A Comprehensive Monograph on Quinapril (DB00881): Pharmacology, Clinical Efficacy, and Regulatory Landscape

1.0 Executive Summary

Quinapril is an orally administered, non-sulfhydryl small molecule drug belonging to the angiotensin-converting enzyme (ACE) inhibitor class.[1] Marketed under brand names including Accupril, it functions as a prodrug, undergoing hepatic bioactivation to its active diacid metabolite, quinaprilat.[1] Its primary clinical indications are the management of hypertension, for which it is considered a first-line therapy, and as an adjunctive treatment for congestive heart failure.[4]

The therapeutic action of quinapril is mediated through the potent inhibition of the renin-angiotensin-aldosterone system (RAAS) by quinaprilat.[2] By blocking the angiotensin-converting enzyme, quinaprilat prevents the conversion of angiotensin I to angiotensin II, a powerful vasoconstrictor and a stimulator of aldosterone secretion. This leads to systemic vasodilation, reduced sodium and water retention, and a decrease in blood pressure.[4]

The pharmacokinetic profile of quinapril is characterized by rapid oral absorption, with the prodrug reaching peak plasma concentrations within one hour.[7] Following hepatic de-esterification, the active metabolite, quinaprilat, exhibits a biphasic elimination pattern, with an effective half-life of approximately 2-3 hours and a prolonged terminal half-life of 25 hours, which is attributed to its tight binding to ACE and allows for a convenient once-daily dosing regimen.[4] Both quinapril and quinaprilat are highly bound to plasma proteins (approximately 97%), and quinaprilat is primarily eliminated via renal excretion, necessitating dose adjustments in patients with impaired renal function.[4]

The safety profile of quinapril is consistent with the ACE inhibitor class. Common adverse effects include dizziness, headache, fatigue, and a characteristic dry cough.[4] More serious, class-specific risks include angioedema, hyperkalemia, hypotension, and significant fetal toxicity, making the drug contraindicated in pregnancy.[4]

A pivotal event in the regulatory history of quinapril occurred in 2022, when multiple manufacturers, including Pfizer, initiated voluntary recalls of quinapril and quinapril/hydrochlorothiazide combination products.[4] These actions were prompted by the detection of the impurity N-Nitroso-quinapril, a probable human carcinogen, at levels exceeding the acceptable daily intake (ADI) established by the U.S. Food and Drug Administration (FDA). This development has raised significant questions regarding the long-term chemical stability and manufacturing processes of the drug, impacting its clinical use and regulatory oversight.

2.0 Drug Identification and Physicochemical Properties

A precise and comprehensive identification of a pharmaceutical agent is foundational to its study and clinical application. This section details the nomenclature, structural characteristics, and physicochemical properties of quinapril, providing a definitive reference profile for the compound and its common salt form.

2.1 Nomenclature and Standardized Identifiers

Quinapril is the International Nonproprietary Name (INN) for the compound.[11] In clinical practice and pharmaceutical formulations, it is most commonly used as its hydrochloride salt, quinapril hydrochloride.[4] The drug was originally developed by Warner-Lambert and is most widely known by its brand name Accupril, marketed by Pfizer.[3] Other brand names include Accupro.[3] Fixed-dose combination products with the diuretic hydrochlorothiazide are marketed under names such as Accuretic and Quinaretic.[11] To ensure unambiguous identification across various chemical, biological, and regulatory databases, a comprehensive set of standardized identifiers has been assigned to quinapril, as detailed in Table 1.

Table 1: Key Identifiers for Quinapril
Identifier Type	Value
DrugBank Accession Number	DB00881
Chemical Abstracts Service (CAS) Number	85441-61-8 (Free Base)
	82586-55-8 (Hydrochloride Salt)
PubChem Compound ID (CID)	54892
FDA Unique Ingredient Identifier (UNII)	RJ84Y44811 (Free Base)
	33067B3N2M (Hydrochloride Salt)
Anatomical Therapeutic Chemical (ATC) Code	C09AA06
IUPHAR/BPS ID	6350
KEGG ID	D03752
ChEMBL ID	CHEMBL1592
Data compiled from sources.1

2.2 Chemical Structure, Stereochemistry, and Formulation

Quinapril is a synthetic organic compound belonging to the class of isoquinolines.[3] Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is (3S)-2-amino]propanoyl]-3,4-dihydro-1H-isoquinoline-3-carboxylic acid.[1] This structure is derived from the condensation of two amino acid-like moieties: an L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid scaffold and an N-substituted ethyl L-homophenylalaninate group.[3]

The molecular formula for the quinapril free base is C25​H30​N2​O5​.[1] For the more commonly used hydrochloride salt, the formula is

C25​H30​N2​O5​⋅HCl.[12] Key structural representations used in cheminformatics include:

• Canonical SMILES: CCOC(=O)C(NC(C(=O)N1Cc2ccccc2CC1C(=O)O)C)CCc1ccccc1 [11]
• InChI: InChI=1S/C25H30N2O5/c1−3−32−25(31)21(14−13−18−9−5−4−6−10−18)26−17(2)23(28)27−16−20−12−8−7−11−19(20)15−22(27)24(29)30/h4−12,17,21−22,26H,3,13−16H2,1−2H3,(H,29,30)/t17−,21−,22−/m0/s1 [1]
• InChIKey: JSDRRTOADPPCHY−HSQYWUDLSA−N [1]

The molecule possesses three defined stereocenters, and its stereochemistry is absolute, with the all-S configuration being essential for its specific and high-affinity binding to the active site of the angiotensin-converting enzyme.[1]

As a pharmaceutical substance, quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents.[16] This solubility is a key property that facilitates its formulation into oral tablets. The tablet formulation includes several inactive ingredients, or excipients, one of which has direct clinical relevance. Quinapril tablets contain a significant amount of magnesium carbonate as an excipient.[17] This choice of formulation component is not merely incidental; it is the direct cause of a clinically significant drug-drug interaction. The high magnesium content chelates with tetracycline antibiotics in the gastrointestinal tract, reducing tetracycline absorption by 28% to 37%.[6] This provides a clear example of how pharmaceutical formulation science directly impacts clinical practice and prescribing guidelines, as co-administration of these drugs must be avoided.

