L14 Clinical Pharmacology ACE inhibitors and angiotensin receptor blockers

Overview

This lecture is in two parts. Part A recaps the Renin-Angiotensin-Aldosterone System (RAAS) including bradykinin, and covers how angiotensin II (Ang II) and aldosterone drive cardiovascular and renal injury — particularly in diabetic nephropathy (DN) and chronic kidney disease (CKD) progression — setting up why blocking the pathway is renoprotective. Part B covers the pharmacology of ACE inhibitors (‘prils, e.g. enalapril, ramipril) and angiotensin receptor blockers (ARBs, ‘sartans, e.g. candesartan): their mechanisms, effects on renal blood flow (RBF) and glomerular filtration rate (GFR), pharmacokinetics, adverse drug reactions (ADRs), clinical guidelines, drug interactions, and the newer angiotensin receptor/neprilysin inhibitor (ARNi) class (sacubitril/valsartan) used in heart failure.

The renin-angiotensin system (RAS) cascade

Renin release from the juxtaglomerular apparatus (JGA) is promoted by three factors:

• Intrarenal modulation: intrarenal baroreceptor pathway; low Na⁺/Cl⁻ concentration presented to the macula densa in the renal distal tubule.
• Extrarenal control: post-ganglionic sympathetic stimulation of β1-adrenoreceptors on JG cells.

Renin release is physiologically terminated by Ang II acting on: AT1 receptors on JG cells, tubular Na⁺ retention, and vasculature (BP effects) — a negative feedback loop.

Cascade, in order:

1. Sympathetic activation (via β1-adrenoreceptors), ↓Na⁺/Cl⁻ delivery to the distal tubule (macula densa activation), and ↓pressure in the afferent arteriole (intrarenal baroreceptor activation) all converge on juxtaglomerular cells.
2. JG cells release renin.
3. Renin cleaves circulating angiotensinogen → angiotensin I.
4. ACE (in vascular endothelium) converts angiotensin I → angiotensin II.
5. Ang II acts on AT1 receptors (stimulatory) → aldosterone release, vasoconstriction, cell growth, fibrosis.
6. Ang II acts on AT2 receptors (inhibitory) → apoptosis.
7. Aldosterone release feeds back negatively on the juxtaglomerular cells.

Ang II terminates its own trigger (negative feedback via AT1R on JG cells, tubular Na⁺ retention, vasculature), so the system is normally self-limiting.

Drug targets on the cascade

• Renin inhibitors block angiotensinogen → angiotensin I.
• ACE inhibitors block angiotensin I → angiotensin II, and also block ACE’s breakdown of bradykinin.
• AT1 blockers (ARBs) block Ang II at the AT1 receptor.
• MR blockers (mineralocorticoid receptor antagonists) block aldosterone release/action.
• AT2 receptor signalling leads to inactive peptides and (via an unclear step, marked ”?” on the slide) nitric oxide; bradykinin acts via the BK receptor to also produce nitric oxide.

ACE’s “Janus effect” and bradykinin

ACE (a kinase enzyme) has a dual (Janus) action: inhibiting it reduces Ang II production and inhibits bradykinin degradation — i.e. ACE inhibitors increase bradykinin levels.

Bradykinin (B2 receptor) stimulation:

• Promotes vasodilatation by stimulating arachidonic acid metabolites, nitric oxide (NO), and endothelium-derived hyperpolarising factor (EDHF).
• Promotes natriuresis via direct tubular effects (inhibits eNCC-1 in the distal convoluted tubule).

Excessive bradykinin adversely:

• Increases vascular permeability.
• Induces coughing by activating B2 receptors on bronchopulmonary C-fibres.
• Augments nasal mucus secretion.

Some polymorphisms cause reduced breakdown of accumulated bradykinin.

Actions of angiotensin II

Ang II is an agonist at AT1R and AT2R (on smooth muscle, cardiomyocytes, nephron, etc.). It is:

• A powerful vasoconstrictor and profibrotic agent.
• Directly promotes Na⁺ and fluid retention by the nephron.
• Stimulates aldosterone release from the adrenal cortex.
• Enhances sympathetic activity — acts within the CNS and at sympathetic nerve endings, stimulates noradrenaline (NA) release and inhibits NA reuptake.
• Stimulates ADH release from the posterior pituitary.
• Stimulates cardiac and vascular hypertrophy.

