Nilvadipine

Very low concentrations of nilvadipine inhibits the influx of calcium into the cell of the smooth vascular musculature and thereby cause vasodilatation. The myogenic vascular-wall tonus is reduced and the peripheral vascular resistance diminished. This in turn results in an antihypertensive effect. In the therapeutic dose range, nilvadipine has no effects on the cardiac conduction system.

In hypertensive patients, the onset of the acute effect is approximately 2 hours after single oral administration. In long-term therapy, the maximum antihypertensive effect is reached after 3-4 weeks.

Nilvadipine has been used in clinical testing phase for up to 36 months without any indication of the development of tolerance (tachyphylaxis).

In solution, nilvadipine – with a half-life of 5-10 minutes, is very rapidly absorbed from the gastrointestinal tract. Maximum concentrations (c_max) were achieved after 40 minutes (t_max).

A dose-dependent pharmacokinetic profile was observed for doses between 6 and 16 mg.

Nilvadipine, like its polar metabolites, is highly bound to plasma proteins (98-99%). Nilvadipine is rapidly and well distributed in the body tissues and is subject to a slow back-diffusion. Due to a distinct first-pass effect, the absolute bioavailability ranges between 14 and 19%, resulting in an apparent distribution volume value of 1 l/kg after single administration and 3.9 l/kg after repeated administration. Under long-term therapy, once-daily administration leads to virtually no accumulation as regards cmax or AUC. The pre-dose values cumulate by a factor of 1.5 as a result of the filling of the tissue compartment. Steady-state is reached after 4-5 days.

Nilvadipine is almost completely transformed into polar, pharmacodynamically inactive metabolites in the liver.

Only 0.1% and less than 0.2% of the oral dose are eliminated as unchanged parent substance in the urine and faeces, respectively. The metabolites are renally eliminated to a degree of 70-80%, the remainder being excreted with the faeces. The terminal half-life for the active substance is approximately 15-20 hours.

The available data showed no effects of mild to moderate renal insufficiency on the plasma pharmacokinetics and on the elimination pattern. There are as yet no data regarding the use of the substance in cases of severe renal function disorders. The oral bioavailability of nilvadipine was found to be significantly higher by 42% in elderly (66 years and older) vs. younger subjects.

In patients with cirrhosis of the liver, due to diminished first-pass effect, the bioavailability is increased by a factor of 2 to 3. The currently available data lead to the recommendation that a daily dose of 1 × 8 mg nilvadipine may only be exceeded under close monitoring in such patients.

In animal experiments (rats), it was shown that nilvadipine is able to cross both the blood-brain barrier as well as the placental barrier and is excreted in breast milk.

Bioavailability

Nilvadipine is released from the prolonged release capsule form independent of the pH. The relative bioavailability of nilvadipine prolonged release capsules is approximately 60-70% as compared with an oral solution.

Acute toxicity

The oral LD₅₀ of Nilvadipine in dogs is 480 mg/kg. The corresponding value is more than twice as high in mice, and three times higher in rats.

After reddening of the oral mucous membranes, conjunctiva, and hairless parts of the body (ears, abdominal skin), effects pharmacodynamically caused by peripheral vasodilatation, the following intoxication symptoms were observed in dogs:

Hyperpnoea, stretching motions, salivation, vomiting, diarrhoea, and collapse. After high doses (from 320 mg/kg up), also ptosis, dilatation of the nictitating membrane, and pale mucous membranes. Animals lethally intoxicated died between 6 hours and 3 days after administration.

Subacute and chronic toxicity

Several trials performed in rats and dogs over periods of up to 53 weeks revealed isolated indications of exaggerated pharmacodynamic or counterregulatory effects only after extreme overdosing. In dogs receiving nilvadipine, doserelated effects include haemorrhaging, inflammation and fibroses of the right atrium. The 40 mg/dog dose (approximately 9 mg/kg) was tolerated without any detrimental effect. Comparison of the serum concentrations based on the maximum human-therapeutic dose (16 mg/day) yields a 31-fold safety margin. Neither species displayed any special toxic-effect reactions. Cases of gingival hyperplasia that occurred after long-term administration of high doses of nilvadipine, effects that have also been observed in man and animal species after other calcium antagonists and after hydantoin compounds, were reversible after discontinuation of medication.

Mutagenic and carcinogenic potential

Extensive mutagenicity investigations all yielded negative results.

Investigations in mice and rats provided no indication of any carcinogenic potential for nilvadipine. In mice, doserelated inflammatory processes and haemorrhages were observed in the region of the urogenital tract.

Reproduction toxicology

Embryotoxicity investigations in rats and rabbits yielded no indication of any teratogenic potential.

In rats, changes in the gestation period and dystocia were observed at the end of pregnancy after doses of 10 mg/kg body weight/day. As a consequence, an increased mortality was seen among the new-born animals.

Investigations in rats yielded no indication of impaired fertility.