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Pronunciation:

(tran DOE la pril)

U.S. Brand Names:

Mavik®

Generic Available:

Canadian Brand Names:

Mavik™

Use:

Management of hypertension alone or in combination with other antihypertensive agents; treatment of left ventricular dysfunction after myocardial infarction

Use - Unlabeled/Investigational:

As a class, ACE inhibitors are recommended in the treatment of systolic congestive heart failure

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/contraindicated

Contraindications:

Hypersensitivity to trandolapril or any component of the formulation; history of angioedema-related to previous treatment with an ACE inhibitor; bilateral renal artery stenosis; 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 severe renal dysfunction (Clcr<30 mL/minute) or in hepatic cirrhosis. 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. If patient has renal impairment then a baseline WBC with differential and serum creatinine should be evaluated and monitored closely during the first 3 months of therapy. Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency.

Adverse Reactions:

Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with CHF. However, the frequency of adverse effects associated with placebo is also increased in this population.

>1%:

Cardiovascular: Hypotension (<1% to 11%), bradycardia (<1% to 4.7%), intermittent claudication (3.8%), stroke (3.3%), syncope (5.9%)

Central nervous system: Dizziness (1.3% to 23%), asthenia (3.3%)

Endocrine & metabolic: Elevated uric acid (15%), hyperkalemia (5.3%), hypocalcemia (4.7%)

Gastrointestinal: Dyspepsia (6.4%), gastritis (4.2%)

Neuromuscular & skeletal: Myalgia (4.7%)

Renal: Elevated BUN (9%), elevated serum creatinine (1.1% to 4.7%)

Respiratory: Cough (1.9% to 35%)

<1% (Limited to important or life-threatening): Chest pain, AV block (first-degree), edema, flushing, palpitation, drowsiness, insomnia, paresthesia, vertigo, pruritus, rash, pemphigus, epistaxis, pharyngitis, upper respiratory tract infection, anxiety, impotence, decreased libido, abdominal distension, abdominal pain, constipation, dyspepsia, diarrhea, vomiting, pancreatitis, leukopenia, neutropenia, thrombocytopenia, increased serum creatinine, increased ALT, muscle pain, gout, dyspnea, angioedema, laryngeal edema, symptomatic hypotension, transaminases elevation, increased bilirubin. Worsening of renal function may occur in patients with bilateral renal artery stenosis or in hypovolemic patients. In addition, a syndrome which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia and positive ANA, and elevated ESR has been reported 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 (see Cardiovascular Considerations) 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, especially the first 4 weeks of therapy.

Mercaptopurine: Risk of neutropenia may be increased.

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 (amiloride, potassium, spironolactone, triamterene): Increased risk of hyperkalemia.

Potassium supplements may increase the 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:

Trandolapril is an ACE inhibitor which prevents the formation of angiotensin II from angiotensin I. Trandolapril must undergo enzymatic hydrolysis, mainly in liver, to its biologically active metabolite, trandolaprilat. A CNS mechanism may also be involved in the hypotensive effect as angiotensin II increases adrenergic outflow from the CNS. Vasoactive kallikrein's may be decreased in conversion to active hormones by ACE inhibitors, thus, reducing blood pressure.

Pharmacodynamics/Kinetics:

Onset of action: 1-2 hours

Peak effect: Reduction in blood pressure: 6 hours

Duration: Prolonged; 72 hours after single dose

Absorption: Rapid

Distribution: Trandolaprilat (active metabolite) is very lipophilic in comparison to other ACE inhibitors

Protein binding: 80%

Metabolism: Hepatically hydrolyzed to active metabolite, trandolaprilat

Half-life elimination:

Trandolapril: 6 hours; Trandolaprilat: Effective: 10 hours, Terminal: 24 hours

Elimination: As metabolites in urine;

Time to peak: Parent: 1 hour; Active metabolite trandolaprilat: 4-10 hours

Excretion: Urine (as metabolites)

Clearance: Reduce dose in renal failure; creatinine clearances 30 mL/minute result in accumulation of active metabolite

Dosage:

Adults: Oral:

Hypertension: Initial dose in patients not receiving a diuretic: 1 mg/day (2 mg/day in black patients). Adjust dosage according to the blood pressure response. Make dosage adjustments at intervals of 1 week. Most patients have required dosages of 2-4 mg/day. There is a little experience with doses >8 mg/day. Patients inadequately treated with once daily dosing at 4 mg may be treated with twice daily dosing. If blood pressure is not adequately controlled with trandolapril monotherapy, a diuretic may be added.

Usual dose range (JNC 7): 1-4 mg once daily

Heart failure postmyocardial infarction or left ventricular dysfunction postmyocardial infarction: Initial: 1 mg/day; titrate patients (as tolerated) towards the target dose of 4 mg/day. If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.

Dosing adjustment in renal impairment: Clcr 30 mL/minute: Recommended starting dose: 0.5 mg/day.

Dosing adjustment in hepatic impairment: Cirrhosis: Recommended starting dose: 0.5 mg/day.

Monitoring Parameters:

Serum potassium, renal function, serum creatinine, BUN, CBC; observe for hypotensive effects within 1-3 hours of first dose or new higher dose

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 unless approved by prescriber. Take exactly as directed; do not discontinue without consulting prescriber. Do not take antacids within 2 hours of this medication. Take first dose at bedtime. 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); or diarrhea (buttermilk, boiled milk, yogurt may help). Report immediately any swelling of face, mouth, lips, tongue or throat. Report chest pain or palpitations; swelling of extremities, mouth, or tongue; skin rash; respiratory difficulty or unusual cough; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: 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 if necessary. Do not breast-feed.

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 of 4 mg daily 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 dizziness, drowsiness, nervousness, or insomnia

Mental Health: Effects on Psychiatric Treatment:

May cause neutropenia; use caution with clozapine and carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels; concurrent use with low potency antipsychotics and TCAs may produce additive hypotensive effects

Dosage Forms:

Tablet: 1 mg, 2 mg, 4 mg

International Brand Names:

Gopten® (AT, AU, BR, CH, CO, CZ, DE, DK, ES, FI, FR, GB, HR, HU, IE, IT, LU, MX, NL, NO, NZ, PL, PT, RO, RU, SE, SI, TR); Mavik™ (CA); Mavik® (ZA); Nortensin® (AR); Odrik® (AU, BR, DK, ES, FR, GB, IE, LU, NZ, PT); Trandolapril Ebewe® (AT); Udrik® (DE)

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. Accessed August 1, 2003.

Kober L, Torp-Pedersen C, Carlsen JE, et al, "A Clinical Trial of the Angiotensin-Converting Enzyme Inhibitor Trandolapril in Patients With Left Ventricular Dysfunction After Myocardial Infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group,"N Engl J Med, 1995, 333(25):1670-6.

Malik RA, Williamson S, Abbott C, et al, "Effect of Angiotensin-Converting Enzyme (ACE) Inhibitor Trandolapril on Human Diabetic Neuropathy: Randomised Double-Blind Controlled Trial,"Lancet, 1998, 352(9145):1978-81.

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.

Pedersen OD, Bagger H, Kober L, et al, "Trandolapril Reduces the Incidence of Atrial Fibrillation After Acute Myocardial Infarction in Patients With Left Ventricular Dysfunction,"Circulation, 1999, 100(4):376-80.

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.

Torp-Pedersen C and Kober L, "Effect of ACE Inhibitor Trandolapril on Life Expectancy of Patients With Reduced Left-Ventricular Function After Acute Myocardial Infarction. TRACE Study Group. Trandolapril Cardiac Evaluation,"Lancet, 1999, 354(9172):9-12.

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