Positive feedback loop: ↑sympathetic activation → β1-adrenoreceptors → JG cells → renin release → angiotensin I → angiotensin II → pre-synaptic AT1 receptors, which loop back to further increase sympathetic activation.

CV/renal effects, by system

System	Mechanisms	Summative effect
Peripheral resistance	Direct vasoconstriction; ↑SNS discharge; ↑peripheral NA effects; ↑catecholamine discharge from adrenal medulla	Rapid pressor response
Renal function	↑Na⁺ reabsorption in proximal tubule; ↑aldosterone release from adrenal cortex → Na⁺/K⁺ influx in distal/collecting tubule; altered renal haemodynamics (renal vasoconstriction; ↑renal SNS/NA discharge and vasotone)	Slow pressor response
CV structure	Haemodynamic: ↑cardiac afterload, ↑vascular wall tension. Non-haemodynamic: ↑growth factors, ↑pro-inflammatory cytokines, ↑ECM deposition	Hypertrophy and remodelling

Multi-organ injury

Ang II acting via AT1R plays a central role in multi-organ injury, converging toward death:

• Vasculature/brain: atherosclerosis, vasoconstriction, vascular hypertrophy, endothelial dysfunction → stroke.
• Heart: LV hypertrophy, fibrosis, remodelling, apoptosis → heart failure/MI.
• Kidney: ↓GFR, proteinuria, aldosterone release, glomerular sclerosis → renal failure.

Renal Ang II specifically promotes mesangial cell growth and contraction, efferent arteriolar vasoconstriction, and Na⁺ retention (proximal tubule).

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Ang II induced endothelial dysfunction: Ang II acting at endothelial AT1R provokes free radical injury via cytosolic NADPH oxidase activity, instrumental in metabolic damage and cell death. AT1R effects are also crucial to extracellular matrix transition and collagen deposition/remodelling in kidney, heart, and vasculature. The RAS pathway is critically important across diabetes mellitus, heart failure, and hypertension, which are often seen as co-morbidities.

Ang II, diabetic nephropathy and fibrosis

Diabetic nephropathy (DN) is a major cause of renal disease. ACE inhibitors may prevent or delay progression of microalbuminuria to overt proteinuria in Type I diabetes (with variable evidence in Type II) with nephropathy (DETAILS study, 2004). This effect is achieved by:

• Decreasing arterial pressure.
• Selectively dilating efferent arterioles and decreasing glomerular filtration pressure.
• Attenuating Ang II-mediated mesangial cell growth and matrix production.

Histology: nodular glomerulosclerosis in DN (periodic acid–Schiff stain) progressing to an entirely sclerotic end stage.

Ang II together with hyperglycaemia is critical to renal mesangial cell proliferation, extracellular matrix transition, and collagen deposition. Multiple hyperglycaemia-driven pathways (glycolytic/DAG, aldose reductase/sorbitol, autoxidation, AGEs, redox imbalance) converge via PKC, MAPK and NF-κB, alongside angiotensinogen → renin/prorenin → Ang I → (via ACE) Ang II, onto TGF-β → Smad signalling, ultimately increasing collagens, fibronectin, α-SMA and fibrosis.

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Profibrotic effects of Ang II (mechanism): ACE converts Ang I to Ang II (blocked by ACE inhibitors); Ang II acts on AT1R on fibroblasts, activating TGFβ → TGFβR → pSmad2/3 signalling, alongside ET-1, CTGF, MCP-1, ROS and VCAM-1/immune cell recruitment (inflammation). Downstream: fibroblast proliferation → transdifferentiation → matrix deposition → matrix degradation (regulated by MMPs/TIMPs), producing differentiated myofibroblasts with cytoplasmic actin and α-SMA stress fibres, and ECM accumulation.