2.3 Physicochemical Characteristics

The physicochemical properties of a drug molecule govern its absorption, distribution, metabolism, and excretion (ADME) profile, as well as its suitability for formulation. The key properties for quinapril and its hydrochloride salt are summarized in Table 2. The molecule adheres to Lipinski's Rule of Five, suggesting good oral bioavailability and druglikeness.[11] Its high protein binding percentage is a critical factor in its pharmacokinetic behavior, influencing its distribution and duration of action.

Table 2: Physicochemical Properties of Quinapril and its Hydrochloride Salt
Property	Quinapril (Free Base)	Quinapril Hydrochloride
Molecular Formula	C25​H30​N2​O5​	C25​H30​N2​O5​⋅HCl
Molecular Weight	438.52 g/mol	474.98 g/mol
Melting Point	120-130 °C	Not specified
pKa (Strongest Acidic)	3.39 - 3.7	Not specified
pKa (Strongest Basic)	5.2	Not specified
Water Solubility	Not specified	0.0085 mg/mL
XLogP / logP	3.16	1.4 - 1.96
Plasma Protein Binding	~97%	~97%
Topological Polar Surface Area	95.94 A˚2	95.94 A˚2
Rotatable Bonds	11	10
Data compiled from sources.3

2.4 Related Compounds, Metabolites, and Impurities

The biological activity and safety profile of quinapril are closely linked to several related molecules.

• Active Metabolite: The primary active metabolite is quinaprilat (CAS 85441-60-7).[1] It is the diacid form of the molecule, created by the hydrolysis of the ethyl ester group of quinapril. Quinaprilat is responsible for virtually all of the therapeutic ACE-inhibiting activity.[6]
• Inactive Metabolites: Minor inactive metabolites, including PD109488 (formed via dehydration) and PD113413 (formed via O-deethylation of PD109488), have also been identified.[19]
• Impurities and Analogs: A wide range of impurities and related compounds are known, reflecting the complexity of the drug's synthesis and potential degradation pathways. These include various ester analogs (e.g., methyl, isopropyl, benzyl), degradation products (e.g., Quinapril EP Impurity D, C, G), and deuterated forms used in research (e.g., Quinapril-D5 Hydrochloride).[15] The existence of such an extensive list of related substances suggests that the parent molecule may be susceptible to numerous chemical transformations under various conditions.
• Nitrosamine Impurity: Of critical importance is the impurity N-Nitroso-quinapril (C25​H29​N3​O6​).[15] The structure of quinapril contains a secondary amine within its tetrahydroisoquinoline ring system, a chemical feature known to be a precursor for nitrosation. Under certain conditions involving nitrosating agents (e.g., nitrites), this secondary amine can be converted to a nitrosamine. The widespread detection of N-Nitroso-quinapril in finished drug products above acceptable limits in 2022 suggests that the conditions for its formation may be an inherent challenge in the manufacturing or storage of quinapril, rather than an isolated incident. This underlying chemical susceptibility likely contributed to the industry-wide recalls that defined a major chapter in the drug's regulatory history.[4]

3.0 Clinical Pharmacology

The clinical utility of quinapril is derived from its targeted modulation of the renin-angiotensin-aldosterone system (RAAS), a critical regulator of cardiovascular and renal physiology. This section elucidates the drug's mechanism of action, its pharmacodynamic effects on the body, and the relationship between dose, response, and duration of action.

3.1 Mechanism of Action: Inhibition of the Renin-Angiotensin-Aldosterone System (RAAS)

Quinapril itself is a pharmacologically inactive prodrug, designed to enhance oral absorption and bioavailability.[1] Following oral administration and absorption, it undergoes rapid and extensive first-pass metabolism, primarily in the liver, where esterase enzymes hydrolyze its ethyl ester group. This bioactivation process converts quinapril into its principal active metabolite,

quinaprilat.[6]

Quinaprilat is a potent, competitive, and non-sulfhydryl inhibitor of the Angiotensin-Converting Enzyme (ACE).[2] ACE, also known as peptidyl dipeptidase or kininase II, is a key zinc-containing metalloenzyme in the RAAS cascade. Its primary function is to catalyze the conversion of the relatively inactive decapeptide, angiotensin I, into the highly potent octapeptide, angiotensin II.[4]

By binding to and inhibiting ACE, quinaprilat effectively blocks the production of angiotensin II. The therapeutic consequences of this inhibition are multifaceted:

