MANAGEMENT OF CHRONIC HEART FAILURE

STEPS IN THE TREATMENT OF CHRONIC HEART FAILURE

Reduce workload of the heart(a) Limit activity level(b) Reduce weight.(c) Control hypertension.

• Restrict sodium.• Restrict water (rarely required).• Give diuretics.• Give ACE inhibitors or angiotensin receptor

blocker.

• Give digitalis if systolic dysfunction with third heart sound or artial fibrillation is present.

• Give beta blockers to patients with stable class II -IV heart failure.

• Give vasodilators.

SODIUM REMOVAL

• Sodium removal is important step----by dietary salt restriction or diuretic….especially if oedema is present.

• In mild failure, it is reasonable to start with a thiazide diuretic, switching to more powerful agents as required. Sodium loss causes secondary loss of potassium, which is particularly hazardous if the patient is to be given digitalis.

• Hypokalaemia can be treated with potassium supplementation or through the addition of a potassium sparing-diuretic such as spironolactone

ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

• In patient with left ventricular dysfunction but no oedema, ACE inhibitors should be used first. Several large studies have compared ACE inhibitors with other traditional therapies for chronic heart failure. The results show clearly that ACE inhibitors are superior to both placebo and to vasodilators and must be considered, along with diuretics, as first-line therapy for chronic failure.

• However, ACE inhibitors cannot replace digoxin in patients already receiving that drug because patients withdrawn from the cardiac glycoside while on ACE inhibitors therapy deteriorate.

• Additional studies suggest that ACE inhibitors are also valuable in asymptomatic patients with ventricular dysfunction. By reducing pre-load and after-load, these drugs appear to slow the rate of ventricular dilatation and thus delay the onset of clinical heart failure. Thus, ACE inhibitors are beneficial in all subsets of patients, from those who are asymptomatic to those in severe chronic failure.

• It appears that all ACE inhibitors tested to date have beneficial effects in patients with heart failure.

• Recent studies have documented beneficial effects with enalapril, captopril, lisinopril, quinapril and ramipril..The angiotensin 11 receptors antagonists (e.g. losartan, valsartan, etc) produce beneficial hemodynamic effects similar to those of the ACE inhibitors. However, large clinical trials suggest that the angiotensin receptors blockers should be used in patients who are intolerant of ACE inhibitors (usually because of cough).

VASODILATORS • Vasodilators drugs can be divided into selective

arteriolar dilators, venous dilators, drugs with non-selective vasodilatory effects. For this purpose, the ACE inhibitors may be considered non-selective arteriolar and venous dilators. The choice of agents should be based on the patient’s signs and symptoms and haemodynamic measurements. Thus, in patients with high filling pressures in whom the principal symptoms is dyspnoea, venous dilators such as long-acting nitrates will be most helpful in reducing filing pressure and the symptoms of pulmonary congestion.

• In patients whom fatigue due to low ventricular output is primary symptom, an arteriolar dilator such as hydralazine may be helpful in increasing forward cardiac output.

• In most patients with severe chronic failure that responds poorly to other therapy, the problem usually involves both elevated filling pressures and reduced cardiac output. In these circumstances, dilation of both arterioles and veins is required. In one trial, combined therapy with hydralazine (arteriolar dilation) and isosorbide dinitrate (venous dilation) prolonged life more than placebo in patients already receiving digitalis and diuretics.

BETA-BLOCKERS AND CALCIUM CHANNEL BLOCKERS

• Many trials have evaluated the potential for beta-blocker therapy in patients with heart failure. The rationale is based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart failure patients contribute to the downward course of heart failure patients. However, such therapy must be initiated very cautiously at low doses, since acutely blocking the supportive effects of catecholamines can worsen heart failure.

• Several months of therapy may be required before improvement is noted, this is usually consists of a slight rise in ejection fraction, slower heart rate, and reduction in symptoms. As noted above, bisoprolol, carvedilol, metoprolol have been shown to reduce mortality.

• The calcium-blocking drugs appear to have no role in the treatment of patients with heart failure. Their depressant effects on the heart may worsen heart failure.

DIGITALIS

• Digoxin is indicated in patients with heart failure and artrial fibrillation. It is also most helpful in patients with a dilated heart and third heart sound.

• It usually given after ACE inhibitors.• Only about 50% of patients with normal sinus

rhythm have documented relief of heart failure from digitalis.

• Because it has a moderate but persistent positive inotropic effect, digitalis can, in theory, reverse the signs and symptoms of heart failure. In appropriate patient, digitalis increases the stroke work and cardiac output.

• The increased output (and possibly a direct action resetting the sensitivity of baroceptors) eliminates the stimuli evoking increased sympathetic outflow, and both heart rate and vascular tone diminish.