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Aldosterone: physiological role and pathological excess

Physiologically, aldosterone is important for Na⁺/K⁺/water handling: renal nerve stimulation → renin → angiotensinogen → angiotensin I → (via ACE) angiotensin II → acts on the adrenal cortex → aldosterone → decreased Na⁺ (and water) excretion → increased extracellular fluid volume.

However, raised aldosterone levels are also pro-fibrotic and lead to renal injury.

Pathway to renal fibrosis: RAAS activation, hyperkalaemia, obesity and low salt intake all raise aldosterone → SGK1 signalling → splits into NF-κB pathway and ROS/redox signalling → five downstream effects (ECM accumulation: fibronectin, collagen, PAI-1; inflammation: COX-2, IL-6, IL-1β, MCP-1; epithelial-to-mesenchymal transition (EMT) of tubules/podocytes; growth factor release: CTGF, TGF-β1; proliferation of myofibroblasts/lymphocytes) → renal fibrosis/inflammatory injury → glomerulosclerosis/interstitial fibrosis/tubular atrophy.

CV sequelae of aldosterone excess: branches to cardiac fibrosis, K⁺ loss, vascular fibrosis, impaired vascular reactivity, and Na⁺/H₂O retention. Vascular fibrosis, impaired reactivity and Na⁺/H₂O retention converge to hypertension; hypertension and cardiac fibrosis converge to left ventricular hypertrophy (LVH) → impaired diastolic function → overt cardiac failure → congestion (also fed by Na⁺/H₂O retention directly). Mineralocorticoid receptor antagonists (e.g. spironolactone) block aldosterone excess at source (Rhee & Pearce 2011).

Ang II regulation of GFR and progression to CKD/ESRD

Physiologically, GFR is maintained by the vasoconstricting effect of Ang II on renal efferent arterioles, which increases glomerular pressure — this is the primary site of Ang II action.

In hypertension, in the face of high systemic pressure, Ang II also vasoconstricts the afferent arteriole to protect the glomerulus from that pressure. However, chronic afferent Ang II vasoconstriction, endothelial injury and atherosclerosis reduce glomerular blood flow, leading to glomerular/tubular ischaemic injury.

Progression of risk (HTN and diabetes to ESRD): risk factors (diabetes, hypertension) → endothelial dysfunction → microalbuminuria → macro-proteinuria → nephrotic proteinuria → end-stage renal disease (ESRD), with microalbuminuria, macro-proteinuria and the risk factors themselves all also contributing directly to cardiovascular disease (CVD) → death.

Albumin:creatinine ratio thresholds given:

• Male: normal 2.5–25 mg/mmol; microalbuminuria (abnormal) >25 mg/mmol.
• Female: normal 3.5–35 mg/mmol; microalbuminuria (abnormal) >35 mg/mmol.

RAS in CKD progression (vicious cycle): ↓renal function → ↑Ang II-dependent processes (systemic hypertension; constriction of efferent arterioles; release of growth factors; release of pro-inflammatory mediators) → glomerular hypertension, mesangial cell proliferation, renal inflammation → glomerular sclerosis and nephron death → which further ↓renal function, closing the loop.

ACE inhibitors: mechanism and renal effects

ACE inhibitors (“the ‘pril drugs”) inhibit ACE conversion of Ang I to Ang II. Consequently, an acute dose has little to no effect on BP in a healthy person unless they are Na⁺-depleted.

ACE inhibition produces several effects:

• Systemic vascular resistance decreases due to: decreased Ang II (vasoconstrictor) and increased bradykinin (vasodilator) — ACE is also involved in kinin breakdown.
• Aldosterone release from the adrenal cortex is reduced → promotes increased Na⁺ and water excretion.
• NB: K⁺ retention in plasma occurs.

Effect on GFR: ACE inhibitors improve glomerular perfusion, but Ang II is physiologically vital to constricting renal efferent arterioles to maintain GFR. ACE inhibitors (and ARBs) block this regulatory step and reduce GFR — this is an expected, indicative sign of ACE inhibitor action.

