Ramipril

1. Drug Name

• Generic Name: Ramipril

• Brand Names: Altace, Ramiprilum, Triatec, and others.

2. Drug Classification

• Class: Antihypertensive, Angiotensin-Converting Enzyme (ACE) Inhibitor

• Subclass: Dicarboxylate-containing ACE Inhibitor

3. Mechanism of Action

Ramipril, like other ACE inhibitors, works by inhibiting the enzyme angiotensin-converting enzyme (ACE), which plays a critical role in converting angiotensin I to the potent vasoconstrictor angiotensin II.

• ACE Inhibition: By blocking ACE, ramipril reduces the production of angiotensin II, which leads to vasodilation, decreased secretion of aldosterone, and a reduction in sodium and water retention in the kidneys. This collectively results in lowered blood pressure and reduced strain on the heart.

• Decreased Preload and Afterload: Lower levels of angiotensin II also reduce systemic vascular resistance (afterload) and volume retention (preload), which is particularly beneficial in patients with heart failure.

• Cardioprotective Effects: In addition to its blood pressure-lowering effect, ramipril has been shown to prevent heart remodeling, improve endothelial function, and reduce proteinuria in patients with chronic kidney disease (CKD).

4. Pharmacokinetics

• Absorption: Ramipril is well absorbed after oral administration, with a bioavailability of approximately 60-70%. Food does not significantly affect the absorption.

• Distribution: It has a volume of distribution (Vd) of 0.5–1.5 L/kg and is about 73% bound to plasma proteins. Ramipril crosses the blood-brain barrier and is found in breast milk.

• Metabolism: Ramipril is a prodrug, meaning it is converted to its active metabolite, ramiprilat, in the liver. The conversion involves hydrolysis and occurs predominantly in the liver.

• Excretion: Ramipril is excreted primarily via the kidneys, with a half-life (t½) of about 13–17 hours for ramiprilat. This allows for once-daily dosing in most patients. A small amount is excreted in the feces.

• Special Considerations: Renal impairment reduces the clearance of both ramipril and ramiprilat, requiring dose adjustments.

5. Indications

• Primary Indications:

  • Hypertension: Ramipril is commonly used to treat high blood pressure.

  • Heart Failure: It is used for the treatment of symptomatic heart failure, both to improve survival and alleviate symptoms.

  • Prevention of Cardiovascular Events: Used in patients at high risk for heart attack or stroke, especially following an MI or in those with diabetes.

  • Chronic Kidney Disease (CKD): It is used to reduce proteinuria and slow the progression of kidney disease, particularly in diabetic nephropathy.

• Off-Label Uses:

  • Diabetic Nephropathy: Ramipril is used to manage kidney damage caused by diabetes.

  • Post-Myocardial Infarction (MI): To reduce the risk of future cardiovascular events.

  • Stroke Prevention: In high-risk individuals, particularly those with hypertension and a history of stroke.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension: Initial dose of 2.5 mg orally once daily, with a typical maintenance dose of 5-10 mg once daily.

  • Heart Failure: Initial dose of 1.25 mg once daily, titrated up to a typical maintenance dose of 10 mg daily.

  • Prevention of Cardiovascular Events: Start with 2.5 mg once daily, with gradual dose increases based on patient tolerance.

  • Chronic Kidney Disease/Proteinuria: A starting dose of 2.5 mg once daily is typically used, adjusted based on renal function.

• Pediatric Dosing: For children ≥1 year of age with hypertension, starting doses range from 0.05–0.1 mg/kg/day, with the dose adjusted based on response.

• Renal Impairment: In patients with a creatinine clearance of <40 mL/min, the dose of ramipril should be reduced, and the patient should be closely monitored for adverse effects.

• Maximum Safe Dose: The maximum recommended daily dose is 10 mg.

7. Contraindications

• Absolute Contraindications:

  • History of angioedema associated with ACE inhibitor therapy.

  • Hereditary or idiopathic angioedema.

  • Pregnancy (Category D): Ramipril is contraindicated during pregnancy due to the risk of fetal injury and death.

  • Hypersensitivity to ramipril or other ACE inhibitors.

