Hydralazine Antihypertensives

The biotransformation of hydrazine and hydrazide derivatives also proceeds by acetylation. The antihypertensive hydralazine (Apresoline) " ""and the MAO inhibitor phenelzine (Nardil) " are two representative hydrazine compounds that are metabolized by this pathway. The initially formed N-acetyl derivative of hydralazine is unstable and cyclizes intramolecularly to form 3-methyl-s-triazolo 3.4-a phtha-lazine as the major isolable hydralazine metabolite in humans. " The antituberculosis drug isoniazid or isonicoli-nic acid hydrazide (INH) is metabolized extensively to N-acetylisoniazid. " ... 

One of the most fascinating products containing multiple components is a combination of the natural product reserpine, hydralazine hydrochloride, and hydrochlorothiazide. This drug product is available in tablet form and contains 0.1 mg of reserpine USP, 25 mg of hydralazine hydrochloride, and 15 mg of hydrochlorothiazide (Fig. 6). Reserpine is an indole alkaloid derived from the dried root of Rauwolfia serpentina and is well known for its complex molecular architecture, the challenges faced during its total synthesis, and its profound effect on the central nervous system as an antihypertensive. Hydralazine is also an antihypertensive and hydrochlorothiazide has diuretic properties. The combination of these three very different molecular structures brings diversity to the analytical testing required. 

Still other important and innovative new drugs were introduced during the same period, including the antihypertensive hydralazine, the anti-inflammatory drug phenylbutazone, the carbonic anhydrase inhibi-tor/diuretic acetazolamide, and isoniazid for the treatment of tuberculosis. 

Burcham PC, Kerr PG, Fontaine F The antihypertensive hydralazine is an efficient scavenger of acrolein. 

Some examples of free-radicals generated by the bioactivation of drug molecules are shown in Fig. 10.31. Isoniazid is acetylated to its major metabolite acetylisoniazid, which is hydrolyzed to acetylhydrazine and isonicotinic acid (Fig. 10.31-1). Acetylhydrazine is further metabolized by the CYP2E1 to an N-hydroxy intermediate that hydrates into an acetyl radical, which can then initiate the process that leads to hepatic necrosis. Other carbon-centered radicals are formed from hydrazines such as the antihypertensive hydralazine, and thio-radicals from the ACE inhibitor captopril (Fig. 10.31-2 and -3). 

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. 

In a study with 3427 male and female patients having DBP of 95—109 mm Hg (12—15 Pa), and no clinical evidence of cardiovascular diseases, half of the patients were placebo-treated and half were SC antihypertensive dmg-treated, ie, step 1, chlorothiazide step 2, methyldopa, propranolol [525-66-6], or pindolol [13523-86-9], and step 3, hydralazine, or clonidine [4205-90-7] (86). Overall, when the DBP was reduced below 100 mm Hg (13 Pa), there were more deaths in the dmg-treated group than in the placebo group. The data suggest reduction of blood pressure by antihypertensive dmg treatment that includes a diuretic is accompanied by increased cardiovascular risks. 

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. 

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... 

Definitive treatment of preeclampsia is delivery, and this is indicated if pending or frank eclampsia (preeclampsia and convulsions) is present. Otherwise, management consists of restricting activity, bedrest, and close monitoring. Salt restriction or other measures that contract blood volume should be avoided. Antihypertensives are used prior to induction of labor if the DBP is >105-110 mm Hg, with a target DBP of 95-105 mm Hg. IV hydralazine is most commonly used IV labetalol is also effective. 

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... 

In Spain, various 6-phenyl-5-aminomethyl-3-hydrazinopyridazines have been prepared and investigated [307]. The antihypertensive activity of compounds of type (75) has been found to exceed the activity of hydralazine. Similar activity has been observed with compound (76) [308]. The activity of the 4-piperazinopyridazine derivative (77) was found to equal that of hydralazine [309]. Also replacement of the phenylpiperazinomethyl substituent in compound (75) by a morpholinomethyl group was found to afford antihypertensive agents [310]. 

Hydralazine exhibits an antihypertensive effect by directly relaxing smooth muscles of the vessels. It has an effect on arterial vessels while having a minimal effect on venous vessels. As a result, resistance of peripheral vessels decreases, and blood pressure is reduced (diastolic more than systolic). 

Second and subsequent weeks Increase dosage to 50 mg 4 times daily. Maintenance Adjust dosage to lowest effective level. Twice daily dosage may be adequate. In a few resistant patients, up to 300 mg/day may be required for a significant antihypertensive effect. In such cases, consider a lower dosage of hydralazine combined with a thiazide or reserpine or a beta-blocker. However, when combining therapy, individual titration is essential to ensure the lowest possible therapeutic dose of each drug. 

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... 

C. Trimethaphan is a ganglionic blocking agent that will lower blood pressure very rapidly. Hydralazine is a vasodilator hydrochlorothiazide and spironolactone are diuretics and methyldopa is a sympatholytic acting in the central nervous system. All of these drugs are used clinically as antihypertensive agents. None work as rapidly as trimethaphan. Clinically, however, either nitroprusside or clonidine is used much more commonly than trimethaphan in this situation. 

Hydralazine is well absorbed (65-90%) after oral administration. Its peak antihypertensive effect occurs in about 1 hour, and its duration of action is about 6 hours. 

Interestingly, the half-hfe of the antihypertensive effect is somewhat longer than the plasma half-hfe. This may occur because hydralazine is specifically accumulated in artery wahs, where it may continue to exert a vasodilator action even though plasma concentrations are low. 

The plasma half-life of hydralazine may be increased fourfold or fivefold in patients with renal failure. If renal failure is present, therefore, both the antihypertensive and toxic effects of hydralazine may be enhanced. Since A-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme A-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) wih result in higher plasma levels of hydralazine therefore, the drug s therapeutic or toxic effects may be increased. 

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. 

Diuretics are frequently used in combination with other antihypertensive agents. The appropriateness of this combination becomes even more apparent when it is realized that nondiuretic antihypertensives (e.g., hydralazine or diazoxide) produce some increase in plasma volume that if not corrected, would lead to an eventual decrease in their activity (see Chapter 20). 

V-Acetylation /V-acetyl transferase Hydralazine (antihypertensive) Lupus erythematosus-like syndrome... 

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. 

---