Heart failure isosorbide dinitrate

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) ... 

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. 

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. 

Isosorbide is available in two forms, isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISDN). ISDN is rapidly metabolised in the liver to the active mononitrate. ISDN is only available in oral form. An intravenous formulation of ISDN is available, but is only used for the treatment of acute heart failure. 

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]... 

Nitroglycerine Isosorbide dinitrate Treatment of angina pectoris and second-line therapy in congestive heart failure... 

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. 

Elkayam U, AminJ, Mehra A, VasquezJ, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure, Circulation 1990 82 1954-1961. 

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). 

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. 

Isosorbide dinitrate (Cedocard) (t20 min) is used for prophylaxis of angina pectoris and for congestive heart failure (tabs sublingual, and to swallow). An i.v. formulation 500 micrograms/ml (Isoket) is available for use in left ventricular failure and unstable angina. 

In eight patients with chronic heart failure taking digoxin 0.25 mg/day, isosorbide dinitrate 10 mg tds caused only a small increase in (15%) and had no effect on the mean steady-state serum concentration or AUC (241). 

Mahgoub AA, El-Medany AH, Abdnlatif AS. A comparison between the effects of diltiazem and isosorbide dinitrate on digoxin pharmacodynamics and kinetics in the treatment of patients with chronic ischemic heart failure. Saudi Med J 2002 23(6) 725-31. 

Nitrates are the drugs of choice in patients with left ventricular impairment, in whom they are of benefit when used in combination with hydralazine (3), and they should be used in preference to the calcium antagonists, which cause deterioration in myocardial function by an as yet unknown mechanism (4). In black patients with congestive heart failure taking ACE inhibitors and beta-block-ers, a combination of isosorbide dinitrate plus hydralazine significantly reduced total mortality (5). 

The combination of isosorbide dinitrate with hydralazine is safe in systolic heart failure. Only headache and palpitation necessitated drug withdrawal and were more common than with enalapril (90). Headache and dizziness were more common with isosorbide dinitrate plus hydralazine than with placebo in patients taking ACE inhibitors and beta-blockers (5). 

Severe postural hypotension has been observed in patients given both isosorbide dinitrate and hydralazine for chronic heart failure (26), although this has not been a problem in large studies (90). 

Massie B, Kramer B, Haughom F. Postural hypotension and tachycardia during hydralazine-isosorbide dinitrate therapy for chronic heart failure. Circulatiou 1981 63(3) 658-64. 

One side effect unique to hydralazine is a dose-dependent drug-induced lupus-like syndrome. Hydralazine is eliminated by hepatic A-acetyltransferase. This enzyme displays genetic polymorphism, and slow acetylators are especially prone to develop drug-induced lupus with hydralazine. This syndrome is more common in women and is reversible on discontinuation. Drug-induced lupus may be avoided by using less than 200 mg hydralazine daily. Other side effects of hydralazine include dermatitis, drug fever, peripheral neuropathy, hepatitis, and vascular headaches. For these reasons, hydralazine has limited usefulness in the treatment of hypertension. However, it is still used with isosorbide dinitrate in patients with heart failure (especially African-Americans) and is useful in patients with severe chronic kidney disease and kidney failure. 

The beneficial effect of ACE inhibitors on mortality has been documented conclusively, with numerous trials showing a 20% to 30% relative reduction in mortality with ACE inhibitor therapy compared with placebo. A long-term (12-year) follow-up of the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials demonstrated sustained survival benefits in patients treated with enalapril. In addition to improving survival, ACE inhibitors also reduce the combined risk of death or hospitalization, slow the progression of heart failure, and reduce the rates of reinfarction.The benefits of ACE inhibitor therapy are independent of the etiology of heart failure (ischemic versus nonischemic) and are observed in patients with mild, moderate, or severe symptoms. ACE inhibitors clearly are superior to vasodilator therapy with hydralazine-isosorbide dinitrate. ... 

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