Quinapril

Mechanism of Action

Quinapril is a non-sulfhydryl ACEi that blocks the action of ACE, which plays a vital role in the renin-angiotensin-aldosterone system (RAAS). Quinapril is metabolized to quinaprilat in the liver, where the drug enters circulation. After conversion, the liver releases quinaprilat into the peripheral circulation, inhibiting ACE; the enzyme converts angiotensin I to angiotensin II. Angiotensin II is the hormone that stimulates the hormone aldosterone, which is responsible for salt and water retention.[8] 

A combination of salt and water retention and peripheral vasculature constriction leads to systemic hypertension. Quinapril (and its metabolite quinaprilat) decreases systemic (peripheral and renal) vascular resistance, thereby decreasing blood pressure. The renal system clears the majority of quinapril, and ACEi maximum observable effect occurs at 5 hours.[4][9] The results of a study demonstrated that long-term treatment with quinapril improves impaired endothelial dysfunction in patients with atherosclerotic risk factors.[10] In addition, quinapril improves coronary microvascular dysfunction and coronary flow reserve.[11]

Pharmacokinetics

Absorption: The time for peak plasma concentration is within 1 hour. The extent of absorption is approximately 60% (based on quinapril and its metabolites).

Distribution: Quinalapril has plasma protein binding of 97%. Distribution is widespread, except for brain tissue.[12]

Metabolism: Quinapril is converted to its active metabolite quinaprilat. Quinaprilat has a short elimination half-life but dissociates from ACE slowly, allowing once or twice daily administration.

Excretion: Quinapril and its metabolites are excreted by the kidney.[13]

Administration

Quinapril is administered via the oral route. The drug is available in 5, 10, 20, and 40 mg tablets—plasma clearance of quinapril correlates to a patient's creatinine clearance. The dosing range that researchers tested was between 0.625 to 80 mg orally daily, but the most effective antihypertensive effects were noted at doses of 20 mg orally daily.[3] Quinapril is also available in fixed-dose combination with hydrochlorothiazide for the management of hypertension.

Hypertension: Dosage 10 to 80 mg by mouth daily. Patients with mild to moderate hypertension should be initiated on a dosage between 5 and 20 mg orally daily, with a dose increase every 2 weeks, if needed. The dosage should be reduced to 2.5 to 20 mg orally daily in patients with renal impairment.[14] Interestingly, twice daily dosing achieves a more significant blood pressure trough effect in hypertensive patients than an equivalent total daily dose. Quinapril and hydrochlorothiazide is administered as 20 mg/12.5 mg fixed dose combination.

Chronic Heart Failure With Reduced Ejection Fraction (HFrEF): Patients with HFrEF are started on a lower dosage of 5 mg twice daily. According to the 2022 AHA/ACC/HFSA heart failure guideline, the target dosage is 20 mg twice daily. The undesirable adverse effects precipitate (hypotension, orthostasis, or azotemia) may require dose reduction.[15]

Specific Patient Population 

Hepatic impairment: The manufacturer package insert has no dose adjustment guidance for patients with hepatic impairment. 

Renal impairment: The apparent elimination half-life of quinaprilat, the active metabolite of quinapril, increases as creatinine clearance (CrCl) decreases. Therefore, the dose should be adjusted based on creatinine clearance. Recommended maximum initial doses are as follows:

• 10 mg if creatinine clearance is more than 60 mL/min

• 5 mg if creatinine clearance is 30 to 60 mL/min

• 2.5 mg if creatinine clearance is 10 to 30 mL/min

• No sufficient dose recommendation data is available when creatinine clearance is below 10 mL/min.

• For hemodialysis or peritoneal dialysis patients, start quinapril at 2.5 mg daily; no supplement is necessary following dialysis.

Pregnancy considerations: Quinapril is considered a former FDA pregnancy category D medicine. Per the manufacturer box warning, discontinuation of quinapril is recommended as soon as pregnancy is detected. Quinapril can cross the placenta, and exposure to ACEi during the first trimester may increase the risk of fetal malformations.[16] According to ACOG, ACEi, including quinapril, is contraindicated in pregnancy as it increases the risk of malformations like renal dysgenesis and fetal growth restriction.[17]

Breastfeeding considerations: The manufacturer advises caution for quinapril therapy in nursing mothers as the drug is present in breast milk.[18]

Pediatric patients: Limited data is available for using quinapril in pediatric patients, although it can be used off-label for hypertension in children aged 6 and older. 

Older patients: The manufacturer recommends a 10 mg daily dosage followed by titration as the initial dosage of quinapril in older patients.

Adverse Effects

Adverse effects of quinapril include dry cough (as is typical among all ACEi class members), hyperkalemia, angioedema, dizziness, hypotension, and renal dysfunction.[19][20][21] Less common adverse effects include skin rash and dysgeusia.[21] 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.[22] 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.

Drug-Drug Interactions

• Diuretic agents: Coadministration of quinapril with other diuretics may occasionally reduce blood pressure after initiating therapy. To minimize the hypotensive effects, either discontinue the diuretic or cautiously increase the salt intake before starting quinapril therapy. The reduced initial dose of quinapril may be used for patients where discontinuing the diuretic is not feasible.

• Agents increasing serum potassium: Coadministration of quinapril with other agents that raise the level of serum potassium may lead to hyperkalemia. Therefore, monitoring the serum potassium level in such patients is recommended.

• Tetracycline and other agents that interact with magnesium: Coadministration of quinapril with tetracycline may reduce tetracycline absorption by 28% to 37% due to the high magnesium content in quinapril tablets. 

• Lithium: Coadministration of quinapril with lithium may increase serum lithium levels, leading to lithium toxicity symptoms.