ACE inhibitors are contraindicated/high-risk in bilateral renal artery stenosis (or stenosis in a single-kidney patient): inhibiting efferent arteriolar constriction here can cause a profound drop in GFR, much greater than the smaller change seen in the ordinary hypertensive setting.

Diagrammatically: Ang II predominantly vasoconstricts the efferent arteriole (raising glomerular pressure and filtration); but at high concentrations Ang II also constricts the afferent arteriole and decreases glomerular perfusion — this is where the ACE inhibitor provides benefit.

Enalapril: oral dosing and pharmacokinetics

• Enalapril is metabolised by first-pass metabolism to the active drug enalaprilat.
  • Hepatic impairment can reduce enalaprilat formation but not its clearance.
  • Renal impairment reduces clearance, raising plasma concentrations of active enalaprilat.
• Oral bioavailability of enalaprilat from oral enalapril: ~40–60%.
• Peak plasma concentrations reached in 1 hour.
• Enalaprilat is eliminated unchanged by the kidneys; T½ 11–14 h.
• Effective for 24–36 h after once-daily dosing.
• Oral bioavailability is relatively affected by food (give prior to food).
• Dose range 0.25–5 mg once daily, adjusted for GFR, condition, concomitant diuretic use, or water/Na⁺ depletion.

"), likely "Na+ depleted" but cut off [slide does not elaborate].

ACE inhibitor adverse drug reactions (ADRs) — class effects

• Initial hypotension.
• Cough (10% of Whites, up to 40% of Asians).
• Upper respiratory mucous augmentation.
• Hyperkalaemia.
• Rash.
• Foetal anomalies.
• Angioedema (2/1000 in Whites, higher in Black/African-descent patients).
• Dysgeusia (altered taste).

(Baş M, et al., N Engl J Med 2015; 372:418–25.)

ARBs: candesartan and the ACEI vs ARB comparison

Candesartan cilexetil is a potent, selective AT1 receptor antagonist. It blocks all AT1R-mediated effects of Ang II — vascular smooth muscle pressor responses, aldosterone secretion, adrenaline release, and thirst.

Theoretical benefits of ARBs over ACE inhibitors:

• Block Ang II effects regardless of how it is formed (ACE vs chymase, etc. — non-ACE pathways).
• Effect is limited to AT1Rs, pushing Ang II onto the beneficial AT2Rs.
• Do not cause bradykinin accumulation (a mixed benefit — avoids bradykinin-related ADRs but loses bradykinin’s vasodilator/natriuretic benefit).

Local/intracellular Ang II synthesis is independent of ACE — via tonin/cathepsin G (bypassing renin) and via chymase (bypassing ACE, converting Ang I directly to Ang II). ACE inhibitors do not block these non-ACE pathways to Ang II; ARBs block the receptor regardless of the source of Ang II. (Adapted from de Gasparo et al. Pharmacol Rev 2000; 52:415.)

ACE inhibitors vs ARBs — do they have equivalent efficacy?

ACE inhibitors:

• Reduce Ang II biosynthesis via ACE, but do not inhibit alternative non-ACE Ang II-generating pathways.
• Increase levels of several ACE substrates, including bradykinin.
• May also increase vasodilating Ang(1–7) levels, since ACE is involved in the clearance of Ang(1–7) produced by ACE2.
• Increase renin release, but block conversion of Ang I to Ang II.

ARBs:

• Reduce activation of AT1 receptors more effectively than ACE inhibitors.
• Block Ang II action via the AT1 receptor regardless of the biochemical pathway that generated it.
• Because AT1 is blocked, the increased Ang II is available to activate AT2 receptors — permitting activation of beneficial AT2 receptors, unlike ACE inhibitors.
• Like ACE inhibitors, ARBs stimulate renin release, but produce a several-fold increase in circulating Ang II available for AT2 receptor activation.

Candesartan oral pharmacokinetics

• Given orally as candesartan cilexetil, rapidly converted by esterase action to candesartan in the GI tract.
• Low bioavailability (formulation-dependent, 15–40%).
• Peak plasma levels ~3 h; T½ ~9 h.
• Elimination: mostly excreted unchanged via urine (glomerular filtration and active tubular secretion) and bile; hepatic metabolism (CYP2C9) plays only a minor role.
• Special populations: hepatic impairment increases AUC slightly (~20%); decreased renal function increases Cmax and AUC (affects clearance).