1. Vasodilation: Angiotensin II is one of the body's most powerful endogenous vasoconstrictors. By reducing its formation, quinaprilat leads to the relaxation of vascular smooth muscle in both arteries and veins. This causes a decrease in total peripheral resistance (afterload), which is the primary mechanism underlying its antihypertensive effect.[4]
2. Reduction in Aldosterone Secretion: Angiotensin II is the primary stimulus for the release of aldosterone from the adrenal cortex. Aldosterone acts on the distal tubules of the kidney to promote the reabsorption of sodium and water and the excretion of potassium. By lowering angiotensin II levels, quinaprilat indirectly reduces aldosterone secretion. This leads to a mild natriuretic (sodium excretion) and diuretic effect, and importantly, a decrease in potassium excretion, which can result in a small increase in serum potassium levels.[4]
3. Increased Plasma Renin Activity: Angiotensin II normally exerts a negative feedback effect on the release of renin from the juxtaglomerular apparatus in the kidneys. By removing this feedback loop, ACE inhibition leads to a compensatory increase in plasma renin activity (PRA). However, the antihypertensive effect of the drug persists because the subsequent step in the cascade (the conversion of angiotensin I to angiotensin II) remains blocked.[6]

A crucial aspect of ACE's function is its identity as kininase II, the primary enzyme responsible for the degradation of bradykinin, a potent endogenous vasodilator peptide.[6] Inhibition of this enzyme by quinaprilat prevents bradykinin breakdown, leading to its accumulation. This accumulation of bradykinin is believed to contribute to the therapeutic vasodilatory effects of ACE inhibitors by stimulating the production of nitric oxide and prostaglandins. This single enzymatic inhibition target thus has a dual clinical consequence: the desired therapeutic effect of vasodilation is augmented by bradykinin, while the accumulation of bradykinin and other tachykinins in the lungs is also the primary mechanism implicated in the most common dose-limiting side effect of the ACE inhibitor class—a persistent, dry cough.[4] This dual role explains why the cough is an inseparable class effect that cannot be engineered out of an ACE inhibitor without fundamentally altering its mechanism of action.

3.2 Pharmacodynamics: Hemodynamic and Neurohormonal Effects

The pharmacological actions of quinaprilat translate into distinct and beneficial hemodynamic changes in patients with hypertension and heart failure.

In patients with hypertension, the reduction in blood pressure produced by quinapril is accompanied by a significant reduction in total peripheral resistance and renal vascular resistance. Notably, this occurs with little or no compensatory change in heart rate, cardiac index, renal blood flow, or glomerular filtration rate (GFR).[6] This hemodynamic profile is highly favorable, as it effectively lowers blood pressure without inducing the reflex tachycardia that can accompany treatment with other types of vasodilators. Quinapril has been shown to be an effective antihypertensive in all races studied, although its effect may be somewhat attenuated in Black patients, a population that often exhibits a low-renin hypertensive state.[6]

In patients with congestive heart failure (CHF), quinapril's effects are even more comprehensive. By reducing systemic vascular resistance (afterload), it lessens the workload on the failing heart. By causing venodilation, it reduces venous return to the heart, thereby decreasing pulmonary capillary wedge pressure (preload). The combination of preload and afterload reduction leads to an overall improvement in cardiac performance, manifested as an increase in cardiac output and cardiac index.[6] Furthermore, long-term treatment with quinapril has been demonstrated to improve endothelial dysfunction in patients with risk factors for atherosclerosis, suggesting a beneficial effect on vascular health beyond simple blood pressure reduction.[7]

3.3 Dose-Response, Onset, and Duration of Therapeutic Action

The antihypertensive effects of quinapril are both rapid in onset and sustained, allowing for effective 24-hour blood pressure control.

• Onset and Peak Effect: Antihypertensive activity commences within one hour of oral administration, with peak blood pressure-lowering effects typically observed between two and four hours post-dose.[5]
• Duration of ACE Inhibition: A single 20 mg dose of quinapril results in greater than 80% inhibition of plasma ACE activity that is sustained for a full 24 hours.[6] This prolonged enzymatic blockade is a key feature of the drug.
• Duration of Clinical Effect: While plasma ACE inhibition is sustained, the functional inhibition of the blood pressure response to angiotensin I is more variable throughout the dosing interval. A 20 mg dose provides approximately 75% inhibition of this pressor response at 4 hours, which decreases to 50% at 8 hours, and 20% by 24 hours.[6] This observation reveals a crucial disconnect between the biochemical measure of plasma ACE inhibition and the functional hemodynamic response. While circulating ACE levels remain suppressed for 24 hours, the clinical effect wanes towards the end of the dosing interval. This suggests that a simple measurement of plasma ACE activity is not a perfect surrogate for the drug's overall antihypertensive efficacy. The waning effect may be due to falling concentrations of quinaprilat in key tissues (such as the vascular endothelium and kidney) below a therapeutic threshold, or the influence of other compensatory pressor systems. This phenomenon explains why the trough blood pressure-lowering effect (measured just before the next dose) is approximately 50% of the peak effect.[6]
• Dose-Response: During chronic therapy, the maximal antihypertensive effect of a given dose is typically achieved within one to two weeks.[6] The dose-response relationship is described as relatively flat. However, higher doses of 40–80 mg per day have been shown to be somewhat more effective at trough than lower doses of 10–20 mg. Furthermore, administering the total daily dose in a twice-daily regimen tends to produce a lower trough blood pressure compared to once-daily dosing, which directly addresses the waning effect observed at 24 hours.[6]

4.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical pharmacology of quinapril is critically dependent on its pharmacokinetic profile, which involves its transformation from an inactive prodrug to a potent active metabolite. Understanding the ADME properties of both quinapril and quinaprilat is essential for optimizing dosing strategies and ensuring safety, particularly in special patient populations. A comparative summary of their key pharmacokinetic parameters is presented in Table 3. The data clearly shows that while the prodrug is rapidly absorbed, the therapeutic profile is entirely dictated by the formation and subsequent disposition of the active metabolite, quinaprilat. A clinician's focus, therefore, should be almost exclusively on the kinetics of quinaprilat when making therapeutic decisions.

