Hydralazine and

In the cinnoline series only derivatives of 3- or 4-aminocinnoline have been found to exhibit biological activity. Some hydrazinophthalazines, in particular 1-hydrazino-(Hydralazin) and 1,4-dihydrazino-phthalazine (Dihydralazin), are excellent hypotensive and antihypertensive agents. 

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. 

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... 

Hydralazine and minoxidil cause direct arteriolar smooth muscle relaxation. Compensatory activation of baroreceptor reflexes results in increased sympathetic outflow from the vasomotor center, producing an increase in heart rate, cardiac output, and renin release. Consequently, the hypotensive effectiveness of direct vasodilators diminishes over time unless the patient is also taking a sympathetic inhibitor and a diuretic. 

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-... 

The ability of hydralazine and similar hydrazino compounds to reduce blood pressure was reported by Gross et al (1) in 1950. Methods of synthesis were published by Druey and Ringier (2) in 1951, along with typical reactions displayed by the compound, including several reactions which later became the bases for analysis of hydralazine and its metabolites. The drug has been widely used for treatment of hypertension, and papers on its properties and methods for its determination have been published in many languages. 

Polarographic studies of hydralazine and related compounds were reported by Giovanoli-Jakubezak et al (72) and by Modras (73) The reduction proceeds in two 2-electron stages with the formation of the tetrahydro derivative. Hydralazine could be determined in the... 

The same procedure, or modifications of it, was used by Zak et al (80), Talseth (42,82,82,83), and Haegele et al (46) for metabolic studies. Zak et al (80) point out that hydrolysis of conjugates of the drug may cause analytical results on biological samples to be variable, depending on the acid concentration during derivatization, and that selective analysis for unchanged hydralazine and acid-labile metabolites can be carried out by suitable adjustment of the acid concentration. 

FIGURE 4.88 Oxidation of the hydrazine (hydralazine) and the hydrazide (isoniazid) leads to the loss of nitrogen. 

Autoantibodies to red blood cells and autoimmune hemolytic anemia have been observed in patients treated with numerous drugs, including procainamide, chlor-propaminde, captopril, cefalexin, penicillin, and methyldopa (Logue et al., 1970 Kleinman et al., 1984). Hydralazine- and procainamide-induced autoantibodies may also result in SLE. Approximately 20% of patients administered methyldopa for several weeks for the treatment of essential hypertension developed a dose-related titer and incidence of autoantibodies to erythrocytes, 1% of which presented with hemolytic anemia. Methlydopa does not appear to act as a hapten but appears to act by modifying erythrocyte surface antigens. IgG autoantibodies then develop against the modified erythrocytes. 

Crush 3 methyldopa tablets and weigh out 2.4 g. Crush 2 tablets of hydralazine and weigh out 0.4 g. Add 0.45 g of lactose, and mix geometrically. Fill 10 capsules appropriately. Capsule size 1 is needed. 

DJ-1461 (XVIII), a hydrazone of hydralazine, is claimed to cause considerably less tachycardia (8). To date it has not been shown that any of these compounds has a significant clinical advantage over hydralazine and therefore, over the last twenty-five years, slight modifications of the hydralazine structure have not produced a better drug of this type. 

Because of their reflex cardiac effect, vasodilators, if used alone in the treatment of hypertension, have not been a successful therapeutic tool. However, the reflex tachycardia and increase in cardiac output can be effectively blocked by the therapeutic association with a sympathetic blocker guanethidine, reserpine, methyldopa, or clonidine. More specifically, blockade of the cardiac beta-adrenergic receptors will also prevent the cardiac response to hydralazine. Thus, the therapeutic combination of hydralazine and propranolol can be successfully employed for effective blood pressure reduction(11). 

Segura-Pacheco, B., Trejo-Becerril, C., Perez-Cardenas, E., Taja-Chayeb, L., Mariscal, I., Chavez, A., Acuna, C., Salazar, A.M., Lizano, M. and Duenas-Gonzalez, A. (2003) Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clinical Cancer Research, 9, 1596-1603. 

The drugs of this class (hydralazine and sodium nitroprusside) lower arterial blood pressure primarily by direct spasmolytic action on smooth musculature of arterioles, which leads to a reduction of resistance of peripheral vessels by causing dilation. Diastolic pressure is usually lowered more than the systolic pressure. 

Pharmacokinetics Hydralazine is rapidly absorbed after oral use. Half-life is 3 to 7 hours. Protein binding is 87%, and bioavailability is 30% to 50%. Plasma levels vary widely among individuals. Peak plasma concentrations occur 1 to 2 hours after ingestion duration of action is 6 to 12 hours. Hypotensive effects are seen 10 to 20 minutes after parenteral use and last 2 to 4 hours. Slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism it is excreted in the urine as active drug (12% to 14%) and metabolites. 

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. 

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. 

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. 

This chapter describes four vasodilators in detail. Two of these agents, hydralazine and minoxidil, are effective orally and are used for the chronic treatment of primary hypertension. The other two drugs, diazoxide and sodium nitroprusside, are effective only when administered intravenously. They are generally used in the treatment of hypertensive emergencies or during surgery. 

Minoxidil (Loniten) is an orally effective vasodilator. It is more potent and longer acting than hydralazine and does not accumulate significantly in patients with renal insufficiency. It depends on in vivo metabolism by hepatic enzymes to produce an active metabolite, minoxidil sulfate. Minoxidil sulfate activates potassium channels, resulting in hyperpolarization of vascular smooth muscle and relaxation of the blood vessel. 

The hemodynamic effects of diazoxide are similar to those of hydralazine and minoxidil. It produces direct relaxation of arteriolar smooth muscle with little effect on capacitance beds. Since it does not impair cardiovascular reflexes, orthostasis is not a problem. Its administration is, however, associated with a reflex increase in cardiac output that partially counters its antihypertensive effects. Propranolol and other -blockers potentiate the vasodilating properties of the drug. Diazoxide has no direct action on the heart. Although renal blood flow and glomerular filtration may fall transiently, they generally return to predrug levels within an hour. 

C. The vasodilation caused by bradykinin, histamine, hydralazine, and acetylcholine depends in part upon nitric oxide release from the endothelium. Minoxidil activates K+ channels, which results in vascular smooth muscle hyperpolarization and thereby relaxation. 

Beta-blockers interact with a large number of other medications. The combination of beta-blockers with calcium antagonists should be avoided, given the risk for hypotension and cardiac arrhythmias. Cimetidine, hydralazine, and alcohol all increase blood levels of beta-blockers, whereas rifampicin decreases their concentrations. Beta-blockers may increase blood levels of phenothiazines and other neuroleptics, clonidine, phen-ytoin, anesthetics, lidocaine, epinephrine, monoamine oxidase inhibitors and other antidepressants, benzodiazepines, and thyroxine. Beta-blockers decrease the effects of insulin and oral hypoglycemic agents. Smoking, oral contraceptives, carbamazepine, and nonsteroidal anti-inflammatory analgesics decrease the effects of beta-blockers (Coffey, 1990). 

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. 

---