Hydralazine nitrate

ACE-I or ARB ACE-I or ARB in appropriate patients Beta-blockers in appropriate patients Rontine nse Dinretics for fluid retention ACE-I Beta-blocker In selected patients Aldosterone antagonist ARB DigitaUs Hydralazine/nitrates UsnaUy for palUation... 

Release of nitric oxide from drug or endothelium Nitroprusside, hydralazine, nitrates,1 histamine, acetylcholine... 

At Cynthia s pharmacy, patients with heart disease are usually on several medications for their heart disease a diuretic, a beta blocker, and an angiotensin-converting enzyme (ACE) inhibitor. Patients with more severe disease may also be on an aldosterone inhibitor such as spironolactone, digoxin, hydralazine nitrate, and/or an angiotensin-receptor blocker (ARB). Some patients are... 

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... 

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... 

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. 

Nitrates (e.g., ISDN) and hydralazine were combined originally in the treatment of HF because of their complementary hemodynamic actions. Nitrates are primarily venodilators, producing reductions in preload. Hydralazine is a direct vasodilator that acts predominantly on arterial smooth muscle to reduce systemic vascular resistance (SVR) and increase stroke volume and cardiac output. Evidence also suggests that the combination may provide additional benefits by interfering with the biochemical processes associated with HF progression. 

The combination of nitrates and hydralazine improves the composite endpoint of mortality, hospitalizations for HF, and quality of life in African Americans who receive standard therapy. A fixed-dose combination product is available that contains ISDN 20 mg and hydralazine 37.5 mg (BiDil). Practice guidelines recommend adding ISDN and hydralazine as part of standard therapy in African Americans with moderately severe to severe HF. The combination may also be reasonable for patients of other ethnicities with persistent symptoms despite optimized therapy with an ACE inhibitor (or ARB) and /Tblocker. The combination is also appropriate as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or possibly hypotension. 

Modras (51) reported spot test reactions to differentiate hydralazine from closely related drugs. Reagents used were aqueous copper (I) chloride, aqueous ammonium molybdate, iodine in potassium iodide solution, aqueous cobalt (II) nitrate, alcoholic ninhydrin, and alcoholic bromophenol blue. The tests were performed on paper or on Silica Gel G. 

Soliman and Belal investigated argentimetric (67,68) and mercurimetric (69) methods. Hydralazine precipitates silver from ammoniacal silver nitrate solution. The silver is dissolved with hot nitric acid and titrated with ammonium thiocyanate solution. Alternatively, mercury is precipitated from alkaline potassium mercuric iodide solution. The precipitated mercury is dissolved by adding excess standard iodine solution. The excess iodine is back-titrated with sodium thiosulfate solution after acidifying with acetic acid. 

Hydralazine (Apresoline/ Others) [Antihypertensive/ Vasodilator] Uses Mod-severe HTN CHF (w/ Isordil) Action Peripheral vasodilator Dose Adults. Initial 10 mg PO qid, T to 25 mg qid 300 mg/d max Peds. 0.75-3 mg/kg/24 h POq6—12h -i in renal impair V CBC ANA before Caution [C, +] -1- Hqjatic Fxn CAD T tox w/ MAOI, indomethacin, BBs Contra Dissecting aortic aneurysm, mitral valveAheumatic heart Dz Disp Tabs, inj SE SLE-like synd w/ chronic high doses SVT following IM route, p ipheral neuropathy Interactions T Effects W/ antih5 pertensives, diazoxide, diuretics, MAOIs, nitrates. 

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... 

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. 

Sodium nitroprusside (SNP) is both a venous and an arterial vasodilator. An important part of its vasodilator action is caused by the release of nitric oxide (NO), similarly as for the organic nitrates. SNP can only be administered via the intravenous route. It is a rapidly and short acting vasodilator. It has been used in the treatment of hypertensive emergencies and in the management of myocardial ischaemia. In spite of its vasodilator action it hardly influences heart rate, in contrast to hydralazine and minoxidil. The dosage of SNP should not be higher than 3 pg/kg/min within 48 h, in order to avoid the rise of cyanide ions and thiocyanate in the blood. 

Vasodilators can be considered as symptom relievers in this stage. However they are not the main agents for HF treatment because a reduction of mortality has not been established. A combination of hydralazine and a nitrate might be a reasonable strategy if HF symptoms are persistent despite ACE-I and -blocker combination therapy. If this ACE-I and -blocker combination is contra-indicated or is not tolerated. Vasodilators can be used without them. 

Captopril (Capoten) was the original prototype product, and it was administered three times a day. A once-a-day preparation was subsequently patented and marketed. Prospective multicenter double-blind placebo-controlled clinical trials have repeatedly demonstrated an early and persistent survival benefit with ACE inhibitors in CHE patients. ACE inhibitors were found superior to hydralazine and nitrates in a direct comparison. ACE inhibitors are now clearly the agents of first choice in the pharmacological management of CHE There are also a number of additional reasons to use ACE inhibitors. The HOPE trial and other studies demonstrated additional survival and renal protective benefits of ACE inhibition in diabetic and/or hypertensive patients long before they develop CHE. 

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. 

B. Prazosin has been shown not to be as effective as the combination of hydralazine and nitrates. 

Carvedilol may be used in patients unable to tolerate an ACE inhibitor. Carvedilol may be used in patients who are not receiving digitalis, hydralazine and nitrate therapy. 

This class of drugs includes the oral vasodilators, hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension the parenteral vasodilators, nitroprusside, diazoxide, and fenoldopam, which are used to treat hypertensive emergencies the calcium channel blockers, which are used in both circumstances and the nitrates, which are used mainly in angina (Table 11-3). 

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. 

Arteriolar dilators Probably increases NO synthesis in endothelium (see Chapter 11) Reduces blood pressure and afterload results in increased cardiac output Hydralazine plus nitrates have reduced mortality Oral 8-12 h duration Toxicity Tachycardia, fluid retention, lupuslike syndrome... 

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... 

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). 

Hydralazine causes direct relaxation of arteriolar smooth muscle. The arteriolar vasodilatation produced by hydralazine requires an intact endothelium. Therefore, one proposed mechanism of action is that hydralazine liberates nitric oxide from the endothelium (similar to the nitrates), which in turn increases cGMP to ultimately prevent the phosphorylation of myosin light chain (which is required for smooth muscle contraction) resulting in arteriolar vasorelaxation. 

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). 

Vasodilators such as nitrates, ACE inhibitors, and hydralazine have been discussed previously. These agents are used to decrease arteriolar (afterload) or venous resistance (preload). A discussion of cardiodynamics is beyond the scope of this book. However, by decreasing preload and afterload these drugs decrease the work that the heart has to do to increase cardiac output this improves perfusion pressure on the arterial side and venous return on the venous side, which contributes to reduced peripheral edema. 

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