A Comprehensive Monograph on Benazepril (DrugBank ID: DB00542)

Section 1: Drug Profile and Chemical Characteristics

Benazepril is a second-generation angiotensin-converting enzyme (ACE) inhibitor widely utilized in cardiovascular medicine. A thorough understanding of its chemical identity, physicochemical properties, and available formulations is fundamental to appreciating its pharmacological behavior and clinical application.

1.1 Identification and Nomenclature

To ensure unambiguous identification across global databases and regulatory frameworks, Benazepril is cataloged under multiple identifiers.

• Generic Name: The universally recognized generic name is Benazepril.[1] International non-proprietary names include the French Bénazépril and the Latin Benazeprilum.[1]
• Systematic Chemical Name: According to IUPAC nomenclature, the compound is named (3S)-3-amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid hydrochloride.[2] An alternate chemical name is 2-amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid.[3]
• Database and Registry Identifiers: The drug is assigned unique codes in various scientific and regulatory databases, including:
• DrugBank ID: DB00542 [1]
• CAS Numbers: A distinction is made between the active moiety and its pharmaceutically relevant salt form. The CAS number for the benazepril free base is 86541-75-5 [4], while the clinically utilized benazepril hydrochloride salt is identified by CAS number 86541-74-4.[2]
• Other Identifiers: Additional identifiers include UNII PX47FSF9B3, ChEBI ID CHEBI:3011, ChEMBL ID CHEMBL838, and the research code CGS-14824A.[1]

1.2 Physicochemical Properties

The molecular structure and physical properties of benazepril govern its absorption, distribution, and interaction with its biological target.

• Chemical Formula and Molecular Weight: The chemical formula for the benazepril free base is C24​H28​N2​O5​.[5] Its corresponding molecular weight is approximately 424.49 g/mol.[5] The hydrochloride salt has the formula C24​H28​N2​O5​⋅HCl and a molecular weight of approximately 460.96 g/mol.[2]
• Structural Classification: Benazepril is categorized as a small molecule drug.[1] Structurally, it is a benzazepine derivative, containing a dicarboxylic acid monoester, an ethyl ester, and a lactam moiety.[4] Critically, it is a non-sulfhydryl ACE inhibitor, which distinguishes it from first-generation agents like captopril and is associated with a different side-effect profile.[4]
• Physical Description and Solubility: In its pharmaceutical form, benazepril hydrochloride is a white to off-white crystalline powder.[9] The selection of the hydrochloride salt is a deliberate and crucial aspect of its pharmaceutical design. This salt form is highly soluble in water (reported as >100 mg/mL), as well as in ethanol and methanol.[9] This high aqueous solubility ensures rapid and consistent dissolution within the gastrointestinal tract, a prerequisite for reliable oral absorption and predictable bioavailability, which underpins its clinical efficacy.

1.3 Formulations and Brand Names

Benazepril is available for clinical use as a single-agent therapy and in fixed-dose combinations to enhance efficacy and improve patient adherence.

• Monotherapy: The primary brand name for benazepril monotherapy is Lotensin®.[1] It is supplied as oral tablets in strengths of 10 mg, 20 mg, and 40 mg for human use.[11] A 5 mg tablet was previously available but has been discontinued.[13]
• Fixed-Dose Combination Products: To target multiple pathways of hypertension, benazepril is co-formulated with other antihypertensive agents:
• With Hydrochlorothiazide: Marketed as Lotensin HCT®, this combination pairs the ACE inhibitor with a thiazide diuretic, providing an additive blood pressure-lowering effect.[7]
• With Amlodipine: Marketed under the brand names Lotrel® and Amlobenz®, this formulation combines benazepril with a dihydropyridine calcium channel blocker, offering a synergistic mechanism for blood pressure control.[7]
• Veterinary Formulations: Benazepril also has important applications in veterinary medicine, where it is marketed under brand names such as Fortekor® (Novartis) and VetACE® (Jurox Animal Health) for the treatment of heart failure and chronic kidney disease in dogs and cats.[12]

Attribute	Value
Generic Name	Benazepril
DrugBank ID	DB00542
CAS Number (Free Base)	86541-75-5
CAS Number (Hydrochloride Salt)	86541-74-4
Chemical Formula (Free Base)	C24​H28​N2​O5​
Molecular Weight (Free Base)	424.49 g/mol
Molecular Weight (HCl Salt)	460.96 g/mol
US Brand Name (Monotherapy)	Lotensin®
US Brand Names (Combination)	Lotensin HCT®, Lotrel®, Amlobenz®
Table 1: Benazepril Identification and Chemical Properties. This table consolidates the key identifiers and physicochemical data for quick, unambiguous reference.

