Hydralazine failure

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

Taylor AL, Ziesche S, Yancy C, Carson P, D Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn IN African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004 Nov ll 351(20) 2049-57. 

Direct Vasodilators Isosorbide dinitrate 20 mg and hydralazine 37.5 (BiDil) 1-2 tablets three times a day Minoxidil (Loniten) Hydralazine Heart failure (isosorbide dinitrate + hydralazine in African-Americans) A-HeFT66 Edema (minoxidil) Tachycardia Lupus-like syndrome (hydralazine) ... 

Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with P-blockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including P-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed.66 The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients.49 For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include P-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure.2,49... 

Hydralazine may cause a dose-related, reversible lupus-like syndrome, which is more common in slow acetylators. Lupus-like reactions can usually be avoided by using total daily doses of less than 200 mg. Other hydralazine side effects include dermatitis, drug fever, peripheral neuropathy, hepatitis, and vascular headaches. For these reasons, hydralazine has limited usefulness in the treatment of hypertension. However, it may be useful in patients with severe chronic kidney disease and in kidney failure. 

Minoxidil is a more potent vasodilator than hydralazine, and the compensatory increases in heart rate, cardiac output, renin release, and sodium retention are more dramatic. Severe sodium and water retention may precipitate congestive heart failure. Minoxidil also causes reversible hyper-... 

Unlabeled uses Hydralazine in doses up to 800 mg 3 times/day has been effective in reducing afterload in the treatment of congestive heart failure (CHF), severe aortic insufficiency, and after valve replacement. 

Cohn IN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure, [see comment]. N. Engl. J. Med. 1991 325 303-10. 

Hydralazine and dihydralazine are predominantly arterial vasodilators which cause a reduction in peripheral vascular resistance but also reflex tachycardia and fluid retention. They were used in the treatment of hypertension, in combination with a -blocker and a diuretic. Long-term use of these compounds may cause a condition resembling lupus erythematodes with arthrosis, dermatitis and LE-cells in the blood. This risk is enhanced in women and in patients with a slow acetylator pattern. When combined with the venous vasodilator isosorbide (an organic nitrate) hydralazine was shown to be mildly beneficial in patients with congestive heart failure (V-HEFT I Study). Hydralazine and dihydralazine have been replaced by other therapeutics, both in hypertension treatment and in the management of heart failure. 

ACE-inhibition will cause a reduction of cardiac afterload and preload in patients with heart failure. In addition, the ACE-inhibitors exert a favourable effect on the neuro-endocrine activation process associated with chronic heart failure. They are more effective than classic vasodilators such as hydralazine and isosorbide, which do not influence these neuroendocrine mechanisms in a favourable manner. 

The combination of hydralazine and nitrates has been shown to improve survival in patients of heart failure. All of the following statements about this combination are true except ... 

D) The VA cooperative study was a landmark trial demonstrating the beneficial effect of hydralazine and nitrate combination in patients of heart failure. 

The plasma half-life of hydralazine may be increased fourfold or fivefold in patients with renal failure. If renal failure is present, therefore, both the antihypertensive and toxic effects of hydralazine may be enhanced. Since A-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme A-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) wih result in higher plasma levels of hydralazine therefore, the drug s therapeutic or toxic effects may be increased. 

Most side effects associated with hydralazine administration are due to vasodilation and the reflex hemodynamic changes that occur in response to vasodilation. These side effects include headache, flushing, nasal congestion, tachycardia, and palpitations. More serious manifestations include myocardial ischemia and heart failure. These untoward effects of hydralazine are greatly attenuated when the drug is administered in conjunction with a (3-blocker. 

Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combination of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients. 

Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine. 

Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart. 

Taylor AL et al Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004 351 2049. [PMID 15533851]... 

Salt and water retention mediated by secondary hyperaldosteronism can complicate hydralazine treatment, leading to weight gain and peripheral edema, loss of blood pressure control, and rarely cardiac failure (SED-8, 474). 

Elkayam U, Bitar F. Effects of nitrates and hydralazine in heart failure clinical evidence before the African American heart failure trial. AmJ Cardiol. 2005 96 37i-43i. 

Nitrates and hydralazine have been used in patients with congestive heart failure. An angiotensinconverting enzyme inhibitor such as lisinopril increases the left ventricular ejection fraction in... 

Clinical benefits and effects on mortality and hospitalization Whether used alone or in combination, hydralazine and isosorbide dinitrate decrease the preload and afterload, decrease mitral regurgitation, improve cardiac output, increase exercise capacity, modestly increase LVEF and prolong survival in patients with HF (63,64). V-Heart Failure Trial (HeFT) II (64) showed that enalapril had a major benefit on survival when compared with the combination of hydralazine-isosorbide dinitrate with enalapril in patients with predominantly NYHA class ll-lll. The African Americans in Heart Failure Trial (A-HeFT) (65) showed a beneficial effect of adding vasodilator therapy to African-American patients already treated with ACE inhibitors, (3 blockers, and spironolactone. There are no results with the same strategy in other patient groups. 

Bauer JA, Fung HL, Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure, Circulation 1991 84 35-39,... 

The CONSENSUS study was performed in 253 patients with severe congestive heart failure. They were randomized to receive either placebo (n = 126) or enalapril (n = 127), from 2.5 mg bid to 20 mg bid with a follow-up period that averaged 182 days. By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group (p =. 003) (313). Later, enalapril was shown to be superior to hydralazine-isosorbide dinitrate (314, 315). 

Examples of specific drugs used in the treatment of chronic heart failure include digitalis glycosides (e.g., digoxin, positive inotropic agent), diuretics (hydrochlortiazide and furosemide), and vasodilators (nitrates such as nitroglycerin, ACE inhibitors, such as captopril, and hydralazine). 

Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance arterial dilators reduce systemic arteriolar resistance and decrease afterload. Nitrates (see p. 175) are commonly employed venous dilators for patients with congestive heart failure. If the patient is intolerant of ACE inhibitors, the combination of hydralazine and isosorbide dinitrate is most commonly used. Amlodipine and felodipine (see p. 188) have less negative inotropic effect than other calcium channel blockers, and seem to decrease sympathetic nervous activity. 

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