• With decreased end-diastolic fiber tension (the result of increased systolic ejection and decreased filling pressure), heart size and oxygen demand decrease.

• Finally, increased renal blood flow improves glomerular filtration and reduces aldosterone-driven sodium reabsorption. Thus, oedema fluid can be excreted, further reduction ventricular pre-load and danger of pulmonary oedema.

• Digitalis reduces hospitalization and death from progressive heart failure at the expense of an increase in sudden death.

• It is important to note that the mortality rate was reduced in patients with serum digoxin concentration of 1ng/mL or less but increased in those with digoxin levels greater than 1.5ng/mL.

CLINICAL USE OF DIGOXIN DIGOXIN

Therapeutic plasma concentration

0.5- 1.5 ng/mL

Toxic plasma concentration

> 2ng/mL

Daily dose (slow loading or maintenance)

0.25 (0.125-0.5) mg

Rapid digitalizing dose (rarely used)

0.5-0.75 mg every 8 hours for three doses

• These values are appropriate for adults with normal renal and hepatic function.

DRUGS WITH POSITIVE INOTROPIC EFFECTS

• Drugs that inhibit phosphodiesterases, the family of enzymes that inactivate cAMP and cGMP, have long been used in the therapy of heart failure.

• The bipyridines inamrinone and milrinone are the most successful of these agents found to date.

• Levosimendan, an investigational drug that appears to inhibit phosphodiesterase and cause some vasodilatation in addition to its inotropic effects.

BIPYRIDINES

• Inamrinone (previously called amrinone) and milrinone are bipyridine compounds that inhibit phosphodiesterase. They are active orally as well as parenterally but only available in parenteral forms.

• • They have elimination half-lives of 3 to6

hours, with 10 to 40% being excreted in the urine.

PHARMACODYNAMICS

• The bipyridines increase myocardial contractility by increasing calcium influx in the heart during the action potential.

• They also important vasodilating effect.• These drugs are relatively selective for

phosphodiesterase isoenzyme 3, a form found in cardiac and smooth muscle.

• Inhibition of this enzyme results in an increase in cAMP and increase in contractility and vasodilatation.

• The toxicity of inamrinone includes nausea and vomiting; arrhythmias, thrombocytopenia and liver enzyme changes.

• Milrinone appears less likely to cause bone marrow and liver toxicity than inamrinone, but it does cause arrhythmias.

• Inamrinone and milrinone are now used only intravenously and only for acute heart failure or exacerbation of chronic heart failure.

BETA ADRENOCEPTOR STIMULANTS

• The selective β1 agonist that has been most widely used in patients with heart failure is dobutamine. This drug produces an increase in cardiac output together with a decrease in ventricular filling pressure

• Some tachycardia and increase in myocardial oxygen consumption have been reported.

• The potential for producing angina or arrhythmias in patients with coronary artery disease must be considered, as well as the tachyphylaxis that accompanies the use of any β stimulant.

• Dopamine has also been used in acute heart failure and be particularly helpful if there is need to raise blood pressure

DIURETICS

• Their major mechanism of action in heart failure is to reduce venous pressure and ventricular pre-load. These reductions have two useful effects: reduction of oedema and its symptoms and reduction of cardiac size, which leads to improved pump efficiency.

VASODILATORS

• The vasodilators are effective in acute heart failure because they provide a reduction in pre-load (through venodilation), or reduction in after load (through arterial dilatation), or both.

• Some evidence suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart.

• A synthetic form of endogenous peptide brain natriuretic peptide (BNP) has recently been approved for use in acute cardiac failure as nesiritide.

• This recombinant product increases cGMP in smooth muscle cells and effectively reduces venous and arteriolar tone in experimental preparations. It also causes diuresis.

• The peptide has a short half-life of about 18 minutes and is administered as a bolus intravenous dose followed by continuous infusion.

• Excessive hypotension is the most common adverse effect.

• Bosentan, an orally active competitive inhibitor of endothelin, has been shown to have some benefit in experimental animal models heart failure, but results in human trials have not been impressive.

• This drug is approved for use in pulmonary hypertension. It has significant teratogenic and hepatotoxic effects.

BETA ADRENOCEPTOR BLOCKERS

• Most patients with chronic heart failure respond favorably to certain beta-blockers in spite of the fact that these drugs can precipitate acute decompensation of cardiac function.

• Studies with bisoprolol, carvedilol, metoprolol showed a reduction in mortality in patients with stable severe heart failure but this effect was not observed with another beta-blocker, bucindolol,

• The full understanding of the beneficial action of beta blockade is lacking, but suggested mechanism include attenuation of the adverse effects of high concentration of catecholamines (including apoptosis), up-regulation of beta-receptors, decrease heart rate, and reduced remodeling through inhibition of mitogenic activity of catecholamines.