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Cilnidipine inhibits Ca2+ influx from N-type voltage-dependent Ca channels present in the cell membrane of the sympathetic nerves. In addition, Ca2+ influx from N-type and L-type voltage-gated Ca channel is suppressed almost equally in the same concentration range. Inhibition of Ca2+ influx from N-type voltage-gated Ca channels in sympathetic nerves inhibits release of noradrenaline from sympathetic nerve endings suppressing the increase in heart rate in response to lowering blood pressure (e.g., reflex tachycardia) and blood pressure increases during times of stress associated with elevated sympathetic nerve activity. Cilnidipine has little or no action at the SA or AV nodes and negative inotropic activity is rarely observed at the therapeutic doses.
Antihypertensive effect: The antihypertensive effects of Cilnidipine have been demonstrated in a number of hypertensive disease models including; spontaneously hypertensive rats, renal hypertensive rats and dogs, DOCA salt hypertensive rats, and spontaneously hypertensive rats with stroke. The antihypertensive effects of Cilnidipine were slow in onset, long lasting, and increased in a dose-dependent manner from 1mg/kg. The antihypertensive effect on normotensive rats was weak. Increased doing did not prolong blood pressure lowering effects of Cilnidipine. The blood pressure lowering effect of Cilnidipine is additive when combined with β-blockers, Angiotensin Converting Enzyme inhibitors, and Angiotensin II Receptor Blockers in renal hypertensive dogs.
Rebound hypertension was not observed upon withdrawal of treatment with Cilnidipine. Cilnidipine did not increase heart rate whilst lowering blood pressure after single dose tests in rats without spontaneous/unconstrained hypertension spontaneous syndrome.
In subjects with essential hypertension, Cilnidipine once daily by oral route, produced an antihypertensive effect lasting for 24 hours. Analysis of heartbeat frequency (RR interval) fluctuation over 24 hours showed no sympathetic nervous activity accompanying Cilnidipine associated blood pressure reduction and no increase in heart rate.
Inhibitory effect of pressurization by sympathetic nerve electrical stimulation: Cilnidipine suppressed blood pressure increases due to sympathetic stimulation in spontaneously hypertensive rats. Suppression of noradrenaline during sympathetic stimulation was suppressed in mesenteric arterial vascular perfusion specimens isolated from spontaneously hypertensive rats.
Effect on cerebral circulation: Cilnidipine did not reduce the cerebral blood flow even at doses showing a 30 to 40% reduction in blood pressure in spontaneously hypertensive rats.
In hypertensive patients with complications or cerebrovascular disease, cerebral blood flow was maintained despite reduction of blood pressure with Cilnidipine.
Effect on cardiac function: At doses, greater than usually employed for reducing blood pressure, Cilnidipine decreased heart rate and myocardial contraction force in dogs. Cilnidipine lowered myocardial oxygen consumption at antihypertensive doses in dogs but did not increase heart rate or suppress cardiac contractile force. In patients with essential hypertension, Cilnidipine did not affect pulse rate during blood pressure reduction and improves Cardiac Thoracic Ratio (CTR) in subjects with CTR abnormality.
Effect on kidney: Cilnidipine increased urine volume, the rate of renal blood flow and glomerular filtration rate at doses which reduce blood pressure in anesthetized spontaneously hypertensive rats. Furthermore, urine volume, the rate of renal blood flow and glomerular filtration rate were increased even when renal function was reduced with administration of endothelin. In patients with essential hypertension, Cilnidipine did worsen kidney function.
Effects on cardiovascular disorders associated with hypertension: Cilnidipine, administered orally once a day in rats with spontaneously stroke prone hypertension, delayed onset of cerebral hemorrhage and stroke, improved survival rate. Cilnidipine was also associated with a reduction in cardiac hypertrophy (increase in heart weight), thickening of the left ventricle wall, myocardium fibrosis, and improved pathology in the kidney. Furthermore, Cilnidipine inhibited thickening of coronary artery media and reduced the calcium content of the aorta. In patients with essential hypertension, Cilnidipine reduces arteriosclerosis index and serum lipid peroxidation.
Pharmacokinetics: Cilnidipine is absorbed from the small intestine. The time to maximum plasma concentration is 1.8 to 2.2 hours. It has a half-life of 7.5 hours. Cilnidipine is metabolized by the liver. 20% of the drug is eliminated in the urine and 80% in the feces.
Plasma concentration: After single oral administration of Cilnidipine 5mg, 10mg, and 20mg in 5 healthy adult male volunteers, Cmax was 4.7 ng/mL, 5.4 ng/mL, and 15.7 ng/mL respectively. AUC 0 to 24 after single oral administration of Cilnidipine 5mg, 10mg, and 20mg, was 23.7 ng·hr/mL, 27.5 ng·hr/mL, and 60.1 ng·hr/mL, respectively. Cmax and AUC 0 to 24 increased dose-dependently. The pharmacokinetic parameters with repeated administration of 10 mg Cilnidipine once a day in 6 healthy adult male patients is shown in Table 1. Steady State was achieved after day 4 of administration. (See Table 1.)
Click on icon to see table/diagram/imagePlasma concentrations of Cilnidipine are increased in subjects with renal impairment (serum creatinine value: 1.5 to 3.1 mg/dL) relative to hypertensive subjects with normal renal function but are not clinically relevant. (See Table 2.)
Click on icon to see table/diagram/imageMetabolism/Excretion: Cilnidipine undergoes demethylation of the methoxyethyl group, followed by hydrolysis of cinnamyl ester group and oxidation of dihydropyridine ring CYP3A4 is mainly involved in the demethylation reaction of the methoxyethyl group in the metabolic process, and CYP2C19 is involved in part (in vitro). The calcium antagonism of the demethylated form of the methoxyethyl group was 1/100 of that of Cilnidipine (rabbit). When 10 mg of Cilnidipine was repeatedly administered orally to healthy adult male for 7 days, no unchanged substance was detected in the urine, and 5.2% of the total dose was excreted as a metabolite. The human serum protein binding rate in vitro was 99.3%.
Toxicology: Impairment and Fertility: In animal experiments (rats), fetal toxicity and prolongation of gestation period and delivery time have been reported. Cilnidipine should not be administered to pregnant women. Cilnidipine was present in the milk of lactating rats. Cilnidipine is not recommended for use in whom are breast feeding children.
