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PH4.6 | PH4.6 | Renin Angiotensin Aldosterone System Modulators — SDL Guide (Part 2)

ACE Inhibitors: PK, PD, Uses, and ADRs

ACE inhibitors revolutionised the management of hypertension, heart failure, and nephropathy since captopril's introduction in 1981. Understanding their pharmacokinetics and adverse effect profile allows you to use them safely across diverse clinical settings.

Pharmacokinetics: Most ACEi are prodrugs — administered as inactive ethyl esters and hydrolysed in the liver to active diacid forms. Enalapril → enalaprilat; ramipril → ramiprilat; perindopril → perindoprilat. Exceptions: captopril and lisinopril are active as administered. The clinical implication: in severe hepatic failure, prodrug bioactivation may be impaired — choose captopril or lisinopril. Most ACEi are eliminated renally → dose reduction required in CKD (eGFR <30 mL/min); fosinopril has dual renal+hepatic elimination and needs less dose adjustment in CKD.

Pharmacodynamics: ACEi lower BP through: (1) decreased Ang II → reduced vasoconstriction and aldosterone secretion; (2) increased bradykinin → vasodilation via NO and prostacyclin. In HFrEF, the reduction in afterload (vasoconstriction) and preload (aldosterone → Na retention) improves cardiac output and reverses remodelling over months. In diabetic nephropathy, ACEi reduce intraglomerular pressure (by dilating the efferent arteriole, which Ang II normally constricts) → slow the progression of albuminuria.

Key therapeutic uses: Hypertension (all grades, all comorbidities except contraindications); HFrEF (LVEF <40%) — first-line unless ARNI is chosen; post-MI within 24–48h (reduce mortality, prevent remodelling — evidence: SAVE with captopril, AIRE with ramipril, TRACE with trandolapril); diabetic nephropathy (reduce albuminuria, slow GFR decline — evidence: Lewis et al. captopril in type 1 DM); non-diabetic CKD with proteinuria; secondary prevention (HOPE trial — ramipril).

Adverse drug reactions:
1. Dry cough (~10–15% of patients; up to 30% in South Asian patients — higher bradykinin sensitivity). Class effect. Managed by switching to ARB.
2. Angioedema (~0.1–0.7%): swelling of face, lips, tongue, larynx — potentially life-threatening. Bradykinin-mediated. Can occur weeks to months after initiation. Absolute contraindication to re-challenging with ACEi. Treat with: airway support, IV adrenaline, C1-esterase inhibitor concentrate, icatibant (bradykinin B2 receptor antagonist). Prior angioedema is an absolute contraindication.
3. Hyperkalaemia: ACEi reduce aldosterone → reduced renal K excretion. Monitor K, especially when combined with K-sparing diuretics, ARBs, NSAIDs, or trimethoprim.
4. Acute kidney injury (AKI): In bilateral renal artery stenosis (or unilateral with a single functioning kidney), GFR is maintained by Ang II-mediated efferent vasoconstriction. ACEi removes this compensation → AKI. Also precipitated by hypovolaemia (NSAID, diarrhoea) + ACEi + diuretic ('triple whammy').
5. First-dose hypotension: particularly in volume-depleted or salt-restricted patients; start low, monitor.
6. Teratogenicity: ACEi are contraindicated in pregnancy — in the second and third trimesters they cause oligohydramnios, renal tubular dysgenesis, hypocalvaria, and fetal growth restriction (FDA category D from 2nd trimester). Even in the 1st trimester, avoidance is preferred; any woman of childbearing potential should be counselled.

ARBs, ARNIs, and Direct Renin Inhibitors: PK, PD, Uses, ADRs

Angiotensin receptor blockers (ARBs) are competitive antagonists at the AT1 receptor and represent the principal alternative to ACEi when the latter are not tolerated. Because ARBs do not block ACE, bradykinin is still degraded normally: no cough (principal advantage) and much lower angioedema risk (~0.3–0.5% vs ~0.5–1.5% for ACEi). The presence of unblocked AT2 receptors (still stimulated by the Ang II that accumulates behind AT1 blockade) may confer additional vasodilatory and anti-remodelling effects.

Individual ARBs: Losartan is the prototype and the shortest-acting; its active metabolite EXP-3174 is 10–40× more potent; losartan has a mild uricosuric effect (LIFE trial population included hypertensives with LVH — losartan reduced stroke and new-onset diabetes more than atenolol). Valsartan is used in HFrEF and post-MI. Irbesartan and olmesartan are frequently used for HTN+diabetic nephropathy. Candesartan for HFrEF (CHARM-Alternative trial). Telmisartan has the longest half-life (~24h), once-daily dosing, and also acts as a weak PPAR-γ agonist (mild insulin-sensitising effect). All ARBs share the same contraindications as ACEi (pregnancy, bilateral renal artery stenosis, prior angioedema to any ARB) and the same ADR of hyperkalaemia and AKI.

Important ONTARGET trial result: Combining ACEi + ARB (dual RAAS blockade) increases hyperkalaemia, AKI, and hypotension without additional cardiovascular benefit compared to monotherapy — ACEi + ARB combination is not recommended (except in specific proteinuric CKD protocols under close monitoring).