Table 3: Summary of Pharmacokinetic Parameters for Quinapril and Quinaprilat
Parameter	Quinapril (Prodrug)	Quinaprilat (Active Metabolite)
Time to Peak Concentration (Tmax)	< 1 hour	~2.5 hours
Oral Bioavailability	~60%	Not applicable (formed via metabolism)
Plasma Protein Binding	~97%	~97%
Volume of Distribution (Vd)	Not specified	13.9 L
Elimination Half-Life	~1-2 hours	Biphasic: ~2-3 hours (initial), 25 hours (terminal)
Primary Route of Elimination	Hepatic metabolism	Renal excretion (up to 96%)
Data compiled from sources.4

4.1 Absorption Profile and Impact of Food

Following oral administration, quinapril is absorbed rapidly from the gastrointestinal tract. Peak plasma concentrations (Tmax) of the parent prodrug are achieved within one hour.[7] The extent of absorption, based on the urinary recovery of quinapril and its metabolites, is estimated to be at least 60% [7], with some data suggesting a bioavailability range of 50-80%.[19] The co-administration of quinapril with a high-fat meal has a moderate impact on its absorption, diminishing both the rate and extent by approximately 25–30%.[8]

4.2 Distribution, Volume, and Plasma Protein Binding

Once in the systemic circulation, both quinapril and its active metabolite, quinaprilat, are extensively bound to plasma proteins, with approximately 97% of the circulating drug being bound.[4] This high degree of protein binding limits the free fraction of the drug available for distribution into tissues and for elimination, contributing to its pharmacokinetic profile. The distribution of the drug is widespread throughout the body, with the notable exception of poor penetration into brain tissue.[7] The mean volume of distribution for the active metabolite quinaprilat is 13.9 L, indicating distribution beyond the plasma volume.[19]

4.3 Metabolic Pathway: Bioactivation to Quinaprilat

Quinapril is a prodrug that requires metabolic activation to exert its therapeutic effect. After absorption, it undergoes rapid and extensive de-esterification, primarily during its first pass through the liver.[3] This enzymatic hydrolysis converts quinapril to its major active metabolite, quinaprilat. This bioactivation is a critical step, with studies indicating that about 38% of an oral dose of quinapril is successfully converted to quinaprilat.[8] In addition to this primary pathway, quinapril can also be metabolized to other minor, inactive compounds, such as PD109488 (via dehydration) and PD113413.[19]

4.4 Route of Elimination and Half-Life

The elimination kinetics of quinapril and quinaprilat differ significantly and are central to the drug's dosing schedule.

• Quinapril (Prodrug): The parent drug is cleared from the plasma very quickly, with an apparent elimination half-life of only one to two hours.[4] Its rapid clearance is due to its swift conversion to quinaprilat.
• Quinaprilat (Active Metabolite): The elimination of quinaprilat is biphasic. There is an initial, relatively rapid phase of elimination with a half-life of approximately 2 to 3 hours, which corresponds to the clearance of unbound drug from the plasma.[4] This is followed by a prolonged terminal elimination phase, with a half-life of about 25 hours.[6] This sophisticated biphasic profile represents a key aspect of its pharmacological design. The long terminal phase is not due to slow metabolic clearance but rather to the very slow dissociation of quinaprilat from its high-affinity binding site on the ACE enzyme.[7] This "tight binding" means that the enzyme remains substantially inhibited long after the bulk of the drug has been cleared from the plasma. This sustained enzymatic blockade is what makes a convenient once-daily dosing regimen clinically effective, a significant advantage for patient adherence compared to older ACE inhibitors like captopril that required dosing multiple times per day.

The primary route of elimination for the active quinaprilat is renal excretion. Studies have shown that up to 96% of an intravenously administered dose is recovered in the urine, highlighting the kidney's crucial role in clearing the active drug from the body.[6]

4.5 Pharmacokinetics in Special Populations

The heavy reliance on renal excretion for quinaprilat clearance makes its pharmacokinetics susceptible to alteration in certain patient populations.

• Renal Impairment: In patients with renal insufficiency, the elimination of quinaprilat is significantly impaired. The apparent elimination half-life of quinaprilat increases as creatinine clearance (CrCl) decreases. There is a well-defined linear correlation between plasma quinaprilat clearance and CrCl, meaning that as kidney function declines, the drug is cleared more slowly, leading to its accumulation.[6] This is a critical clinical consideration that mandates dosage adjustments in patients with renal impairment to avoid potential toxicity.[24]
• End-Stage Renal Disease (ESRD): For patients with ESRD, standard renal replacement therapies such as chronic hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) have been shown to have little to no clinically significant effect on the elimination of either quinapril or quinaprilat.[22]
• Hepatic Impairment: While the liver is the site of bioactivation, the manufacturer's package insert does not provide specific guidance for dose adjustments in patients with hepatic impairment.[7]
• Elderly Patients: In elderly patients (≥65 years of age), the elimination of quinaprilat is often reduced. This reduction is primarily attributable to the natural age-related decline in renal function rather than an independent effect of age itself.[22]

5.0 Clinical Applications and Efficacy

Quinapril has established itself as a cornerstone therapy for major cardiovascular conditions. Its efficacy, supported by extensive clinical trials, extends from the primary management of hypertension to its use as a crucial adjunctive therapy in heart failure and in mitigating the progression of diabetic kidney disease.