• Relative Contraindications:

  • Renal Artery Stenosis: Ramipril should be used with caution or avoided in patients with bilateral renal artery stenosis, as it can exacerbate renal dysfunction.

  • Hyperkalemia: Contraindicated in patients with severe hyperkalemia (>5.5 mEq/L).

8. Warnings and Precautions

• Black Box Warnings:

  • Fetal Toxicity: Ramipril can cause injury or death to the fetus, particularly during the second and third trimesters. It is contraindicated during pregnancy.

• Special Warnings:

  • Angioedema: Ramipril can cause life-threatening angioedema, including laryngeal edema. Discontinue immediately if angioedema occurs.

  • Hyperkalemia: Use with caution in patients with high potassium levels or those using potassium-sparing diuretics.

  • Hypotension: Particularly after the first dose, there is a risk of significant hypotension, especially in patients who are volume-depleted or on diuretic therapy.

• Monitoring Parameters:

  • Regular monitoring of serum electrolytes, especially potassium and creatinine.

  • Renal function (serum creatinine, BUN) should be monitored frequently, especially in patients with pre-existing renal impairment or those on diuretics.

9. Adverse Effects

• Common Adverse Effects:

  • Dizziness

  • Fatigue

  • Headache

  • Cough (due to bradykinin accumulation)

• Less Common but Clinically Significant Side Effects:

  • Hyperkalemia

  • Elevated serum creatinine and renal dysfunction

  • Hypotension, particularly after the first dose

• Rare/Serious Adverse Reactions:

  • Angioedema (swelling of the face, lips, tongue, and throat)

  • Stevens-Johnson syndrome

  • Hepatic dysfunction (rare)

10. Drug Interactions

• Major Drug Interactions:

  • Potassium-Sparing Diuretics (e.g., spironolactone): Increased risk of hyperkalemia.

  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): May reduce the antihypertensive effects of ramipril and increase the risk of renal dysfunction.

  • Lithium: Increased risk of lithium toxicity when used with ACE inhibitors.

  • Diuretics: Co-administration with diuretics can increase the risk of hypotension, especially after the first dose.

• Food-Drug Interactions: There are no significant food interactions. However, it is recommended to take ramipril at the same time every day to maintain consistent blood levels.

11. Clinical Pharmacology

Ramipril reduces blood pressure by inhibiting the conversion of angiotensin I to angiotensin II. This action results in decreased vasoconstriction, reduced aldosterone release, and increased renal excretion of sodium and water, ultimately lowering systemic blood pressure. It also has beneficial effects on the heart, reducing afterload and preventing adverse heart remodeling.

12. Special Populations

• Pregnancy: Contraindicated in pregnancy, especially in the second and third trimesters due to risk of fetal injury and death.

• Lactation: Ramipril passes into breast milk, so it is not recommended during breastfeeding.

• Pediatrics: Ramipril is safe for use in children with hypertension and heart failure, but dosing adjustments are required.

• Geriatrics: Older adults may require dose adjustments due to changes in renal function with age.

13. Therapeutic Uses

• First-Line Indications: Hypertension, heart failure, and chronic kidney disease.

• Second-Line Indications: Stroke prevention in high-risk individuals.

14. Monitoring and Follow-Up

• Monitor blood pressure regularly.

• Periodic testing for kidney function (serum creatinine, BUN) and electrolytes (especially potassium).

• Monitor for symptoms of angioedema and hyperkalemia, especially during the initial stages of treatment.

15. Overdose Management

• Symptoms of Overdose: Severe hypotension, hyperkalemia, and renal dysfunction.

• Treatment Protocols: Management of overdose involves intravenous fluids to restore blood pressure, and in cases of severe toxicity, hemodialysis may be considered to remove ramipril from the bloodstream.

16. Patient Counseling Information

• Patients should be advised to take ramipril consistently at the same time each day.

• They should be instructed to monitor for symptoms of hypotension (e.g., dizziness, light-headedness) especially after the first dose.

• Patients should avoid potassium supplements and salt substitutes containing potassium unless advised by their healthcare provider.

• Women of childbearing age should be informed of the risks during pregnancy and advised to avoid pregnancy while on ramipril.