Source: Health Products and Food Branch (CA) Revision Year: 2019
Therapeutic classification: Antihypertensive Agent
Although the precise mechanism of action of APRESOLINE (hydralazine hydrochloride USP) is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state.
The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The vasodilating effect is much greater on arterioles than on veins and vascular resistance decreases more in the coronary, cerebral, splanchnic and renal circulations than in skin and muscle.
Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption and fluid retention.
Sodium retention and excessive sympathetic stimulation of the heart caused by hydralazine may be precluded by co-administration of a thiazide diuretic and a betablocker. Beta-adrenergic blocking drugs and APRESOLINE are complementary in their pharmacologic effects, a beta-adrenergic blocking agent minimizes hydralazine-induced increases in cardiac rate and output, and hydralazine prevents the reflex increase in peripheral resistance induced by beta-blockers.
After intravenous administration of APRESOLINE no first-pass effect occurs; acetylator status therefore has no influence on the plasma levels. In the plasma only small amounts of the free drug can be traced, the bulk circulating in conjugated form, i.e. mainly as pyruvic acid hydrazone. Only the so-called “apparent” hydralazine, i.e. the sum of the free and conjugated hydralazine, can be measured reliably.
Hydralazine becomes bound to plasma proteins (chiefly albumin) to the extent of 88-90%. It is rapidly distributed in the body and displays a specific affinity for muscle tissue in the arterial walls. It crosses the placental barrier and also passes into breast milk.
The pattern of the metabolites depends on the subject’s acetylator and presumably hydroxylator status. Urinary excretion of NAc-HPZ (N-acetyl-hydrazine-phthalazinone), the main metabolite from the acetylation pathway, may be used to determine acetylator phenotype. The plasma half-life generally ranges from 2 to 3 hours, but in rapid acetylators it is shorter, averaging 45 minutes. In patients with impaired renal function, the plasma half-life is prolonged to up to 16 hours at a creatinine clearance of <20 mL/min.
Hydralazine and its metabolites are rapidly excreted by the kidney. The bulk of the hydralazine excreted is in the form of acetylated and hydroxylated metabolites, some of which are conjugated with glucuronic acid; 2-14% is excreted as “apparent” hydralazine. Renal elimination may be impaired in patients of advanced age.
APRESOLINE (hydralazine hydrochloride USP) acts directly on peripheral arterioles, where it has a relaxing effect on the smooth muscle of the vessel wall, with a resultant decrease in arteriolar resistance, decreasing arterial blood pressure, diastolic often more than systolic.
Hydralazine exerts no direct actions on the heart. When the drug decreases arterial pressure and thereby activating the baroreceptors, cardiovascular reflexes result in increased sympathetic discharge. Since APRESOLINE does not increase venous capacitance or depress cardiac function, sympathetic stimulation increases heart rate, left ventricular velocity, stroke volume and cardiac output.
The acute toxicity of hydralazine, as determined intravenously in female white rats is comparatively low: the LD50 is 34 mg/kg.
Single doses of 20 mg/kg intravenously and 200 mg/kg orally were tolerated. The test animals manifested tachycardia, depression, and emesis. Vomiting occurred at doses of 8 and 16 mg/kg and central nervous system stimulation at 32 and 64 mg/kg.
Hydralazine in oral doses of 30 mg/kg given 5 days per week for 3 months was well tolerated.
Doses of 7.4 mg/day to males and 5.4 mg/day to females administered orally throughout the lifespan resulted in increased incidence of lung tumours (classified as adenomas and adenocarcinomas).
Hydralazine was given in oral doses of 1, 3 and 10 mg/kg per day for 6 months. Heinz bodies were detected in the erythrocytes of the high dosage group. Other changes observed included: reversible elevations and depressions of the ST-segment; dose-related tachycardia; dose-related conjunctivitis and in one animal conjunctivitis sicca with pannus formation; in one intermediate dose animal, a small area of subendocardial fibrosis was observed histologically.
Doses of 20, 60, 120 and 150 mg/kg were used. Somnolence and dyspnea, as well as death, at the highest doses indicate that maximum tolerated doses had been exceeded. A dose-related increase in the incidence of cleft palate, agnathia, and hypognathia was observed.
Doses of 20, 60 and 180 mg/kg were used. Maximum tolerated doses were again exceeded, but teratogenic manifestations were not observed, although there was a delay in ossification characterized by unossified calcanei, sternebrae and phalangeal nuclei.
Doses of 10, 30 and 60 mg/kg were used. At the high dose level, some somnolence, as well as one apparent drug-related death, indicated that doses were in the maximum tolerated range.
In the 60 mg/kg dose group one out of 84 fetuses showed mandibular aplasia (agnathia inferior). This malformation is considered to be of spontaneous origin, however, a drug related effect cannot be entirely discounted.
Hydralazine was teratogenic in rabbits where oral doses equal to and greater than 75 mg/kg/day caused phalangeal defects.
Hydralazine induces gene mutations, chromosomal aberrations and DNA damage in mammalian cells in vitro, as well as gene mutations in bacteria, yeast and Drosophila. The potential for similar effects in vivo has not been adequately reported.
In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumours (adenomas and adenocarcinomas) of both male and female mice given hydralazine hydrochloride continuously in their drinking water at a dosage of about 50-200 mg/kg/day; a “no effect” dose has not been established.
In a 2-year carcinogenicity study of Sprague-Dawley albino rats given hydralazine hydrochloride by gavage at dose levels of 15, 30 and 60 mg/kg/day showed increases in the incidences of hepatic neoplasms in both sexes and of Leydig cell tumours in males. Benign interstitial (Leydig) cell tumours of the testes were also significantly increased in male rats from the high-dose group. The tumours observed are common in aged rats and the increased incidence was not observed until 18 months of treatment.
Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rat and one rabbit hepatocyte in-vitro DNA repair studies. In the latter study the effect was evident in cells from slow acetylator rabbits but not from fast acetylators. Additional in-vivo and in-vitro studies using lymphoma cells, germinal cells, and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine.
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