Hydralazine hypertension

Spokas E G, Folco G, Quilley J et al 1983 Endothelial mechanism in the vascular action of hydralazine. Hypertension 5 1107-1111... 

Hydralazine Hypertension Hypotension, tachycardia, flushing, headache... 

Pinacidil (Pindac) More potent than hydralazine. Hypertension. Fewer side effects than minoxidil. May cause dizziness, headache, or edema. 

Lin M-S, McNay JL, Shepherd AMM, Musgrave GE, Keeton TK. Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine. Hypertension (1983) 5,257-63. 

A third study (85) enrolled 7825 hypertensive patients (55% males and 45% females) having diastoHc blood pressures (DBP) of 99—104 mm Hg (13—14 Pa) there were no placebo controls. Forty-six percent of the patients were assigned to SC antihypertensive dmg therapy, ie, step 1, chlorthaUdone step 2, reserpine [50-55-5] or methyldopa [555-30-6], and step 3, hydralazine [86-54-4]. Fifty-four percent of the patients were assigned to the usual care (UC) sources in the community. Significant reductions in DBP and in cardiovascular and noncardiovascular deaths were noted in both groups. In the SC group, deaths from ischemic heart disease increased 9%, and deaths from coronary heart disease (CHD) and acute myocardial infarctions were reduced 20 and 46%, respectively. 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

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 answer is d. (Hardman, pp 794-795.) Hydralazine, minoxidil, diazoxide, and sodium nitroprusside are all directly acting vasodilators used to treat hypertension. Because hydralazine, minoxidil, nifedipine, and diazoxide relax arteriolar smooth muscle more than smooth muscle in venules, the effect on venous capacitance is negligible. Sodium nitroprusside, which affects both arterioles and venules, does not increase cardiac output, a feature that enhances the utility of sodium nitroprusside in the management of hypertensive crisis associated with MI. 

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. 

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. 

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. 

Perry, H.M., Tane, M. and Camody, S. (1970). Relationship of acetyl transferase activity to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine. J. Lab. Clin. Med. 76 114-125. 

Indeed, hydralazine has been effectively used for the management of hypertension for over 20 years. The decrease in... 

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). 

Clinically, clonidine has shown great versatility effective in mild, moderate and severe hypertension. The major side effects are drowsiness and dry mouth. Clonidine can be effectively used in combination with a diuretic(32). In addition, a vasodilator (hydralazine) can be usefully added. The brady-cardiac effect of clonidine prevents the reflex tachycardia induced by the vasodilator. 

Pildralazine (65), when administered i.v. or orally, displays a high antihypertensive activity in conscious hypertensive animals (rats, dogs). The hypotensive effect, caused by oral doses of 0.1 mg/kg to 1 mg/kg, has been reported to last more than 24 h. The therapeutic index (LD50/ED25 rats oral administration) has been found to be 70-times higher than that of hydralazine due to both higher potency and reduced toxicity [197]. It has been concluded that (65), like hydralazine, acts on peripheral smooth muscle on specific receptors which are physiologically affected by ATP released from... 

By itself, hydralazine is used for hypertension however, it is not even the drug of choice for weak forms of this condition. Synonyms of this drug are apressin, hypatol, depressan, and others. 

Renal function impairment In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. Renal function may improve where control values were below normal prior to administration. Use with caution in patients with advanced renal damage. 

Pulmonary hypertension - Use hydralazine with caution in patients with pulmonary hypertension. Severe hypotension may result. Monitor carefully. 

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. 

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. 

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. 

Hydralazine is generally reserved for moderately hypertensive ambulatory patients whose blood pressure is not well controlled either by diuretics or by drugs that interfere with the sympathetic nervous system. It is almost always administered in combination with a diuretic (to prevent Na+ retention) and a p-blocker, such as propranolol (to attenuate the effects of reflex cardiac stimulation and hyperreninemia). The triple combination of a diuretic, -blocker, and hydralazine constitutes a unique hemodynamic approach to the treatment of hypertension, since three of the chief determinants of blood pressure are affected cardiac output (p-blocker). 

Although hydralazine is available for intravenous administration and has been used in the past for hypertensive emergencies, it is not generally employed for this purpose. The onset of action after intravenous injection is relatively slow, and its actions are somewhat unpredictable in comparison with those of several other vasodilators. 

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. 

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. 

Hydralazine Causes nitric oxide release Vasodilation reduce vascular resistance arterioles more sensitive than veins reflex tachycardia Hypertension minoxidil also used to treat hair loss Oral Toxicity Angina, tachycardia Hydralazine Lupus-like syndrome... 

The drug hydralazine is a vasodilator used for the treatment of hypertension. In a significant proportion of individuals, it causes a serious adverse effect, drug-induced systemic lupus erythematosus (SLE). This is a systemic kind of toxic effect, as there is no particular target organ or tissue. It is an example of immune-media ted toxicity that involves autoimmunity and shows a number of interesting features. 

The peripheral receptors activated by noradrenaline fall into at least two classes, a-receptors and /3-receptors, which differ in their function and in their response to drugs. The a-receptors cause constriction of blood vessels and compounds used to block them include indoramin (216), prazosin (217) and phentolamine (218). Another imidazoline, tolazoline (2-benzyl-2-imidazoline), is a useful vasodilator but is unsuitable for the treatment of hypertension since it stimulates the heart. Other drugs described as peripheral vasodilators are diazoxide (219), which is related to the thiazide diuretics, hydralazine (220) which also depresses the CNS, hydracarbazine (221) and minoxidil (222). The /3-receptors control the action of adrenaline on the heart (among other effects) and the agents that block them are mostly nonheterocyclic aromatic compounds with aminoethanol or 3-amino-2-hydroxypropoxy side-chains. They have proved effective in the treatment of hypertension. One heterocyclic compound of this class, timolol (223), is in use. 

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