Chapter 24  ·  Module 1
The RAAS, ACE Inhibitors, and Direct Renin Inhibitors
Cascade anatomy, drug mechanisms, contraindications, and key interactions
The Renin-Angiotensin-Aldosterone Cascade
Step 1
Renin
Cleaves angiotensinogen → Angiotensin I
Kidney (JG cells)
→
Step 2
ACE
Converts Ang I → Ang II; also degrades bradykinin
Lung endothelium
→
Step 3
Angiotensin II
AT1 receptor: vasoconstriction + aldosterone release
Vascular smooth muscle
→
Step 4
Aldosterone
Na&sup+; retention, K&sup+; excretion in collecting duct
Adrenal cortex / Kidney
Drug Classes Targeting the Cascade
Step 2 Blocker
ACE Inhibitors (e.g. enalapril, lisinopril, captopril)
  • Block ACE active site → less Ang II, more bradykinin
  • Dry cough (bradykinin in lung) — class effect
  • Angioedema (bradykinin-mediated, not histamine)
  • Hyperkalemia (reduced aldosterone)
  • Most: prodrugs requiring hepatic activation
  • Renal elimination; reduce dose if kidney impaired
  • Fosinopril: dual hepatic/renal — preferred in advanced kidney disease
Step 1 Blocker
Direct Renin Inhibitor (aliskiren)
  • Blocks renin active site → no Ang I, Ang II, or aldosterone
  • No bradykinin effect → no cough, no angioedema
  • Poor oral bioavailability (~2–3%)
  • Hepatobiliary elimination; does not accumulate in kidney disease
  • Do NOT combine with ACE inhibitors or ARBs in diabetes or kidney disease (ALTITUDE trial)
ACE Inhibitor Contraindications
ContraindicationReason
Bilateral renal artery stenosis Ang II maintains GFR via efferent constriction; blocking ACE collapses filtration pressure → acute kidney injury
Pregnancy (all trimesters) Fetal RAAS required for renal development; suppression causes oligohydramnios, fetal anuria, pulmonary hypoplasia
Prior ACE inhibitor angioedema Bradykinin-driven; permanent class contraindication
Concurrent sacubitril-valsartan Both raise bradykinin; combination markedly increases angioedema risk
Key Drug Interactions
Combined WithRisk
NSAIDs / COX-2 inhibitors Reduced afferent dilation + reduced efferent constriction → acute kidney injury, especially in elderly or chronic kidney disease patients
Potassium-sparing diuretics Additive potassium retention → hyperkalemia
Lithium Increased proximal tubular lithium reabsorption → lithium toxicity