5.1 Primary Indication: Management of Hypertension

Quinapril is indicated for the treatment of high blood pressure (hypertension) and is recognized as a first-line therapeutic option.[1] It can be administered as monotherapy or, for enhanced efficacy, in combination with other classes of antihypertensive agents, most commonly thiazide diuretics.[4]

Clinical trials have consistently demonstrated quinapril's ability to effectively lower both systolic and diastolic blood pressure. In multiple-dose studies involving daily doses ranging from 10 to 80 mg, quinapril produced a trough blood pressure reduction (the effect measured just before the next dose) of approximately 5–11 mmHg for systolic pressure and 3–7 mmHg for diastolic pressure.[6] Beyond its primary blood pressure-lowering effect, long-term therapy with quinapril has also been shown to improve endothelial dysfunction in patients with atherosclerotic risk factors, suggesting a broader benefit for vascular health.[7]

The clinical trial landscape for quinapril reflects the maturation of a successful pharmaceutical product. Initial pre-approval studies focused on establishing fundamental efficacy and dose-response relationships. In contrast, the post-approval, Phase 4 clinical trial program has explored its role in broader cardiovascular risk management. For instance, trial NCT00651287 was a large-scale study designed to evaluate the efficacy and safety of quinapril in patients with mild to moderate hypertension, both as monotherapy and in combination with hydrochlorothiazide.[25] Another major study, NCT00295542, included quinapril as part of a multi-drug protocol to assess the utility of ambulatory blood pressure monitoring in predicting cardiovascular events.[25] This evolution from basic efficacy trials to broader outcomes studies demonstrates the drug's integration as a standard of care and the ongoing effort to refine its place in complex therapeutic strategies.

5.2 Adjunctive Therapy for Congestive Heart Failure

Quinapril is also indicated as an adjunctive therapy in the management of congestive heart failure (CHF).[3] In this setting, it is typically added to a conventional treatment regimen that may include diuretics and/or digoxin. The therapeutic benefit of quinapril in heart failure stems from its favorable hemodynamic effects. By reducing systemic vascular resistance (afterload) and pulmonary capillary wedge pressure (preload), it decreases the workload on the compromised myocardium and improves overall cardiac efficiency, leading to increased cardiac output.[6]

5.3 Other Investigated Therapeutic Uses

The benefits of RAAS inhibition with quinapril have been explored in several other related conditions, consistent with the known class effects of ACE inhibitors.

• Diabetic Kidney Disease: Quinapril is used to slow the rate of progression of renal disease in patients with diabetes.[4] This nephroprotective effect is a hallmark of the ACE inhibitor class and is attributed to a reduction in intraglomerular pressure and a decrease in proteinuria.
• Left Ventricular Dysfunction: The medication is also used in the management of left ventricular dysfunction, often in the post-myocardial infarction setting, to prevent adverse cardiac remodeling.[13]
• Prevention of Atrial Fibrillation: The potential role of quinapril in cardiovascular prevention has been investigated in Phase 4 trials. Study NCT00438113 was a completed trial that explored whether aggressive blood pressure lowering with a regimen that could include quinapril could modify the atrial substrate to prevent the recurrence of atrial fibrillation.[28]
• Cardiovascular Disease and Stroke Prevention: In a similar vein, trial NCT00741585 included quinapril as a potential therapy in a study designed to assess the prognostic value of circadian ambulatory blood pressure patterns for a range of cardiovascular risks, including stroke and chronic kidney disease.[29]

5.4 Efficacy of Combination Formulations (with Hydrochlorothiazide)

To enhance antihypertensive efficacy and simplify treatment regimens, quinapril is available in fixed-dose combination tablets with the thiazide diuretic hydrochlorothiazide (HCTZ).[13] This combination is based on a sound pharmacological rationale. Thiazide diuretics lower blood pressure by promoting sodium and water excretion, which reduces plasma volume. However, this can trigger a compensatory activation of the RAAS, leading to increased renin and aldosterone levels, which can blunt the diuretic's long-term effectiveness. The co-administration of an ACE inhibitor like quinapril directly counteracts this reactive RAAS activation. Furthermore, ACE inhibitors tend to cause a slight increase in serum potassium, which helps to offset the potassium-losing (kaliuretic) effect of thiazide diuretics, resulting in a more neutral effect on potassium balance.[20]

The superior efficacy of this combination was established during the drug's development. A statistical review from the original New Drug Application (NDA) for Accuretic concluded that the combination product is significantly more effective at lowering blood pressure than either quinapril or HCTZ administered as monotherapy.[30] Following the patent expiry of the brand-name product, numerous bioequivalence studies, such as NCT00872781 and NCT00872235, have been conducted to support the approval of generic versions, ensuring continued market access to this effective combination therapy.[31]

6.0 Safety, Tolerability, and Risk Management

The safety profile of quinapril is well-characterized and is largely defined by the predictable, mechanism-based effects of the angiotensin-converting enzyme inhibitor class. While generally well-tolerated, the drug carries several important warnings and contraindications that require careful consideration by prescribing clinicians.