Section 2: Comprehensive Pharmacological Profile

The clinical effects of benazepril are a direct result of its molecular interactions within the body (pharmacodynamics) and the processes of its absorption, distribution, metabolism, and excretion (pharmacokinetics). A key feature of benazepril is its nature as a prodrug, which dictates its metabolic fate and onset of action.

2.1 Pharmacodynamics: Mechanism of Action

Benazepril's therapeutic effects are mediated through the targeted inhibition of the Renin-Angiotensin-Aldosterone System (RAAS), a critical regulator of blood pressure and fluid balance.

• Prodrug Bioactivation: Benazepril itself is a pharmacologically inactive prodrug.[4] Following oral administration, it is rapidly absorbed and undergoes extensive first-pass metabolism, primarily in the liver. Hepatic esterase enzymes hydrolyze the ethyl ester group, converting benazepril into its active diacid metabolite, benazeprilat.[1] It is benazeprilat that functions as the potent, non-sulfhydryl ACE inhibitor responsible for the drug's clinical effects.[9]
• Inhibition of the Renin-Angiotensin-Aldosterone System (RAAS):
• The molecular target of benazeprilat is Angiotensin-Converting Enzyme (ACE), a peptidyl dipeptidase also known as kininase II.[10]
• Benazeprilat competitively binds to and inhibits ACE, thereby preventing the conversion of the inactive decapeptide angiotensin I to angiotensin II, a powerful vasoconstrictor and key effector of the RAAS.[1]
• This inhibition leads to a significant reduction in circulating and tissue levels of angiotensin II. The downstream physiological consequences include:

1. Vasodilation: With lower levels of the vasoconstrictor angiotensin II, vascular smooth muscle relaxes, leading to a decrease in systemic vascular resistance (afterload) and a subsequent reduction in blood pressure.[14] This is the primary antihypertensive mechanism, confirmed in hemodynamic studies showing reduced peripheral arterial resistance.[10]
2. Reduced Aldosterone Secretion: Angiotensin II is a potent stimulus for the release of aldosterone from the adrenal cortex. By suppressing angiotensin II formation, benazeprilat indirectly decreases aldosterone secretion.[1] This natriuretic effect promotes the excretion of sodium and water while causing a mild retention of potassium, which may result in a small, clinically insignificant increase in serum potassium in most patients.[9]

• Effects on Bradykinin and Renal Hemodynamics:
• ACE (kininase II) is also the primary enzyme responsible for degrading bradykinin, a potent endogenous vasodilator. ACE inhibition by benazeprilat leads to an accumulation of bradykinin, which is believed to contribute to the drug's vasodilatory and antihypertensive effects.[10] This same mechanism is implicated as a primary cause of the characteristic dry, nonproductive cough associated with all ACE inhibitors.
• Notably, benazepril exerts an antihypertensive effect even in patients with low-renin forms of hypertension, suggesting that mechanisms beyond RAAS suppression, such as the bradykinin potentiation, play a role.[9]
• In terms of renal effects, single doses in healthy individuals have been shown to increase renal blood flow without altering the glomerular filtration rate.[10]

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

The clinical utility of a drug is determined not only by its mechanism but also by how it is processed by the body. The pharmacokinetic profile of the active metabolite, benazeprilat, is the most critical determinant of benazepril's dosing schedule and therapeutic timeline. The parent drug, benazepril, functions primarily as a delivery system for benazeprilat.