Clinical trial evidence and guidelines

• ACE inhibitors are commonly advocated as first-line antihypertensive agents.
• Tight BP control (<130/80 mmHg) is essential in diabetes, to reduce progression of diabetic nephropathy and CV/renal disease risk.
• Both ACEIs and ARBs prevent progression from microalbuminuria to clinical proteinuria in type 2 diabetes; ARBs provide better renal protection in patients with severe nephropathy, though the level of evidence for this is not high.
• Study-based evidence shows ACEIs and ARBs provide cardiovascular protection in type 2 diabetes.

K/DOQI guidelines on hypertension and antihypertensive agents in CKD:

• ACE inhibitors and ARBs can be used safely in most CKD patients.
• Should be used at moderate-to-high doses, as used in clinical trials.
• Can be used as alternatives to each other if the preferred class cannot be used.
• Can be combined to lower BP or reduce proteinuria.
• Patients should be regularly monitored for hypotension, decreased GFR, and hyperkalaemia.

Overall conclusions from RAS inhibitor studies: RAS inhibitors ↓progression of albuminuria, ↓progression of GFR decline, ↓risk of ESRD. Their beneficial effects are only in part due to BP reduction — main effects are on Na⁺ handling, plus antifibrotic, antiproteinuric and anti-inflammatory effects extending to cardio-renal disease intervention. These occur with both ACEIs and ARBs, and at recommended doses, ACEI + ARB combination is better than either alone.

RAS-modulator prescribing guidance and drug interactions

Guidelines for using RAS modulators:

• To minimise risk of initial rise in serum creatinine: omit (or reduce) diuretics for 24 h before the first dose; stop NSAIDs.
• To minimise hyperkalaemia risk: stop K⁺ supplements and K⁺-sparing diuretics (reduce dietary K⁺ intake).
• Reduce doses in renal impairment; use initial low doses in patients with high creatinine, high plasma renin, or Na⁺/water depletion from diuretics.
• Review symptoms, BP, and serum/urine chemistry (creatinine and electrolytes); titrate to maximum tolerated dose, reassessing chemistry.

"Triple whammy": the combination of ACE inhibitors/ARBs, thiazide diuretics, and NSAIDs (including COX-2 selective NSAIDs) is implicated in a significant number of drug-induced renal failure cases in the elderly with decreasing GFR.

Mechanism: NSAIDs inhibit prostaglandin (PGI2, PGE2) production, which are the major determinant of afferent arteriolar vasodilation — causing afferent vasoconstriction and reduced GFR. ACE inhibitors/ARBs block Ang II, the major determinant of efferent vasoconstriction, which normally maintains renal perfusion when it is low (e.g. bilateral renal artery stenosis, volume depletion, elderly patients with CHF). Blocking both mechanisms together (diuretic reducing plasma volume plus NSAID afferent constriction plus ACEI/ARB efferent dilation) can cause acute renal failure. Clinical data show creatinine clearance trends downward as the number of these target drugs used together increases (Br J Clin Pharmacol. 2005; 59(2): 239–243).

Care is also needed combining an ACE inhibitor, ARB and a mineralocorticoid receptor antagonist (spironolactone) together, due to K⁺ retention issues.

Neprilysin and ARNi (sacubitril/valsartan)

Neprilysin is a widely distributed membrane endopeptidase, with high concentrations in the renal tubule. It cleaves:

• Vasoactive peptides (bradykinin).
• Biologically active natriuretic peptides (ANP, BNP — increasing vasoactive guanylate cyclase/cGMP signalling).
• Adrenomedullin.
• Vasoconstrictors: endothelin-1, Ang I and Ang II.
• GLP-1.

(Bozkurt B, et al. J Am Coll Cardiol Basic Trans Science. 2023;8(1):88–105.)

