Chemical formula: C₂₀H₂₉N₅O₃ Molecular mass: 387.484 g/mol PubChem compound: 5639
Urapidil has both central and peripheral effects.
Peripheral: Urapidil predominantly blocks postsynaptic alpha-receptors and consequently inhibits the vasoconstrictor effect of catecholamines.
Central: Urapidil has also a central effect. It modulated the activity of the cerebral centers which control the circulatory system. Thus, a reactive increase in sympathetic tone is inhibited or the sympathetic tone is reduced.
Urapidil results in a drop in the systolic and diastolic blood pressure through a reduction in the peripheral resistance.
Heart rate remains largely constant.
Cardiac output is not modified; cardiac output reduced as a result of increased afterload may increase.
80% to 90% of urapidil is resorbed in the gastrointestinal tract after oral administration.
The plasma protein binding of urapidil is about 80%, with the distribution volume of 0.77 L/kg body weight. The maximum plasma concentration of the delayed formulations is reached after about 4–6 hours, with an elimination half-life of about 4.7 (3.3–7.6) hours.
Following intravenous administration of 25 mg urapidil, the serum concentration (initial distribution phase, terminal elimination phase) is biphasic. The distribution phase has a half-life of approx. 35 min. The volume of distribution is 0.8 (0.6-1.2) l/kg.
The absolute bioavailability of prolonged-release capsules in comparison with the i.v. standard is about 72 (63-80)%.
The relative bioavailability of the prolonged-release capsules in comparison with the orally applied solution is 92 (83-103)%.
Urapidil is primarily metabolised in the liver. The primary metabolite is a urapidil hydroxilated in the 4-position on the phenyl core, which has no significant antihypertensive effect. The metabolite of O-demethylated urapidil has roughly the same biological activity as urapidil, but arises to a much lesser extent.
50-70% of urapidil and its metabolites are eliminated in humans via the kidneys, including about 15% of the dose administered as pharmacologically active urapidil; the remainder is excreted in the faeces as metabolites, primarily as para-hydroxylated urapidil which does not lower the blood pressure.
After intravenous bolus injection, the elimination half-life from the serum has been found to be 2.7 (1.8-3.9) h. Plasma protein binding of urapidil (human serum) is 80% in vitro. This relatively low plasma protein binding of urapidil could explain why to date no interactions are known between urapidil and drugs bound strongly to plasma protein.
In advanced hepatic and/or renal insufficiency and in elderly patients, the volume of distribution and clearance of urapidil is reduced, and the elimination half-life extended. Urapidil penetrates the blood-brain barrier and passes through the placenta.
Studies with urapidil hydrochloride have been performed in mice and rats to test acute toxicity. The LD50 (referring to urapidil base) following oral administration is between 508 and 750 mg/kg BW and following intravenous administration, between 140 and 260 mg/kg BW. Toxicity was observed predominantly as sedation, ptosis, reduced motility, loss of the protective reflex and hypothermia, gasping for breath, cyanosis, tremor and convulsions before death.
Studies on chronic toxicity have been performed in rats after oral administration with food over 6 and 12 months, using doses up to 250 mg/kg BW/day. Sedation, ptosis, reduced increase in body weight, lengthening of the oestrus cycle and reduced uterus weight were observed. Chronic toxicity was investigated in the dog in studies over 6 and 12 months with doses up to 64 mg/kg BW. Doses from 30 mg/kg BW/day caused sedation, hypersalivation and tremor. No clinical or histopathological changes were found in the dog.
In bacterial studies (the AMES test, the host-mediated assay), investigations on human lymphocytes and the bone marrow metaphase test on the mouse, urapidil exhibited no mutagenic characteristics. A test of DNA repair on rat hepatocytes was negative.
Carcinogenic studies in mice and rats over 18 and 24 months produced no indications relevant to humans of tumour inducing potential. In special studies in rats and mice urapidil was found to raise the prolactin level. In the rodent a raised prolactin level leads to stimulation of the growth of mammary tissue. In view of what is known of the mechanism of action, this effect is not expected to occur in humans receiving therapeutic doses, and could not be established in clinical trials.
Studies on reproduction toxicity in the rat, mouse and rabbit produced no indication of a teratogenic effect.
Studies in rats and rabbits have shown reproductive toxicity of urapidil. The adverse effects consisted of decreased pregnancy rate in rats; reduced body weight gain and food and water intake in pregnant rabbits; a decreased rate of live rabbit foetuses; and a decreased perinatal survival rate and body weight gain of newborn rats.
The reproduction study established that the oestrus cycle of female rats was lengthened, as the study for chronic toxicity had also established. This effect, like the decreased weight of the uterus in the chronic test, is considered a result of the raised prolactin level occurring in rodents after treatment with urapidil. The fertility of the females was not impaired.
Owing to the considerable differences between the species however, these results cannot be considered as applicable to humans. In long-term clinical studies no influence on the pituitary gonad axis in the woman could be established.
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