• Absorption: Following oral administration, at least 37% of a benazepril dose is absorbed from the gastrointestinal tract.[1] Peak plasma concentrations of the parent prodrug, benazepril, are achieved very rapidly, typically within 0.5 to 1.0 hour.[9] The presence of food does not alter the overall extent of absorption (bioavailability) but does slow the rate, delaying the time to peak concentration of the active metabolite, benazeprilat.[9]
• Distribution: Both benazepril and benazeprilat are extensively bound to plasma proteins, with binding percentages of approximately 96.7% and 95.3%, respectively.[1] This high degree of protein binding limits the volume of distribution of the free, pharmacologically active drug. The population pharmacokinetic model estimates a volume of distribution of 203 L.[1]
• Metabolism: As a prodrug, benazepril is almost completely metabolized to benazeprilat via hepatic esterase cleavage.[9] Peak plasma concentrations of benazeprilat are reached between 1-2 hours after an oral dose in a fasting state and are delayed to 2-4 hours when taken with food.[9] The onset of blood pressure reduction (within 1 hour) and the time of peak antihypertensive effect (2-4 hours) correlate directly with the appearance and peak levels of benazeprilat, not the parent drug.[10] Both benazepril and benazeprilat also undergo glucuronidation to form conjugates that are then excreted.[1]
• Excretion: The clearance of benazepril and its metabolites is primarily through renal excretion in individuals with normal kidney function.[1] However, a notable secondary pathway exists, with non-renal (biliary) excretion accounting for approximately 11-12% of benazeprilat elimination.[1] This dual excretion pathway provides a partial compensatory mechanism in cases of renal impairment, though it is not sufficient to prevent drug accumulation in severe cases, thus necessitating dose adjustments.[19] The pharmacokinetics are dose-proportional in the 10-80 mg range.[9] The effective accumulation half-life of benazeprilat is 10-11 hours, which provides sustained ACE inhibition over a 24-hour period and is the basis for the convenient once-daily dosing regimen.[1] Steady-state concentrations are typically achieved after two to three doses.[9]

Parameter	Benazepril (Prodrug)	Benazeprilat (Active Metabolite)
Oral Bioavailability	At least 37% absorbed 9	N/A (formed via metabolism)
Time to Peak Plasma Conc. (Tmax)	0.5 - 1.0 hour 9	1 - 2 hours (fasting); 2 - 4 hours (fed) 9
Serum Protein Binding	~96.7% 9	~95.3% 9
Effective Half-Life of Accumulation	~2.7 hours 1	10 - 11 hours 9
Primary Elimination Route	Hepatic metabolism to benazeprilat 9	Renal excretion (~88-89%); Biliary excretion (~11-12%) 9
Table 2: Summary of Key Pharmacokinetic Parameters for Benazepril and Benazeprilat. This table highlights the critical differences between the prodrug and its active form, which govern the drug's clinical use.

Section 3: Clinical Applications and Therapeutic Efficacy

Benazepril is a well-established therapeutic agent with a primary role in the management of hypertension, supported by additional applications in other cardiovascular and renal conditions, as well as in veterinary medicine.

3.1 Approved and Off-Label Indications in Human Medicine

• Hypertension (FDA Approved): The sole FDA-approved indication for benazepril is the treatment of hypertension.[1] It is effective as a monotherapy or can be used in combination with other antihypertensive drugs, most commonly thiazide diuretics.[20] The clinical benefit of its use extends beyond simple blood pressure reduction to a decreased risk of major cardiovascular events, including stroke and myocardial infarction.[4]
• Heart Failure (Off-Label Use): Benazepril is frequently used off-label for the management of congestive heart failure.[12] Clinical evidence indicates that it can improve indices of cardiac function, alleviate clinical symptoms, and enhance exercise capacity in this patient population.[22]
• Diabetic Kidney Disease / Nephropathy (Off-Label Use): The renoprotective effects of benazepril make it a valuable agent for treating diabetic kidney disease.[5] It is recommended for patients with diabetes and persistent albuminuria, as it has been shown to slow the rate of disease progression.[1]
• Left Ventricular Dysfunction (Off-Label Use): The drug is also used in the broader context of managing patients with left ventricular dysfunction post-myocardial infarction.[5]

3.2 Synthesis of Clinical Trial Evidence

The efficacy of benazepril is supported by a robust body of clinical trial data.

