Drugs used in congestive heart failure

A. Learning objective

A.1. Competency Standard from InaMc

Please refer to Competency Standard from Indonesian Medical Council / Konsil Kedokteran
Indonesia and Level of competency of……………

Heart failure 3B

A.2 You should be able to

• Describe the strategies and lisl the major drag groups used in the treatment of congestive
heart failure.
• Describe the probable mechanism of action of digitalis.
• Describe the nature and mechanism of digitalis's toxic effects on the heart.
• List some positive inotropic drugs that have been investigated as digitalis substitutes.
• Describe the beneficial effects of diuretics, vasodilators. ACE inhibitors, and other drugs that
lack positive inotropic effects in congestive heart failure.

Learn the definitions that follow.

1

A. Recent clinical results show that beta-adrenoceptor blockers and spironolactone. also have long-term beneficial effects. (4) Cardiomegaly---enlargement of the heart is a slower compensatory response. Pathophysiology: The fundamental physiologic defect in congestive heart failure is a decrease in cardiac contractility. The homeostatic responses of the body to depressed cardiac output are extremely important and are mediated mainly by the sympathetic nervous system and the renin- angiotensinaldosterone system. the increased load contributes to further long-term decline in cardiac function. Operation at point B is intrinsically less efficient than operation at shorter fiber lengths because of the increase in myocardial oxygen requirement associated with increased fiber stretch (see Figure 12-2). Recent evidence suggests that aldosterone may also play a direct role in cardiac changes. Figure 13- 2). This is best shown by the ventricular function curve (Frank-Starling curve. direct treatment of the depressed hear! with positive inotropic drugs such as digitalis glycosides: reduction of preload or aflerload with vasodilators. an aldosterone antagonist. Chronic failure is best treated with diuretics (often a loop agent plus 2 . the end-diastolic fiber length increases as shown by the shift from point A to point B in Figure 13-2. Current clinical evidence suggests that acute congestive failure should be treated with a loop diuretic. The ventricular function curve reflects some compensatory responses of the body and may also be used to demonstrate the response to drugs. they also increase the load on the heart. Therapeutic Strategies in Congestive Heart Failure: Pharmacologic therapies for congestive heart failure include the removal of retained salt and water with diuretics. While these compensatory responses may temporarily improve cardiac output (and may be lifesaving). considerable evidence suggests that ACE inhibitors beneficially alter the structural changes that often follow myocardial infarction and lead to congestive failure. a prompt-acting positive inotropic agent such as a beta agonist or phosphodiesterase inhibitor. The use of diuretics is discussed in Chapter 15. and reduction of afterload and retained salt and water by angiotensin-converting enzyme inhibitors. The result of this defect is that cardiac output is inadequate for the needs of the body. B. Angiotensin II also plays an important role. and vasodilators as required to optimize filling pressures and blood pressure. (2) Increased peripheral vascular resistance--another early response. As ventricular ejection decreases. In addition. mediated by the renin-angiotensin-aldosterone system and facilitated by increased sympathetic outflow. mediated at least in part by sympathetic discharge. Increased blood volume results in edema and pulmonary congestion and contributes to the increased end-diastolic fiber length. The major responses include the following: (1) Tachycardia--an early manifestation of increased sympathetic tone. (3) Retention of salt and water by the kidney--an early compensatory response. also mediated by increased sympathetic tone. They are summarized in Figure 13-3.CONCEPTS PATHOPHYSIOLOGY OF CONGESTIVE HEART FAILURE & TREATMENT STRATEGIES The drugs used in congestive heart failure are shown in Figure 13-1.

spironolactone) plus an ACE inhibitor and. a beta blocker. 3 . if tolerated. Digitalis is used if systolic dysfunction is prominent.

