Quinapril

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antihypertensives

120-130 °C

120 - 130 °C

205.79 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

204.4 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

Adverse effects of quinapril include dry cough (as is typical among all ACEi class members), hyperkalemia, angioedema, dizziness, hypotension, and renal dysfunction. Less common adverse effects include skin rash and dysgeusia. Angioedema is a rare but well-documented adverse effect of ACEi, which often presents as facial, tongue, and lip swelling. However, unique instances present with isolated swelling of the small bowel. This presentation, also called intestinal-type angioedema, may manifest in patients taking ACEi presenting with abdominal pain, nausea, vomiting, and diarrhea. Although one report of agranulocytosis is available in a neutropenic patient using quinapril, no other reports of agranulocytosis were noted in the literature, as found in rare cases of captopril use, one of the original ACE inhibitors.

Peak plasma concentrations of quinapril occur within one hour following oral administration. The extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered during a high-fat meal.

Overdosing ACEi may lead to significant hypotension, renal failure, hyperkalemia, and hyponatremia. After ingesting 20 times the daily amount, significant hypotension occurred within the first 6 hours of ingestion. Clinicians could consider activated charcoal if a patient presents within an hour of ingestion. To date, no true antidote for quinapril is available.

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Quinaprilat, the principle active metabolite of quinapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Quinaprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

quinapril

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

Quinapril

0.5

2.0

The recommended initial dosage of quinapril hydrochloride in patients not on diuretics is 10 or 20 mg once daily. Most patients have required dosages of 20, 40, or 80 mg/day, given as a single dose or in two equally divided doses.

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 20 mg/day, Lowest Therapeutic Dose (LTD): 0.3 mg/kg-day, and Screening Dose: 0.00008 mg/kg-day.

9-Sep-09

C09AA06

C - Cardiovascular system

QC - Cardiovascular system

Quinapril is a prodrug of an angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension or adjunct in the treatment of heart failure. Quinapril has a wide therapeutic window and a long duration of action as it is given in doses of 10-80mg once daily.

Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Angiotensin II also stimulates production of plasminogen activator inhibitor-1 (PAI-1), increasing the risk of thrombosis. Quinaprilat prevents the conversion of angiotensin I to angiotensin II by inhibition of angiotensin converting enzyme, and also reduces the breakdown of bradykinin. Reduced levels of angiotensin II lead to lower levels of PAI-1, reducing the risk of thrombosis, especially after a myocardial infarction.

Quinapril is de-esterified to the active quinaprilat or dehydrated to form the inactive PD109488. PD109488 can undergo O-deethylation to form another inactive metabolite, PD113413.

Hepatic. Route of Elimination: Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose Half Life: Elimination half life is 2 hours with a prolonged terminal phase of 25 hours.

RJ84Y44811

QUINAPRIL

Established Pharmacologic Class [EPC] - Angiotensin Converting Enzyme Inhibitor

Mechanisms of Action [MoA] - Angiotensin-converting Enzyme Inhibitors

Quinapril is an Angiotensin Converting Enzyme Inhibitor. The mechanism of action of quinapril is as an Angiotensin-converting Enzyme Inhibitor.

QUINAPRIL

A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume.

Quinapril if 50-80% bioavailable. Quinapril has a Tmax of <1 hour, while quinaprilat has a Tmax of 2.5h. The Cmax of quinaprilat is highly variable but reaches 1526ng/mL with an AUC of 2443ng\*h/mL in healthy males given a 10mg dose. A high fat meal reduces the absorption of quinapril by 25-30%.

Quinaprilat is up to 96% eliminated in the urine. The eliminated metabolites PD109488 and PD113413 account for approximately 6% of a dose of quinapril each. A small fraction of the dose recovered in the urine is accounted for by unmetabolized quinapril.

The mean volume of distribution of quinaprilat is 13.9L.

The clearance of quinaprilat is 68mL/min.

Use (kg; approx.) in Germany (2009): >500

For the treatment of hypertension and as adjunct therapy in the treatment of congestive heart failure. May also be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.