONOLACTONE 4(CEls: ENALAPRIL, LISINOPRIL and RAMIPRIL (also AT receptor antagonist, ¢.2., LOSARTAN) B,-Adrenoceptor Antagonists: BISOPROLOL,CARVEDILOL and METOPROLOL Vasodilators: HYDRALAZINI TROPRUSSIDE, ISOSORBIDE DINITRATE and NESIRITIDE Vasopressin Receptor Antagonists: CONIVAPTAN and TOLVAPTAN ° 2 The basic pharmacology of B-adrenergic agonists (Ch. 12), B,-adrenoceptor antagonists (Ch. 12, 19 & 20), diuretics (Ch 16 & 19), ACEIs (Ch. 18 & 19) and vasodilators (Ch. 19) has been discussed in detail in other chapters, hence these drugs will be discussed here only in context of the treatment of heart failure. Accordingly, the use of drugs, with positive inotropic effects, in the management of heart failure will be discussed in detail DRUGS WITH POSITIVE INOTROPIC EFFECTS Cardiac Glycosides Chemistry If a sugar molecule is joined together with a non- sugar molecule by a ether linkage it is called a glycoside. [Gogo 0 [honseear] "ARDIAC GLYCOSIDE 1 to 4 sugars Aglycone (genin) GLYCOSIDE In cardiac glycosides the sugar partis | or4 molecules of digitoxose while the non-sugar part (aglycone or genin) is a steroidal lactone, The pharmacological activity of cardiac glycosides resides in its non-sugar moiety called aglycone or genin. The sugar par, however, governs the pharmacokinetic characteristics such as lipid solubility and cell permeability, Source Leaves of Digitalis lanata provide two active principles—Digoxin and Digitoxin—while leaves of Digitalis purpurea (Fox glove) are the major source of digitoxin. Seeds of Strophanthus gratus provide two active glycosides—strophanthin-G and ouabain—while seeds of Strophanthus kombe yield primarily strophanthin-K. Mechanism of Action Normal Ionic Movements During the Contraction of Cardiac Muscle. The force of contraction of the cardiac muscle is directly related to the concentration of free cytosolic Ca’*. Therefore, any drug that can increase the cytosolic Ca** levels can not only increase the force of contraction of heart muscle but can also increase the sensitivity of the contractil machinery to Ca**. Voltage-sensitive Py ca” 3Na* Lttype Ca channel aa [= 1 - Sarcoplasmic reticulum: 2 - Na‘/Ca** exchange pump 3 - Na‘/k* ATPase ES er pea Scanned with CamScannerlly, the Ca* entry, through voltage-sensitive \ channels, triggers the release of a much sntity of Ca from the sarcoplasmic reticulum mitochondria) by activating SR-Ca® release | (cyanodine receptor), The increased Ca”* ‘ation then initiates the contractile process. py. oe cestorative process of periodic contraction of muscle, Ca® ions are removed by reuptake - sarcoplasmic reticulum by SR-Ca** ATPase vivochondria) as well as by its expulsion from Ji by a Ca®*/Na* exchange pump. Intracellular slance is then restored by Na‘/K* ATPase (Fig. Lt lar (2 ch Cellular Mechanism of Digitalis Action. Digitalis pinds to.and reversibly inhibits cardiac cell membrane associated Na‘/K* ATPase (Fig. 22.3). This leads to progressive accumulation of intracellular Na’ and loss of intracellular K*, Increase in the intracellular Na* concentration prompts the influx of Ca from the outside and outflux of Na* from inside by Ca"*/Na* exchange mechanisms. It should be noted that Na‘/ Ca" exchanger normally extrudes Ca” in exchange for Nat (see above). However, in the presence of concentration (as occurs ), it extrudes Na’ in increased intracellular Na* under the effect of digitalis exchange of extracellular C: ‘There is also an increase in Ca’ permeability through voltage-sensitive L-type Ca°* channels, during plateau phase. Increased cytosolic free Ca” by these two mechanisms then triggers the release of more Ca from sarcoplasmic reticulum and mitochondria, Digitalis also inhibits SR-Ca™*-ATPase and thus reduces the reuptake of Ca” by sarcoplasmic reticulum. Ultimately, the increased Ca’* concentration in the cytosol triggers the contractile mechanisms of the failing heart. In short, the inotropic action of digitalis