Hydralazine-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) ... 

Isosorbide Dinitrate Hydralazine (BiDil) [Antianginal, Antihypertensive/Vasodilator, Nitrate] Uses HF in African Amer-icans improve survival functional status, prolong time between hospitalizations Action Relaxes vascular smooth muscle peripheral vasodilator Dose Initially 1 tab tid PO (if not tol ated reduce to 1/2 tab tid), titrate >3-5 d as tolerated Max 2 tabs tid Caution [C, /-] recent MI, syncope, hypovolemia, hypotension, hep impair Contra For children, concomitant use w/ PDE5 inhibitors (sildenafil) Disp Tabs SE HA, dizziness, orthostatic hypotension, sinusitis, GI distress, tach, paresthesia, amblyopia Interactions t Risk of severe hypotension W/ antihypertensives, ASA, CCBs, MAOIs, phenothiazides, sildenafil, tadalafil, vardenafil, EtOH X pressor response Wf i -1- effects W7 NSAIDs EMS Use ASA, antihypertensives and CCBs w/ caution, may t hypotension concurrent Viagra-type drug use can lead to profound hypotension concurrent EtOH use can t effects OD May cause N/V, profound hypotension, skin flushing, HA from ICP, bradycardia, confusion, and circulatory collapse activated charcoal may be effective, epi use is contraindicated... 

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. 

Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for angiotensin II antagonism in those unable to tolerate an ACE inhibitor or ARB, or as add-on therapy in African-Americans. 

The nitrate-hydralazine combination was first shown to improve survival compared to placebo.27 Subsequently, the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg, both given four times daily, was compared to the ACE inhibitor enalapril.28 Enalapril produced a 28% greater decrease in mortality. Therefore, the combination is considered a third-line vasodilatory option for patients truly intolerant of ACE inhibitors and ARBs. 

More recently, the value of adding the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg three times daily to therapy including ACE inhibitors, P-blockers, digoxin, and diuretics was evaluated in a prospective, randomized trial26 The study enrolled only African-American patients and demonstrated a significant reduction in mortality, as well as first hospitalization for HF. Quality-of-life scores were also improved over placebo. Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for angiotensin II antagonism... 

Develop a medication regimen to slow the progression of HF with the use of neurohormonal blockers such as vasodilators (ACE inhibitors, ARBs, or hydralazine/ isosorbide dinitrate), P-blockers, and aldosterone antagonists. Utilize digoxin if the patient remains symptomatic despite optimization of the above therapies. 

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. 

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. 

Hydralazine plus isosorbide dinitrate fixed dose (BiDil)... 

Oral 37.5 mg hydralazine + 20 mg isosorbide dinitrate tablets Inamrinone (generic)... 

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

Pathophysiology Hydralazine and isosorbide dinitrate are effective vasodilators which may interfere with the biochemical and molecular mechanisms responsible for the progression of HF Combined use may interfere with the development of nitrate tolerance (62). 

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. 

ACC/AHA guidelines (II), the combined use of hydralazine-isosorbide dinitrate may be considered as a therapeutic option in patients with reduced LV dysfunction already taking ACE inhibitors and (3 blockers and with persistent symptoms. Despite the lack of data about this vasodilator combination in patients who are intolerant of ACE inhibitors, the combined use of hydralazine and isosorbide dinitrate may be considered as an additive therapeutic option in such patients, However, compliance with this combination has generally been poor because of the large number of tablets required and the high incidence of adverse reactions. 

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). 

Hydralazine solutions reacts with metals, hence injections must be prepared using nonmetal filters and doses must be withdrawn prior to administration.113114 Percussion or excessive heat may cause an explosion of undiluted isosorbide dinitrate and must be handled carefully. 

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. 

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). 

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