• Dose-ranging studies in patients with mild-to-moderate hypertension demonstrated that 10 mg once daily is the minimal effective dose, with additional blood pressure lowering observed at doses up to 80 mg daily.[17]
• Head-to-head comparative trials have shown that benazepril (10-20 mg) has antihypertensive efficacy comparable to that of other first-line agents, including the ACE inhibitor captopril and the beta-blocker propranolol.[17]
• Its efficacy in pediatric hypertension was confirmed in a randomized, placebo-controlled withdrawal study in patients aged 7 to 16 years.[17]
• The drug's role in renal protection has been explored in dedicated Phase 3 trials, such as studies designed to prevent microalbuminuria (NCT00503152) and end-stage renal disease (NCT00494715) in patients with type 2 diabetes.[24]
• The landmark ACCOMPLISH trial (NCT00170950) was a major cardiovascular outcomes study that investigated a benazepril-based strategy, comparing the combination of benazepril plus amlodipine to benazepril plus hydrochlorothiazide in high-risk hypertensive patients.[25] This trial highlighted the importance of benazepril as a component of combination therapy.

3.3 Comparative Efficacy Analysis: Benazepril vs. Lisinopril and Ramipril

While ACE inhibitors share a common mechanism, subtle differences in their clinical profiles can influence drug selection.

• Approved Indications: Benazepril's FDA label is specific to hypertension.[26] In contrast, lisinopril and ramipril have broader approvals that include heart failure and improving survival after a myocardial infarction, reflecting a larger body of evidence from major cardiovascular outcome trials for those specific conditions.[26]
• Dosing Frequency: Lisinopril and ramipril are typically administered once daily.[26] Benazepril offers greater flexibility, as it can be given once or twice daily. The twice-daily regimen provides superior control of trough (pre-dose) blood pressure, which can be advantageous for patients with inadequate 24-hour coverage on a single dose.[20]
• Efficacy and Outcomes: While generally considered a class effect, some evidence suggests potential differences between agents. One network meta-analysis of ACE inhibitors in chronic heart failure (which did not include benazepril) found that ramipril was associated with the lowest all-cause mortality, whereas lisinopril was associated with the highest.[30] This underscores that not all ACE inhibitors may be interchangeable for every indication. Benazepril's modern clinical value is often realized not as a monotherapy for complex conditions like heart failure, but as a reliable and effective component of fixed-dose combination products. The success of formulations like Lotrel® and the focus of major trials like ACCOMPLISH on benazepril-based combinations demonstrate its role as a foundational agent in strategies that align with current guidelines recommending early use of multi-drug therapy for hypertension.[25]
• Side Effect Profile: The characteristic side effects, particularly dry cough and dizziness, are common to all three agents.[32] User-reported data indicates a cough incidence of around 20% for benazepril, 19% for ramipril, and up to 29% for lisinopril.[12]

3.4 Applications in Veterinary Medicine

Benazepril is an important therapeutic agent in veterinary cardiology and nephrology.

• Marketed as Fortekor® and VetACE®, it is approved for the treatment of congestive heart failure in dogs.[12]
• It is also a standard treatment for chronic kidney failure in both cats and dogs, where it helps to manage proteinuria and slow disease progression.[12]
• Pharmacokinetic and pharmacodynamic studies conducted in dogs have confirmed that benazepril is a potent, long-acting ACE inhibitor in this species, validating its once-daily dosing for these indications.[33]

Attribute	Benazepril	Lisinopril	Ramipril
FDA-Approved Indications	Hypertension 26	Hypertension, Heart Failure, Post-MI 26	Hypertension, Heart Failure Post-MI, Stroke/MI Risk Reduction 28
Typical Dosing Frequency	Once or twice daily 29	Once daily 29	Once daily 29
Prodrug Status	Yes (active metabolite: benazeprilat) 4	No (active as parent drug)	Yes (active metabolite: ramiprilat)
Primary Elimination Route	Renal and Biliary 10	Renal	Renal
Key Differentiating Features	Flexible dosing; strong role in combination products (e.g., Lotrel®)	Available as oral solution; broad indications	Strong evidence for cardiovascular risk reduction (HOPE trial)
Table 5: Comparative Profile of Benazepril, Lisinopril, and Ramipril. This table provides a high-yield comparison of three commonly prescribed ACE inhibitors.