results due to an increase in cytoplasmic Ca?" concentration that enhances cardiac muscle contractility and ultimately the cardiac output (Fig.22.3). Higher serum K* co binding to Na‘/K* ATPase, can reduce digitalis toxicity while hypokalaemia will increase the risk of digitalis toxicity (tachyarthythmias). Analogously, hypercaleaemia or hhypomagnesaemia can increase the risk for digitalis- induced arrhythmias (magnesium actions are opposite of calcium). Pharmacological Actions of Digitalis Ventricular Function Curves in Normal Heart, in Heart Failure and After Digitalis Treatment ‘The three major determinants of cardiac function in the intact heart are preload (ventricular end- diastolic volume), afterload and myocardial contractility. When stroke volume, which is the measure of left ventricular performance, is plotted against left ventricular filling pressure (preload; Fig. 22.4) the resulting curve is termed as the left ventricular function curve (A). As per Frank Starling law, the stroke volume increases as the preload, or LV filling pressure, increases till 15 mm Hg. Beyond this point-A, there is plateau level of performance and preload greater than 25 mm Hg results in pulmonary oedema, ncentration inhibits digitalis therefore, hyperkalaemia Scanned with CamScanner | PRINCIPLES OF PHARMACOLOGY | 8a | PRINCIPLES OF PHARMACOL o¥ In heart failure, an increase in PVR and a decrease in contractility will provide a depressed LV function curve (B). Because this curve of the failing heart is lower, the plateau is reached at much lower values of stroke output. The downward shift of curve Ato curve B shows that although the preload is same (15 mm Hg) butthe stroke volume has dropped from ‘Y” which is the minimal cardiac output (stroke volume) required to meet the normal metabolic needs of the body. In curve B even if preload increases to 25 mm Hg from 15 mm Hg, as a compensatory mechanism, there will only be a marginal improvement in the stroke volume. On the contrary, at this value of preload there would be exudation of fluid in the alveoli leading to pulmonary oedema (elevated pressure in the pulmonary capillaries pushes more fluid into the pulmonary interstitial space). As is clear with the curve “B’, the stroke volume is still not adequate to meet the metabolic needs of the patient having heart failure. Digitalis treatment shifts ventricular function curve ‘B’ to ‘C’ (more towards normal) by increasing contractility which in turn would lead to a decrease in PVR and preload. 7 Cardie Effects of Digitalis. Effects of digitalis ‘én normal heart are different than on the failing heart. In normal heart, digitalis increases force of contraction, and causes constriction of peripheral blood vessels. Heart rate and cardiac output (CO) are almost unchanged. In normal heart, digitalis has no effect on CO as the normal heart is emptying completely even otherwise. In heart failure, digitalis increases the contractility of the myocardium leading to an increase in cardiac output. Cardiac systole is shortened so that more time is provided for ventricular rest and filling, Heart rate is reduced both due to direct (Na*/K* ATPase inhibition) as well as indirect (vagal stimulation) effects on SA node. The overall effect of, digitalis is an improvement in ventricular performance of the failing heart without significantly increasing the oxygen requirement; because an increase in myocardial O, demand due to increase in the force of contraction is neutralised by the reduction in HR and reduction in ventricular size, which ultimately reduces the O, requirement of the heart. Digitalis decreases the conduction velocity of AV node and His-Purkinje system and prolongs their effective refractory period (ERP) by both vagal and extra-vagal (Na*/K* ATPase inhibition) action. Increased ERP and decreased conductivity of AV node protects ventricles from atrial flutter or atrial fibrillation, In relatively smaller doses, digitalis