Benazepril

Overview

Benazepril (Lotensin®) is an angiotensin converting enzyme (ACE) inhibitor used in dogs and cats for the management of congestive heart failure (CHF), systemic hypertension, chronic kidney disease (CKD), and proteinuria. It is commonly incorporated into multimodal therapy protocols where modulation of the renin–angiotensin–aldosterone system (RAAS) is desired.

In dogs, benazepril is frequently used as part of combination therapy for CHF, particularly in patients with myxomatous mitral valve disease or dilated cardiomyopathy. In cats, it is most often prescribed for CKD and proteinuric renal disease, where reduction of glomerular hypertension and urine protein loss is a primary therapeutic goal.

Mechanism of Action (MOA): Benazepril is a prodrug that is converted in the liver to its active metabolite, benazeprilat. Benazeprilat inhibits angiotensin converting enzyme (ACE), preventing the formation of angiotensin II. This results in decreased vasoconstriction, reduced aldosterone secretion, lowered systemic vascular resistance, and reduced sodium and water retention. In the kidneys, dilation of efferent arterioles decreases intraglomerular pressure, contributing to reduced proteinuria but potentially causing mild increases in serum creatinine at initiation of therapy.

Indications

Benazepril is used in dogs and cats for cardiovascular and renal conditions where inhibition of the renin–angiotensin–aldosterone system (RAAS) provides clinical benefit. It is most commonly prescribed as part of multimodal therapy rather than as sole treatment.

• Congestive heart failure (CHF) – Dogs: Used as a vasodilator in dogs with CHF, particularly those with myxomatous mitral valve disease or dilated cardiomyopathy. Current consensus guidelines recommend inclusion of an ACE inhibitor such as benazepril as part of multimodal therapy in Stage C and Stage D heart disease.
• Subclinical heart disease – Dogs: Use in dogs with preclinical (Stage B2) myxomatous mitral valve disease remains controversial. Evidence of benefit is inconsistent, and routine use in asymptomatic patients is debated.
• Systemic hypertension – Dogs and Cats: May be used as adjunctive therapy for management of high blood pressure. Some patients may require combination therapy with additional antihypertensive agents for adequate control.
• Chronic kidney disease (CKD) – Dogs and Cats: Used as adjunctive therapy to reduce glomerular hypertension and slow progression of renal disease. Particularly beneficial in patients with proteinuria.
• Proteinuria / Protein-losing glomerulopathy – Dogs and Cats: Demonstrated to reduce urine protein:creatinine (UP:C) ratios in both canine and feline CKD. In cats with CKD and significant proteinuria, benazepril has been associated with improved survival.
• Adjunctive therapy with spironolactone – Dogs: Combination therapy with spironolactone may provide additional benefit in dogs with CHF receiving diuretics.

Dosage (Reference)

Dog

In dogs, benazepril is administered orally and is typically given once daily, although twice-daily dosing may be used in selected cases. Dose adjustments are based on clinical response, blood pressure, renal values, and proteinuria status.

Cat

In cats, benazepril is administered orally once daily. Dosing is typically adjusted according to renal function, degree of proteinuria, and blood pressure response.

Warnings & Precautions

Benazepril affects renal hemodynamics and systemic blood pressure through inhibition of the renin–angiotensin–aldosterone system (RAAS). Careful patient selection and appropriate monitoring are essential, particularly in animals with cardiovascular instability or impaired renal function.

• Acute kidney injury (AKI): Generally avoided in critically ill patients with acute kidney injury, as ACE inhibitors may decrease glomerular filtration rate (GFR) and worsen azotemia.
• Volume depletion / hypovolemia: Use cautiously in dehydrated, sodium-depleted, or hypotensive patients, including those that recently received aggressive diuretic therapy. These patients should be monitored closely for progressive azotemia after initiation.
• Renal function changes: Mild increases in serum creatinine may occur at the start of therapy, particularly in patients with CKD. Significant or progressive azotemia warrants reassessment of therapy.
• Hypotension: Risk is increased in patients with preexisting hypotension, severe CHF, coronary or cerebrovascular insufficiency, or when combined with other antihypertensive agents.
• Electrolyte abnormalities: Use cautiously in patients with hyponatremia or those at risk for hyperkalemia. Monitoring of serum electrolytes is recommended.
• Hematologic or collagen vascular disorders: Use cautiously in patients with preexisting hematologic abnormalities or collagen vascular diseases (e.g., systemic lupus erythematosus), as ACE inhibitors have been associated with blood dyscrasias in other species.
• Hypersensitivity: Contraindicated in patients with known hypersensitivity to ACE inhibitors.
• Pregnancy: Avoid use during pregnancy. ACE inhibitors cross the placenta and have been associated with fetal toxicity and malformations in other species. Use only if benefits clearly outweigh risks.
• Drug name confusion: Benazepril may be confused with “Benadryl®” on written prescriptions. Clear prescribing practices (e.g., tall-man lettering) are recommended to prevent dispensing errors.

Drug Interactions

Most clinically significant interactions with benazepril are related to additive hypotension, altered renal perfusion, or effects on potassium balance. When combined with other cardiovascular, renal, or centrally acting drugs, careful monitoring of blood pressure, renal values, and electrolytes is recommended.