Section 4: Dosage, Administration, and Use in Specific Populations

Effective and safe use of benazepril requires adherence to established dosing guidelines and appropriate adjustments for specific patient populations.

4.1 Dosing and Administration Guidelines

• Adult Hypertension:
• Initial Dose (No Diuretic): Therapy is typically initiated at 10 mg once daily.[9]
• Initial Dose (Concomitant Diuretic): In patients already receiving a diuretic, the risk of first-dose hypotension is increased. To mitigate this, the starting dose of benazepril should be reduced to 5 mg once daily.[20]
• Maintenance Dose: The usual therapeutic dose is 20-40 mg per day. This can be given as a single daily dose or split into two equally divided doses.[9] Clinical studies have shown that a divided regimen provides more consistent control of blood pressure over a 24-hour period.[9]
• Maximum Dose: While a dose of 80 mg daily may provide additional benefit, clinical experience at this level is limited.[9]
• Pediatric Hypertension (≥6 years of age):
• Dosing in children is based on body weight to ensure safety and efficacy. The recommended starting dose is 0.2 mg/kg once daily.[15]
• The dose may be titrated upwards as needed to a maximum of 0.6 mg/kg once daily, with the total daily dose not to exceed 40 mg.[15]
• Administration: Benazepril tablets can be taken orally without regard to meals, as food does not affect the extent of absorption.[23]
• Preparation of Oral Suspension: The significant pharmacokinetic differences between children and adults, including faster clearance in pediatric patients, necessitate precise, weight-based dosing that is often impossible with available tablet strengths.[9] To address this clinical need, the FDA-approved label provides a specific, validated protocol for compounding a 2 mg/mL oral suspension. This procedure involves crushing fifteen 20 mg tablets and suspending them in 75 mL of Ora-Plus® followed by 75 mL of Ora-Sweet®. The resulting suspension is stable for up to 30 days when refrigerated, providing a safe and accurate method for pediatric administration.[20]

4.2 Dosing Adjustments in Special Populations

• Renal Impairment:
• Adults: For patients with significantly impaired renal function, defined as a Glomerular Filtration Rate (GFR) below 30 mL/min/1.73 m2 (or serum creatinine >3 mg/dL), the initial dose should be reduced to 5 mg once daily. The dose can then be carefully titrated up to a maximum of 40 mg per day.[11] No dose adjustment is necessary for patients with mild-to-moderate renal impairment (GFR >30 mL/min).[18]
• Pediatrics: Benazepril has not been studied in and is not recommended for pediatric patients with a GFR <30 mL/min/1.73 m2.[20]
• Hepatic Impairment: Benazepril is converted to its active form in the liver. However, studies in patients with hepatic insufficiency from cirrhosis have shown that the pharmacokinetics of the active metabolite, benazeprilat, are not substantially altered. Therefore, dose adjustment is generally not required in this population.[9]
• Geriatric Patients: While clinical trials have not shown an overall difference in efficacy or safety in older adults, the physiological decline in renal function with age is a key consideration. Dose selection should be cautious, often starting at the lower end of the adult range, and monitoring of renal function is advisable.[18]
• Lactation: Benazepril and benazeprilat are excreted into human breast milk in very small quantities. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.[12]
• Neonates (with in utero exposure): Newborns exposed to benazepril in utero should be closely monitored for hypotension and oliguria. Supportive care to maintain blood pressure and renal perfusion is paramount. In severe cases, exchange transfusions or dialysis may be considered to remove the drug from circulation.[20]

Patient Population	Initial Dose	Maintenance Dose Range	Maximum Dose	Notes
Adults (Hypertension)	10 mg once daily	20 - 40 mg/day (once or twice daily)	80 mg/day	Start with 5 mg if on a diuretic 20
Pediatrics (≥6 years)	0.2 mg/kg once daily	Titrate as needed	0.6 mg/kg/day or 40 mg/day	Not recommended if GFR <30 20
Geriatrics	Start at lower end of adult range	20 - 40 mg/day	80 mg/day	Monitor renal function 20
Renal Impairment (GFR <30)	5 mg once daily	Titrate as needed	40 mg/day	For adults only 20
Hepatic Impairment	No adjustment needed	20 - 40 mg/day	80 mg/day	Pharmacokinetics of active metabolite are unaltered 20
Table 3: Dosing Guidelines for Benazepril Across Patient Populations. This table provides a consolidated reference for clinical dosing.

