Benazepril

Pronunciation

(ben AY ze pril)

U.S. Brand Names

Lotensin®

Synonyms

Benazepril Hydrochloride

Generic Available

Yes

Canadian Brand Names

Lotensin®

Use

Treatment of hypertension, either alone or in combination with other antihypertensive agents

Pregnancy Risk Factor

C/D (2nd and 3rd trimesters)

Pregnancy Implications

Cranial defects, hypocalvaria/acalvaria, oligohydramnios, persistent anuria following delivery, hypotension, renal defects, renal dysgenesis/dysplasia, renal failure, pulmonary hypoplasia, limb contractures secondary to oligohydramnios, and stillbirth reported. ACE inhibitors should be avoided during pregnancy, particularly in the 2nd and 3rd trimesters.

Lactation

Enters breast milk/compatible

Contraindications

Hypersensitivity to benazepril or any component of the formulation; angioedema or serious hypersensitivity related to previous treatment with an ACE inhibitor; bilateral renal artery stenosis; patients with idiopathic or hereditary angioedema; pregnancy (2nd and 3rd trimesters)

Warnings/Precautions

Anaphylactic reactions can occur. Angioedema can occur at any time during treatment (especially following first dose). Angioedema may involve head and neck (potentially affecting the airway) or the intestine (presenting with abdominal pain). Careful blood pressure monitoring with first dose (hypotension can occur especially in volume depleted patients). Dosage adjustment needed in renal impairment. Use with caution in hypovolemia; collagen vascular diseases; valvular stenosis (particularly aortic stenosis); hyperkalemia; or before, during, or immediately after anesthesia. Avoid rapid dosage escalation which may lead to renal insufficiency. Rare toxicities associated with ACE inhibitors include cholestatic jaundice (which may progress to hepatic necrosis) and neutropenia/agranulocytosis with myeloid hyperplasia. Hypersensitivity reactions may be seen during hemodialysis with high-flux dialysis membranes (eg, AN69). Deterioration in renal function can occur with initiation. Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency.

Adverse Reactions

1% to 10%:

Cardiovascular: Postural dizziness (2%)

Central nervous system: Headache (6%), dizziness (4%), fatigue (3%), somnolence (2%)

Endocrine & metabolic: Hyperkalemia (1%), increased uric acid

Gastrointestinal: Nausea (2%)

Renal: Increased serum creatinine (2%), worsening of renal function may occur in patients with bilateral renal artery stenosis or hypovolemia

Respiratory: Cough (1% to 10%)

<1% (Limited to important or life-threatening): Hypotension, postural hypotension (0.3%), syncope, angina, palpitation, peripheral edema, angioedema, laryngeal edema, shock, Stevens-Johnson syndrome, pemphigus, hypersensitivity, dermatitis, rash, pruritus, photosensitivity, flushing, pancreatitis, constipation, gastritis, vomiting, melena, thrombocytopenia, hemolytic anemia, anxiety, decreased libido, hypertonia, insomnia, nervousness, paresthesia, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, diaphoresis, gynecomastia

Eosinophilic pneumonitis, neutropenia, anaphylaxis, renal insufficiency and renal failure have been reported with other ACE inhibitors. In addition, a syndrome including fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia, and elevated ESR has been reported to be associated with ACE inhibitors.

Overdosage/Toxicology

Mild hypotension has been the primary toxic effect seen with acute overdose. Bradycardia may also occur. Hyperkalemia occurs even with therapeutic doses, especially in patients with renal insufficiency and those taking NSAIDs. Treatment is symptom-directed and supportive.

Drug Interactions

Alpha1 blockers: Hypotensive effect increased.

Aspirin: The effects of ACE inhibitors may be blunted by aspirin administration, particularly at higher dosages and/or increase adverse renal effects.

Diuretics: Hypovolemia due to diuretics may precipitate acute hypotensive events or acute renal failure.

Insulin: Risk of hypoglycemia may be increased.

