Continuing Education Activity

Quinapril is a medication utilized to manage hypertension, a significant risk factor for coronary heart disease. This activity reviews the indications, mechanism of action, administration, adverse events, contraindications, monitoring, and toxicity of quinapril. In addition, this article aims to highlight pertinent points regarding quinapril as needed by interprofessional teams managing patients with hypertension and other cardiovascular co-morbidities.

Objectives:

• Identify the FDA and non-FDA-approved indications for the use of quinapril.
• Summarize the potential adverse effects of quinapril.
• Outline the appropriate monitoring of quinapril.
• Review interprofessional team strategies for improving care coordination and communication regarding the use of quinapril and improve overall outcomes.

Indications

Quinapril is an angiotensin-converting enzyme (ACE) inhibitor developed in the 1980s. Researchers determined that quinapril had a lower incidence of adverse events than other ACE inhibitors like captopril and enalapril, as well as the thiazide diuretic chlorthalidone.[1] Quinapril has demonstrated effectiveness in lowering systolic blood pressure by 13 mm Hg and diastolic blood pressure by 10 mm Hg in approximately two out of three individuals.[2][3][4]

• The FDA approved quinapril for the treatment of hypertension in 1989.[1]
• Quinapril is used off labeled (non-FDA-approved) for chronic heart failure (CHF) and slowing the progression of renal disease in patients with diabetes. According to the SOLVD trial, as a class, ACE inhibitors have shown to be beneficial in chronic heart failure (CHF).[5] The primary therapeutic effects include reducing heart failure hospitalizations, hospitalizations for any reason, and risk of death. Additionally, the HOPE trial found that patients taking ACE inhibitors reduce the risk of ischemic stroke, non-fatal myocardial infarction, and cardiovascular death.[6] 
• As a class, ACE inhibitors have been shown to reduce proteinuria in diabetic patients. More importantly, research has demonstrated quinapril to be an agent that reduces microalbuminuria in essential hypertension and diabetic patients without significantly affecting insulin effectiveness or lipid levels.[7]

Mechanism of Action

Quinapril is a non-sulphylhydryl ACE inhibitor that acts by blocking the action of ACE, which plays a vital role in the renin-angiotensin-aldosterone system (RAAS). Quinapril is metabolized into quinaprilat in the liver, where the drug enters circulation. After conversion, the liver releases quinaprilat into the peripheral circulation, inhibiting ACE; the enzyme is responsible for converting angiotensin I to angiotensin II. Angiotensin II is the hormone that promotes the stimulation of the hormone aldosterone, which is responsible for salt and water retention.[8] A combination of salt and water retention, coupled with peripheral vasculature constriction, leads to the development of systemic hypertension. Quinapril (and its metabolite quinaprilat) decreases systemic (peripheral and renal) vascular resistance, thereby decreasing blood pressure. Distribution is widespread, except for brain tissue.[9] The renal system clears the majority of quinapril, and the maximum observable effect of ACE inhibitors takes place at 5 hours.[4][10]

Pharmacokinetics

• Time for peak plasma concentration: within 1 hour
• Extent of absorption: approximately 60% (based on quinapril and its metabolites)
• Food ( high fatty meal): rate and extent of absorption decrease to 30%
• Plasma protein binding: 97%

Administration

The administration of quinapril is via the oral route. It is available in 5 mg, 10 mg, 20 mg, and 40 mg tablets. Plasma clearance of quinapril correlates to the creatinine clearance of a patient. The dosing range that researchers tested was between 0.625 to 80 mg orally once daily, but the most effective antihypertensive effects were noted at doses of 20 mg orally once daily.[3] 

Hypertension: Patients with mild to moderate hypertension should be initiated on a dose between 5 and 40 mg orally once daily. In patients with renal impairment, the dose should be reduced to 2.5 to 20 mg orally once daily.[11] Interestingly, twice daily dosing has been noted to achieve a more significant blood pressure trough effect in hypertensive patients than a similar total dose administered daily.

Chronic Heart Failure: Patients with CHF are started on a lower dose of 5 mg twice daily. It requires higher doses to increase exercise duration for patients with CHF. Doses are titrated upwards weekly until 20 to 40 mg daily dose is reached or undesirable adverse effects precipitate(hypotension, orthostasis, or azotemia).

Specific Patient Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. 
• Patient with Renal Impairment: The apparent elimination half-life of quinaprilat, active metabolite of quinapril, increases as creatinine clearance decreases. Therefore 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 30-60 mL/min
  • 2.5 mg if creatinine clearance is 10–30 mL/min
  • There is no sufficient data for dose recommendation available when creatinine clearance is below 10 mL/min.
• Pregnant Women: It is considered as pregnancy category D medicine. As per the manufacturer box warning, discontinuation of quinapril is recommended as soon as pregnancy is detected. Quinapril can cross the placenta, and any exposure to ACE inhibitor during the first trimester may lead to an increased risk of fetal malformations.
• Breastfeeding Women: The manufacturer recommends exercising caution for quinapril therapy in nursing mothers as the drug presents in breast milk.[12]
• Pediatric Patients: Limited data is available for the use of quinapril in pediatric patients. 
• Geriatric Patients: The manufacturer recommends 10 mg once daily dose followed by titration as the initial dosage of quinapril in geriatric patients.