and aftedoad permit the heart to function more efficiently (point C in Figure 13-2). and increased renal perfusion. Electrical effects: Electrical effects include early cardiac parasympathomimetic re- sponses and later arrhythmogenic responses. 2. is the most important manifestation of toxicity. Cardiac Effects: 1.CARDIAC GLYCOSIDE A. decreased end-systolic and end-diastolic size. The cardiac glycosides are often called "digitalis" because several come from the digitalis (foxglove) plant. most also have one or more sugar residues. a. Early responses: Increased PR interval. Prototypes and Pharmacokinetics: All cardiac glycosides include a steroid nucleus and a lactone ring. Toxic responses: Increased automaticity. caused by intracellular calcium overload. a shorter-acting glycoside. digitoxin. Mechanism of Action: Inhibition of Na+/K + ATPase of the cell membrane by digitalis is well-documented and is considered to be the primary biochemical mechanism of action of digitalis (Figure 13-4). The increased sodium alters the driving force for sodium-calcium exchange so that less calcium is removed from the cell. A very similar molecule. and flattening of the T wave are often seen. is now rarely used. preload. and ST depression may occur later. The increase in the atrioventricular nodal refractory period is particularly important when atrial flutter or fibrillation is present because the refractoriness of the AV node de- termines the ventricular rate in these arrhythmias. and this action has effects on the electrical properties of the heart. B. which also comes from the foxglove. Digoxin is the prototype agent and the one most commonly used in the USA. caused by the decrease in atrioventricular conduction velocity. These beneficial effects permit a decrease in the compen- satory sympathetic and renal responses previously described. Digitalis-like drugs come from many other plants. and the steroid nucleus plus lactone ring comprise the "'genin" portion. tachycardia. The increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release increases contractile force. Other mechanisms of action for digitalis have been proposed. inversion of the T. or fibrillation in any part of the 4 . and ouabain are summarized in Table 13-2. The sugar residues constitute the glycoside portion of the molecule. Inhibition of Na+/K + ATPase results in an increase in intracellular sodium. which may evoke extrasystoles. Translation of this effect into an increase in cardiac contractility involves the Na+/Ca 2+ exchange mechanism. Shortened QT. b. The effect of digitalis is to slow ven- tricular rate. is derived from a tropical plant. though some evidence suggests that it is synthesized in mammals as well. The effects on the atria and AV node are largely parasympathetic in origin and can be partially blocked by atro- pine. The pharmacokinetics of digoxin. The consequences of Na+/K + ATPase inhibition are seen in both the mechanical and the electrical function of the heart. but they are probably not as important as the ATPase effect. increased cardiac output. They are summarized in Table 13-3. and a few come from animals. C. The decrease in sympathetic tone is especially beneficial: reduced heart rate. Mechanical effects: The increase in contractility evoked by digitalis results in increased ventricular ejection. digitoxin. It results from delayed afterdepolariza- tions. Digitalis also modifies autonomic outflow. Ouabain.

In the ventricles. 5 . ACE inhibitors. the rhythm is called bigeminy (Figure 13-5). Correction of potassium or magnesium deficiency: Correction of potassium deficiency (caused. However. Antiarrhythmic drugs: Antiarrhythmic drugs may be useful if increased automaticity is prominent and does not respond to normalization of serum potassium. Severe. and diarrhea. Potassium should not be raised above the normal level of 3. Interactions: Quinidine causes a well-documented reduction in digoxin clearance and often increases the serum digoxin level if digoxin dosage is not adjusted. F. Clinical Uses: 1. Digitalis ar- rhythmia is more likely if serum potassium or magnesium is lower than normal or if serum cal- cium is higher than normal. Severe acute intoxication (as in suicidal overdoses) usually causes marked hy- perkalemia and should not be treated with supplemental potassium. Rarely. the extrasystoles are recognized as premature ventricular beats (PVBs). Several other drugs have been shown to have the same effect (amiodarone. acute intoxication is caused by suicidal or accidental extreme overdose and results in cardiac depression leading to cardiac arrest rather than tachycardia or fibrillation. by diuretic use) is useful in chronic digitalis intoxication. The treat- ment of digitalis arrhythmias is important because this manifestation of digitalis toxicity is common and dangerous. Similarly. Other agents (diuretics. Antiarrhythmic drugs are dangerous in such patients.5-5 meq/L. Mild toxic- ity may often be managed by omitting one or two doses of digitalis and giving oral or par- enteral K + supplements. Congestive heart failure: Digitalis is the traditional positive inotropic agent used in the treatment of congestive heart failure. Because the half-lives of cardiac glycosides are long. of- ten used in treating heart failure. These ion interactions are important in treating digitalis toxicity (see below). nausea. vomiting. D. E.heart. may significantly reduce serum potassium and thus precipitate digitalis toxicity. Severe acute digitalis overdose usually causes marked inhibition of all pacemaker cells. Digitalis-induced vomiting may deplete serum magnesium and similarly facil- itate toxicity. for example. it is desirable to reduce the conduction velocity or increase the refractory period of the atrioventricular node so that ventricular rate is decreased. 2. Treatment of digitalis toxicity includes the following: 1. if hypomagnesemia is present. it should be treated by normalizing serum magnesium. vasodilators) may be equally effective and less toxic in some patients. Chronic intoxication is an extension of the therapeutic effect of the drug and is caused by excessive calcium accumulation in cardiac cells (calcium overload). Loop diuretics and thiazides. This overload triggers abnormal automaticity and the arrhythmias noted in Table 13-3. Agents that do not severely impair cardiac contractility (eg. but the interactions with these drugs are not clinically significant. verapamil. confusion or hallucinations and visual aberrations may occur. lidocaine or phenytoin) are favored but drugs such as propranolol have also been used successfully. others). The parasympathomimetic action of digitalis effectively accomplishes this therapeutic objective. Digitalis effects are inhibited by extracellular potas- sium and magnesium and facilitated by extracellular calcium. and some of these alternative therapies do prolong life (see below). 2. Digitalis Toxicity: The major signs of digitalis toxicity are arrhythmias. Atrial fibrillation: In atrial flutter and fibrillation. careful clinical studies indicate that while digitalis improves functional status (reducing symptoms). When PVBs are coupled to normal beats in a 1:1 fashion. the drugs accumulate significantly in the body. it does not prolong life. and dosing regimens must be carefully designed and monitored.