Lithium: Risk of lithium toxicity may be increased; monitor lithium levels.

NSAIDs: May attenuate hypertensive efficacy; effect has been seen with captopril and may occur with other ACE inhibitors; monitor blood pressure. May increase adverse renal effects.

Potassium-sparing diuretics or potassium supplements (amiloride, potassium, spironolactone, triamterene): Increased risk of hyperkalemia.

Trimethoprim (high dose) may increase the risk of hyperkalemia.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).

Mechanism of Action

Competitive inhibition of angiotensin I being converted to angiotensin II, a potent vasoconstrictor, through the angiotensin I-converting enzyme (ACE) activity, with resultant lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion

Pharmacodynamics/Kinetics

Reduction in plasma angiotensin-converting enzyme (ACE) activity:

Onset of action: Peak effect: 1-2 hours after 2-20 mg dose

Duration: >90% inhibition for 24 hours after 5-20 mg dose

Reduction in blood pressure:

Peak effect: Single dose: 2-4 hours; Continuous therapy: 2 weeks

Absorption: Rapid (37%); food does not alter significantly; metabolite (benazeprilat) itself unsuitable for oral administration due to poor absorption

Distribution: Vd: ~8.7 L

Metabolism: Rapidly and extensively hepatic to its active metabolite, benazeprilat, via enzymatic hydrolysis; extensive first-pass effect

Half-life elimination: Benazeprilat: Effective: 10-11 hours; Terminal: Children: 5 hours, Adults: 22 hours

Time to peak: Parent drug: 0.5-1 hour

Excretion: Clearance: Nonrenal clearance (ie, biliary, metabolic) appears to contribute to the elimination of benazeprilat (11% to 12%), particularly patients with severe renal impairment; hepatic clearance is the main elimination route of unchanged benazepril

Dialysis: ~6% of metabolite removed in 4 hours of dialysis following 10 mg of benazepril administered 2 hours prior to procedure; parent compound not found in dialysate

Dosage

Oral: Hypertension:

Children 6 years: Initial: 0.2 mg/kg/day as monotherapy; dosing range: 0.1-0.6 mg/kg/day (maximum dose: 40 mg/day)

Adults: Initial: 10 mg/day in patients not receiving a diuretic; 20-40 mg/day as a single dose or 2 divided doses; the need for twice-daily dosing should be assessed by monitoring peak (2-6 hours after dosing) and trough responses.

Note: Patients taking diuretics should have them discontinued 2-3 days prior to starting benazepril. If they cannot be discontinued, then initial dose should be 5 mg; restart after blood pressure is stabilized if needed.

Elderly: Oral: Initial: 5-10 mg/day in single or divided doses; usual range: 20-40 mg/day; adjust for renal function; also see "Note" in Adults dosing.

Dosing interval in renal impairment: Clcr<30 mL/minute:

Children: Use is not recommended.

Adults: Administer 5 mg/day initially; maximum daily dose: 40 mg.

Hemodialysis: Moderately dialyzable (20% to 50%); administer dose postdialysis or administer 25% to 35% supplemental dose.

Peritoneal dialysis: Supplemental dose is not necessary.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Take exactly as directed; do not alter dose or discontinue without consulting prescriber. Take first dose at bedtime. Do not take potassium supplements or salt substitutes containing potassium without consulting prescriber. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, or lightheadedness (use caution when driving or engaging in tasks that require alertness until response to drug is known); postural hypotension (use caution when rising from lying or sitting position or climbing stairs); nausea, vomiting, abdominal pain, dry mouth, or transient loss of appetite (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); report if these side effects persist. Report mouth sores; fever or chills; swelling of extremities, face, mouth, or tongue; respiratory difficulty or unusual cough; or other persistent adverse reactions. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 2nd or 3rd trimester of pregnancy. Consult prescriber for appropriate contraceptive measures.