increases the conduction velocity and decreases the ERP of atrial muscle via vagal action while in high doses it increases automaticity and contractility but shortens Scanned with CamScanner© eaaapren 22 DRUG THERAPY OF HEART FAILURE [317 of atrial muscle and ventricles causing sles, pulsus bigeminus and ventricular the fibrillation ‘crent parts of heart show different sensitivity sitalis as follows: \ vode> Atrial muscles> Purkinje fibres>Ventricles since cholinergic innervation is only up to AV node, effects of digitalis are more pronounced at de and atria than on Purkinje system or CG shows prolongation of PR interval (delayed sy conduction), shortening of QT interval (shorter eniricular systole), depression of ST segment and inversion or disappearance of T wave. Later, extrasystoles, AV block and ventricular fibrillation appear as terminal events. Extracardiac Effects of Digitalis Blood Vessels. In normal persons, digitalis has direct vasoconstrictor effects. In heart failure, digitalis ‘opposes compensatory sympathetic overactivity and causes a decrease in HR, decrease in PVR (J in afterload) and decrease in venous tone (Lin preload). Since lesser blood reaches the heart, end-diastolic volume is reduced. There is no prominent effect on BP as it is secondary to the improvement in circulation. Kidney. Diuresis occurs due to improvement in renal perfusion, which brings about a shift of oedematous fluid into circulation. Other contributing factors producing diuresis are: a decrease in compensatory sympathetic discharge, a decrease in activation of RAS (Lrenin, LAng-II, Laldosterone release and Jin salt and water retention). GIT. The effects include anorexia, diarrhoea, nausea and vomiting (stimulation of chemoreceptor trigger zone). CNS Effects. These include disorientation, hallucinations (in elderly), visual disturbance and ‘aberrations of colour perception. Pharmacokinetics The pharmacokinetic characteristics of three typical cardiac glycosides—digoxin, digitoxin and ouabain— have been compared in Table 22.1. Therapeutic Uses Digoxinis the most commonly preferred drug amongst the three glycosides discussed above, even for the patients having hepatic insufficiency. Digitoxin is, however, preferred in the cases having renal impairment. Ouabain is reserved for acute heart failure Slow digitalisation (Table 22.1) is always preferred over faster digitalisation to avoid cardiotoxicity. As digitalis has cumulative effect and exhibits smaller therapeutic window, itis always safer to prescribe a dose that provides digitalis plasma concentrations of 0.8to 1.2 ng/ml. Such a dose reduces the incidence of side effects and optimises the benefits. Congestive Heart Failure. Digitalis is a drug of choice for “low output heart failure” due to HT, THD, or arrhythmias. It is not a suitable drug for “high output heart failure” due to thyrotoxicosis or arteriovenous shunt (see above). It provides relief from dyspnoea and cyanosis by subsiding pulmonary congestion. It increases urinary output and reduces ‘oedematous fluid by increasing renal perfusion. Because it diminishes systemic venous pressure, engorged tender liver regresses and engorgement of neck veins disappears. With decreased end-diastolic fibre tension, heart size and O, demand of myocardium decreases. There is bradycardia and improved myocardial circulation with the development of a sense of well being. Paroxysmal Supraventricular Tachycardia. Itis a common arthythmia due to reentry phenomenon taking place at SA or AV node. They frequently respond to digitalis favourably, because of reflex vagal activation which slows the conduction of impulses. However, adenosine or verapamil or B-blockers are more preferred these days as they take a shorter time for providing improvement. Digitalis is, now, reserved for preventing recurrences. ‘Atrial Flutter and Atrial Fibrillation. Atrial flutter (rate 200-300 beats/min) and atrial fibrillation (rate 500 beats/min) are