ARNI (sacubitril/valsartan): Entresto® combines sacubitril (a prodrug converted to LBQ657, a neprilysin inhibitor) with valsartan (AT1 blocker). Neprilysin degrades natriuretic peptides (ANP, BNP) and bradykinin. Inhibiting neprilysin → raises ANP and BNP → vasodilation, natriuresis, anti-fibrosis, and anti-hypertrophic signalling. Combined with AT1 blockade, this produces superior neurohormonal modulation compared to ACEi alone. The PARADIGM-HF trial (8,442 patients with HFrEF LVEF ≤40%) compared sacubitril/valsartan to enalapril: sacubitril/valsartan reduced the composite of cardiovascular death or first HF hospitalisation by 20% (hazard ratio 0.80, p<0.001) — a landmark result that has made ARNI the recommended RAAS agent in HFrEF for patients who can tolerate it. The 36-hour washout rule: because sacubitril (neprilysin inhibitor) and ACEi each independently increase bradykinin levels, combining them would cause dangerous bradykinin excess — severe angioedema. Switch from ACEi to ARNI only after 36 hours off the ACEi.

Direct renin inhibitors (DRIs) — aliskiren: Inhibits renin's catalytic site, blocking the entire cascade from step 1. Despite an attractive mechanism (prevents reactive hyperreninaemia), the ALTITUDE trial demonstrated harm when aliskiren was added to existing ACEi or ARB in patients with T2DM + CKD or CVD — increased risk of renal failure, hyperkalaemia, and hypotension. The trial was stopped early. Aliskiren monotherapy is approved for hypertension but is rarely used clinically; it is absolutely contraindicated in combination with ACEi or ARBs.

Clinical Decision-Making: Choosing Among RAAS Modulators

Selecting the optimal RAAS modulator requires aligning the drug class's established benefits (from trials) with the patient's indication, comorbidities, tolerability, and monitoring capacity.

ACEi as first choice when: (1) HFrEF — unless ARNI is preferred or not tolerated; (2) post-MI — start within 24–48h in all patients without contraindication; (3) hypertension with diabetic nephropathy — first-line; (4) CKD with proteinuria (non-diabetic) — nephroprotective evidence; (5) secondary prevention in high-risk patients without HF (HOPE — ramipril).

Switch to ARB when: ACEi is indicated but the patient develops intolerable cough. All nephroprotective and cardiovascular benefits are preserved with ARBs. Do NOT combine ACEi + ARB (ONTARGET evidence of harm without benefit).

Choose ARNI (sacubitril/valsartan) when: HFrEF (LVEF ≤40%) is the indication AND the patient can tolerate the BP reduction AND has no history of angioedema. Requires washout from ACEi. Most guidelines now recommend ARNI over ACEi in HFrEF if accessible and affordable.

Monitoring essential for all RAAS modulators:
- Serum creatinine and eGFR: at baseline, 1–2 weeks after initiation (a ≤30% increase in creatinine is acceptable and expected; >30% rise = evaluate bilateral RAS or hypovolaemia; stop if creatinine doubles)
- Serum potassium: at baseline, 1–2 weeks after initiation (target K <5.5 mEq/L)
- Blood pressure: assess for hypotension, especially in volume-depleted patients
- Urine ACR/albumin: to monitor nephroprotective response

Absolute contraindications (apply to all ACEi and ARBs):
- Pregnancy (teratogenic)
- History of angioedema related to ACEi/ARB
- Bilateral renal artery stenosis (or unilateral with single functioning kidney)
- Hyperkalaemia (K >5.5 mEq/L, uncorrected)

Special prescribing note — diabetes + CKD: ACEi/ARB are the preferred antihypertensives in these patients even when BP is at target, because their intraglomerular pressure-lowering effect (independent of BP) slows nephropathy. Monitor K and creatinine every 3 months.

Self-Assessment: RAAS Blockade Mechanisms and Clinical Scenarios

Consolidate your understanding of RAAS modulators with these self-assessment prompts.

Mechanism quick-reference:
- ACEi → block ACE → ↓Ang II (no vasoconstriction, no aldosterone) + ↑bradykinin (vasodilation + cough/angioedema)
- ARBs → block AT1 → ↓Ang II effects + AT2 still stimulated (vasodilation, anti-fibrosis) + normal bradykinin (no cough)
- ARNI → sacubitril (↑ANP/BNP by blocking neprilysin) + valsartan (↓Ang II at AT1) — superior neurohormonal blockade
- DRI (aliskiren) → blocks renin → blocks entire cascade; contraindicated with ACEi/ARBs

Contraindication matrix:

Contraindication	ACEi	ARB	ARNI
Pregnancy	Yes (teratogenic)	Yes (teratogenic)	Yes
Bilateral RAS	Yes	Yes	Yes
Prior ACEi angioedema	Yes	Relatively safer	Avoid
Hyperkalaemia >5.5 mEq/L	Yes	Yes	Yes
Concurrent ACEi + ARB	—	ONTARGET: not recommended	Contraindicated with ACEi

ADR distinction — ACEi vs ARBs:

ADR	ACEi	ARBs
Dry cough	Yes (~10–15%; up to 30% in S.Asia)	No
Angioedema	Yes (~0.1–0.7%)	Rare (~0.1%)
Hyperkalaemia	Yes	Yes
First-dose hypotension	Yes	Yes
Teratogenicity	Yes	Yes