Basic and Clinical Pharmacology

C13 DRUGS USED IN HEART FAILURE

A.Q. Sangalang, MD, MHPEd, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

• Heart failure results when the cardiac output is inadequate for the needs of the body
• A defect in cardiac contractility is complicated by multiple compensatory processes that
further weaken the failing heart
• Homeostatic responses of the body to depressed cardiac output (CO) are mediated mainly
by the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS)
o Tachycardia - early manifestation of increased sympathetic tone
o Increased peripheral vascular resistance - early response, sympathetic tone
o Retention of salt and water by the kidneys-an early compensatory mechanism
mediated by the RAAS
o Cardiomegaly- slower compensatory response mediated by at least in part by
sympathetic discharge

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THERAPEUTIC STRATEGIES
• Removal of retained salt and water with diuretics
• Direct treatment of the depressed heart with positive inotropic drugs
• Reduction of preload and afterload with vasodilators
• Reduction of afterload and retained salt and water by ace inhibitors

• Acute heart failure should be treated with a loop diuretic, beta agonist and a vasodilator
to optimize filling pressures and BP
• Chronic failure is best treated with diuretics plus an ace inhibitor and if tolerated , a beta-
blocker

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CARDIAC GLYCOSIDES
• Include a steroid nucleus and a lactone ring ( “genin” portion)
• With one or more sugar residues (glycoside portion)
• “Digitalis”, come from the digitalis (foxglove) plant
• Digoxin
Mechanism of action
• Inhibition of the Na+/K ATPase of the cell membrane
• nIncrease in cardiac contractility involves Na+-Ca2+ exchange mechanism
• Small increase of intracellular sodium which alters the driving force for Na+-Ca2+ exchange
• less calcium is removed from the cell
• Increased calcium level is stored in the sarcoplasmic reticulum and upon release increase
contractile force

CARDIAC EFFECTS
1. Mechanical effects
• Increased contractility
• Increase in ventricular ejection
• Increase in CO
• Increase in renal perfusion
• Decrease in end-systolic and end-diastolic size

Permits decrease in compensatory sympathetic

Reduced heart rate
Reduced preload and afterload
Reduced renal responses

2. Electrical effects
Early cardiac parasympathomimetic responses and late arrhythmogenic responses
a. Early responses
• Effects on the atria and AV node are parasympathetic
• Slows ventricular rate
b. Toxic responses
• Increased automaticity caused by intracellular calcium overload
• May evoke extrasystole, tachycardia or fibrillation in any part of the heart

CLINICAL USES
• Congestive heart failure
• Traditional drug used in the treatment of chronic heart failure
• Improves functional status but does not prolong life
• Half-lives are long, drug can accumulate
• Other agents maybe equally effective and less toxic (diuretics, ACE inhibitors, and
vasodilators)
• Atrial fibrillation
• Parasympathomimetic action
• Reduces the conduction velocity
o Or increases the refractory period of the AV node so that ventricular rate is controlled

INTERACTIONS
• Quinidine

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 o Causes a well-documented reduction in digoxin clearance and can increase serum
digoxin levels
• Loop diuretics and thiazides
o Used in the treatment of heart failure
o Significantly reduce serum potassium and precipitate digitalis toxicity
• Extracellular potassium and magnesium
o Inhibits digitalis effects
• Extracellular calcium
o Facilitates digitalis effects

DIGITALIS TOXICITY
• Arrhythmias
• Diarrhea
• Nausea and vomiting
• Confusion and hallucination
• Chronic intoxication is an extension of the therapeutic effect of the drug
• Caused by excessive accumulation of calcium in cardiac cells (calcium
overload) abnormal automaticity and arrhythmia

DIGITALIS TOXICITY TREATMENT

• Correction of potassium
o Caused by diuretic use or magnesium deficiency
o Mild toxicity is managed by omitting 1 or 2 doses of digitalis
o Oral or parenteral K+ supplements (5 mEq/L)
o Hypomagnesemia should also be treated
• Antiarrhythmic drugs
o In the presence of increased automaticity
o In cases that do not respond to normalization of serum K+
o Lidocaine, phenytoin, propranolol
• Digoxin antibodies
o Digibind
o Fragments
o Extremely effective
o Used only if other therapies fail
o Effective in poisoning with many cardiac glycosides
• Severe acute intoxication
o Suicidal overdose
o Marked hyperkalemia
o Marked inhibition of all pacemaker cells
o Should not be treated with potassium supplementation and antiarrhythmic drugs

OTHER DRUGS USED IN CONGESTIVE HEART FAILURE

DIURETICS
• Often used before digitalis and other drugs
• Furosemide
• Immediate reduction of pulmonary congestion and edema
• Thiazides sufficient for mild chronic failure
• Spironolactone and eplerenone have long term benefits

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ANGIOTENSIN ANTAGONISTS
• Reduce morbidity and mortality in chronic heart failure
• Reduce aldosterone secretion
• Reduce salt and water retention and vascular resistance
• First-line drug along with diuretics
• Losartan, ACE inhibitors

BETA1-SELECTIVE ADRENOCEPTOR AGONIST

• Dobutamine and dopamine
• Useful in many cases of acute heart failure in which systolic function is markedly
depressed
• Not appropriate for chronic use
• Develop tolerance
• Lack of oral efficacy
• Significant arrhythmogenic effects
• Carvedilol, labetalol, metoprolol
• Reduce progression of chronic heart failure
• No value for acute failure and maybe detrimental if systolic dysfunction is marked

PHOSPHODIESTERASE INHIBITORS
Amnrinone and milrinone
• Infrequently used
• Not used in chronic renal failure
• Increase cAMP by inhibiting breakdown by phosphodiesterase and cause an increase
• in intracellular calcium
• Can also cause vasodilation, major part of the beneficial effect

VASODILATORS
• Nitroprusside or nitroglycerine
• For acute severe failure with congestion
• Reduce in cardiac size and improved efficiency
• Nesiritide
o Natriuretic peptide acts by causing vasodilatation
o Given by IV infusion for acute heart failure only
• Chronic heart failure sometimes respond to oral vasodilators such as hydralazine or
isosorbide dinitrate

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