No

Angiotensin-Converting Enzyme (ACE) Inhibitors

Treatment of hypertension, alone or in combination with thiazide diuretics; treatment of congestive heart failure; treatment of left ventricular dysfunction after myocardial infarction

C/D (2nd and 3rd trimesters)

Hypersensitivity to ramipril or any component; 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 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. Neutropenia/agranulocytosis with myeloid hyperplasia can rarely occur. 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. Hypersensitivity reactions may be seen during hemodialysis with high-flux dialysis membranes (eg, AN69). 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.

1% to 10%: Central nervous system: Headache (1.2% to 5.4%), dizziness (2.2% to 4.1%), fatigue (2%), vertigo (1.5%)

Cardiovascular: Hypotension (10.7%), angina (2.9%), postural hypotension (2.2%), syncope (2.1%)

Endocrine and metabolic: Hyperkalemia (1% to 10%)

Gastrointestinal: Nausea/vomiting (1.1% to 2.2%)

Neuromuscular & skeletal: Chest pain (noncardiac) (1.1%)

Renal: Renal dysfunction (1.2%), elevation in serum creatinine (1.2% to 1.5%), increased BUN (0.5% to 3%); transient elevations of creatinine and/or BUN may occur more frequently

Respiratory: Cough (estimated 1% to 10%)

<1% (Limited to important or life-threatening symptoms): Anaphylactoid reaction, symptomatic hypotension, syncope, angina, arrhythmia, palpitation, myocardial infarction, cerebrovascular events, pancytopenia, hemolytic anemia, thrombocytopenia, angioedema, pancreatitis, abdominal pain, anorexia, constipation, diarrhea, xerostomia, dyspepsia, dysphagia, gastroenteritis, hepatitis, increased salivation, taste disturbance, hypersensitivity reactions (urticaria, rash, fever), erythema multiforme, pemphigus, photosensitivity, purpura, anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, vision disturbances, arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, weight gain, decreased hemoglobin, decreased hematocrit, elevated transaminase levels, hyponatremia, eosinophilia, proteinuria.

Case reports: Agitation

Worsening of renal function may occur in patients with bilateral renal artery stenosis or in hypovolemia. 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. Pancreatitis and agranulocytosis (particularly in patients with collagen vascular disease or renal impairment) have been associated with ACE inhibitors.

Mild hypotension has been the only toxic effect seen with acute overdose. Bradycardia may also occur; mild hyperkalemia may occur even with therapeutic doses, especially in patients with renal insufficiency and those taking NSAIDs.

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.

Alpha₁ blockers: Hypotensive effect increased.

Aspirin and NSAIDs may decrease ACE inhibitor efficacy and/or increase risk of 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.

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

Potassium supplements may increase the risk of hyperkalemia.

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

Stable for 24 hours at room temperature or 48 hours under refrigeration.

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor which prevents the formation of angiotensin II from angiotensin I and exhibits pharmacologic effects that are similar to captopril. Ramipril must undergo enzymatic saponification by esterases in the liver to its biologically active metabolite, ramiprilat. The pharmacodynamic effects of ramipril result from the high-affinity, competitive, reversible binding of ramiprilat to angiotensin-converting enzyme thus preventing the formation of the potent vasoconstrictor angiotensin II. This isomerized enzyme-inhibitor complex has a slow rate of dissociation, which results in high potency and a long duration of action; a CNS mechanism may also be involved in the hypotensive effect as angiotensin II increases adrenergic outflow from CNS; vasoactive kallikreins may be decreased in conversion to active hormones by ACE inhibitors, thus reducing blood pressure

Onset of action: 1-2 hours

Duration: 24 hours

Absorption: Well absorbed from GI tract (50% to 60%)

Distribution: Plasma levels decline in a triphasic fashion; rapid decline is a distribution phase to peripheral compartment, plasma protein and tissue ACE (half-life 2-4 hours); 2nd phase is an apparent elimination phase representing the clearance of free ramiprilat (half-life: 9-18 hours); and final phase is the terminal elimination phase representing the equilibrium phase between tissue binding and dissociation (half-life: >50 hours)

Metabolism: Hepatic to the active form, ramiprilat

Half-life: Ramiprilat: >50 hours

Time to peak serum concentration: ~1 hour

Elimination: Ramipril and its metabolites are eliminated primarily through the kidneys (60%) and feces (40%)

Adults: Oral:

Heart failure postmyocardial infarction: Initial: 2.5 mg twice daily titrated upward, if possible, to 5 mg twice daily.

Note: The dose of any concomitant diuretic should be reduced. If the diuretic cannot be discontinued, initiate therapy with 1.25 mg. After the initial dose, the patient should be monitored carefully until blood pressure has stabilized.

Dosing adjustment in renal impairment:

Cl_cr <40 mL/minute: Administer 25% of normal dose.

Renal failure and hypertension: Administer 1.25 mg once daily, titrated upward as possible.

Renal failure and heart failure: Administer 1.25 mg once daily, increasing to 1.25 mg twice daily up to 2.5 mg twice daily as tolerated.

Increases BUN, creatinine, potassium, positive Coombs' [direct]; decreases cholesterol (S); may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent

A recently completed trial (HOPE), examining the use of ramipril (at a dose of between 2.5-10 mg daily) in patients at high risk for cardiovascular events but who did not have heart failure, documented a significant improvement in cardiovascular outcome in the treated group. Thus, the benefits of ACE inhibitor therapy may also include a cardioprotective effect when used in patients at risk for cardiovascular events.

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. 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.

May cause dizziness or drowsiness; may rarely cause nervousness, amnesia, insomnia, or depression

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

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. Do not take potassium supplements or salt substitutes containing potassium without consulting prescriber. May cause dizziness, fainting, lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); postural hypotension (use caution when rising from lying or sitting position or climbing stairs); nausea or vomiting (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help) - report if these persist. Report chest pain or palpitations; difficulty in breathing or unusual cough; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Do not get pregnant; use appropriate contraceptive measures. If you are, or plan to be pregnant, notify your prescriber at once. Breast-feeding is not recommended.

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; may be mixed in water, apple juice, or applesauce and will remain stable for 48 hours if refrigerated or 24 hours at room temperature

Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg

Aurell M, Delin K, Herlitz H, et al, "Pharmacokinetics and Pharmacodynamics of Ramipril in Renal Failure," Am J Cardiol, 1987, 59(10):65D-69D.

Becker RA and Scholkens B, "Ramipril: Review of Pharmacology," Am J Cardiol, 1987, 59(10):3D-11D.

Herings RM, deBoer A, Stricker BH, et al, "Hypoglycaemia Associated With Use of Inhibitors of Angiotensin Converting Enzyme," Lancet, 1995, 345(8959):1195-8.

Konstam MA, Drakup K, Baker DW, et al, "Heart Failure: Evaluation and Care of Patients With Left Ventricular Systolic Dysfunction," Clinical Practice Guideline No 11, Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, 1994.

McAreavey D and Robertson JIS, "Angiotensin Converting Enzyme Inhibitors and Moderate Hypertension," Drugs, 1990, 40(3):326-45.

Todd PA and Benfield P, "Ramipril: A Review of its Pharmacological Properties and Therapeutic Efficacy in Cardiovascular Disorders," Drugs, 1990, 39(1):110-35.

Williams JF, Bristow MR, Fowler MB, et al, "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)," J Am Coll Cardiol, 1995, 26:1376-8.

Woo OF, "Captopril and Related Drugs," Poisoning and Drug Overdose, 2nd ed, Olson KR< ed, 1994, 117-8.