Neprilysin inhibition monotherapy has only modest efficacy in essential hypertension and heart failure, because inhibiting neprilysin also increases levels of plasma vasoconstrictors Ang II, endothelin-1, and noradrenaline. Therefore a dual strategy is used: neprilysin inhibitor combined with ARB (to block Ang II) — ARNi, sacubitril/valsartan (LCZ696, Entresto), which is approved.

• The BP-lowering potential of ARNi is superior to conventional RAS inhibitors.
• Natriuresis is considered a key mechanism of the BP-lowering effect in heart failure patients.
• Combining a neprilysin inhibitor with an ACE inhibitor failed in clinical trials due to double build-up of bradykinin, leading to angioedema risk — this is why ARNi pairs neprilysin inhibition with an ARB, not an ACE inhibitor.

ARNi mechanism of action (sacubitril/valsartan, LCZ696): in heart failure (HFpEF example), the natriuretic peptide system (pro-BNP → NT-pro BNP [not a neprilysin substrate] and ANP/BNP/CNP, adrenomedullin, substance P, bradykinin, Ang II) and the RAAS (angiotensinogen → Ang I → Ang II) are both engaged. Sacubitril (active metabolite sacubitrilat) blocks neprilysin; valsartan blocks the AT1 receptor. This produces vasodilatation (↓BP, ↓sympathetic tone, ↓aldosterone, ↓myocardial fibrosis/hypertrophy, ↑natriuresis/diuresis) while blocking vasoconstriction (↓BP, ↓sympathetic tone, ↓aldosterone, ↓ventricular hypertrophy via the blocked pathway).

ARNi effects on GFR: compared with baseline, an ARB (valsartan) causes afferent vasodilation, decreased intraglomerular pressure, and decreased albumin excretion. ARNi (valsartan plus sacubitril, which additionally induces efferent vasodilation) causes increased intraglomerular pressure, increased glomerular permeability, and increased albumin excretion — with a concomitant increase in eGFR and urine albumin:creatinine ratio following ARNi treatment (Hypertens Res 44, 1239–1250 (2021)).

ARNi (sacubitril/valsartan) in heart failure simultaneously blocks RAAS and the endopeptidase neprilysin. Trial evidence: PARAMOUNT, PARADIGM-HF. Combining with an ARB (rather than an ACE inhibitor) reduces bradykinin-related angioedema risk.

Advances in heart failure therapy

Initiating quadruple treatment in HFrEF (and HF with LV ejection fraction <49%), per current (2021) European Society of Cardiology (ESC) guidelines:

1. SGLT2 inhibitors with a mineralocorticoid receptor antagonist (MRA), started as early as possible; assess tolerability within 1 week.
2. Gradually titrate β-blockers over 4 weeks.
3. Titrate ARNi over 5 weeks, introduced once BP stabilises.
4. Add a loop diuretic in cases of fluid retention.

Depending on patient phenotype, β-blockers may instead be given immediately, followed by ARNi. For HF with preserved ejection fraction, current guidelines recommend SGLT2 inhibitors and diuretics for fluid retention, alongside managing comorbidities.

