CVS Pharmacology: ACE Inhibitors, Angiotensin Receptor Blockers, and the RAAS Pathway

Introduction/Overview

The renin–angiotensin–aldosterone system (RAAS) represents a central endocrine pathway that regulates arterial pressure, fluid and electrolyte balance, and systemic vascular resistance. Dysregulation of this system is implicated in a variety of cardiovascular disorders including hypertension, heart failure, chronic kidney disease, and ischemic heart disease. Pharmacologic modulation of RAAS, primarily through angiotensin‑converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), has revolutionized the management of these conditions. The present chapter is intended for medical and pharmacy students; it systematically reviews the pharmacology of ACE inhibitors and ARBs, elucidating their mechanisms of action, pharmacokinetic properties, clinical indications, adverse effect profiles, and interaction potential. In doing so, the chapter integrates current therapeutic guidelines with mechanistic insights to foster a comprehensive understanding of RAAS‑targeted therapy.

Learning Objectives

• Describe the physiological roles of the RAAS and the impact of pharmacologic inhibition on cardiovascular homeostasis.
• Differentiate between ACE inhibitors and ARBs in terms of chemical structure, pharmacodynamic mechanisms, and clinical utility.
• Identify key pharmacokinetic parameters that influence dosing and therapeutic monitoring of ACE inhibitors and ARBs.
• Recognize the spectrum of adverse effects, contraindications, and drug interactions associated with RAAS blockade.
• Apply knowledge of special patient populations to optimize RAAS blockade while minimizing harm.

Classification

Drug Classes and Categories

ACE inhibitors and ARBs are both classified as antihypertensive agents, yet they belong to distinct chemical families and exert their effects through separate receptor targets within the RAAS. ACE inhibitors are further subdivided into N‑terminal and C‑terminal inhibitors, reflecting the site of enzymatic interaction. ARBs are grouped according to the specific angiotensin II type 1 (AT₁) receptor antagonist they possess; most agents exhibit high selectivity for AT₁ over AT₂ receptors.

Chemical Classification

ACE inhibitors generally contain a captopril-like sulfhydryl group or a tripeptide backbone that mimics the natural substrate of ACE. Representative examples include captopril, enalapril, lisinopril, and ramipril. ARBs, in contrast, are synthetic heterocyclic compounds featuring a biphenyl or quinazoline core and a carboxylate side chain that confers high affinity for the AT₁ receptor. Common ARBs include losartan, valsartan, irbesartan, and candesartan.

Mechanism of Action

Pharmacodynamics

ACE inhibitors competitively bind to the catalytic zinc ion at the active site of ACE, thereby preventing the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). This reduction in Ang II levels leads to vasodilation, decreased aldosterone secretion, and attenuation of sympathetic nervous system activity. In addition, ACE inhibition raises bradykinin concentrations due to decreased degradation; bradykinin contributes to vasodilatory and natriuretic effects, which may amplify antihypertensive action. ARBs, on the other hand, occupy the AT₁ receptor, blocking Ang II-mediated vasoconstriction, sodium and water retention, and trophic effects on cardiac and vascular tissues. Because ARBs do not affect bradykinin metabolism, the incidence of cough and angioedema is markedly reduced compared to ACE inhibitors.

Receptor Interactions

The AT₁ receptor is a G‑protein–coupled receptor located on vascular smooth muscle cells, adrenal zona glomerulosa, and various renal and cardiac tissues. Binding of Ang II to AT₁ activates phospholipase C, leading to inositol triphosphate production, calcium release, and subsequent vasoconstriction. ACE inhibitors indirectly reduce AT₁ activation by lowering Ang II availability, while ARBs directly prevent receptor engagement. Notably, blockade of AT₁ receptors can shift Ang II signaling toward the AT₂ receptor, which mediates vasodilatory, anti‑proliferative, and anti‑fibrotic effects; this shift may confer additional therapeutic benefits.

Molecular/Cellular Mechanisms

Beyond receptor antagonism, ACE inhibitors influence downstream pathways such as the nitric oxide (NO) signaling cascade. Elevated bradykinin enhances endothelial NO synthase activity, increasing NO production and vasorelaxation. ARBs, by displacing Ang II from AT₁, relieve the inhibitory influence of Ang II on NO synthesis, thereby promoting vasodilation. Both classes also modulate the renin–angiotensin–aldosterone system’s negative feedback loop, leading to a gradual reduction in plasma renin activity over time.