Adverse Effects

Adverse effects of quinapril include dry cough (as is typical among all ACE inhibitor class members), hyperkalemia, angioedema, dizziness, hypotension, and renal dysfunction.[13][14][15] Less common adverse effects include skin rash and dysgeusia.[15]

Angioedema is a rare but well-documented side effect of ACE inhibitors, which often presents as facial, tongue, and lip swelling. However, there may be unique instances when patients present with isolated swelling of the small bowel. This presentation, also called intestinal-type angioedema, may manifest in patients taking ACE inhibitors presenting with abdominal pain, nausea, vomiting, and/or diarrhea.[16]

Although there was one report of agranulocytosis in a neutropenic patient using quinapril, there are no other reports of agranulocytosis noted in the literature, as found in rare cases of captopril use, one of the original ACE inhibitors.

Drug Interactions

• Diuretic agents: Coadministration of quinapril with other diuretics may occasionally lead to reduce blood pressure after initiation of therapy. To minimize the hypotensive effects, either discontinue the diuretic or cautiously increase the salt intake before initiation of quinapril therapy. The reduced initial dose of quinapril may be used for the patients where the discontinuation of 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 cause hyperkalemia. It is recommended to monitor the level of serum potassium in such patients.
• Tetracycline and other agents that interact with magnesium: Coadministration of quinapril with tetracycline may lead to reducing the absorption of tetracycline by 28% to 37% due to the high magnesium content in quinapril tablets. 
• Lithium: Coadministration of quinapril with lithium may lead to an increase in serum lithium levels and this might cause symptoms of lithium toxicity.
• Gold: Coadministration of quinapril with injectable gold may lead to nitritoid reactions which lead to cause 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 geriatric patients may result in deterioration of renal function or acute renal failure. 
• Agents that inhibit mTOR: Coadministration of quinapril with mTOR inhibitor (temsirolimus) may lead to an increase in the risk for angioedema.

Contraindications

ACE inhibitors, including quinapril, are contraindicated in pregnancy since they counteract the RAAS, which is essential for fetal renal development.[15] Possible complications of the use of 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 presenting with hyperkalemia, history, or current angioedema (regardless of the ACE inhibitor used), bilateral renal artery stenosis, acute kidney injury leading to renal failure with prior ACE inhibitor use, and aliskiren use within the last 36 hours.

Monitoring

Following the initial dose of quinapril, the patient should be kept in medical observation for at least two hours for the presence of hypotension or orthostasis and, if present, until blood pressure normalizes. For each dose increase, similar medical care should be provided to patients to avoid the risk of adverse effects.

The most serious side effects that require monitoring are angioedema and hyperkalemia. Clinicians need to inform patients about potential facial, tongue, and lip swelling so that they monitor themselves for angioedema. Additionally, patients and physicians need to be cognizant of abdominal symptoms like abdominal pain, nausea, vomiting, and diarrhea, which may suggest intestinal-type angioedema.[16] 

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. 

Patients should receive instruction to avoid high-potassium foods (i.e., alternative salt in hypertension, bananas, avocados) and be advised against concurrent use of other agents that contribute to hyperkalemia (i.e., aldosterone antagonists). Patients that take many antihypertensive agents also need to be cautious as quinapril may contribute to significant hypotension, especially following 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/or hepatic enzyme elevation may occur.

If patients report a persistent, dry cough while taking quinapril, the clinician may consider a therapeutic switch to an angiotensin receptor blocking agent(ARB).

Toxicity

Overdosing on ACE inhibitors may lead to significant hypotension, renal failure, hyperkalemia, and hyponatremia.[13][14][15] After ingestion of 20-times of the daily amount, significant hypotension occurred within the first 6 hours of ingestion. Clinicians could consider activated charcoal if a patient were to present within an hour of ingestion.[17] To date, there is no true antidote for quinapril.

As per the manufacturer label, hemodialysis and peritoneal dialysis may only have little effect on the elimination of quinapril and its metabolite. Angiotensin II can be used as a specific antidote in the setting of quinapril overdose. However, it is only available in research facilities. As quinapril causes hypotension through vasodilation and effective hypovolemia, the infusion of the normal saline solution may help during the treatment of quinapril overdose.

Enhancing Healthcare Team Outcomes

Since quinapril has been available on 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 like hyperkalemia, renal dysfunction, and angioedema. [Level 2]

Clinicians should determine the dose of quinapril based on the patient's clinical diagnosis and other medical conditions. Nurses need to monitor vitals and verify the dose before administering it to the patients. Pharmacists need to perform medication reconciliation and counsel patients for the safe use of medicine. The prescribing, administering, and monitoring of quinapril requires the coordinated effort of an interprofessional healthcare team comprised of clinicians, specialists, mid-level providers, nurses, and pharmacists, all communicating openly and coordinating activity to drive optimal patient outcomes. [Level 5]