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Benazepril
Clinical Particulars
Pharmacokinetics
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).
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.
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).
Availability
UK Formulations
Oral Forms: 2.5 mg, 5mg and 20mg Tablets
UK Availability: Sole agent or combined with other diuretics such as hydrochlorothiazide.
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)