6.1 Profile of Adverse Events from Clinical Trials

Clinical trial data indicates that adverse experiences associated with quinapril are typically mild and transient in nature.[6] In large, placebo-controlled trials, the rate of discontinuation due to adverse events was relatively low, at 4.7% in patients treated for hypertension and 6.8% in the more clinically complex population with heart failure.[6]

The most frequently reported side effects are consistent with the ACE inhibitor class. In hypertension trials, these included headache, dizziness, fatigue, and the characteristic dry cough. In heart failure trials, the incidence of dizziness and hypotension was notably higher, reflecting the greater hemodynamic fragility of this patient population. A comparative summary of the most common adverse events is provided in Table 4.

Table 4: Incidence of Common Adverse Events in Placebo-Controlled Trials (%)
Adverse Event	Hypertension - Quinapril (N=1563)	Hypertension - Placebo (N=579)	Heart Failure - Quinapril (N=585)
Dizziness	3.9	2.6	7.7
Headache	5.6	10.9	1.7
Coughing	2.0	0.0	4.3
Fatigue	2.6	1.0	2.6
Nausea and/or Vomiting	1.4	1.9	2.4
Hypotension	Not specified	Not specified	2.9
Chest Pain	Not specified	Not specified	2.4
Data compiled from sources.6

Less frequent but clinically significant events reported in trials include palpitations, syncope, hyperkalemia, constipation, depression, and rash.[6]

6.2 Contraindications and High-Risk Patient Groups

The use of quinapril is strictly contraindicated in several specific clinical situations:

• Pregnancy: Quinapril carries a black box warning for fetal toxicity. Use of drugs that act on the RAAS during the second and third trimesters of pregnancy can cause injury and death to the developing fetus. Potential effects include fetal renal failure, oligohydramnios, lung hypoplasia, and skeletal deformities. Quinapril should be discontinued as soon as pregnancy is detected.[4]
• History of Angioedema: The drug is contraindicated in patients with a history of angioedema, whether related to previous ACE inhibitor therapy or from other causes.[4]
• Concomitant use with Aliskiren: Co-administration of quinapril with the direct renin inhibitor aliskiren is contraindicated in patients with diabetes due to an increased risk of renal impairment, hypotension, and hyperkalemia.[5]
• Concomitant use with Neprilysin Inhibitors: Due to a significantly increased risk of angioedema, quinapril must not be administered concomitantly with or within 36 hours of switching to or from a neprilysin inhibitor, such as sacubitril (found in sacubitril/valsartan).[5]
• Other contraindications include known hypersensitivity to the drug, bilateral renal artery stenosis, and pre-existing hyperkalemia.[4]

6.3 Warnings and Precautions: Angioedema, Hypotension, and Fetal Toxicity

• Angioedema: This is a rare (0.1% incidence) but potentially life-threatening adverse effect of ACE inhibitors. It can manifest as swelling of the face, extremities, lips, tongue, glottis, and/or larynx. Angioedema involving the larynx can be fatal due to airway obstruction. A rarer form, intestinal angioedema, can present with severe abdominal pain. Patients with a prior history of angioedema from any cause are at an increased risk.[4]
• Hypotension: While excessive hypotension is uncommon in patients with uncomplicated hypertension, it can occur, particularly upon initiation of therapy in patients who are volume- or salt-depleted, such as those on high-dose diuretic therapy, on dialysis, or with severe heart failure.[6]
• Impaired Renal Function: Quinapril can cause or exacerbate renal dysfunction. Increases in serum creatinine and blood urea nitrogen (BUN) may occur, especially in patients with pre-existing renal disease, heart failure, or those receiving concomitant diuretics. Careful monitoring of renal function is essential, and dose adjustments are required for patients with reduced creatinine clearance.[6]
• Hyperkalemia: By reducing aldosterone production, quinapril decreases potassium excretion and can lead to elevated serum potassium levels. The risk is highest in patients with renal insufficiency, diabetes mellitus, and those taking concomitant medications that also increase potassium, such as potassium-sparing diuretics, potassium supplements, or certain NSAIDs.[4]
• Cough: A persistent, nonproductive cough is a very common class effect, affecting a significant minority of patients. It is thought to be caused by the accumulation of bradykinin and other inflammatory mediators in the respiratory tract. The cough typically resolves upon discontinuation of the drug.[4]
• Hepatotoxicity: Although rare, ACE inhibitors as a class have been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis. Quinapril itself has been associated with a low rate (<2%) of transient elevations in serum aminotransferases, and clinically apparent severe liver injury has not been definitively linked to the drug. This relatively benign hepatic profile may be due to its limited hepatic metabolism beyond the initial bioactivation step.[33]

6.4 Clinically Significant Drug-Drug and Drug-Food Interactions

The safety and efficacy of quinapril can be significantly altered by concomitant medications and food. A summary of the most important interactions is provided in Table 5. The safety profile is largely dominated by these predictable, mechanism-based interactions. A notable exception is the interaction with tetracycline, which is not a pharmacological class effect but rather a direct consequence of the specific formulation of quinapril tablets. As previously discussed, the high magnesium carbonate content in the tablets chelates tetracycline, impairing its absorption.[7] This underscores the importance of considering not just the active pharmaceutical ingredient but also the excipients when evaluating potential drug interactions.

