Norplus Mechanism of Action

Angiotensin-converting enzyme (ACE) inhibitor, diuretic, antihypertensive.
Pharmacology: Pharmacodynamics: Imidapril HCl: Imidapril is an ester prodrug which is hydrolyzed after oral administration to form the active ACE inhibitor imidaprilat. Imidaprilat has potent ACE inhibitory effects, 1.2 times and 2.6 times that of enalaprilat and captopril, respectively.
The blood pressure lowering effect of imidapril is mainly due to ACE inhibition and consequent reduction in angiotensin II, resulting in dilatation of peripheral vessels and reduction in vascular resistance. The blood pressure lowering effect of imidapril is comparable to enalapril and 5-10 times more potent than that of captopril.
Imidapril decreases total peripheral vascular resistance without an increase in heart rate or cardiac contractility. Imidapril increases renal blood flow and reduces renal vascular resistance mainly due to dilatation of the efferent arteriole. Imidapril showed no specific effect on the central nervous, digestive, respiratory, smooth muscle, reproductive, urologic, hematologic and metabolic systems.
Hydrochlorothiazide: Hydrochlorothiazide (HCTZ), a thiazide diuretic, increases the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The excretion of potassium and magnesium is also increased while the elimination of calcium and uric acid is decreased. Thiazide diuretics usually do not affect the normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known; however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction.
Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion, urinary potassium loss and decreased serum potassium.
Diuresis begins with 2 hrs, peaks in about 4 hrs and lasts about 6-12 hrs after oral administration of HCTZ.
Pharmacokinetics: Imidapril HCl: About 70% of imidapril is absorbed from the gastrointestinal tract and reaches peak plasma concentration (C_max) within 2 hrs after oral administration. Plasma imidapril concentrations decline monophasically with a t_½ of about 2 hrs. A fat-rich meal significantly decreases imidapril absorption.
Imidapril undergoes de-esterification in the liver to form imidaprilat. Peak plasma imidaprilat concentrations are reached within 7 hrs, and decline biphasically with an initial t_½ of 7-9 hrs and a terminal t_½ of >24 hrs. The absolute bioavailability of imidaprilat is 42%. After multiple dosing, steady state imidaprilat concentrations are reached after 5 days. Protein-binding of imidapril and imidaprilat is 85% and 53%, respectively.
After single oral dosing, imidapril absorption appeared linear with doses of 10-240 mg based on plasma and urinary excretion data. Drug elimination is primarily via renal (40%) and hepatobiliary (50%) routes.
Hydrochlorothiazide: Hydrochlorothiazide is well absorbed from the gastrointestinal tract. Oral bioavailability is approximately 65-75%. After oral administration of HCTZ at doses of 12.5-100 mg, C_max of 70-490 ng/mL are observed within 1-5 hrs of dosing.
Approximately 40-60% of the drug is bound to plasma proteins. HCTZ crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. It appears to be preferentially bound to red blood cells.
HCTZ is not metabolized but is eliminated rapidly as unchanged drug in the urine. HCTZ's plasma half-life ranged from 5.6 to 15 hours when plasma levels were followed for at least 24 hours. At least 61% of an oral dose is eliminated unchanged within 24 hours.
Special Populations: Renal Impairment: Increased plasma levels and area under the curve (AUC) of imidapril and imidaprilat were reported in patients with renal impairment. There was a two-fold increase in the AUC of imidaprilat in patients with creatinine clearance 30 to 80 mL/min and an almost ten-fold increase in patients with creatinine clearance 10 to 29 mL/min.
In patients with renal impairment (mean creatinine clearance of 19 mL/min), the elimination half-life of HCTZ was prolonged to 20.7 hours.
Hepatic Impairment: In patients with hepatic impairment, the AUC of imidapril and imidaprilat were slightly higher than in normal subjects while the time to peak plasma concentration (T_max) for both was similar in the two groups. The half-life of imidaprilat, but not that of imidapril, was significantly increased in patients with hepatic impairment.
Monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.