Presentation on theme: "Agents used in therapy of Congestive Heart Failure Dr. Thomas Abraham PHAR417: Fall 2006."— Presentation transcript:
Agents used in therapy of Congestive Heart Failure Dr. Thomas Abraham PHAR417: Fall 2006
Pathophysiology of Congestive Heart Failure CHF is characterized by tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary edema, decreased urine output and cardiomegaly. Decreases in myocardial contractility leads to increased sympathetic nervous system activity to improve cardiac output and maintain tissue perfusion.
Pathophysiology of Congestive Heart Failure
Cardiac remodelling, increasing cardiac work and sustained sympathetic nervous system stimulation of the heart muscle may lead to enlargement of cardiac cells, specific chambers or the organ in general (hypertrophy). Right ventricle dilated Normal Heart
Pathophysiology of Congestive Heart Failure This eventually leads to decreased overall pump efficiency of the heart, further aggravating the heart failure. Right heart failure peripheral edema, pulmonary hypo- or hypertension, ascitis, hepatic congestion Left heart failurepulmonary edema, congestion, SOB, decreased renal function, peripheral edema Right ventricle dilated Normal Heart
Cardiac performance in CHF is influenced by four important parameters: 1. Preload – the amount of blood returning to the heart from the venous circulation. - increased venous return due to increased SNS activity and due to increased blood volume lead to increased preload. Pathophysiology of Congestive Heart Failure - Alters myocardial contractility by altering ventricular filling volume (pressure) which alters myocardial stretch; remember the Frank-Starling relationship? - During early heart failure the increased SNS activity and Na+/water retention maintains preload to maintain stroke volume (compensated cardiac function). - Positive inotropic agents maintain stroke volume without altering preload.
2. Afterload – is the pressure against which the heart has to pump blood; the pressure in the aorta. - TPR determines the afterload and as TPR rises the amount of blood ejected per beat decreases, unless cardiac contractility increases. - Agents that lower TPR may have a beneficial effect in CHF. 3. Cardiac contractility – patients with chronic low output failure have lowered capacity to generate sufficient myocardial force to eject the blood in the ventricles; leads to increased end-diastolic pressure. - Positive ionotropic agents improve contractility to improve the pumping actions of the heart muscle. Congestive Heart Failure
4. Heart rate – along with contractility it is responsible for cardiac output maintenance. With diminished contractility the SNS attempts to maintain C.O. by increasing heart rate ( -receptor stimulation). - Improved myocardial contractility often leads to decreased heart rate. Most of the agents in management of CHF increase contractility (positive ionotropic); decrease TPR (vasodilators, ACEIs, ARBs); or decrease blood volume (diuretics, ACEIs). Congestive Heart Failure
Cardiac Glycosides in CHF Digoxin (Lanoxin) and digitoxin (Crystodigin®) are the only ones approved in the US. Cardiac glycosides have lipophilic (steroid nucleus) and hydrophilic (sugars, lactone, hydroxyls) portions. Both agents have good oral absorption rates however 10% of the population has decreased oral absorption of digoxin due to metabolic activity of enteric bacteria.
They have wide distribution through the body with times higher levels in the heart, kidneys and liver as compared to plasma. Digoxin and its metabolites are primarily eliminated in the kidneys, while digitoxin is extensively metabolized in the liver and eliminated in the bile. Digitoxin can undergo enterohepatic circulation. Digoxin may be safer in pts. with failure. Digitoxin may be safer in pts. with failure Cardiac Glycosides in CHF
Pharmacodynamics of cardiac glycosides Cardiac glycosides inhibit the plasma membrane Na + /K + -ATPase pump that normally maintains the appropriate distribution of Na + and K + inside and outside the myocardial cell. During normal cardiac cell depolarization Na + enters the cell and K + moves to the outside. The actions of the Na + /K + -ATPase restores the normal ion gradients by carrying Na + out and bringing K + into the cell. Cardiac Glycosides in CHF
Pharmacodynamics of cardiac glycosides Cardiac Glycosides in CHF Inhibition of the ATPase leads to accumulation of Na + ions in the myocardial cells which triggers the Na + /Ca 2+ -exchanger to remove less Ca 2+ in exchange. Increased Ca 2+ levels in cells leads to increased actin-myosin interaction: increased contractility.