• Gold: Coadministration of quinapril with injectable gold may lead to nitritoid reactions, which lead to symptoms like facial flushing, nausea, vomiting, and hypotension.

• Non-steroidal anti-inflammatory agents, including selective cyclooxygenase-2 inhibitors: Coadministration of quinapril with NSAIDs or selective COX-2 inhibitors in older patients may result in deterioration of renal function or acute renal failure. 

• Agents that inhibit mTOR: Coadministration of quinapril with an mTOR inhibitor (eg, temsirolimus) may increase the risk for angioedema.

FDA Safety Alert: In December 2022, quinapril (4 batches) was withdrawn from the market in a voluntary nationwide recall due to nitrosamine impurity. Nitrosamine is a potential carcinogen; in consequence, clinicians should remain cautious while prescribing.[23]

Contraindications

ACE inhibitors (ACEi), including quinapril, are contraindicated in pregnancy since they counteract RAAS, which is essential for fetal renal development.[21] Possible complications of using quinapril in pregnancy may include but are not limited to fetal lung hypoplasia, fetal renal hypoplasia/failure, oligohydramnios, skeletal hypoplasia, hypotension, and death. Quinapril is also contraindicated in patients with hyperkalemia, current angioedema (regardless of the ACEi), bilateral renal artery stenosis, acute kidney injury leading to renal failure with prior ACEi use, and aliskiren use within the last 36 hours. The use of quinapril is contraindicated in patients taking neprilysin inhibitors (ARNI) such as sacubitril due to the increased risk of angioedema. A period of 36 hours is recommended before switching to or from sacubitril/valsartan and quinapril.[24]

Monitoring

Following the initial dose of quinapril, the patient should be kept under medical observation for at least 2 hours for hypotension or orthostasis. If present, they should remain under observation until blood pressure normalizes. For each dose increase, similar medical care should be provided to patients to avoid the risk of adverse effects.[22] The most serious adverse effects requiring monitoring are angioedema and hyperkalemia. Clinicians need to inform patients about potential facial, tongue, and lip swelling so that they can monitor for angioedema. Patients and clinicians must also be cognizant of abdominal symptoms like abdominal pain, nausea, vomiting, and diarrhea, which may suggest intestinal-type angioedema.[22] 

Routine laboratory assessment should be performed, including a basic metabolic panel to monitor serum potassium levels and renal function. The current recommendation is to monitor serum electrolytes and renal function 2 to 3 weeks after initiation and at every dose titration. In addition, patients should receive instruction to avoid high-potassium foods (ie, alternative salt in hypertension, bananas, avocados) and be advised against concurrent use of other agents that contribute to hyperkalemia (ie, aldosterone antagonists). Patients who take many antihypertensive agents also need to be cautious, as quinapril may contribute to significant hypotension, especially following the administration of the first dose. 

Occasional or rare monitoring of liver function tests and complete blood counts may be warranted in quinapril as rare adverse effects such as agranulocytosis and hepatic enzyme elevation may occur.[19] If patients report a persistent, dry cough while taking quinapril, the clinician may consider a therapeutic switch to an angiotensin receptor-blocking agent (ARB). According to Primary Prevention of Cardiovascular Disease guidelines by ACC/AHA, the atherosclerotic cardiovascular disease (ASCVD) risk estimator plus should be used to guide treatment decisions. For patients with hypertension, comprehensive lifestyle interventions are suggested. The goal blood pressure is <130/80mm Hg.[25] Volume status, weight, and vitals should be monitored each visit for patients with heart failure on quinapril therapy. Hemodynamic status should be monitored during acute decompensation by assessment of perfusion and congestion.  Assessment of patient-reported health status using a standardized questionnaire like the Kansas City Cardiomyopathy Questionnaire (KCCQ) or the Minnesota Living with Heart Failure questionnaire is useful as it provides information regarding the patient's overall functional status and quality of life.[6][26]

Toxicity

Overdosing ACEi may lead to significant hypotension, renal failure, hyperkalemia, and hyponatremia.[19][20][21] 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.[27] To date, no true antidote for quinapril is available.

Per the manufacturer, hemodialysis and peritoneal dialysis may only significantly eliminate quinapril and its metabolite. Angiotensin II can be used as a specific antidote in instances of a quinapril overdose. However, angiotensin II is only available in research facilities. Since quinapril causes hypotension through vasodilation and effective hypovolemia, the infusion of the normal saline solution may be helpful when treating quinapril overdose. Insertion of the central line and administration of norepinephrine may be required in refractory hypotension.[28]

Enhancing Healthcare Team Outcomes

Since quinapril joined the market, it has been an effective medication for treating hypertension and chronic heart failure. Key points to remember are that 1) average systolic blood pressure change is approximately 13 mm Hg while average diastolic blood pressure change is approximately 10 mm Hg with maximum effect at 5 hours, and 2) patients require close monitoring for adverse effects such as hyperkalemia, renal dysfunction, and angioedema.

Clinicians should determine the dose of quinapril based on the patient's clinical diagnosis and other medical conditions. Nursing staff must monitor vitals, verify the dose before administering the drug, and consult with the prescriber about their concerns and recommendations. Pharmacists must perform medication reconciliation and counsel patients on the safe use of the drug. During hypertensive urgency and emergency, clinicians should rapidly stabilize the patient. Medical toxicologist consultation may be required in complex overdose. If the overdose is intentional, a psychiatrist consultation is necessary. All interprofessional healthcare team members must communicate openly with each other to ensure optimal patient treatment and outcomes. Prescribing, administering, and monitoring quinapril requires the coordinated effort of an interprofessional healthcare team. According to AHA/ACC/HFSA 2022 guidelines, multiple clinical trials have shown that patient care provided by an interprofessional team improves outcomes related to hypertension and heart failure therapy.[6]