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
- 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
- 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
| Contraindication | Reason |
|---|
| 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 With | Risk |
|---|
| 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 |