Ramipril

Generic Name: Ramipril
Brand Names: Altace (US), Tritace (UK/EU), Ramace, Vasotop (veterinary)
Drug Class: Angiotensin-Converting Enzyme (ACE) Inhibitor
Formulations: Oral capsules (1.25 mg, 2.5 mg, 5 mg, 10 mg), Oral tablets (in some regions)
Route of Administration: Oral

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Therapeutic Indications and Clinical Use

Ramipril is widely prescribed for cardiovascular and renal protection in various conditions. As an ACE inhibitor, it lowers blood pressure and mitigates progression of cardiovascular and renal disease by interfering with the renin-angiotensin-aldosterone system (RAAS).

Approved Indications:

1. Hypertension (high blood pressure)
   – Monotherapy or in combination with other antihypertensives

2. Heart failure (symptomatic or asymptomatic left ventricular dysfunction)
   – Post-myocardial infarction with reduced ejection fraction
   – Improves survival and reduces hospitalizations

3. Post-myocardial infarction (MI)
   – To reduce risk of reinfarction, stroke, or cardiovascular death

4. Cardiovascular risk reduction
   – In high-risk patients without overt heart failure (HOPE study)

5. Diabetic and non-diabetic nephropathy (off-label in some regions)
   – Slows progression of kidney disease in patients with proteinuria

6. Secondary prevention in stroke and peripheral artery disease (PAD)
   – In select patients with vascular disease risk

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Mechanism of Action

Ramipril is a prodrug converted in the liver to its active form, ramiprilat. It inhibits angiotensin-converting enzyme (ACE), thereby suppressing the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.

Pharmacodynamic Effects:

• Decreases angiotensin II levels → vasodilation

• Reduces aldosterone secretion → decreased sodium and water retention

• Increases bradykinin levels (via decreased breakdown) → vasodilation (but also associated with cough and angioedema)

• Lowers total peripheral resistance and blood pressure

• Reduces glomerular capillary pressure → nephroprotective

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Dosing and Administration

A. Hypertension (Adults):

• Initial: 2.5 mg once daily

• Maintenance: 2.5–10 mg/day, in 1 or 2 divided doses

• Max: 10 mg/day

B. Heart Failure/Post-MI:

• Initial: 1.25–2.5 mg twice daily

• Titrate slowly to max 5 mg twice daily as tolerated

C. Cardiovascular Risk Reduction:

• Initiate at 2.5 mg once daily for 1 week → 5 mg/day for 3 weeks → target 10 mg/day

D. Renal Impairment or Elderly Patients:

• Start at lower doses: 1.25 mg once daily

• Use with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²)

E. Pediatric Use:

• Not approved for children in most regions

• Off-label weight-based dosing under specialist supervision

Administration Notes:

• Can be taken with or without food

• Take at the same time daily

• Capsules can be opened and mixed with applesauce or water if swallowing is difficult

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Pharmacokinetics

• Absorption: ~60% orally absorbed (as prodrug)

• Bioactivation: Rapid hepatic conversion to active ramiprilat

• Onset: 1–2 hours (BP lowering); peak effect in 3–6 hours

• Half-life: Ramiprilat ~13–17 hours (allows once-daily dosing)

• Excretion: 60% via urine, 40% via feces (mostly as metabolites)

• Protein binding: ~73%

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Contraindications

• Hypersensitivity to ramipril or other ACE inhibitors

• History of angioedema related to previous ACE inhibitor use

• Pregnancy and lactation

• Bilateral renal artery stenosis or stenosis in a solitary kidney

• Severe hypotension or hemodynamic instability

• Concurrent use with aliskiren in diabetic patients

• Patients with hereditary or idiopathic angioedema

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Black Box Warning (US FDA)

Fetal Toxicity:
– Discontinue as soon as pregnancy is detected
– Drugs that act on the RAAS can cause injury and death to the developing fetus

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Warnings and Precautions

1. Hypotension:
   – Especially after first dose in volume-depleted or salt-depleted patients
   – Start at lower doses and monitor BP

2. Renal Impairment:
   – May cause increases in serum creatinine and BUN
   – Monitor renal function closely in high-risk patients