Digibind) are extremely effec- tive and should always be used if other therapies appear to be failing. D. Thiazides such as hydrochlorothiazide are often used in the management of mild chronic failure. in which systolic function is markedly depressed. which may be responsible for a major part of their beneficial effect. and vascular resis- tance. these agents may increase the sensitivity of the contractile protein system to calcium (site 6 in Figure 13- 6 . At sufficiently high concentrations. They are effective for poisoning with many cardiac glycosides in addition to digoxin and may save patients who would otherwise die. losartan) probably have similar benefits al- though long-term studies have not been completed with these newer drugs. they are not appropriate for chronic failure because of tolerance. However. Beta-blockers are not of value in acute failure and may be detrimental if systolic dysfunction is marked. although theophylline (in the form of its salt. and significant arrhythmogenic effects. ACE inhibitors reduce aldosterone secretion. salt and water retention. lack of oral efficacy. E. Phosphodiesterase Inhibitors: Amrinone and milrinone are the major representatives of this infrequently used group. Furosemide is a very useful agent for immediate reduction of the pulmonary congestion and severe edema associated with acute congestive heart failure or severe chronic failure. Phosphodiesterase inhibitors also cause vasodilation. Angiotensin receptor antagonists (eg. Digoxin antibodies: Digoxin antibodies (FAB fragments. Although they have no direct positive inotropic ac- tion. along with diuretics. Recent clinical studies suggest that spironolactone (an aldosterone antagonist diuretic) has particularly significant long-term benefits in chronic failure. B Angiotensin-Converting Enzyme lnhibitors: These agents have been shown to reduce mor- bidity and mortality in chronic heart failure. OTHER DRUGS USED IN CONGESTIVE HEART FAILURE A Diuretics: Diuretics are often used in congestive heart failure before digitalis and other drugs are considered. F. They are now considered among the first line drugs for chronic heart failure. aminophylline) was commonly used in the past.3. BetacSelective Adrenoceptor Agonists: Dobutamine and dopamine are useful in many cases of acute failure. metoprolol) have been shown in long-term studies to reduce progression of chronic heart failure. These drugs increase cAMP by inhibiting its breakdown by phosphodiesterase and cause an increase in cardiac intracellular calcium similar to that produced by beta adrenoceptor agonists. This benefit of [-blockers had long been recognized in patients with hypertrophic cardiomyopathy but has now been shown to also occur in patients without cardiomyopathy. The pharmacology of the diuretics is discussed in Chapter 15. labetalol. Beta-Adrenoceptor Antagonists: Several beta blockers (carvedilol.

continuing hypertension in an individual who has just had an infarct). 4). Chronic congestive heart failure sometimes responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate. Vasodilators: Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe congestive failure. G. The use of these vasodilator drugs is based on the reduction in cardiac size and improved efficiency that can be realized with proper adjustment of venous return and reduction of resistance to ventricular ejection. DRUGS LIST 7 . especially in cases in which increased afterload is a major factor in causing the failure (eg. Vasodilator therapy can be dramatically effective. These agents should not be used in chronic failure: they have been shown to increase morbidity and mortality.

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2008 3.11th. Basic & Clinical Pharmacology. 2002 2.219 – 228. Goodman & Gilman’s the Pharmacological Basis of Therapeuti.2008 10 .References 1. p. BG Katzung. Katzung & Trevor’s Pharmacology.

including important notes about drug mechanism.Appendix Assignment Assignment 1 Please answer : poin A. specific pharmacokinetic. An example of the pocket book/notes of drugs: (available in Indonesia) Generic Pharmaco Pharma Presentati and Cost Class & prototipe . co. Assignment 2 Make notes in the form of a pocket book containing the Drugs used in astma. safety. Each subgroup chooses one P-drug case (the P drug is taken from the pocket book). important side effects. 11 . suitability.  This assignment is done at home BEFORE skill lab activity (read the materials already provided). formulations of the medicine (written at home before skill lab activity).2.  Each group divides itself into 8 subgroups (with a maximum of 4-5 people per subgroup). and cost). Each group formulates P-drug. P-Treatment Assignment:  Each group works on one P-treatment case (make a P-treatment based on efficacy. on and Brand / etc dynamic kinetic Dosage Name Assignment 3 P-Drug Assignment:  Each class is divided into groups.

 P-treatment practice. infrastructure and human resources). Assignment 5 Structured Assignment after Skill Lab: a) Complete the pocket book of drug form and shapes. 12 . b) Complete P drugs used in asthma Assignment 6 This concept is applied during assistantship (Co As) in every clinic and also consists of independent training during the internship. It is hoped that this 'habit' of knowledge application would be carried on until the student is a physician working under the professional standard (based on ethics. disciplined/ competent. using various drug forms.Assignment 4 During the Skill Lab:  A short summary of Rational Drug Use  P-Drug practice and prescription writing practice: for normal adults. and service standards consistent with the local means.