Ramipril

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Therapeutic Class
ACE Inhibitor
Antihypertensive

Mechanism of Action

Ramipril, an angiotensin-converting enzyme (ACE) inhibitor, is metabolized to a more potent ramiprilat (active drug). Both prevent the conversion of angiotensin I to angiotensin II, a vasoconstrictor agent, which decreases vasopressor activity and aldosterone secretion .

Mechanism of Action - Pharmacokinetics

Ramipril (prodrug), Protein binding: about 73%
Ramipril (prodrug)-Hepatic; almost completely metabolized
Ramipril (prodrug): time to peak concentration, within 1 h
Ramiprilat (active drug): greater than 50 h
Active metabolite: ramiprilat (active drug)
Ramipril (prodrug), Bioavailability: 28%

Ramiprilat (active drug), Protein binding: about 56%
Ramipril (prodrug), Effect of food: reduces rate of absorption

Clinical Advice

  • Patient should avoid activities requiring mental alertness or coordination until drug effects are realized, as drug may cause dizziness.
  • Advise patient to rise slowly from a sitting or lying position.
  • This drug may cause nausea, vomiting, persistent cough, and fatigue.
  • Tell patient to report signs/symptoms of angioedema (deep swelling around eyes and lips and sometimes hands and feet), intestinal angioedema (abdominal pain), unusual bleeding, or infection.
  • Instruct patient to maintain adequate hydration to prevent volume depletion and symptomatic hypotension.
  • Patient should avoid using potassium-containing supplements or salts while taking this drug.
    Dosing - Adult
  • withdraw concurrent diuretic therapy 2 to 3 days before initiating ramipril if possible; if a diuretic cannot be discontinued, use an initial dose of 1.25 mg orally once daily; reinstate diuretic therapy if blood pressure is not controlled by ramipril alone
  • observe patients following the initial dose of ramipril for at least 2 hours and until blood pressure has stabilized for at least an additional hour
  • Cardiovascular event risk, Reduction: initial, 2.5 mg ORALLY once daily for 1 wk followed by 5 mg ORALLY once daily for 3 weeks
  • Cardiovascular event risk, Reduction: maintenance, 10 mg (if tolerated) ORALLY once daily or in 2 divided doses
  • Congestive heart failure - Myocardial infarction: initial, 1.25 to 2.5 mg ORALLY twice daily for 1 wk; maintenance, 5 mg (if tolerated) ORALLY twice daily; dose titration at 3 wk intervals
  • Hypertension: (in patients not receiving a diuretic) initial, 2.5 mg ORALLY once daily; maintenance, 2.5 to 20 mg ORALLY once daily or in 2 divided doses
  • Hypertension: lower initial dose to 1.25 mg daily if given with a diuretic

Dosing - Dose Adjustment
CrCl less than 40 mL/min/1.73 m(2): use 25% of normal dose
renal impairment in hypertensive patients: starting dose, 1.25 mg ORALLY once daily, titrate to effect, MAX 5 mg daily
renal impairment in heart failure patients: starting dose, 1.25 mg ORALLY once daily; increase to 1.25 mg twice daily; titrate to effect, MAX 2.5 mg twice daily
volume depletion (eg, past and current diuretic use) or renal artery stenosis: use initial starting dose of 1.25 mg ORALLY once daily

Contraindications

  • angioedema related to prior therapy with an ACE inhibitor
  • hypersensitivity to ramipril/other ACE inhibitors
    Warnings - Precautions
    pregnancy, second and third trimesters; can cause fetal and neonatal morbidity and death; discontinue ramipril therapy
    agranulocytosis, neutropenia, and pancytopenia have been reported
    anaphylactoid reactions have been reported
    anaphylaxis during lipid apheresis with dextran sulfate membranes and hemodialysis with high flux membranes has been reported
    angioedema, history of; increased risk of head and neck angioedema; discontinue therapy
    congestive heart failure, history of, with or without renal impairment; risk for excessive hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death
    collagen vascular disease; increased risk of agranulocytosis, neutropenia, and pancytopenia concomitant diuretic therapy; increased risk for symptomatic hypotension and increases in blood urea nitrogen and serum creatinine may occur
    cough (nonproductive) has been reported with all ACE inhibitors
    hepatic failure, potentially fatal, has occurred; discontinue therapy in patients who develop jaundice or have marked elevations in hepatic enzymes
    hepatic impairment; increased plasma levels of ramipril
    hyperkalemia has been reported; increased risk with renal disease, diabetes, and concomitant use of potassium supplements, potassium containing salt substitutes, and potassium-sparing diuretics
    insect venom allergy, hymenoptera venom immunotherapy; may exacerbate the allergic response
    intestinal angioedema has been reported
    renal artery stenosis, unilateral or bilateral; increases in blood urea nitrogen and serum creatinine may occur; may consider dosage reduction or discontinuation of therapy if warranted
    renal impairment; risk for excessive hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death
    renal impairment; increased risk of agranulocytosis, neutropenia, and pancytopenia
    surgery/anesthesia; excessive hypotension has been reported
    volume and/or salt depletion, presence of; increased risk for symptomatic hypotension

Clinical Effects - Treatment
ACE INHIBITORS: Decontamination: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
ACE INHIBITORS: Hypotensive episode: IV 0.9% NaCl 10-20 ml/kg, dopamine, norepinephrine. Naloxone effective in animal models and several case reports. Angiotensin Amide - IV infusion 8.5 to 18 mcg/min effective in several case reports.
ACE INHIBITORS: Monitoring of patient: Monitor BP, continuous cardiac monitoring, electrolytes, renal function, ECG and urinalysis in symptomatic patients.
Toxicology - Clinical Effects
ACE INHIBITORS: OVERDOSE: Hypotension most common overdose effect; acute renal failure is rare. Onset of hypotension is generally within 6 hours of ingestion. ADVERSE EFFECTS: Hypotension, bradycardia, bronchospasm, cough, renal insufficiency, nephrotic syndrome, hyperkalemia, and neutropenia can develop.

Adverse Effects - Serious
Gastrointestinal: Intestinal angioedema
Hepatic: Liver failure, starting with cholestatic jaundice (rare)
Other: Angioedema, Face, lips, throat; more frequent in Black patients (rare)
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