Drugs Used in Congestive Heart Failure

1. Drugs Used inCongestive Heart Failure By Dr. A. Narendra Babu Dept. of Pharmacology

2. Introduction • Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body. • The most common cause of heart failure is coronary artery disease. • Heart failure may be low output (more common) or high out put (rare) • In low output heart failure, cardiac output is below the normal range. Two major types exist: • Systolic failure • Diastolic failure

3. Systolic failure: reduced cardiac output and reduced ejection fraction (<45%), is typical of acute failure (MI). • Diastolic failure: is a result of hypertrophy, stiffening and loss of adequate relaxation of the myocardium. Cardiac output is reduced but ejection fraction may be normal. • Heart failure due to diastolic dysfunction does not respond to positive inotropic drugs. • High-output failure can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts. • This form of failure should be treated by correcting the underlying cause. • The manifestations of all types of heart failure include: tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary edema, and cardiomegaly.

4. The primary defect in early heart failure resides in the excitation-contraction coupling of the heart • Therapy directed at noncardiac targets is more valuable in the long-term treatment of heart failure than positive inotropic agents. • Positive inotropic drugs can be very helpful in acute failure. They also reduce symptoms in chronic failure.

5. Normal Cardiac Contractility • Contraction results from the interaction of activator calcium (during systole) with the actin - troponin - tropomyosin system • The amount released depends on the amount stored in the SR and on the amount of trigger calcium during the plateau of the action potential. • A. Sensitivity of the contractile proteins to calcium • Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. • B. The amount of calcium released from the sarcoplasmic reticulum • C. The amount of calcium stored in the sarcoplasmic reticulum • D. The amount of trigger calcium

6. A. Sensitivity of the contractile proteins to calcium • Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. • B. The amount of calcium released from the sarcoplasmic reticulum • C. The amount of calcium stored in the sarcoplasmic reticulum • D. The amount of trigger calcium

7. E. Activity of the sodium-calcium exchanger • This antiporter uses the sodium gradient to move calcium against its concentration gradient from the cytoplasm to the extracellular space. • The sodium-calcium exchanger's ability to carry out this transport is thus strongly dependent on the intracellular concentrations of both ions, especially sodium. • F. Intracellular sodium concentration and activity of Na+/k+ATPase • Na+/k+ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell.

8. Cardiac Performance • Cardiac performance is a function of four primary factors: Preload Afterload Contractility Heart rate

9. Drugs Used In Heart Failure • Digitalis • Other positive inotropic drugs: • Bipyridines • β stimulants • Drugs without positive inotropic effects: • Diuretics • ACE inhibitors & angiotensin receptor blockers • Vasodilators • β blockers

10. Digitalis • All of the cardiac glycosides, or cardenolides of which digoxin is the prototype combine a steroid nucleus. • They are extract of many common plants: • Digitalis purpurea (Red foxglove) • Digitalis lutea • Convallariamajalis (Lily of the valley) • Helleborusniger (Christmas rose)

11. Each of the cardiac glycosides contains: • i) A steroid nucleus • ii) a lactone ring at C17 – essential for cardioactivity; and • (iii) a sequence of sugars at C3 hydroxyl group • The steroid lactone system freed of the sugars by hydrolysis, with a free hydroxyl group at C3 is called an aglycone or genin

12. Digoxin • Digoxin is obtained from Digitalis lanata(white foxglove). • It inhibits Na+/K+ATPase (the sodium pump). • Cardiac effects • Mechanical effects • Electrical effects • Effects on other organs • Interactions with K+, Ca2+ and Mg2+ • Digoxin Toxicity

17. Mechanical effects • Cardiac glycosides increase contractility of the cardiac sarcomere by increasing the intracellular calcium concentration • This effect occurs in both normal and failing myocardium. • The responses are modified by cardiovascular reflexes and the pathophysiology of heart failure.

18. Electrical Effects • At first action potential duration decreases which is the result of increased potassium conductance due to increased intracellular calcium. • At higher concentrations, resting membrane potential is made less negative due to inhibition of the sodium pump. • As toxicity progresses, afterpotentials ”delayed afterdepolarizations, DADs” appear due to overloading of the intracellular calcium stores.

