Enalapril and Ramipril

Mechanism

Pharmacological Class and Group

Antihypertensives and vasodilators from the group of Angiotensin Converting Enzyme Inhibitors (ACEI). Both are dicarboxylic prodrugs that require hepatic hydrolysis to convert to their active metabolites.

Mechanism of Action

The renin-angiotensin-aldosterone system (RAAS) is the main hormonal axis that regulates blood pressure and intravascular volume. Angiotensin-converting enzyme (ACE) is a soluble, transmembrane zinc-metallopeptidase that hydrolyzes target peptides.

Molecular Inhibition Cascade of RAAS and Kallikrein-Kinin

1. Inhibition of Angiotensin II synthesis: Enalaprilat and ramiprilat (active forms) bind competitively to the active site of ACE coordinating with the catalytic zinc atom. This blocks the conversion of Angiotensin I (inactive deca-peptide) into Angiotensin II (octa-peptide with potent vasoconstrictive and pro-fibrotic effects):

Angiotensin I ACE Angiotensin II ↓ AT_{1 Receptor Stimulation}

2. Reduction in Aldosterone secretion: The drop in circulating levels of Angiotensin II decreases the trophic stimulus in the glomerular zone of the adrenal cortex, reducing the expression and activity of epithelial sodium transporters (ENaC) in the renal collecting duct, which promotes natriuresis and potassium retention.

3. Bradycidin Accumulation (Kininin Pathway): ACE is identical to kininase II, the enzyme responsible for degrading bradycidin (a vasodilator peptide dependent on nitric oxide and prostaglandins). When kininase II is inhibited, bradycidin levels increase substantially in the tissue interstitium and at the lung level:

↑ [Bradycidin] Activation of B₂ receptors ↑ Nitric Oxide and PGI₂ Additional vasodilation

This increase in bradycidin stimulates sensory nerve endings in the airways and promotes the release of inflammatory mediators, which explains the genesis of dry cough and refractory angioedema.

Pharmacokinetics

Comparative Pharmacokinetics

Indicators and dose

Clinical Indications and Uses

• Systemic Arterial Hypertension: First line, especially in patients with metabolic or renal co-morbidities.
• Heart Failure with Reduced Ejection Fraction (HFrEF): Indicated to reduce morbidity and mortality, pathological ventricular remodeling and hospitalizations.
• Diabetic Nephropathy (Micro and Macroalbuminuria): Nephroprotective effect due to preferential vasodilation of the renal efferent arteriole, reducing intraglomerular pressure and preserving long-term filtration function.
• Post-Acute Myocardial Infarction: Initiated within the first 24 hours to attenuate left ventricular dilation and improve overall survival.

Dosage and Clinical Adjustment

Enalapril:

• Heart Failure / Hypertension: Initial dose of 2.5 mg to 5 mg every 12 or 24 hours orally. Target maintenance dose of 10 mg to 20 mg every 12 hours.
• Renal Adjustment: If the stimulated glomerular filtration rate (eGFR) is 30 to 60 mL/min/1.73 m², the initial dose should be reduced to 2.5 mg per day. If eGFR is less than 30 mL/min, start with 1.25 mg to 2.5 mg daily and titrate with caution.

Ramipril:

• Hypertension / Post-MI: Initial dose of 1.25 mg to 2.5 mg once daily. Maintenance dose of 5 mg to 10 mg once a day.
• Renal Adjustment: If the eGFR is less than 30 mL/min/1.73 m², the maximum allowed dose of ramipril is 5 mg per day.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• History of angioedema induced by ACEI or of a hereditary/idiopathic nature.
• Pregnancy: Absolute contraindication due to teratogenicity and fetotoxicity in the second and third trimester (oligohydramnios, fetal pulmonary hypoplasia, neonatal renal failure).
• Co-administration with Aliskiren in patients with diabetes mellitus or glomerular filtration rate less than 60 mL/min/1.73 m².
• Use together with sacubitril (requires a strict washing period of 36 hours).

Relative Contraindications

• Bilateral renal artery stenosis (or single kidney stenosis), because the drop in intraglomerular pressure due to vasodilation of the efferent arteriole can precipitate irreversible anuric acute renal failure.
• Basal severe hyperkalemia (K⁺ > 5.5 mEq/L).
• Symptomatic arterial hypotension or extreme volume depletion.

Adverse Effects and Specific Toxicities

• Persistent dry cough (10% - 20%): Does not respond to centrally acting cough suppressants and requires rotation to an ARB.
• Hyperkalemia: Secondary to decreased aldosterone, especially in patients with renal failure or receiving potassium supplements/potassium savers.
• Functional Acute Renal Failure: Tolerable initial elevation of creatinine of up to 30% that usually stabilizes. Higher increases require a reduction in the dose or temporary suspension of the drug.
• Angioedema (0.1% - 0.5%): Rapid edema of the face, lips, tongue, glottis and larynx that can compromise the airway.

Emergency Alert: Clinical Management of Angioedema due to ACEI

Bradycidin-mediated angioedema is resistant to antihistamines and conventional systemic corticosteroids because its etiology is independent of IgE-mediated mast cell degranulation. First-line management in the event of imminent airway compromise includes:

Discontinue ACEI Secure Airway Consider Icatibant (B₂ Antagonist) or C1 Inhibitor Concentrate

In severe refractory cases where targeted drugs are not available, fresh frozen plasma (containing functional kininase II) can be used to accelerate the degradation of endogenous bradycidin.

Relevant Drug Interactions

• Potassium-sparing diuretics (Spironolactone, Eplerenone, Amiloride) and supplements: Severe hyperkalemia pharmacodynamic synergism. Requires frequent serum electrolyte controls.
• Non-steroidal anti-inflammatory drugs (NSAIDs): They inhibit the synthesis of renal prostaglandins, attenuating the vasodilation of the afferent arteriole. Its co-administration reduces the antihypertensive effect of ACEIs and substantially increases the risk of acute renal failure (the feared "triple association": ACEI + Diuretic + NSAID).
• Lithium: ACEIs reduce renal excretion of lithium, increasing its plasma concentration and favoring neurotoxicity and lytic nephrotoxicity.