Hydralazine - BioPharma Notes

Hydralazine is a direct arterial vasodilator and is used for treatment of hypertension and heart failure. It is used as anti-hypertensive agent since 1950s.
It was first synthesized and tested for anti-histaminic activity. Some further research found out its hypotensive action instead of anti-histaminic action.

Indications of Hydralazine

Used as adjunctive agent in treatment of hypertension. It is very useful for treating chronic hypertension in combination with other agents.
Used in severe hypertension or hypertension crisis.
Used to treat congestive heart failure in combination with other agents like nitrates.
To treat hypertensive emergencies in pregnant women (especially preeclampsia). However, it use as first line agent in hypertension is not supported.

It causes direct relaxation of arteriolar vascular smooth muscle by reducing sarcoplasmic reticulum calcium release. This leads to peripheral vasodilation resulting in lowering of blood pressure.
It also causes release of nitric oxide (NO) from endothelial cells resulting in NO-cGMP induced vasodilation.
It dilates only arterioles, not veins. Due to preferential action on arteriole, there is less risk of orthostatic hypertension.

Figure 1- NO-cGMP mechanism of vasodilation

It lowers BP by direct relaxation of arteriolar smooth muscle. The fall in BP is followed by decrease in total peripheral resistance, compensatory tachycardia, increase in stroke volume and cardiac output. It lowers BP equally in supine and upright position
It may increase cerebral, coronary and renal blood flow and plasma renin activity.

It is well absorbed through GI tract, but systemic bioavailability is low. Maximum blood level reaches within 3-4 hours of oral administration. It has slow, but prolonged onset of action. Even when administered through IV route, the lowering of BP occurs only after 15-20 minutes.
It is N-acetylated in bowel or liver. An individual may be fast acetylator or slow acetylator. The rate of acetylation determines its bioavailability but doesn’t play role in systemic clearance of drug. The fast acetylators require higher dose of drug than slow acetylators to produce equivalent effect.
Its half-life is about 1 hour. Although its half-life is only an hour, its hypotensive action lasts for about 12 hours. Less than 5 % is excreted unchanged in urine. Hence, it can be used in patients with renal damage.

It causes side effects related to vasodilation like headache, vasodilation, flushing, sweating and nausea. GI related side effects include nausea, vomiting, diarrhea and gastric hypersecretion.
When used in large dose, it can cause drug induced lupus like syndrome. It usually occurs after at least 6 months of treatment with hydralazine and is related to dose, sex and acetylator phenotype. The only option to treat is to discontinue the drug.
Myocardial ischemia may occur because of increased oxygen demand. Rarely, it can produce pyridoxine responsive polyneuropathy.
When used in pregnant woman, can cause maternal side effects, lower birthweight and higher maternal heart rate.

In patients hypersensitive to hydralazine.
In patients with coronary artery disease and mitral valvular rheumatic heart disease.