Section 5: Safety, Tolerability, and Risk Management

The safety profile of benazepril is well-characterized and is largely consistent with the ACE inhibitor class. Management involves awareness of common side effects, recognition of rare but serious adverse reactions, and adherence to contraindications and drug interaction warnings.

5.1 Profile of Adverse Drug Reactions (ADRs)

• Common ADRs: The most frequent side effects are generally mild and do not necessitate discontinuation of therapy.
• Cough: A persistent, dry, nonproductive cough is the most characteristic side effect of the ACE inhibitor class. It is attributed to the accumulation of bradykinin and is reported to occur in approximately 20% of patients treated with benazepril.[12]
• Central Nervous System: Headache (up to 6%) and dizziness (up to 4%) are the most common CNS effects. Fatigue and somnolence (drowsiness) are also reported.[1]
• Cardiovascular: Postural dizziness or orthostatic hypotension (light-headedness upon standing) can occur, particularly at the start of therapy.[1]
• Gastrointestinal: Nausea is a commonly reported GI side effect.[1]
• Serious ADRs:
• Angioedema: This is a rare (<1%) but potentially life-threatening reaction involving rapid swelling of the dermis, subcutaneous tissue, and mucosa. It can affect the face, extremities, lips, tongue, glottis, or larynx. Laryngeal involvement can cause fatal airway obstruction.[12] The incidence of angioedema is significantly higher in Black patients compared to other populations.[23]
• Hypotension: While mild dizziness is common, severe symptomatic hypotension can occur, especially in patients who are volume- or salt-depleted, such as those on high-dose diuretic therapy or with severe heart failure.[12]
• Hyperkalemia: ACE inhibitors can cause an increase in serum potassium levels by reducing aldosterone secretion. This is of greatest concern in patients with pre-existing renal impairment, diabetes mellitus, or those concurrently taking other medications that increase potassium.[12]
• Renal Failure: In patients whose renal function is highly dependent on the RAAS (e.g., those with bilateral renal artery stenosis or severe heart failure), benazepril can precipitate acute renal failure.[12]
• Hepatotoxicity: Rarely, ACE inhibitors have been associated with a syndrome that begins as cholestatic jaundice and can progress to fulminant hepatic necrosis, which can be fatal.[4]

5.2 Contraindications and Black Box Warning

There are absolute contraindications to the use of benazepril.

• FDA Black Box Warning: Fetal Toxicity: Drugs that act directly on the renin-angiotensin system, including benazepril, can cause significant fetal and neonatal morbidity and mortality when used during pregnancy, particularly during the second and third trimesters. Potential effects include hypotension, neonatal skull hypoplasia, anuria, renal failure, and death. If pregnancy is detected, benazepril must be discontinued as soon as possible.9
• Contraindications:
• Hypersensitivity: A history of hypersensitivity to benazepril or any other ACE inhibitor is an absolute contraindication.[15]
• History of Angioedema: Patients with a prior history of angioedema, regardless of its cause (idiopathic or related to previous ACE inhibitor use), should not receive benazepril.[11]
• Concomitant Use with Aliskiren: The combination of benazepril and the direct renin inhibitor aliskiren is contraindicated in patients with diabetes due to an increased risk of renal impairment, hyperkalemia, and hypotension.[23]
• Concomitant Use with Sacubitril/Valsartan: To minimize the risk of angioedema, benazepril is contraindicated for use within 36 hours of switching to or from the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan.[16]

5.3 Clinically Significant Drug Interactions

Benazepril can interact with several other medications, requiring cautious co-administration or avoidance.

