No

Angiotensin-Converting Enzyme (ACE) Inhibitors

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

C/D (2nd and 3rd trimesters)

Hypersensitivity to trandolapril or any component; history of angioedema related to previous treatment with an ACE inhibitor; bilateral renal artery stenosis; primary hyperaldosteronism; pregnancy (2nd and 3rd trimesters)

Anaphylactic reactions can occur. Angioedema can occur at any time during treatment (especially following first dose). Careful blood pressure monitoring with first dose (hypotension can occur especially in volume depleted patients). Dosage adjustment needed in severe renal dysfunction (Cl_cr <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. Neutropenia/agranulocytosis with myeloid hyperplasia can rarely occur with captopril (another ACE inhibitor). 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.

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

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

Central nervous system: Dizziness (1.3% to 23%), syncope (5.9%), 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 symptoms): Chest pain, AV block (first-degree), edema, flushing, palpitations, 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, transaminase 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.

Symptoms include hypertension, vertigo, dizziness

Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated. Hypotension usually responds to I.V. fluids or Trendelenburg positioning. If unresponsive to these measures, the use of a parenteral inotrope may be required (eg, norepinephrine 0.1-0.2 mcg/kg/minute titrated to response). Seizures commonly respond to diazepam (I.V. 5-10 mg bolus in adults every 15 minutes if needed up to a total of 30 mg) or to phenytoin or phenobarbital.

Alpha₁ blockers: Hypotensive effect increased.

Aspirin and NSAIDs may decrease ACE inhibitor efficacy.

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.

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.

Trandolapril is an angiotensin-converting enzyme (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.

Onset of effect: 1-2 hours

Peak reduction in blood pressure: 6 hours postdose

Peak levels: 6 hours

Trandolaprilat (active metabolite) is very lipophilic in comparison to other ACE inhibitors which may contribute to its prolonged duration of action (72 hours after a single dose)

Absorption: Rapid

Metabolism: Hydrolyzed, mainly in liver, to the active metabolite, trandolaprilat

Half-life: 24 hours

Elimination: As metabolites in urine; reduce dose in renal failure; creatinine clearances less than or equal to 30 mL/minute result in accumulation of active metabolite

Adults: Oral:

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: Cl_cr less than or equal to 30 mL/minute: Recommended starting dose: 0.5 mg/day.

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

Serum potassium, renal function, serum creatinine, BUN, CBC

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 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.

May cause dizziness, drowsiness, nervousness, or insomnia

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

No information available to require special precautions

No effects or complications reported

Take exactly as directed; do not discontinue without consulting prescriber. Take first dose at bedtime. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); diarrhea (buttermilk, boiled milk, yogurt may help). Report chest pain or palpitations; swelling of extremities, mouth or tongue; skin rash; difficulty in breathing or unusual cough; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Do not breast-feed.

May cause depression in some patients; discontinue if angioedema of the face, extremities, lips, tongue, or glottis occurs; watch for hypotensive effects within 1-3 hours of first dose or new higher dose

Tablet: 1 mg, 2 mg, 4 mg

Bevan EG, McInnes GT, Aldigier JC, et al, "Effect of Renal Function on the Pharmacokinetics and Pharmacodynamics of Trandolapril," Br J Clin Pharmacol, 1993, 35(2):128-35.

Caren H and Brunner HR, "Pharmacologic Profile of Trandolapril, A New Angiotensin-Converting Enzyme Inhibitor," Am J Heart, 1993, 125(5 Part 2):1524-31.

Conen H and Brunner HR, "Pharmacologic Profile of Trandolapril, A New Angiotensin-Converting Enzyme Inhibitor," Am Heart J, 1993, 125(5 Pt 2):1525-31.

Zannad F, "Trandolapril. How Does It Differ From Other Angiotensin-Converting Enzyme Inhibitors?" Drugs, 1993, 46(Suppl 2):172-81.