The vasodilation produced by hydralazine (Apresoline) depends in part on the presence of an intact blood ves-sel endothelium. This implies that hydralazine causes the release of nitric oxide, which acts on the vascular smooth muscle to cause relaxation. In addition, hy-dralazine may produce vasodilation by activating K+ channels.
Hydralazine is well absorbed (65–90%) after oral ad-ministration. Its peak antihypertensive effect occurs in about 1 hour, and its duration of action is about 6 hours.
The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjuga-tion and N-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic cir-culation. The first-pass metabolism occurs in the intes-tinal mucosa (mostly N-acetylation) and the liver. The primary excretory route is through renal elimination, and about 80% of an oral dose appears in the urine within 48 hours. About 10% is excreted unchanged in the feces.
Approximately 85% of the hydralazine in plasma is bound to plasma proteins. Although this does not ap-pear to be a major therapeutic concern, the potential for interactions with other drugs that also bind to plasma proteins does exist. The plasma half-life of hydralazine in patients with normal renal function is 1.5 to 3 hours.
Interestingly, the half-life of the antihypertensive effect is somewhat longer than the plasma half-life. This may occur because hydralazine is specifically accumulated in artery walls, where it may continue to exert a vasodila-tor action even though plasma concentrations are low.
The plasma half-life of hydralazine may be in-creased fourfold or fivefold in patients with renal fail-ure. If renal failure is present, therefore, both the anti-hypertensive and toxic effects of hydralazine may be enhanced. Since N-acetylation of hydralazine is an im-portant metabolic pathway and depends on the activity of the enzyme N-acetyltransferase, genetically deter-mined differences in the activity of this enzyme in cer-tain individuals (known as slow acetylators) will result in higher plasma levels of hydralazine; therefore, the drug’s therapeutic or toxic effects may be increased.
Hydralazine produces widespread but apparently not uniform vasodilation; that is, vascular resistance is de-creased more in cerebral, coronary, renal, and splanch-nic beds than in skeletal muscle and skin. Renal blood flow and ultimately glomerular filtration rate may be slightly increased after acute treatment with hy-dralazine. However, after several days of therapy, the renal blood flow is usually no different from that before drug use.
In therapeutic doses, hydralazine produces little ef-fect on nonvascular smooth muscle or on the heart. Its pharmacological actions are largely confined to vascular smooth muscle and occur predominantly on the arterial side of the circulation; venous capacitance is much less affected. Because cardiovascular reflexes and venous ca-pacitance are not affected by hydralazine, postural hy-potension is not a clinical concern. Hydralazine treat-ment does, however, result in an increase in cardiac output. This action is brought about by the combined ef-fects of a reflex increase in sympathetic stimulation of the heart, an increase in plasma renin, and salt and water re-tention. These effects limit the hypotensive usefulness of hydralazine to such an extent that it is rarely used alone.
Hydralazine is generally reserved for moderately hy-pertensive ambulatory patients whose blood pressure is not well controlled either by diuretics or by drugs that interfere with the sympathetic nervous system. It is al-most always administered in combination with a di-uretic (to prevent NA+ retention) and a β-blocker, such as propranolol (to attenuate the effects of reflex cardiac stimulation and hyperreninemia). The triple combina-tion of a diuretic, β-blocker, and hydralazine constitutes a unique hemodynamic approach to the treatment of hy-pertension, since three of the chief determinants of blood pressure are affected: cardiac output ( β-blocker), plasma volume (diuretic), and peripheral vascular re-sistance (hydralazine).
Although hydralazine is available for intravenous administration and has been used in the past for hyper-tensive emergencies, it is not generally employed for this purpose. The onset of action after intravenous in-jection is relatively slow, and its actions are somewhat unpredictable in comparison with those of several other vasodilators.
Most side effects associated with hydralazine adminis-tration are due to vasodilation and the reflex hemody-namic changes that occur in response to vasodilation. These side effects include headache, flushing, nasal con-gestion, tachycardia, and palpitations. More serious manifestations include myocardial ischemia and heart failure. These untoward effects of hydralazine are greatly attenuated when the drug is administered in conjunction with a β-blocker.
When administered chronically in high doses, hy-dralazine may produce a rheumatoidlike state that when fully developed, resembles disseminated lupus erythematosus.