• Diuretics: The combination can lead to an additive hypotensive effect. When initiating benazepril in a patient on a diuretic, a lower starting dose (5 mg) is recommended to prevent an excessive drop in blood pressure.[10]
• Potassium-Sparing Diuretics and Potassium Supplements: Co-administration with agents like spironolactone, amiloride, or potassium supplements significantly increases the risk of developing hyperkalemia. Frequent monitoring of serum potassium is mandatory if this combination is deemed necessary.[10]
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): This interaction represents a critical risk of renal injury. ACE inhibitors cause vasodilation of the efferent (outgoing) arteriole of the glomerulus. In states of reduced renal perfusion, the kidney maintains its filtration pressure via prostaglandin-mediated vasodilation of the afferent (incoming) arteriole. NSAIDs block prostaglandin synthesis, causing afferent vasoconstriction.[36] The simultaneous efferent dilation and afferent constriction can cause a precipitous fall in glomerular filtration pressure, leading to acute renal failure. This risk is highest in the elderly and volume-depleted patients. NSAIDs can also blunt the antihypertensive effect of benazepril.[23]
• Lithium: Benazepril can decrease the renal clearance of lithium, leading to elevated serum lithium levels and an increased risk of lithium toxicity. If co-administration is necessary, frequent monitoring of serum lithium concentrations is essential.[10]
• Dual RAAS Blockade: Combining benazepril with another RAAS inhibitor, such as an angiotensin receptor blocker (ARB) or aliskiren, is generally not recommended. This dual blockade offers little additional benefit and substantially increases the risk of hypotension, hyperkalemia, and renal dysfunction.[23]
• mTOR and Neprilysin Inhibitors: The concomitant use of benazepril with mTOR inhibitors (e.g., sirolimus) or neprilysin inhibitors (e.g., sacubitril) markedly increases the risk of angioedema and is contraindicated in the case of sacubitril.[23]

Interacting Drug/Class	Potential Clinical Outcome	Clinical Management Strategy
NSAIDs	Acute renal failure, attenuated antihypertensive effect 36	Avoid combination in at-risk patients (elderly, volume-depleted, CKD). Monitor renal function and blood pressure.
Potassium-Sparing Diuretics / K+ Supplements	Hyperkalemia 15	Use with caution only for documented hypokalemia. Monitor serum potassium frequently.
Lithium	Lithium toxicity due to decreased renal clearance 15	Co-administer with caution. Monitor serum lithium levels frequently.
Neprilysin Inhibitors (e.g., Sacubitril)	Markedly increased risk of angioedema 23	Contraindicated. Do not administer within 36 hours of each other.
Dual RAAS Blockers (ARBs, Aliskiren)	Increased risk of hypotension, hyperkalemia, renal failure 23	Generally avoid combination. Contraindicated with aliskiren in diabetic patients.
Table 4: Clinically Significant Drug-Drug Interactions and Management. This table provides a practical guide for prescribers to mitigate risks associated with benazepril co-administration.

5.4 Overdosage

Human experience with benazepril overdosage is limited. The most probable clinical manifestation is severe hypotension.[1] Treatment is supportive and should focus on correcting hypotension via intravenous infusion of normal saline solution. Benazeprilat, the active metabolite, is only slightly dialyzable, meaning hemodialysis is of limited utility in overdose management.[9]

Section 6: Regulatory and Commercial Landscape

The history of benazepril illustrates a typical pharmaceutical lifecycle, from its development by an innovator company to its current status as a widely available and prescribed generic medication.

6.1 Development and Regulatory History

• Invention and Patent: Benazepril was developed by Ciba-Geigy Corporation (a predecessor of Novartis) and was first disclosed in U.S. Patent 4,410,520.[37] The compound was patented in 1981, with its first medical use occurring in 1990.[12]
• FDA Approval: The brand name product, Lotensin® (benazepril hydrochloride), received its initial approval from the U.S. Food and Drug Administration (FDA) on June 25, 1991, under New Drug Application (NDA) 19-851.[13]
• Generic Entry: The patent and market exclusivity for Lotensin® eventually expired, paving the way for generic competition. The first Abbreviated New Drug Applications (ANDAs) for generic benazepril hydrochloride tablets were approved by the FDA on February 11, 2004. Companies such as Mylan immediately launched their generic versions, significantly increasing the accessibility and affordability of the medication.[13]
• Market Presence: Despite the availability of many other antihypertensive agents, benazepril maintains a strong market presence. In 2023, it was the 172nd most commonly prescribed medication in the United States, accounting for over 2 million prescriptions, which speaks to its established role in clinical practice.[12]

