Tanatril Mechanism of Action



Mitsubishi Tanabe Pharma


Full Prescribing Info
Selective angiotensin-converting enzyme inhibitor.
Pharmacology: Imidapril HCl is a prodrug which is hydrolyzed after oral administration to form the dicarboxylic acid form (imidaprilat), an active angiotensin-converting enzyme inhibitor. Imidaprilat inhibits the activity of angiotensin-converting enzyme (ACE), an enzyme widely distributed in blood and endothelial cells of many tissues. The antihypertensive effects of imidapril HCl are caused by ACE inhibition and the subsequent reduction in the formation of angiotensin II, which either directly or indirectly results in dilatation of peripheral vessels and reduction of vascular resistance.
ACE Inhibition: The active metabolite imidaprilat competitively inhibits the activity of ACE preparations derived from swine renal cortex and human serum in a dose-dependent manner.
In rats, orally administered imidapril HCl and imidaprilat inhibits the elevation of blood pressure induced by angiotensin I in a dose-dependent manner.
Antihypertensive Action: Orally administered imidapril HCl had significant dose-dependent antihypertensive effects in spontaneously hypertensive rats (SHR) and in 2-kidney-1-clip Goldblatt hypertensive rats. It had slight hypotensive effects in normotensive rats, but it was not effective in DOCA/saline hypertensive rats.
Oral administration of imidapril in SHR for 2 weeks had stable antihypertensive effects and had no effect on heart rate.
Repeated oral administration of 5-10 mg of imidapril HCl once a day in patients with essential hypertension had stable antihypertensive effects and had no effect on the circadian variation of blood pressure.
Other Actions: Renal blood flow and glomerular filtration rate significantly increased in dogs after IV or intraduodenal administration of imidapril HCl or imidaprilat.
In SHR, long-term treatment with imidapril for 9-10 weeks prevented genetic hypertension development and cardiac hypertrophy due to hypertension.
Clinical Studies: Tanatril was evaluated by clinical trials, including double-blind comparative clinical trials, at 133 institutions.
Essential Hypertension (mild to moderate): In clinical studies including a double-blind comparative clinical trial, Tanatril was effective in 80.8% (361/447) of the patients with mild to moderate essential hypertension.
Patients with Severe Hypertension and Hypertensive Patients with Renal Impairment: In clinical studies involving patients with severe hypertension and hypertensive patients with renal impairment, Tanatril was effective in 100% (19/19) of the patients with severe hypertension and 84% (21/25) of the hypertensive patients with renal impairment.
Renal Parenchymal Hypertension: In a clinical study involving patients with renal parenchymal hypertension, Tanatril was effective in 80.6% (25/31) of the patients.
Pharmacokinetics: Imidapril HCl is metabolized to 4 metabolites, which were detected and identified, in addition to unchanged imidapril HCl. The dicarboxylic acid form (imidaprilat) alone is pharmacologically active.
Absorption: Following single oral administration of 10 mg of imidapril HCl in healthy subjects, imidapril HCl reached the peak plasma concentration in about 2 hrs and was eliminated from the plasma with a half-life of about 2 hrs. Imidaprilat reached the peak plasma concentration (about 15 ng/mL) 6-8 hrs after administration, and was gradually eliminated from the plasma with a half-life of about 8 hrs.
Metabolism and Excretion: Following single oral administration of 10 mg of imidapril HCl in healthy subjects, 25.5% of the dosage was excreted in the urine within 24 hrs.
Accumulation: Plasma concentration of imidaprilat reached the steady state 3-5 days after the initiation of repeated oral administration of 10 mg of imidapril HCl once a day for 7 days in healthy subjects; there was no sign of accumulation. In patients with impaired renal function, peak imidaprilat plasma levels increased, and its elimination from the plasma may be delayed.
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