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Benazepril

Pharmacology

Clinical Particulars

Regulatory Class

Benazepril is a prodrug that inhibits the conversion of angiotensin-I to angiotensin-II by inhibiting angiotensin-converting enzyme (ACE) after being hydrolysed in the liver to benazeprilat (Booth, 2011; Maddison, 2008; Plumb, 2024).

Pharmacodynamics

Pharmacokinetics

Mechanism of Action

Benazeprilat is a highly potent and selective inhibitor of ACE, thus preventing the conversion of inactive angiotensin I to active angiotensin II and reducing aldosterone synthesis. Benazeprilat blocks effects mediated by angiotensin II and aldosterone, including vasoconstriction of both arteries and veins, sodium and water retention by the kidney, and remodelling effects (including pathological cardiac hypertrophy and degenerative renal changes).

  • Arterial and venous vasodilation - decrease preload - decrease afterload: Veno- and artery dilatation and decreased salt and water retention (reduced aldosterone production). Renal vasoconstrictive activity and stimulation of secretion of aldosterone by the adrenal cortex.

  • Reduced glomerular filtration pressure: Proteinuria may be reduced.

Mechanism

  • ACE inhibitors inhibit the conversion of angiotensin-I to angiotensin-II, resulting in veno- and artery dilatation and decreased salt and water retention (through reduced aldosterone production). Efferent renal arteriolar dilatation results in a reduced glomerular filtration pressure.

  • The enzymatic cascade by which angiotensin-II is produced consists of renin, which cleaves angiotensinogen to form the decapeptide angiotensin-I. Angiotensin-I is then cleaved by angiotensin-converting enzyme (ACE) to produce angiotensin-II, the physiologically active component of the system.

  • Systemic actions of angiotensin-II are mainly hypertensive. Bradykinin, an endogenous vasodilator peptide, is also metabolised by ACE. Inhibition of ACE contributes to vasodilatation by decreasing the angiotensin-II production and inhibiting the bradykinin catabolism.

  • Angiotensin-II also increases water volume through sodium (via aldosterone) and water (via anti-diuretic hormone) retention. In renal pathophysiological conditions, it is also responsible for the growth and profibrogenic actions, cell proliferation, production of cytokines and extracellular matrix proteins and renal inflammatory cell infiltration.

Applications

  • Congestive heart failure

  • Protein-losing glomerulopathy

  • Hypertension

  • Ischaemic stroke

Pharmacodynamics

Metabolism

  • Benazepril hydrochloride is a pro-drug hydrolysed in vivo to benazeprilat, which inhibits angiotensin-converting enzyme (ACE), thus preventing the conversion of inactive angiotensin-I into active angiotensin-II.

  • Benazepril reduces all effects mediated by angiotensin-II, including vasoconstriction of arteries and veins and kidney retention of sodium and water.

Elimination

  • Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function.

  • Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects.

Pharmacokinetics

Precautions

Adverse Effects 

  • Severe CHF: Monitor for progressive azotaemia, especially where aggressive diuresis has recently occurred. Avoid use in cardiac output failure due, for example, to aortic stenosis.

  • GI Distress: Typically, anorexia, vomiting, and diarrhoea.

  • Hypotension:  Animals may experience excessive hypotension, and fatigue, lethargy, ataxia, and incoordination may be observed.

  • Azotaemia: Renal dysfunction, azotaemia and hyperkalemia may occur. Plasma creatinine concentration may increase at the start of therapy in patients with CKD or dehydration.

Contraindications

  • AKI: Avoid use in animals at risk of azotaemia as use may decrease GFR and worsen azotemia

  • Hypersensitivity: Avoid use in patients with known hypersensitivity to ACE inhibitors.

  • Hyponatremia or Sodium Depletion: Avoid use.

  • Hypotension:  Avoid use in animals with or at risk of hypotension.

  • Hypovolemia:  Avoid use.

  • Coronary or Cerebrovascular Insufficiency:  Avoid use.

  • Pre-existing Hematologic Abnormalities: Avoid use.

  • SLE or Collagen Vascular Disease: Avoid use (e.g., systemic lupus erythematosus [SLE]).

Reproductive Safety

  • Pregnancy: Avoid use. Benazepril crosses the placenta. Embryotoxic effects (foetal urinary tract malformation) were seen in trials with laboratory animals (rats) at maternally non-toxic doses (SPC data).

  • Lactation: Benazepril is not expected to cause adverse effects in an infant being nursed. However, in some countries, its use is contraindicated during pregnancy and lactation (SPC data).

  • Male Fertility: No data located.

  • Female Fertility: Avoid use. Benazepril reduced ovary/oviduct weights in cats when administered daily at 10 mg/kg body weight for 52 weeks (SPC data).

  • Neonates: Benazepril is not expected to cause adverse effects in an infant being nursed (SPC data).

Potentially Significant Interactions

  • Anti-hypertensive agents: e.g. calcium channel blockers, β-blockers or diuretics), anaesthetics or sedatives may lead to additive hypotensive effects (SPC data).

  • NSAIDs: e.g., carprofen, meloxicam, robenacoxib): can lead to reduced anti-hypertensive efficacy or impaired renal function (SPC data).

Precautions

Availability

UK Formulations

  • Oral Forms:  2.5 mg, 5mg and 20mg Tablets

  • UK Availability: Sole agent or combined with other diuretics such as hydrochlorothiazide.

Availability

Identifiers

  • Systematic IUPAC Name:  2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid

  • Formula: C24H28N2O5

  • Pharmacotherapeutic group: Cardiovascular system, ACE Inhibitor,

  • ATC code: C09AA07 (WHO)

  • ATC vet code: QC09AA07 (WHO)

Identifiers

Evidence Base

  1. Acierno, M.J., Brown, S., Coleman, A.E., Jepson, R.E., Papich, M., Stepien, R.L., Syme, H.M., 2018a. ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med 32, 1803–1822. https://doi.org/10.1111/jvim.15331

  2. Acierno, M.J., Brown, S., Coleman, A.E., Jepson, R.E., Papich, M., Stepien, R.L., Syme, H.M., 2018b. ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. Journal of Veterinary Internal Medicine 32, 1803–1822. https://doi.org/10.1111/jvim.15331

  3. Adin, D., Atkins, C., Wallace, G., Klein, A., 2021. Effect of spironolactone and benazepril on furosemide‐induced diuresis and renin‐angiotensin‐aldosterone system activation in normal dogs. J Vet Intern Med 35, 1245–1254. https://doi.org/10.1111/jvim.16097

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Evidence

Monograph Details

Mono Details
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