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| __NOTOC__
| | #REDIRECT [[Benazepril#Pharmacology]] |
| {{Benazepril}}
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| {{CMG}} ; {{AE}} {{AM}}
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| ==Clinical Pharmacology==
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| ====Mechanism of Action====
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| Benazepril and benazeprilat inhibit [[angiotensin-converting enzyme]] ([[ACE]]) in human subjects and animals. [[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]].
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| 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]]. [[Hypertensive]] patients treated with Lotensin alone for up to 52 weeks had elevations of serum [[potassium]] of up to 0.2 mEq/L. Similar patients treated with Lotensin and [[hydrochlorothiazide]] for up to 24 weeks had no consistent changes in their serum potassium (see PRECAUTIONS).
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| Removal of [[angiotensin II]] negative feedback on [[renin]] secretion leads to increased plasma [[renin]] activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to [[angiotensin II]] and did not interfere with the hemodynamic effects of the autonomic [[neurotransmitters]] [[acetylcholine]], [[epinephrine]], and [[norepinephrine]].
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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 Lotensin remains to be elucidated.
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| While the mechanism through which benazepril lowers [[blood pressure]] is believed to be primarily suppression of the [[renin-angiotensin-aldosterone system]], benazepril has an [[antihypertensive]] effect even in patients with low-renin [[hypertension]] (see INDICATIONS AND USAGE).
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| ====Pharmacokinetics and Metabolism====
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| Following oral administration of Lotensin, peak plasma concentrations of benazepril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.
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| Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, [[hepatic dysfunction]], or concentration (over the concentration range of 0.24-23.6 µmol/L).
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| Benazepril is almost completely metabolized to benazeprilat, which has much greater [[ACE]] inhibitory activity than benazepril, and to the [[glucuronide]] conjugates of benazepril and benazeprilat. Only trace amounts of an administered dose of Lotensin can be recovered in the urine as unchanged benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide.
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| The kinetics of benazepril are approximately dose-proportional within the dosage range of 10-80 mg.
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| In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily.
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| The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
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| Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. In patients with [[renal failure]], biliary clearance may compensate to an extent for deficient [[renal clearance]]. | |
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| In patients with [[renal insufficiency]], the disposition of benazepril and benazeprilat in patients with mild-to-moderate [[renal insufficiency]] ([[creatinine clearance]] >30 mL/min) is similar to that in patients with normal renal function. In patients with [[creatinine clearance]] ≤30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed (see DOSAGE AND ADMINISTRATION).
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| When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not detected in the dialysate.
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| In patients with [[hepatic insufficiency]] (due to [[cirrhosis]]), the pharmacokinetics of benazeprilat are essentially unaltered. The pharmacokinetics of benazepril and benazeprilat do not appear to be influenced by age.
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| In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of Lotensin (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults.
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| ====Pharmacodynamics====
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| Single and multiple doses of 10 mg or more of Lotensin cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LOTENSIN (BENAZEPRIL HYDROCHLORIDE) TABLET [NOVARTIS PHARMACEUTICALS CORPORATION] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4d954024-a191-46e3-ba71-2a7d5b0c65d5#nlm34067-9 | 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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