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

Originator

Apresoline HCl,Ciba,US,1952

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

Uses

Inhibits DNA methyltransferase and modulates epigenetic regulation of gene expression. Non-selective MAO-A/B inhibitor; semicarbazide sensitive amine oxidase inhibitor. Antihypertensive

Uses

Hydralazine is a non-nucleoside analog that inhibits DNA methylation and reactivates the expression of tumor suppressor genes. Non-selective MAO-A/B inhibitor; semicarbazide-sensitive amine oxidase inhibitor. Antihypertensive.

Definition

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

Manufacturing Process

30 parts by weight of phthalazone are converted to 1-chlorophthalazine by the method described in Ber. d. deutsch. chem. Ges., vol 26, page 521 (1893). The freshly obtained yet moist chloro compound is heated on the water bath for two hours in a mixture of 100 parts by volume of ethyl alcohol and 90 parts by volume of hydrazine hydrate. Preferably after filtering, 1-hydrazinephthalazine crystallizes out in yellow needles on cooling.
It is filtered with suction and washed with cold ethyl alcohol. The compound is crystallized from methyl alcohol, and melts, when rapidly heated, at 172° to 173°C. On warming in alcoholic or aqueous hydrochloric acid, the hydrochloride of MP 273°C (with decomposition) is obtained.

brand name

Apresoline (Novartis); Dralzine (Teva).

Therapeutic Function

Antihypertensive

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.

Biochem/physiol Actions

Hydralazine hydrochloride has therapeutic effects against heart failure and high blood pressure.

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.

Pharmacokinetics

Hydralazine is well absorbed from the GI tract and is metabolized in the GI mucosa (prehepatic systemic metabolism) and in the liver by acetylation, hydroxylation, and conjugation with glucuronic acid. Little of the hydralazine dose is excreted unchanged in urine but mainly as metabolites, which are without significant therapeutic activity. A small amount of hydralazine is reportedly converted to a hydrazone, most likely with vitamin B6 (pyridoxine), which may be responsible for some its neurotoxic effects. Following the oral administration of hydralazine, its antihypertensive effect begins in 20 to 30 minutes and lasts 2 to 4 hours. The plasma half-life of hydralazine generally is 2 to 4 hours but, in some patients, may be up to 8 hours (i.e., slow acetylators). In slow acetylator patients or those with impaired renal function, the plasma concentrations for hydralazine are increased and, possibly, prolonged. Approximately 85% of hydralazine in the blood is bound to plasma proteins following administration of usual doses.
First-pass acetylation in the GI mucosa and liver is related to genetic acetylator phenotype. Acetylation phenotype is an important determinant of the plasma concentrations of hydralazine when the same dose of hydralazine is administered orally. Slow acetylators have an autosomal recessive trait that results in a relative deficiency of the hepatic enzyme N-acetyl transferase, thus prolonging the elimination half-life of hydralazine. This population of hypertensive patients will require an adjustment in dose to reduce the increased overactive response. Approximately 50% of African Americans and Caucasians, and the majority of American Indians, Eskimos, and Orientals are rapid acetylators of hydralazine. This population of patients will have subtherapeutic plasma concentrations of hydralazine because of its rapid metabolism to inactive metabolites and shorter elimination times. Patients with hydralazine-induced systemic lupus erythematosus frequently are slow acetylators.

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.

Metabolism

Hydralazine undergoes considerable first-pass metabolism by acetylation in the gastrointestinal mucosa and liver. The rate of metabolism is genetically determined and depends upon the acetylator status of the individual. Systemic metabolism in the liver is by hydroxylation of the ring system and conjugation with glucuronic acid; most sources suggest that N-acetylation is not of major importance in systemic clearance and that therefore acetylator status does not affect elimination. Hydralazine is excreted mainly in urine as metabolites.

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.

References

[1] Tetrahedron, 2016, vol. 72, # 50, p. 8282 - 8286