Anesthesia and Critical Care Concerns/Other Considerations

Aging patients with a decrease in glomerular filtration (also creatinine clearance), severe congestive heart failure, and renal failure may experience an exaggerated response with administration of ACE inhibitors. Diabetic proteinuria is reduced and insulin sensitivity is enhanced. In general, the side effect profile is favorable in elderly and causes little or no CNS confusion.

ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, congestive heart failure. ACE inhibitors are also indicated in patients postmyocardial infarction in whom left ventricular ejection fraction is <40%. When used in patients with heart failure, the target dose or maximum tolerated dose, should be achieved, if possible. Lower daily doses of ACE inhibitors have not demonstrated the same cardioprotective effects. ACE inhibitors have renal protective effects in patients with proteinuria and possibly cardioprotective effects in high-risk patients.

ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin-receptor blocker therapy instituted. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.

Cardiovascular Considerations

ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, congestive heart failure. According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion or LVEF <0.4, in the absence of hypotension or known contraindications to that class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. When used in patients with heart failure, the target dose or maximum tolerated dose, should be achieved, if possible. Lower daily doses of ACE inhibitors have not demonstrated the same cardioprotective effects. ACE inhibitors have renal protective effects in patients with proteinuria and possibly cardioprotective effects in high-risk patients.

ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin receptor blocker therapy instituted. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.

In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or CHF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended for all post-ACS individuals (Class IIa).

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause drowsiness

Mental Health: Effects on Psychiatric Treatment

May decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels

Dosage Forms

Tablet, as hydrochloride: 5 mg, 10 mg, 20 mg, 40 mg

Extemporaneously Prepared

To prepare a 2 mg/mL suspension, mix 15 benazepril 20 mg tablets in a bottle with Ora-Plus® 75 mL. Shake for 2 minutes, allow suspension to stand for

1 hour, then shake again for at least 1 additional minute. Add Ora-Sweet® 75 mL to suspension and shake to disperse. Will make 150 mL of a 2 mg/mL suspension. Store under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 30 days. Shake prior to each use.

References

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)," J Am Coll Cardiol , 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Chase MP, Fiarman GS, Scholz FJ, et al, "Angioedema of the Small Bowel Due to an Angiotensin-Converting Enzyme Inhibitor," J Clin Gastroenterol , 2000, 31(3):254-7.

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure," Am J Cardiol , 1999, 83(2A):1A-38A.

"Guidelines for the Evaluation and Management of Heart Failure. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure)," Circulation , 1995, 92(9):2764-84.

Hunt SA, Baker DW, Chin MH, et al, "ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure)," J Am Coll Cardiol , 2001, 38(7):2101-13.

"K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative," Am J Kidney Dis , 2002, 39(2 Suppl 2):1-246. Available at: http://www.kidney.org/professionals/doqi/kdoqi/toc.htm. Acessed August 1, 2003.

Konstam MA, "Heart Failure Evaluation and Care of Patients With Left-Ventricular Systolic Dysfunction," Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. Clinical Practice Guideline: Number 94-0612.

Packer M, Poole-Wilson PA, Armstrong PW, et al, "Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure," Circulation , 1999, 100(23):2312-8.

Pfeffer MA, Greaves SC, Arnold JM, et al, "Early Versus Delayed Angiotensin-Converting Enzyme Inhibition Therapy in Acute Myocardial Infarction. The Healing and Early Afterload Reducing Therapy Trial," Circulation , 1997, 95(12):2643-51.

Smoger SH and Sayed MA, "Simultaneous Mucosal and Small Bowel Angioedema Due to Captopril," South Med J , 1998, 91(11):1060-3.

International Brand Names

Benace® (IN); Briem® (FR); Cibacen® (BE, CH, DE, DK, ES, ID, IE, IL, LU, MT, NL, NZ, TR); Cibacène® (FR); Cibace® (ZA); Cibadrex® (MT, TR); Labopal® (ES); Lotensin® (BR, CA, HU, MX, PL); Tensanil® (IT); Zinadril® (IT)

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