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| __NOTOC__
| | #REDIRECT [[Fosinopril#Pharmacology]] |
| {{Fosinopril}}
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| {{CMG}}; {{AE}} {{AM}}
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| ==Clinical Pharmacology==
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| ====Mechanism of Action====
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| In animals and humans, fosinopril is hydrolyzed by esterases to the pharmacologically active form, fosinoprilat, a specific competitive inhibitor of angiotensin converting enzyme (ACE).
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| ACE is a peptidyl dipeptidase that catalyzes the conversion of [[angiotensin I]] to the vasoconstrictor substance, [[angiotensin II]]. Angiotensin II also stimulates [[aldosterone]] secretion by the [[adrenal cortex]]. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
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| In 647 hypertensive patients treated with fosinopril alone for an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were observed. Similar increases were observed among all patients treated with fosinopril, including those receiving concomitant diuretic therapy. Removal of angiotensin II negative feedback on [[renin]] secretion leads to increased plasma renin activity.
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| ACE is identical to kininase, an enzyme that degrades [[bradykinin]]. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of fosinopril remains to be elucidated.
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| While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the [[renin-angiotensin-aldosterone system]], fosinopril has an antihypertensive effect even in patients with low-renin hypertension.
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| Although fosinopril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.
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| In patients with heart failure, the beneficial effects of fosinopril are thought to result primarily from suppression of the renin-angiotensin-aldosterone system; inhibition of the angiotensin converting enzyme produces decreases in both preload and afterload.
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| ====Pharmacokinetics and Metabolism====
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| Following oral administration, fosinopril (the [[prodrug]]) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine ([[duodenum]]/[[jejunum]]). While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected.
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| Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs), and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours.
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| After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20 to 30% as a [[glucuronide]] conjugate of fosinoprilat, and 1 to 5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.
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| After intravenous administration, fosinoprilat was eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/min.
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| In healthy subjects, the terminal elimination half-life (t1/2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1/2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1/2 was 14 hours.
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| In patients with mild-to-severe [[renal insufficiency]] ([[creatinine clearance]] 10 to 80 mL/ min/1.73m2), the clearance of fosinoprilat does not differ appreciably from normal, because of the large contribution of hepatobiliary elimination. In patients with [[end-stage renal disease]] (creatinine clearance < 10 mL/min/1.73m2) the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function.
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| Fosinopril is not well dialyzed. Clearance of fosinoprilat by [[hemodialysis]] and [[peritoneal dialysis]] averages 2% and 7%, respectively, of [[urea]] clearances. | |
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| In patients with [[hepatic insufficiency]] (alcoholic or [[biliary cirrhosis]]), the extent of hydrolysis of fosinopril is not appreciably reduced, although the rate of hydrolysis may be slowed; the apparent total body clearance of fosinoprilat is approximately one-half of that in patients with normal hepatic function.
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| In elderly (male) subjects (65 to 74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20 to 35 years old).
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| In pediatric patients – (N=20) age 6 to 16 years, with [[glomerular filtration rate]] ≥25 mL/min, given a single dose of fosinopril (0.3 mg/kg given as solution), the mean AUC and Cmax values of fosinoprilat (the active form of fosinopril) were similar to those seen in healthy adults receiving 20 mg (about 0.3 mg/kg for a 70 kg adult) of fosinopril as a solution. The terminal elimination half-life of fosinoprilat in pediatric patients was 11 to 13 hours, also similar to that observed in adults.
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| Fosinoprilat was found to cross the placenta of pregnant animals.
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| Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier.
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| ====Pharmacodynamics====
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| Serum ACE activity was inhibited by ≥90% at 2 to 12 hours after single doses of 10 to 40 mg of fosinopril. At 24 hours, serum ACE activity remained suppressed by 85%, 93%, and 93% in the 10, 20, and 40 mg dose groups, respectively.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = FOSINOPRIL NA (FOSINOPRIL SODIUM) TABLET [APOTEX CORP.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=eaa753e8-9fda-af0b-9d54-bdf0d1674832 | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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