Pharmacokinetics

Absorption

ACE inhibitors are typically administered orally; absorption differs among agents. Captopril is rapidly absorbed, with peak plasma concentrations occurring within 1–2 h. Enalapril and lisinopril exhibit lower oral bioavailability (≈ 30 % and 25 % respectively) due to first‑pass metabolism or limited intestinal permeability. In contrast, ARBs generally possess high oral bioavailability, with losartan reaching peak plasma concentrations at ~4 h and valsartan at ~2 h. Food intake may delay absorption for certain ARBs (e.g., valsartan) but does not significantly alter overall bioavailability.

Distribution

ACE inhibitors are predominantly hydrophilic, limiting extensive tissue distribution. Captopril possesses a small volume of distribution (~5 L), whereas lisinopril and enalapril have volumes ranging from 20–30 L. ARBs are more lipophilic, facilitating broader tissue penetration; valsartan exhibits a volume of distribution of ~10 L/kg, indicating extensive extravascular distribution. Plasma protein binding is generally moderate for ACE inhibitors (≈ 30–80 %) and high for ARBs (≥ 95 % for losartan and valsartan).

Metabolism

ACE inhibitors undergo limited hepatic metabolism. Captopril is partially metabolized by the liver but excreted largely unchanged. Enalapril is a prodrug; it is converted to its active form, enalaprilat, via hepatic esterases. Lisinopril and ramipril undergo minimal metabolism, with renal excretion predominating. ARBs are metabolized by the liver through various cytochrome P450 (CYP) isoforms. Losartan is metabolized to an active metabolite (losartan carboxylate) via CYP2C9; valsartan undergoes hydrolysis and oxidation via CYP3A4; irbesartan and candesartan are metabolized by CYP2C9 and CYP2C19 respectively. The metabolic pathways influence potential drug–drug interactions, particularly with CYP inhibitors or inducers.

Excretion

Renal excretion is the primary elimination route for both ACE inhibitors and ARBs. Captopril and lisinopril are predominantly excreted unchanged by glomerular filtration and tubular secretion. Enalaprilat is also eliminated via the kidneys, requiring dose adjustment in renal impairment. ARBs are excreted as active metabolites and parent compounds; losartan carboxylate and valsartan metabolites are cleared renally. Hepatic excretion is minimal for most agents, but exceptions exist (e.g., irbesartan undergoes biliary excretion of metabolites).

Half‑Life and Dosing Considerations

The terminal half‑life of ACE inhibitors ranges from 2–16 h, with captopril having the shortest half‑life (≈ 2 h) and lisinopril the longest (≈ 12 h). Dose titration is guided by clinical response and tolerability; typical starting doses are captopril 12.5 mg twice daily, lisinopril 10 mg daily, and ramipril 2.5 mg daily. ARBs possess longer half‑lives (losartan 10 h, valsartan 6–7 h), allowing once‑daily dosing. Dose escalation is generally performed every 2–4 weeks to achieve target blood pressure or heart failure outcomes. Renal impairment necessitates careful monitoring of serum creatinine and potassium; dose adjustments are recommended based on estimated glomerular filtration rate (eGFR).

Therapeutic Uses/Clinical Applications

Approved Indications

ACE inhibitors are first‑line agents for essential hypertension, post‑myocardial infarction therapy, heart failure with reduced ejection fraction (HFrEF), and diabetic nephropathy. Renal protective effects are particularly pronounced in patients with proteinuria and microalbuminuria. ARBs are similarly indicated for hypertension, HFrEF, and diabetic nephropathy; they serve as alternatives for patients who experience ACE inhibitor‑associated cough or angioedema.

Off‑Label Uses

Both drug classes are occasionally employed off‑label for conditions such as pulmonary hypertension (particularly ARBs), preeclampsia (in the second trimester with caution), and certain forms of neurodegenerative disease, where modulation of the RAAS may confer neuroprotective benefits. However, evidence supporting these applications remains limited, and such use should be reserved for clinical trial settings or individualized patient care.

Adverse Effects

Common Side Effects

Cough, dizziness, and hyperkalemia are the most frequently reported adverse events. The cough is linked to increased bradykinin levels and is more prevalent with ACE inhibitors than ARBs. Dizziness, often orthostatic, may result from vasodilatory effects and requires patient education. Hyperkalemia arises from reduced aldosterone secretion and diminished renal potassium excretion; it necessitates periodic serum potassium monitoring, especially in patients on potassium‑sparing diuretics or with renal impairment.

