Hydralazine hydrochloride

Description

Hydralazine is an orally bioavailable vasodilator and antihypertensive agent. It decreases DNA methylation in Jurkat cells at a concentration of 10 μM and inhibits extracellular and intracellular production of reactive oxygen species (ROS) in rat macrophages activated by phorbol 12-myristate 13-acetate (PMA; ) at a concentration of 100 μM. Hydralazine (100 μM) also decreases nitric oxide production and mRNA expression of inducible nitric oxide synthase (iNOS) in rat macrophages activated by LPS (Item Nos. 19660| 19661| 19662) and interferon-γ (IFN-γ). It reduces contraction of rat aortic arterial strips induced by potassium and norepinephrine (; IC₅₀s = 2.2 and 3.06 mM, respectively). Hydralazine (2.6 mg/kg) lowers mean arterial blood pressure (MAP) by 41.76% in conscious rats. Formulations containing hydralazine have been used in the treatment of high blood pressure and heart failure.

Chemical Properties

White Crystalline Solid

Uses

Hydralazine hydrochloride has been used:

• as a vasodilator to study its effects on hypertension in T-cell frequencies in juvenile rats
• as a semicarbazide-sensitive amine oxidase (SSAO) inhibitor to study its effects on myocardial ischemia-reperfusion (I/R) injury
• as a vasodilator to study its effects on insulin secretion and glucose tolerance

Definition

ChEBI: The hydrochloride salt of hydralazine; a direct-acting vasodilator that is used as an antihypertensive agent.

General Description

Hydralazine hydrochloride,1-hydrazinophthalazine monohydrochloride(Apresoline hydrochloride), originated from the work of achemist attempting to produce some unusual chemicalcompounds and from the observation that this compoundhad antihypertensive properties. It occurs as yellow crystalsand is soluble in water to the extent of about 3%. A 2%aqueous solution has a pH of 3.5 to 4.5.

Contact allergens

Hydralazine is a hydrazine derivative used as a antihypertensive drug. Skin rashes have been described during treatment. Exposure occurs mainly in the pharmaceutical industry. Cross-sensitivity is frequent with hydrazine, which is considered to be a potent sensitizer.

Mechanism of action

The only drug in this group, hydralazine, does not fit neatly into the other mechanistic classes, in part because its mechanism of action is not entirely clear. It appears to have multiple, direct effects on the VSM. Hydralazine, a phthalazine-substituted hydrazine antihypertensive drug with a pKa of 7.3, is highly specific for arterial vessels, producing its vasodilation by a couple of different mechanisms. First, it causes smooth muscle hyperpolarization, quite likely through the opening of K+ channels. Activation therefore increases the efflux of potassium ions from the cells, causing hyperpolarization of VSM cells and, thus, prolonging the opening of the potassium channel and sustaining a greater vasodilation on arterioles than on veins. It also may inhibit the second messenger, IP3-induced release of calcium from the smooth muscle sarcoplasmic reticulum (the PIP2 signal transduction pathway). Finally, hydralazine stimulates the formation of NO by the vascular endothelium, leading to cGMP-mediated vasodilation. The arterial vasodilator action of hydralazine reduces systemic vascular resistance and arterial pressure. Diastolic blood pressure usually is decreased more than systolic pressure is. The hydralazine-induced decrease in blood pressure and peripheral resistance causes a reflex response, which is accompanied by increased heart rate, cardiac output, stroke volume, and an increase in plasma renin activity. It has no direct effect on the heart. This reflex response could offset the hypotensive effect of arteriolar dilation, limiting its antihypertensive effectiveness. Hydralazine also causes sodium and water retention and expansion of plasma volume, which could develop tolerance to its antihypertensive effect during prolonged therapy. Thus, coadministration of a diuretic improves the therapeutic outcome.

Clinical Use

Hydralazine hydrochloride is useful in the treatment ofmoderate-to-severe hypertension. It is often used in conjunctionwith less potent antihypertensive agents, becauseside effects occur frequently when it is used alone in adequatedoses. In combinations, it can be used in lower andsafer doses. Its action appears to be centered on the smoothmuscle of the vascular walls, with a decrease in peripheralresistance to blood flow. This results in increased bloodflow through the peripheral blood vessels. It also has theunique property of increasing renal blood flow, an importantconsideration in patients with renal insufficiency.Hydralazine hydrochloride acts on vascular smooth muscleto cause relaxation. Its mechanism of action is unclear. Itinterferes with Ca2⁺ entry andCa2⁺release from intracellularstores and reportedly causes activation of guanylate cyclase,resulting in increased levels of cGMP. All of thesebiochemical events can cause vasodilation.

Drug interactions

The coadministration of diuretics and other hypotensive drugs may have a synergistic effect, resulting in a marked decrease in blood pressure.

Purification Methods

It crystallises from MeOH and has m 172-173o(dec). [Druey et al. Helv Chim Acta 34 195 1951, Beilstein 25 III/IV 4552.] It is an antihypertensive.