effectively treated with digitalis as it decreases conduction velocity and increases ERP of AV node, If the ventricular rate of 72-80 beats! minute (therapeutic end point) is not achieved by giving digitalis alone; a f-blocker or verapamil may be added. Scanned with CamScanner | PRINCIPLES OF PHARMACOLOGY | 8< S < | PRINCIPLES OF SECTION 4s DRUGS AFFECTING RENAL AND CARDIOVASCU! LAR SYSTEM, & RELATED AUTACOIBEI 318 © DD rermacokinetic Profiies of Three Typical Cardiac Glycosides Digitoxin* Digoxin' ow! al absorption 95% -100% 75%-90%" 0 (nil) Administration Oral Oral iv. 4 3. avd (L/kg)* 06 6-7 18 4. Protein binding 90 30 0 (nil) 5. Plasma half-life 6-7 days 38-40 hr 18-20 hr 6. Onset of action 2. hours 3/2 hour Very rapid (given 1.V.) 7. Duration of action Very long Intermediate Short 8. Metabolised (%) 80 (liver)? 20 (liver) 0 9. Excretion Mainly bile, also urine 10.Doses a) Digi dose 1.0 mg in 24 hr ‘or 0.4 mg every 12 hr for total 3 doses orally 0.1 mg single dose per day ising b) Maintenance dose Urine (unchanged) Urine (unchanged) 0.2-0.5 mg LV. in cases of acute heart failure 0.5-0.75 mg 8 hriy for total 3 doses orally 0.25-0.5 mg per day + These digitalis preparations have cumulative effect 2 Undergoes enterohepatic circulation which contributes to prolonged ty2 2 About 10% of population harbour enteric bacteria which inactivates digoxin in the ‘gut and reduces bioavailability Apparent volume of distribution Dilated Heart. Digitalis is still the most preferred drug for patients having dilated heart and low ejection fraction as it is helpful in restoring cardiac compensation. It is usually prescribed when the patient’s condition is not controlled by diuretic or ACE inhibitor. Digoxin therapy in HF, at present, remains controversial. Recent trials have failed to show any ‘mortality benefits with digoxin use, A small mortality benefit may exist at blood levels below 1.0 ng/ml but ‘recent reports reveal an increased mortality at higher blood levels that were earlier regarded as therapeutic. Besides, there are multiple factors governing its blood levels, efficacy and toxicity including numerous drug interactions, Adverse Effects and Management of Toxicity Cardiac Side Effects. These include bradycardia, partial or complete heart block, atrial or ventricular extrasystoles, coupled beats (bigeminy), ventricular fibrillation and fatal cardiac arrhythmias. If cardiac arrhythmias develop, Ca**, Mg? and K® status should be corrected (see above). For brief. ‘Scanned with CamScanner‘Serious, parenteral K’ and lidocaine may be most glycosides. ed (see Ch. 21). Propranolol can be used _Extracardi ek is absent. Atropine can be used to CI K* levels are misleading as rar). Contraindications ‘CHAPTER 22 | DRUG THERAPY OF HEART FAILURE | 319) of bigeminy, oral K* supplementation and 0.6 mg of digoxin stored in the body. These are Iwal of digoxin may be sufficient. Ifarhythmias extremely useful in reversing severe intoxication with jide Effects. GIT: Anorexia, nausea, lar oF supraventricular tachycardia, vomiting, diarthoea and abdominal cramps. 5: Headache, fatigue, neuralgia, blurred vision, yeardia and different degrees of loss of colour perception (as discussed above) isa severe digitalis intoxication, Endocrinal: Gyanecomastia in males (but very because of K* loss from Management of extracardiac side effects requires ents of various tissues-and no more than reducing the dose of digoxin. = Hypokalaemia enhances digitalis toxicity as it potentiates its binding to Na‘/K* ATPase. = Inchildren below 10 years and in elderly patients with hepatic or renal impairment, because such patients are more sensitive to digitalis action Displace digitalis from protein binding sites Amiodarone <—|Quinidine Verapamil Tetracyctines Catecholamines Succinylcholine cause arrhythmias Erythromycin Increase metabolism of digoxin Enzyme inducers Phenytoin Phenobarbitone Scanned with CamScanner | PRINCIPLES OF PHARMACOLOGY | R