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Self-test

1. Name the three factors that promote renin release from the juxtaglomerular apparatus, and the mechanisms by which Ang II physiologically terminates renin release.
2. Describe the steps of the renin-angiotensin cascade from initial trigger through to AT1R and AT2R signalling.
3. Explain the “Janus effect” of ACE inhibition on bradykinin, and list the beneficial and adverse consequences of raised bradykinin.
4. List the CV/renal effects of Ang II under the three headings given (peripheral resistance, renal function, CV structure), with each column’s summative effect.
5. Why do ACE inhibitors delay progression of diabetic nephropathy — what three mechanisms are given?
6. Distinguish the physiological role of aldosterone from the pathological consequences of aldosterone excess.
7. Explain why Ang II vasoconstricts the efferent arteriole physiologically, and why it also vasoconstricts the afferent arteriole in hypertension.
8. Describe the vicious cycle by which RAS activation drives progression of CKD.
9. Explain the mechanism by which ACE inhibitors reduce GFR, and why this is an expected sign of drug action rather than an adverse effect.
10. A patient with bilateral renal artery stenosis is started on an ACE inhibitor and develops a profound drop in GFR. Explain why this occurs, referencing the roles of the afferent and efferent arterioles.
11. Describe enalapril’s pharmacokinetic profile: activation, bioavailability, time to peak, elimination route/half-life, and dosing considerations.
12. List the class ADRs of ACE inhibitors.
13. Distinguish the mechanism of ARBs (e.g. candesartan) from ACE inhibitors, including their handling of non-ACE Ang II-generating pathways, AT2 receptor activation, and bradykinin.
14. An elderly patient on a thiazide diuretic and an ACE inhibitor is prescribed an NSAID for joint pain and develops acute kidney injury. Explain the “triple whammy” mechanism responsible.
15. Describe the role of neprilysin and explain why neprilysin inhibitor monotherapy has only modest efficacy in hypertension and heart failure.
16. Describe the mechanism of action of ARNi (sacubitril/valsartan), and explain why it is combined with an ARB rather than an ACE inhibitor.
17. Explain why ARNi increases GFR and albumin excretion compared to an ARB alone, referencing the afferent and efferent arterioles.
18. Integrative: Using the shared roles of Ang II at the efferent arteriole, explain both why ACE inhibitors/ARBs are renoprotective in diabetic nephropathy/CKD, and why the same drugs are dangerous in bilateral renal artery stenosis or when combined with diuretics and NSAIDs.