20. Effects On Other Organs • The GI tract is the most common extra cardiac site of digitalis toxicity. It causes anorexia, nausea, vomiting, and diarrhea. • Central nervous system effects include vagal and CTZ stimulation. • In the elderly disorientation, hallucinations and visual disturbances (as color misperception) may occur.

21. Pharmacokinetics • Digitoxin (D.purpurea) – most lipid solube • Digoxin (D.lanata)

23. Digoxin Toxicity • Toxicity of digitalis is high, margin of safety is low • Extracardiac : • Anorexia, Nausea, vomiting and abdominal pain – reported first - due to gastric irritation, mesentric vasoconstriction and CTZ stimulation. • Fatigue malaise, headache, mental confusion, restlessness, hyperapnoea, disorientation, psychosis and visual disturbances • Occassionallydiarrhoea, rarely skin rashes and gynaecomastia • Cardiac : • Every type of arrhythmias can be produced • Nodal and ventricular extrasystoles, ventricular tachycardia, fibrillation • Partial to complete AV block • Severe bradycardia, atrialextrasystoles, AF, AFl

24. Treatment: • Further doses of digitalis must be stopped at the earliest sign of toxicity • For tachyarrhythmias – caused by chronic use of digitalis and diuretics (induces K+ depletion) – infuse KCl 20 m.mol/hr, i.v or give in milder cases. • For Ventricular Arrhythmias – Lidocainei.v • For supraventricular arrhythmias – Propranolol may be given i.v. or Orally depending on urgency • For A-V block and bradycardia – Atropine 0.6-1.2 mg i.m

25. Interactions With K+, Ca2+, Mg2+ • Potassium and digitalis inhibit each other's binding to Na+/K+ ATPase • Hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions. • Moderately increased extracellular K+ therefore reduces the (toxic) effects of digitalis. • Ca2+ facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores. • Hypercalcemia increases the risk of a digitalis induced arrhythmia. • The effects of Mg2+ is opposite to those of calcium.

26. Other Interactions: • Adrenergic drugs can induce arrhythmias in difgitalized patients • Quinidine reduces binding of digoxin to tissue proteins and its renal clearance • Digoxin absorption can be reduced by metoclopramide (gastrointestinal hurrying) and sucralfate which adsorbs digoxin. • Antacids, neomycin, sulfasalazine reduce digoxin absorption • Propranolol, verapamil, diltiazem and disopyramide additively depress A-V conduction • Phenobarbitone and other enzyme inducers expedite digoxin metabolism and decrease its t ½

27. Precautions and Contraindications: • Hypolkalemia – enhances digitalis toxicity by ↑ its binding to Na+/K+ATPase. • Elderly, renal or severe hepatic disease – more sensitive to digitalis • MI – severe arrhythmias • Thyrotoxicosis – reduces responsiveness to digitalis • Myxoedema – these patients eliminate digoxin more slowly • Ventricular tachycardia – contraindicated may precipitate ventricula fibrillation • Partial A-V block – may be converted to complete A-V block • Acute myocarditis – Diphtheria, acute rheumatic carditis – inotropic response is poor

28. Bipyridines • Bipyridines that inhibit phosphodiesterases, are used in heart failure. • Inhibition of phosphodiesterase increases cAMP and increases contractility and vasodilation. • The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential. • Although they have positive inotropic effects, most of their benefits derive from vasodilation. • Two successful bipyridines are: Inamrinone and Milrinone. • Inamrinone and milrinone are used only for acute heart failure or severe exacerbation of chronic heart failure.

29. β– Stimulants • Dobutamine (selective β1 agonist) has been widely used in heart failure. • It increases cardiac output together with a decrease in ventricular filling pressure. • Tachycardia may occur. • Tachyphylaxis may be seen with any β-stimulant. • Dopamine is also used in acute heart failure and is helpful if blood pressure should be raised.

30. Diuretics • They reduce venous pressure and ventricular preload. • This results in reduction of edema and cardiac size, which improves pump efficiency. • Aldosterone may cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects. • For this reason the aldosterone antagonists, spironolactone and eplerenone, decrease morbidity and mortality in severe heart failure.

31. ACE Inhibitors & ARBs • These drugs reduce peripheral resistance and afterload. • They also reduce salt and water retention and in that way reduce preload. • The reduction in tissue angiotensin also reduces sympathetic activity. • These drugs reduce the long-term remodeling of the heart and vessels.