Serious or Rare Adverse Reactions

Angioedema, while rare, can be life‑threatening and typically manifests within the first few weeks of therapy. Renal dysfunction may progress to acute kidney injury if volume depletion or nephrotoxic agents are co‑administered. Rarely, ACE inhibitors may precipitate angiotensin‑mediated hypotension and syncope in susceptible individuals. ARBs carry a lower risk of angioedema but may still cause hypotension, especially when combined with other vasodilators.

Black Box Warnings

Both ACE inhibitors and ARBs possess black box warnings for pregnancy category X, indicating teratogenicity and fetal harm. They are contraindicated in the first and second trimesters, with caution advised during the third trimester. Additionally, caution is warranted in patients with bilateral renal artery stenosis, severe hepatic impairment, or those receiving nephrotoxic contrast agents.

Drug Interactions

Major Drug‑Drug Interactions

Concomitant use of ACE inhibitors or ARBs with potassium‑sparing diuretics, potassium supplements, or sodium‑glucose cotransporter‑2 inhibitors increases the risk of hyperkalemia. Non‑steroidal anti‑inflammatory drugs (NSAIDs) and angiotensin II‑receptor stimulating agents (e.g., epinephrine) may blunt antihypertensive efficacy by inhibiting prostaglandin synthesis or stimulating renin release. Calcium channel blockers (particularly dihydropyridines) may potentiate hypotension when combined with ACE inhibitors or ARBs. CYP inhibitors (e.g., ketoconazole, clarithromycin) may elevate ARB serum levels, especially for losartan and valsartan, necessitating dose adjustment.

Contraindications

Absolute contraindications include hypersensitivity to the drug or any excipient, a history of angioedema related to prior ACE inhibitor therapy, bilateral renal artery stenosis, and pregnancy. Relative contraindications encompass severe hepatic impairment, uncontrolled hyperkalemia, and advanced chronic kidney disease (eGFR <30 mL/min), which may require dose reduction or avoidance.

Special Considerations

Use in Pregnancy/Lactation

Both drug classes are contraindicated during pregnancy due to teratogenic risk, particularly renal dysgenesis and oligohydramnios. Lactation is generally avoided; minimal excretion into breast milk has been documented, but caution is advised. Alternative antihypertensive agents, such as labetalol or nifedipine, are preferred during pregnancy.

Pediatric/Geriatric Considerations

Pediatric use is limited primarily to hypertension management in adolescents; dosing is weight‑based and requires close monitoring. In geriatric patients, decreased renal clearance and altered pharmacodynamics may necessitate lower initial doses and slower titration. Age‑related changes in body composition and comorbidities heighten the risk of orthostatic hypotension and hyperkalemia.

Renal/Hepatic Impairment

Renal impairment reduces drug clearance; ACE inhibitors should be initiated at low doses and titrated cautiously, with regular assessment of serum creatinine and potassium. ARBs are similarly affected, though some agents (e.g., losartan) exhibit a more favorable renal safety profile. Hepatic impairment modestly influences metabolism but does not necessitate dose adjustments for most agents; however, caution is warranted with irbesartan and candesartan due to CYP involvement.

Summary/Key Points

• The RAAS governs vascular tone, fluid balance, and electrolyte homeostasis; its dysregulation underlies hypertension and heart failure.
• ACE inhibitors reduce Ang II formation and elevate bradykinin; ARBs block AT₁ receptors and shift Ang II signaling toward AT₂ pathways.
• Pharmacokinetic profiles differ: ACE inhibitors are largely renally excreted with variable bioavailability; ARBs are highly lipophilic, undergo hepatic metabolism, and have longer half‑lives.
• Primary indications include hypertension, HFrEF, and diabetic nephropathy; off‑label uses remain experimental.
• Common adverse effects are cough (ACE inhibitors), dizziness, and hyperkalemia; serious risks include angioedema and acute kidney injury.
• Drug interactions with potassium‑sparing agents, NSAIDs, and CYP inhibitors must be managed to prevent hyperkalemia and hypotension.
• Contraindications encompass pregnancy and angioedema history; caution is advised in renal, hepatic, pediatric, and geriatric populations.
• Optimal therapy requires individualized titration, regular monitoring of renal function and electrolytes, and patient education regarding symptom vigilance.

These concepts collectively inform the rational application of ACE inhibitors and ARBs in contemporary cardiovascular care, ensuring therapeutic efficacy while mitigating risk.

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