Pharmacology · Cardiovascular

The RAAS, ACE Inhibitors, and Direct Renin Inhibitors

Cascade anatomy, drug mechanisms, contraindications, and key interactions

The RAAS cascade operates in four sequential steps: renin from juxtaglomerular cells cleaves angiotensinogen to angiotensin I; ACE on pulmonary endothelium converts angiotensin I to angiotensin II and simultaneously degrades bradykinin; angiotensin II acts at AT1 receptors to cause vasoconstriction and stimulate aldosterone release; aldosterone drives sodium retention and potassium excretion in the renal collecting duct — making the system a continuous loop linking blood pressure, volume, and electrolyte homeostasis.
ACE inhibitors block step 2, producing two parallel effects: less angiotensin II (lowering blood pressure and reducing cardiac and renal fibrosis) and more bradykinin (responsible for the class-wide dry cough in 10 to 15 percent of patients and the rarer but serious angioedema — both bradykinin-mediated, not histamine-mediated, which is why antihistamines do not treat ACE inhibitor angioedema).
Most ACE inhibitors are prodrugs requiring hepatic conversion to the active diacid form; fosinopril is the exception with dual hepatic and renal elimination, making it the preferred agent in advanced kidney disease where other ACE inhibitors accumulate.
Aliskiren blocks step 1 by occupying the renin active site, preventing generation of angiotensin I and all downstream products including aldosterone — no bradykinin accumulation means no cough and no angioedema; however, the ALTITUDE trial showed that combining aliskiren with ACE inhibitors or ARBs in patients with diabetes or CKD increased renal complications and hyperkalemia without cardiovascular benefit, making this combination contraindicated.
The four absolute ACE inhibitor contraindications each reflect specific mechanisms: bilateral renal artery stenosis (efferent arteriolar dilation collapses GFR); pregnancy (fetal RAAS essential for renal development, suppression causes oligohydramnios); prior ACE inhibitor angioedema (permanent bradykinin sensitivity); and concurrent sacubitril-valsartan (both agents raise bradykinin, dramatically increasing angioedema risk — requiring a 36-hour washout between them).

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

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

Suggested References

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