6.2 Global Availability and Brand Portfolio

The commercial lifecycle of benazepril exemplifies a common pharmaceutical strategy of extending a product's value beyond the patent expiration of the original molecule. While the monotherapy patent for Lotensin® expired, leading to generic entry in 2004, the innovator company had already developed and patented fixed-dose combination products.[13] For example, the patent for the benazepril/amlodipine combination (Lotrel®) was filed in 1992 and issued in 2000, providing an extended period of market exclusivity for this branded combination therapy long after the parent molecule became generic.[39] This strategy allowed the manufacturer to retain a significant market share in the hypertension space by shifting prescribing habits toward a more convenient, still-patented combination product.

• United States:
• Monotherapy: Available as branded Lotensin® and numerous generic versions from manufacturers like Amneal, Aurobindo, and Teva.[13]
• Combinations: The fixed-dose combinations are widely available as Lotensin HCT® (with hydrochlorothiazide) and Lotrel® or Amlobenz® (with amlodipine).[7]
• International and Veterinary:
• The drug is available globally under its generic name and various local brand names.[1]
• In the veterinary market, it is prominently sold under the brand names Fortekor® and VetACE®.[12]

Section 7: Expert Synthesis and Conclusion

This comprehensive analysis consolidates the chemical, pharmacological, clinical, and regulatory data on benazepril, providing a holistic perspective on its position in modern cardiovascular pharmacotherapy.

• Summary of Core Profile: Benazepril is a well-characterized, non-sulfhydryl ACE inhibitor that acts as a prodrug. Its therapeutic effects are mediated by its active metabolite, benazeprilat, which potently inhibits the renin-angiotensin-aldosterone system. The key pharmacokinetic feature of benazeprilat is its long effective half-life of 10-11 hours, which allows for sustained 24-hour blood pressure control and supports a convenient once-daily or flexible twice-daily dosing regimen.
• Clinical Position and Value: While its FDA-approved indication is limited to hypertension, benazepril has demonstrated efficacy in off-label uses such as heart failure and diabetic nephropathy. In the contemporary therapeutic landscape, which includes numerous ACE inhibitors with broader indications backed by large-scale outcome trials, benazepril's primary clinical value lies in its role as a reliable, well-tolerated, and cost-effective antihypertensive agent. Its most significant contribution to modern practice is arguably its successful integration into highly effective fixed-dose combination therapies, such as with amlodipine (Lotrel®) and hydrochlorothiazide (Lotensin HCT®). These combinations align perfectly with current hypertension guidelines that advocate for early and aggressive blood pressure control, often with multi-drug regimens, thereby simplifying treatment and improving patient adherence.
• Key Considerations for Clinical Practice: The safe and effective use of benazepril hinges on diligent clinical management. Prescribers must remain vigilant for the hallmark ACE inhibitor class effects, including persistent cough and the rare but serious risk of angioedema, with a heightened awareness of the increased risk in Black patients. Routine monitoring of renal function and serum potassium is essential, especially in at-risk populations. A thorough understanding of its significant drug interactions—particularly the synergistic risk of acute kidney injury with NSAIDs and the potential for hyperkalemia with potassium-sparing agents—is critical for preventing adverse events. Furthermore, strict adherence to dosage adjustments in patients with severe renal impairment and the use of weight-based dosing via a compounded suspension in children are non-negotiable aspects of safe prescribing.
• Concluding Remarks: Over three decades since its introduction, benazepril remains a relevant and valuable therapeutic agent. Its evolution from a novel, patented molecule to a widely prescribed generic and a cornerstone of effective combination therapies is a testament to its enduring efficacy, safety, and versatility. Its continued high prescription volume is not merely a legacy effect but reflects its established place as a dependable and economical tool in the long-term management of hypertension and related cardiovascular conditions.

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