Table 5: Clinically Significant Drug-Drug Interactions with Quinapril
Interacting Agent/Class	Potential Clinical Outcome	Management Recommendation / Mechanism
Diuretics	Enhanced hypotensive effect, particularly at initiation.	Initiate quinapril at a low dose, consider temporarily holding the diuretic, or ensure adequate hydration.
Potassium-Sparing Diuretics, Potassium Supplements, Salt Substitutes	Increased risk of hyperkalemia.	Avoid routine co-administration if possible. Monitor serum potassium closely.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), including COX-2 inhibitors	Attenuation of antihypertensive effect; increased risk of renal impairment, including acute renal failure.	Avoid combination in high-risk patients (elderly, volume-depleted). Monitor blood pressure and renal function. Mechanism: Inhibition of renal prostaglandin synthesis.
Dual RAAS Blockade (ARBs, Aliskiren)	Increased risk of hypotension, hyperkalemia, and renal failure compared to monotherapy.	Combination is generally not recommended. Co-administration with aliskiren is contraindicated in patients with diabetes.
Lithium	Increased serum lithium levels and risk of lithium toxicity.	Monitor lithium levels frequently if co-administration is necessary. Mechanism: Reduced renal clearance of lithium.
Tetracycline	Reduced absorption of tetracycline by 28-37%.	Avoid simultaneous administration. Mechanism: Chelation by magnesium carbonate in the quinapril tablet formulation.
mTOR Inhibitors (e.g., temsirolimus, everolimus)	Increased risk of angioedema.	Use with caution and monitor for signs of angioedema.
Injectable Gold (sodium aurothiomalate)	Rare nitritoid reactions (facial flushing, nausea, vomiting, hypotension).	Monitor patients for symptoms during and after gold injection.
High-Fat Food	Reduced absorption of quinapril by 25-30%.	Administer consistently with regard to meals.
Data compiled from sources.3

7.0 Regulatory and Commercial History

The trajectory of quinapril from its initial patent to its current status as a widely used generic medication has been shaped by key regulatory milestones, market dynamics, and a significant, recent manufacturing quality crisis.

7.1 Timeline of FDA Approval and Market Introduction

Quinapril was first patented in 1980 by the pharmaceutical company Warner-Lambert and entered medical use in 1989.[4] The New Drug Application (NDA) for the single-agent product, quinapril hydrochloride, was approved by the U.S. Food and Drug Administration (FDA) on

November 19, 1991, under the brand name Accupril.[27]

The regulatory journey for the fixed-dose combination product, Accuretic (quinapril/HCTZ), was considerably more complex and lengthy. An original NDA was submitted by Parke-Davis (a division of Warner-Lambert) on December 13, 1990.[30] Clinical and statistical reviews were favorable, and the FDA issued an "approvable letter" in May 1992.[30] However, this was followed by a "not approvable" letter in September 1992, not due to any concerns about safety or efficacy, but because of the "unavailability of a manufacturing site for the final product".[30] This led Parke-Davis to withdraw the application in October 1992. This nine-year gap between the initial submission and final approval reveals that the scientific and clinical development of a drug is only one part of its path to market. The Chemistry, Manufacturing, and Controls (CMC) aspect, including securing a compliant and available manufacturing facility, can represent a significant and, in this case, decade-long logistical and regulatory bottleneck. The NDA for Accuretic was eventually resubmitted in May 1999 and received final FDA approval on

December 28, 1999.[30]

7.2 Brand Names and Generic Market Landscape

In the United States, the primary brand name for quinapril is Accupril, and for the combination product, Accuretic, both now under the ownership of Pfizer.[5] Following the expiration of market exclusivity, the first generic versions of quinapril hydrochloride tablets began to receive FDA approval in the mid-2000s. Notable approvals include those for Chartwell RX in March 2005, Lupin in June 2006, and Aurobindo Pharma in April 2013.[27]

The entry of multiple generic manufacturers has made quinapril an affordable and accessible medication. Its established efficacy and safety profile, combined with its low cost, have cemented its status as a widely prescribed drug. In 2020, it was the 253rd most commonly prescribed medication in the United States, accounting for more than 1 million prescriptions.[4]

7.3 Analysis of the N-Nitroso-quinapril Impurity and Subsequent Product Recalls

In 2022, the long-established safety record of quinapril was challenged by a significant manufacturing and quality control issue involving the detection of a nitrosamine impurity.

• The Impurity and its Risk: The impurity was identified as N-Nitroso-quinapril, which was found in some batches of the finished drug product at levels exceeding the FDA's Acceptable Daily Intake (ADI) limit.[4] Nitrosamines are a class of compounds that are considered probable human carcinogens based on animal studies. The risk is not believed to be immediate but is associated with the potential for an increased risk of cancer with long-term, chronic exposure above acceptable levels.[4] These compounds are common at low levels in water and certain foods, such as cured and grilled meats.[9]
• The Recalls: The discovery of this impurity prompted a series of voluntary recalls by major manufacturers throughout 2022, summarized in Table 6. The staggered, multi-manufacturer nature of these recalls over several months is highly significant. It points away from the conclusion of an isolated quality control failure at a single company and strongly suggests a systemic chemical stability or synthesis issue inherent to the quinapril molecule itself. The common factors across all recalls were the active pharmaceutical ingredient (quinapril) and the specific impurity (N-Nitroso-quinapril). This indicates that the formation of this nitrosamine is likely an intrinsic risk associated with the common synthesis pathways or degradation of the quinapril molecule, which contains a secondary amine susceptible to nitrosation. This shifts the perspective from a "bad batch" problem to a more fundamental "problematic molecule" issue, with broad implications for all manufacturers and the regulatory agencies that oversee them.