• Other antihypertensive agents (e.g., amlodipine): Additive blood pressure–lowering effects may occur. Combination therapy is sometimes required, but monitor closely for hypotension.
• Diuretics (e.g., furosemide, hydrochlorothiazide): May enhance hypotensive effects. Commonly used together in heart failure, but risk of azotemia or hypovolemia increases.
• Potassium-sparing diuretics (e.g., spironolactone, triamterene): Increased risk of hyperkalemia; serum potassium should be monitored.
• Potassium supplements: Increased risk of hyperkalemia, especially in patients with renal compromise.
• Angiotensin receptor blockers (e.g., telmisartan): Concurrent use may increase risk of hypotension, hyperkalemia, syncope, and renal dysfunction.
• NSAIDs (e.g., carprofen, meloxicam, robenacoxib): May reduce the antihypertensive effect of ACE inhibitors and increase the risk of nephrotoxicity, particularly in patients with cardiac or renal disease.
• Alpha-2 agonists (e.g., dexmedetomidine): Additive effects on blood pressure and heart rate may occur.
• Opioids: May contribute to additive hypotension and orthostatic effects.
• Phenothiazines (e.g., acepromazine): Increased risk of orthostatic hypotension and syncope due to vasodilation.
• Corticosteroids (e.g., dexamethasone, prednis(ol)one): May reduce antihypertensive efficacy through sodium and fluid retention.
• Cyclosporine: May increase risk of hyperkalemia or acute renal dysfunction.
• Heparin: Increased risk of hyperkalemia when used concurrently.
• Sulfamethoxazole/Trimethoprim: May increase risk of hyperkalemia.
• QT-prolonging drugs (e.g., amiodarone, cisapride, fluoroquinolones, ondansetron): Concurrent use may increase the risk of arrhythmias in susceptible patients.
• Antidiabetic agents (e.g., insulin, oral hypoglycemics): Potential increased risk of hypoglycemia; enhanced monitoring may be required.
• Lithium: ACE inhibitors may increase serum lithium concentrations; monitoring is recommended.

Side Effects & Overdose

Side Effects

Benazepril is generally well tolerated in dogs and cats. Adverse effects are uncommon and are typically mild when they occur. Most reported effects are related to gastrointestinal upset, blood pressure changes, or alterations in renal function.

• Gastrointestinal signs: Vomiting, diarrhea, anorexia, and decreased appetite are the most commonly reported adverse effects.
• Hypotension: May occur, particularly in volume-depleted, diuretic-treated, or severely cardiac-compromised patients.
• Renal function changes: Serum creatinine may increase after initiation of therapy, especially in patients with CKD or dehydration. Mild increases can be expected; progressive azotemia requires reassessment.
• Hyperkalemia: Possible due to reduced aldosterone secretion, particularly when combined with potassium-sparing diuretics or supplements.
• Lethargy or weakness: Occasionally observed and may be associated with hypotension.
• Hematologic changes (rare): Decreased red blood cell counts have been reported at very high chronic doses.

Overdose

Benazepril has a relatively wide margin of safety in dogs and cats. In overdose situations, the primary clinical concern is excessive hypotension and potential secondary renal compromise.

• Hypotension: Most significant expected effect following acute overdose.
• Lethargy or weakness: May accompany reduced blood pressure.
• Gastrointestinal upset: Vomiting may occur.
• Renal effects: Azotemia may worsen if hypotension compromises renal perfusion.
• Management: Supportive care is recommended. If hypotension is documented and cardiac function permits, IV fluid therapy may be used for volume expansion.
• Monitoring: Prolonged monitoring of blood pressure, renal parameters, and electrolytes may be necessary due to the drug’s long duration of action.
• Decontamination: Recent large oral ingestions may be managed with standard decontamination protocols when appropriate.

Key Notes

Practical clinical considerations to optimize safe and effective use of benazepril in dogs and cats:

• Prodrug activation: Benazepril itself has minimal activity and must be converted in the liver to benazeprilat to exert its clinical effect.
• Dual elimination pathway: In dogs, elimination occurs through both renal and hepatic routes, which may provide an advantage over ACE inhibitors cleared primarily by the kidneys in patients with reduced renal function.
• Nonlinear ACE binding in cats: In cats, doses above approximately 0.25 mg/kg produce only small incremental increases in ACE inhibition due to high-affinity enzyme binding.
• Proteinuria response marker: The urine protein:creatinine (UP:C) ratio is an important parameter for evaluating therapeutic response in proteinuric patients.
• Aldosterone breakthrough: Incomplete suppression of aldosterone secretion may occur during chronic ACE inhibitor therapy, which may influence long-term cardiac or renal remodeling.
• Administration flexibility: May be administered with or without food; giving with food can improve tolerance in patients prone to mild gastrointestinal upset.
• Monitoring timeline: Reassessment of renal values and electrolytes is typically performed within 3–14 days after initiating therapy or adjusting dose.
• Combination therapy considerations: Clinical benefit in heart disease is most commonly achieved when benazepril is used as part of a broader multimodal protocol rather than as monotherapy.