Apreszine 25/Apreszine 50 Mechanism of Action

Pharmacotherapeutic group: Apreszine 50: Arteriolar smooth muscle, agents acting on; hydrazinophthalazine derivatives. ATC code: C02DB02.
Pharmacology: Pharmacodynamics: Apreszine 25: Mechanism of action: Hydralazine reduces peripheral resistance and blood pressure as a result of direct vasodilatory effect on vascular smooth muscle; the effect on arterioles is greater than on veins.
Apreszine 50: Mechanism of action: Hydralazine is a direct acting vasodilator which exerts its effects primarily on the arterioles, with little effect on veins. Its exact mechanism of action is unknown.
Pharmacodynamic effects: Administration of hydralazine decreases peripheral resistance and arterial blood pressure, producing a reflex increase in heart rate and cardiac output. These reflex effects can be reduced by concomitant administration of a beta-blocker, thus enhancing the antihypertensive effect. Increased plasma renin activity and sodium and water retention, producing oedema and reduced urinary volume, may also occur with hydralazine administration attenuating its antihypertensive action. These effects can be prevented by concomitant administration of a diuretic.
Pharmacokinetics: Apreszine 25: Absorption: Rapidly absorbed after oral administration.
Metabolism: Hepatically acetylate; extensive first-pass effect (oral).
Excretion: Urine (as metabolite).
Time to peak: 1-2 hours.
Half-life elimination: 3-7 hours.
Protein-binding: 87%.
Bioavailability: Increase with food.
Apreszine 50: Absorption: Hydralazine is well absorbed (up to 90%) after oral administration but is subject to a dose-dependent first-pass effect. Systemic bioavailability ranges from 26-55% and is dependent on individual acetylator status. Food may enhance the bioavailability of hydralazine by reducing first-pass metabolism in the gut wall. Peak plasma concentrations are reached after 0.5-1.5 hours.
Distribution: Hydralazine is rapidly distributed in the body and displays a particular affinity for the blood vessel walls. It is highly protein bound (~90%) in the plasma. Within 24 hours after an oral dose, the quantity recovered in the urine averages 80% of the dose.
Elimination: Hydralazine appears in the plasma chiefly in the form of a readily hydrolysable conjugate with pyruvic acid. Its plasma half-life averages 2-3 hours but is prolonged up to 16 hours in severe renal failure (creatinine clearance <20 mL/min) and shortened to approximately 45 minutes in rapid acetylators.
The bulk of the dose excreted as acetylated and hydroxylated metabolites, some of which are conjugated with glucuronic acid.
Toxicology: Apreszine 50: Preclinical safety data: Studies in animals found hydralazine to be teratogenic in mice at oral doses ranging from 20-120 mg/kg (20-30 times the maximum human daily dose). Teratogenic effects included cleft palate and malformations of facial and cranial bones. Hydralazine was not found to be teratogenic in rats or rabbits.
In high (cyto-) toxic concentrations, hydralazine induces gene mutations in single cell organisms and in mammalian cells in vitro. No unequivocally mutagenic effects have been detected in-vivo in a great number of test systems.
In lifetime carcinogenicity studies, hydralazine, towards the end of the experiments, caused small but statistically significant increase in lung tumours in mice and hepatic and testicular tumours in rats. These tumours also occur spontaneously with fairly high frequency in aged rodents.
With due consideration of these toxicological findings, hydralazine in therapeutic doses does not appear to bear a risk that would necessitate a limitation of its administration.
Years of clinical experience have not suggested that the use of hydralazine is associated with any risk of cancer in humans.