Table 6: Summary of 2022 Quinapril Recalls due to N-Nitroso-quinapril Impurity
Date of Announcement	Manufacturer	Product(s) Recalled	Key Details
March 2022	Pfizer / Greenstone	Accuretic (quinapril/HCTZ) and authorized generic quinapril/HCTZ tablets	Recall of multiple lots of combination products.
April 2022	Pfizer	Accupril (quinapril HCl) tablets	Recall of five lots of the single-agent brand name product.
October 2022	Aurobindo Pharma USA, Inc.	Quinapril and Hydrochlorothiazide Tablets, USP 20mg/12.5mg	Recall of two lots of the generic combination product.
December 2022	Lupin Pharmaceuticals, Inc.	Quinapril Tablets, USP 20mg and 40mg	Recall of four lots of the generic single-agent product. Lupin had already discontinued marketing the drug in September 2022.
Data compiled from sources.4

• Regulatory and Patient Guidance: Throughout this period, the FDA and manufacturers issued guidance advising patients not to abruptly stop taking their medication, as the immediate health risks of uncontrolled hypertension were considered greater than the potential long-term risk from the impurity. Patients were advised to consult with their healthcare providers to discuss alternative treatment options and to determine if their specific prescription was affected by the recalls.[9]

8.0 Synthesis and Recommendations

This monograph has provided a comprehensive examination of quinapril, from its fundamental chemical properties and pharmacological mechanism to its clinical applications and complex regulatory history. The synthesis of this information allows for a clear definition of its place in modern therapy and provides actionable considerations for healthcare providers.

8.1 Integrated Clinical Profile and Place in Therapy

Quinapril is an effective and generally well-tolerated angiotensin-converting enzyme inhibitor with a robust evidence base for its use in hypertension and as adjunctive therapy in heart failure. Its pharmacological profile is advantageous, featuring a convenient once-daily dosing regimen made possible by the prolonged terminal elimination half-life of its active metabolite, quinaprilat. This feature likely enhances patient adherence compared to older agents in its class.

Its role as a first-line agent for hypertension is well-established, and its proven benefits in slowing the progression of diabetic nephropathy and managing left ventricular dysfunction are consistent with the valuable, pleiotropic effects of the ACE inhibitor class. While its antihypertensive efficacy may be slightly attenuated in low-renin populations, it remains a valuable tool across a broad spectrum of patients. The widespread availability of low-cost generic formulations has solidified its position as a workhorse medication in the management of cardiovascular disease.

8.2 Key Considerations for Prescribers and Healthcare Providers

Based on the comprehensive data, the following key considerations should guide the clinical use of quinapril:

• Patient Selection and Screening: Rigorous screening for contraindications is essential before initiating therapy. This includes confirming the patient is not pregnant and has no plans to become pregnant, inquiring about any personal or family history of angioedema, and avoiding use in patients with known bilateral renal artery stenosis. Concomitant use with aliskiren in diabetic patients or with sacubitril/valsartan is contraindicated.
• Dosing, Initiation, and Monitoring: Therapy should be initiated at a low dose, particularly in patients at risk for hypotension, such as those on high-dose diuretics or with severe heart failure. Following initiation and any subsequent dose titration, routine monitoring of blood pressure, renal function (serum creatinine and BUN), and serum potassium levels is critical to ensure safety and efficacy.
• Patient Counseling: Effective patient education is paramount. Patients must be counseled on the potential for developing a dry, persistent cough. They must be educated on the signs and symptoms of angioedema (e.g., swelling of the face, lips, or tongue; difficulty breathing) and instructed to seek immediate emergency medical attention if these occur. The absolute contraindication in pregnancy must be clearly and repeatedly communicated to all patients of childbearing potential.
• Navigating the Nitrosamine Issue: Clinicians must be aware of the 2022 product recalls due to N-Nitroso-quinapril contamination. While regulatory bodies did not recommend that patients stop treatment abruptly, this event warrants a conversation with patients currently taking quinapril. This discussion may involve verifying that the patient's current supply is not from a recalled lot and, if necessary, switching to an alternative therapeutic agent (such as another ACE inhibitor not affected by recalls, or an angiotensin II receptor blocker) to alleviate patient concerns and mitigate any potential long-term risk.

8.3 Future Outlook and Unresolved Issues

The primary unresolved issue surrounding quinapril is the long-term consequence of the N-Nitroso-quinapril impurity findings. This industry-wide event will almost certainly lead to more stringent regulatory oversight of manufacturing processes, not only for quinapril but for other pharmaceutical agents with chemical structures susceptible to nitrosation. Manufacturers will be required to implement more robust control strategies to prevent the formation of such impurities.

The future clinical use of quinapril may be influenced by prescriber and patient confidence. The high-profile nature of the recalls could lead to a durable shift in prescribing patterns towards other ACE inhibitors or alternative drug classes like ARBs, even if the manufacturing issues are fully resolved.

Given its mature status as a generic drug, future research is unlikely to focus on discovering new indications for quinapril. Instead, the focus will remain on pharmacovigilance, ensuring manufacturing quality and supply chain integrity, and generating real-world evidence to further confirm its long-term benefits in reducing cardiovascular morbidity and mortality.

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