32. Vasodilators • The vasodilators are effective in acute heart failure. • They reduce preload (venodilation), or afterload (arteriolar dilation), or both. • Long-term use of hydralazine and isosorbidedinitrate can also reduce damaging remodeling of the heart. • Bosentan, an inhibitor of endothelin, is used in pulmonary hypertension. It has significant teratogenic and hepatotoxic effects.

33. β-blockers • Most patients respond favorably to CERTAIN β-blockers. • These drugs can cause acute decompensation of cardiac function. • Bisoprolol, Carvedilol, and Metoprolol showed a reduction in mortality. • This effect was not observed with another β blocker, Bucindolol.

34. Clinical Pharmacology • Diuretics are first-line therapy. • Digitalis is reserved for patients who do not respond adequately to diuretics, ace inhibitors, and β blockers. • Steps in the treatment of chronic heart failure. 1. Reduce workload of the heart    • Limit activity, put on bed rest    • Reduce weight    • Control hypertension 2. Restrict sodium intake 3. Restrict water (rarely required) 4. Give diuretics

35. 5. Give ACE inhibitor or angiotensin receptor blocker 6. Give digitalis if systolic dysfunction with 3rd heart sound or atrial fibrillation is present 7. Give β blockers to patients with stable class II-IV heart failure 8. Give vasodilators 9. Cardiac resynchronization if wide QRS interval is present in normal sinus rhythm

36. Sodium Removal • In mild failure, start with a thiazide diuretic, switching to furosemide as required. • Hypokalemia can be treated with potassium supplementation or through the addition of an ACE inhibitor or a potassium-sparing diuretic. • Spironolactone or eplerenone should be considered in all patients with moderate or severe heart failure. • Serum potassium should be monitored in patients receiving any of these agents.

37. ACE Inhibitors & ARBs • In patients with left ventricular dysfunction but no edema, an ACE inhibitor should be used first. • ACE inhibitors are superior to vasodilators and must be considered, along with diuretics, as first-line therapy for chronic failure. • ACE inhibitors cannot replace digoxin in patients already receiving that drug. • ACE inhibitors are beneficial in asymptomatic patients to those with severe chronic failure. • ARBs (losartan, candesartan) should only be used in patients who are intolerant of ACE inhibitors (usually because of cough).

38. Vasodilators • The ACE inhibitors are nonselective arteriolar and venous dilators. • The choice of agent should be based on the patient status and hemodynamic measurements. • Poor response to other therapy usually involves both elevated filling pressures and reduced cardiac output. β Blockers & Ca2+ Channel Blockers • Such therapy is beneficial if initiated very cautiously at low doses. • Acutely blocking the supportive effects of catecholamines can worsen heart failure. • Several months of therapy may be required before improvement is noted.

39. Digitalis • Digoxin is indicated in patients with heart failure and atrial fibrillation. • It is also most helpful in patients with a dilated heart and third heart sound. • It is usually given only if diuretics and ACE inhibitors have failed to control symptoms. • Only 50% of patients with normal sinus rhythm benefit from digitalis. • When symptoms are mild, slow “digitalization” (0.125-0.25 mg/d) is safer and as effective as the rapid method (0.5-0.75 mg every 8 hours for 3 doses, followed by 0.125-0.25 mg/d). • In atrial fibrillation, reduction of ventricular rate is the best measure of glycoside effect. • In normal sinus rhythm, symptomatic improvement and reductions in heart size and rate signify optimum drug levels.

40. Acute Heart Failure • A common cause of acute failure is MI. • Patients with MI are treated with emergency revascularization using either coronary angioplasty and a stent or a thrombolytic agent. • Measurements of arterial pressure, cardiac output, stroke work index, and pulmonary capillary wedge pressure are useful in patients with MI and acute heart failure. • Such patients can be characterized on the basis of three hemodynamic measurements: arterial pressure, left ventricular filling pressure, and cardiac index. • Among patients with acute decompensation, a small subset is found to have hyponatremia, due to increased vasopressin activity. • A new V1a and V2 receptor antagonist, conivaptan, has recently been approved for the parenteral treatment of euvolemichyponatremia.

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