3. Hyperkalemia:
   – Due to aldosterone suppression
   – Caution in patients with renal impairment, on potassium-sparing diuretics, or potassium supplements

4. Cough:
   – Dry, persistent, non-productive cough due to bradykinin accumulation
   – May require discontinuation

5. Angioedema:
   – Rare but potentially life-threatening
   – More common in African ancestry

6. Neutropenia and Agranulocytosis:
   – Rare; monitor WBCs in patients with renal dysfunction or autoimmune disease

7. Hepatic Impairment:
   – Caution due to prodrug activation in liver

8. Surgery/Anesthesia:
   – May cause hypotension; temporary discontinuation advised

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Adverse Effects

Common (≥1%):

• Cough

• Dizziness

• Headache

• Fatigue

• Hypotension

• Nausea, abdominal discomfort

• Hyperkalemia

• Increased creatinine or BUN

• Angioedema (less frequent but serious)

Uncommon (<1%):

• Rash, pruritus

• Anemia

• Taste disturbance (dysgeusia)

• Hepatitis (rare)

• Pancreatitis

• Neutropenia or leukopenia

• Gynecomastia (rare reports)

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Drug Interactions

1. Diuretics (esp. thiazides, loop):
   – May enhance hypotensive effect
   – Risk of volume depletion

2. Potassium-sparing diuretics (spironolactone, amiloride):
   – ↑ Risk of hyperkalemia
   – Avoid or monitor K+

3. NSAIDs:
   – May blunt antihypertensive effect
   – ↑ Risk of renal dysfunction and hyperkalemia

4. Lithium:
   – Increased serum lithium levels and toxicity risk

5. Aliskiren:
   – Avoid especially in diabetics and patients with renal impairment

6. Antihypertensives and vasodilators:
   – Additive hypotensive effects

7. Insulin and antidiabetics (e.g., sulfonylureas):
   – ACE inhibitors may enhance insulin sensitivity → risk of hypoglycemia

8. Gold injections (sodium aurothiomalate):
   – Rare nitritoid reactions (facial flushing, hypotension) reported

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Monitoring Parameters

• Blood pressure: baseline, during dose adjustment, and regularly

• Renal function: serum creatinine, BUN

• Serum potassium: particularly in patients with renal impairment

• CBC: if patient is at risk for neutropenia

• Signs of angioedema: facial swelling, difficulty breathing

• Cough: persistent dry cough requiring medication switch

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Use in Special Populations

Pregnancy:
– Contraindicated (Category D); teratogenic and fetotoxic
Lactation:
– Not recommended; excreted in human milk
Elderly:
– Start at lower doses; monitor renal function
Pediatrics:
– Not routinely used unless under specialist advice
Renal Impairment:
– Dose adjustments required; monitor closely
Hepatic Impairment:
– Activation of prodrug may be impaired; use caution

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Comparison to Other ACE Inhibitors

ACE Inhibitor	Dosing Frequency	Prodrug	Duration	Lipophilicity	Renal Dosing Needed
Ramipril	Once/twice daily	Yes	Long	Moderate	Yes
Enalapril	Twice daily	Yes	Intermediate	Low	Yes
Lisinopril	Once daily	No	Long	Low	Yes
Perindopril	Once daily	Yes	Long	High	Yes

Ramipril is often favored for its cardiovascular protection in high-risk patients (per HOPE trial data).

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Patient Counseling Points

• Take consistently at the same time each day

• May be taken with or without food

• Monitor for signs of dizziness or lightheadedness, especially after the first dose

• Inform provider of any swelling of the face, lips, or tongue

• Report persistent dry cough or unusual fatigue

• Do not use salt substitutes containing potassium without approval

• Maintain adequate hydration but avoid excessive fluid intake

• Regular blood tests for kidney function and electrolytes are necessary

• Do not stop medication abruptly without medical advice

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Storage and Stability

• Store at room temperature (20–25°C)

• Protect from moisture and light

• Keep out of reach of children

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Availability and Regulatory Status

• Prescription-only medication globally

• Included in WHO Model List of Essential Medicines

• Widely available under generic and brand names in all major regions

• Covered in national and international guidelines for hypertension and cardiovascular risk reduction