Systemic Effects of Cardiac Glycosides Increased cardiac contractility improves cardiac output to increase renal perfusion and decrease baroreceptor-mediated SNS activity. This results in improved urine production, decreased tissue and pulmonary edema and lowered TPR. Also decreases in HR seen. Exercise tolerance is improved. Digoxin has actions to sensitize baroreceptors to enhance parasympathetic nerve activity to decrease atrial rate and AV conduction. Cardiac Glycosides in CHF
Adverse effects: anorexia, nausea, vomiting, diarrhea, disorientation, hallucinations, visual disturbances (altered color perception, halos around lights), arrythmias. Low therapeutic index of these agents requires careful monitoring for toxicity; Digibind® may be used bind and remove cardiac glycosides from the blood. Interactions with other drugs: hypokalemia due to diuretic etc. can potentiate toxicity to cardiac glycoside – due to glycoside and K + competing for same binding site on the ATPase. Hypercalcemia (thiazides) causes increased Ca 2+ loading into cells – arrhythmias in digitalis pts. Cardiac Glycosides in CHF
Inamrinone (Inocor®), milrinone (Primacor®) Have actions to inhibit phosphodiesterase III isoforms in cardiac and vascular smooth muscle to cause cAMP accumulation. Phosphodiesterase Inhibitors
Enhanced PKA activation in vascular smooth muscle may decrease cytoplasmic Ca 2+ to cause vasodilation (decreased TPR). Enhanced PKA activity leads to increased Ca 2+ influx and release of Ca 2+ in myocardial cells: positive inotropic effect to increase C.O. Vascular smooth muscle Phosphodiesterase Inhibitors
These agents are only used parenterally in acute heart failure for brief periods of time, cardiac support. Adverse effects: nausea, vomiting, thrombocytopenia (less with milrinone) liver toxicity (less with milrinone), arrhythmias (less with inamrinone). adrenoceptor Agonists Dobutamine (Dobutrex®), dopamine -agonists improve myocardial contractility with decreased ventricular filling pressures. Also may cause tachycardia and increased myocardial oxygen consumption. Administered by infusion intermittently for advanced heart failure. Phosphodiesterase Inhibitors
Diuretics: decreased Na + /water retention to decrease blood volume which decreases edema and cardiac size; loop diuretics are usually administered. ACE inhibitors: decrease TPR (afterload), decrease Na + /water retention (preload), prevent the tissue remodeling that occurs in dilated cardiac myopathy. Vasodilators: hydralazine and nitrates may have beneficial effects with long-term therapy (decrease afterload and preload, respectively). Adjunctive Agents in CHF
Angiotensin Receptor Blockers: may prove to be beneficial when combined with a -blocker, ACE inhibitor or aldosterone antagonist. blocker therapy: 1 -selective antagonists (metaprolol) and - nonselective, 1 -selective carvedilol appear to have beneficial effects on improving cardiac left ventricular ejection fraction (cardiac contractility) with prolonged therapy. Adjunctive Agents in CHF
Nesiritide (Natrecor): Recombinant human brain naturetic peptide (BNP) approved to treat dyspnea due to CHF. BNP/ANP secreted by cardiac myocytes in response to stretch and counters the effects of angiotensin II and norepinephrine to produce vasodilation, naturesis and diuresis. Drug administered by i.v. infusion to decrease symptoms of congestion; dose-limiting factor would be low systolic blood pressure. Infusion produces a vasodilation. Adjunctive Agents in CHF