Answers

Reveal answers

1. Renin release is promoted by: (1) intrarenal baroreceptor pathway, (2) low Na⁺/Cl⁻ concentration at the macula densa in the distal tubule, and (3) post-ganglionic sympathetic stimulation of β1-adrenoreceptors on JG cells. It is terminated by Ang II acting on AT1R on JG cells, tubular Na⁺ retention, and vasculature (BP effects) — negative feedback.
2. Sympathetic activation, ↓Na⁺/Cl⁻ delivery to the distal tubule, and ↓afferent arteriole pressure converge on JG cells → renin release → angiotensinogen cleaved to angiotensin I → ACE converts angiotensin I to angiotensin II → Ang II acts on AT1R (aldosterone release, vasoconstriction, cell growth, fibrosis) and AT2R (apoptosis).
3. ACE also degrades bradykinin, so inhibiting ACE both reduces Ang II production and raises bradykinin levels. Beneficial: bradykinin promotes vasodilatation (via arachidonic acid metabolites, NO, EDHF) and natriuresis (inhibits eNCC-1 in the distal convoluted tubule). Adverse (excessive bradykinin): increased vascular permeability, cough (via B2 receptors on bronchopulmonary C-fibres), and augmented nasal mucus secretion.
4. Peripheral resistance (direct vasoconstriction, ↑SNS discharge, ↑peripheral NA effects, ↑catecholamine discharge) → rapid pressor response. Renal function (↑Na⁺ reabsorption in PT, ↑aldosterone → Na⁺/K⁺ influx in DT/CT, altered renal haemodynamics) → slow pressor response. CV structure (↑afterload, ↑wall tension, ↑growth factors, ↑pro-inflammatory cytokines, ↑ECM deposition) → hypertrophy and remodelling.
5. ACE inhibitors delay DN progression by decreasing arterial pressure, selectively dilating efferent arterioles to decrease glomerular filtration pressure, and attenuating Ang II-mediated mesangial cell growth and matrix production.
6. Physiologically aldosterone is important for Na⁺/K⁺/water handling (decreases Na⁺ and water excretion, raises ECF volume). Pathologically, raised aldosterone is pro-fibrotic (via SGK1 → NF-κB and ROS/redox signalling), driving ECM accumulation, inflammation, EMT, growth factor release and proliferation, leading to renal fibrosis/glomerulosclerosis, and separately drives cardiac/vascular fibrosis, K⁺ loss, hypertension, LVH and eventually cardiac failure.
7. Ang II constricts the efferent arteriole to maintain glomerular filtration pressure/GFR (its primary physiological site of action). In hypertension, Ang II additionally constricts the afferent arteriole to protect the glomerulus from high systemic pressure; chronically this afferent constriction, plus endothelial injury/atherosclerosis, reduces glomerular blood flow and causes ischaemic injury.
8. ↓Renal function raises Ang II-dependent processes (systemic hypertension, efferent arteriole constriction, growth factor release, pro-inflammatory mediator release), which cause glomerular hypertension, mesangial cell proliferation, and renal inflammation, leading to glomerular sclerosis and nephron death — which further reduces renal function, perpetuating the cycle.
9. ACE inhibitors block Ang II-mediated efferent arteriolar constriction, which is needed to maintain glomerular filtration pressure; removing it drops GFR. This drop is expected and is used as a sign the drug is acting as intended.
10. In bilateral renal artery stenosis, the kidney depends on Ang II-mediated efferent constriction to sustain glomerular pressure under low renal perfusion. Blocking this with an ACE inhibitor removes the compensatory efferent constriction, causing a profound (rather than modest) fall in GFR.
11. Enalapril is a prodrug converted by first-pass metabolism to active enalaprilat (hepatic impairment reduces formation but not clearance; renal impairment reduces clearance and raises plasma levels). Oral bioavailability of enalaprilat ~40–60%, peak plasma at 1 h, eliminated unchanged renally with T½ 11–14 h, effective 24–36 h once daily; food reduces bioavailability (give before food); dosed 0.25–5 mg once daily, adjusted for GFR, condition, diuretic use, or Na⁺/water depletion.
12. Initial hypotension, cough (10% Whites, up to 40% Asians), upper respiratory mucous augmentation, hyperkalaemia, rash, foetal anomalies, angioedema (more common in Black/African-descent patients), and dysgeusia.
13. ACE inhibitors reduce Ang II biosynthesis via ACE only, leaving non-ACE (e.g. chymase) pathways unblocked; they raise bradykinin and possibly vasodilating Ang(1–7). ARBs block Ang II at the AT1 receptor regardless of how Ang II was generated, so they capture non-ACE-generated Ang II too; because AT1 is blocked, extra circulating Ang II is pushed onto beneficial AT2 receptors (which ACE inhibitors do not achieve); ARBs do not raise bradykinin.
14. The diuretic reduces plasma volume; the NSAID inhibits prostaglandins that maintain afferent arteriolar vasodilation, causing afferent constriction; the ACE inhibitor blocks Ang II-mediated efferent constriction that normally maintains perfusion when renal blood flow is low. Combined afferent constriction and efferent dilation collapse glomerular filtration pressure, precipitating acute renal failure.
15. Neprilysin is a membrane endopeptidase (high in renal tubule) that cleaves vasoactive/natriuretic peptides (bradykinin, ANP, BNP, adrenomedullin) as well as vasoconstrictors (endothelin-1, Ang I, Ang II) and GLP-1. Inhibiting it alone raises both beneficial natriuretic peptides and harmful vasoconstrictors (Ang II, endothelin-1, noradrenaline), limiting efficacy.
16. Sacubitril (active metabolite sacubitrilat) blocks neprilysin, preserving natriuretic peptides; valsartan blocks the AT1 receptor, preventing the vasoconstrictor rise that neprilysin inhibition would otherwise cause. It is paired with an ARB rather than an ACE inhibitor because combining a neprilysin inhibitor with an ACE inhibitor caused double bradykinin build-up and angioedema risk in trials.
17. An ARB alone causes afferent vasodilation only, lowering intraglomerular pressure and albumin excretion. ARNi adds efferent vasodilation (via sacubitril), which raises intraglomerular pressure and glomerular permeability, increasing both eGFR and albumin excretion relative to ARB alone.
18. Ang II’s efferent-arteriole vasoconstriction is protective when moderate (sustaining GFR) but harmful when chronic/excessive (driving glomerular hypertension, mesangial proliferation and sclerosis in DN/CKD) — so blocking it with ACE inhibitors/ARBs is renoprotective long-term. But this same efferent dilation removes a compensatory mechanism that is essential when renal perfusion is already critically low (bilateral stenosis, volume depletion from diuretics, or afferent constriction from NSAIDs), so in those settings the same mechanism precipitates acute GFR collapse.