Mednotes

L07 Clinical Pharmacology ACE inhibitors and angiotensin receptor blockers

Properties2
tagsclinicalpharmacology, lecture
aliasesL07 Clinical Pharmacology ACE inhibitors and angiotensin receptor blockers

18 min read

Overview

This lecture reviews the renin-angiotensin-aldosterone system (RAAS) and then covers the two drug classes that interrupt it: ACE inhibitors, exemplified by enalapril, and angiotensin receptor blockers, exemplified by candesartan. Part A establishes the physiology, the three triggers for renin release, the two forms of ACE, and the opposing actions of the AT1 and AT2 receptors, which together explain why RAAS overactivity drives hypertension, heart failure and fibrosis. Part B maps each drug class onto a point in that cascade, giving mechanism, pharmacokinetics, therapeutic indications and adverse effects, and finishes with a summary of every intervention target in the pathway (renin inhibitors, ACE inhibitors, AT1 blockers, AT2 blockers, and mineralocorticoid receptor inhibitors covered in the diuretics lecture).

The RAAS cascade

The system works synergistically with the autonomic nervous system to form the vasoactive peptide angiotensin II and to stimulate release of the mineralocorticoid aldosterone from the adrenal cortex (zona glomerulosa). Its physiological purposes are control of Na+ and water retention in the renal tubules, and control of vascular tone/constriction in blood pressure regulation.

Steps in order:

  1. The liver produces angiotensinogen, a plasma globulin.
  2. Renin, released from the kidney, cleaves angiotensinogen to angiotensin I (inactive, low biological activity).
  3. Angiotensin converting enzyme (ACE) cleaves angiotensin I to angiotensin II (active).
  4. Angiotensin II acts as an agonist at AT1 and AT2 receptors, on vascular smooth muscle, cardiomyocytes, the renal nephron and elsewhere.
  5. Angiotensin II acts on the adrenal cortex to release aldosterone, on the pituitary to release ADH, on systemic vasculature to cause vasoconstriction, on the heart and vessels to promote hypertrophy and fibrosis, and centrally to cause thirst.
  6. Aldosterone and ADH act on the kidney to increase renal sodium and fluid retention, raising blood volume, which feeds back into the cycle.

Aldosterone is a mineralocorticoid and is profibrotic; it increases reabsorption of Na+ and water. Its release is stimulated not only by angiotensin II but also by K+, corticotropin, catecholamines, endothelins and low Na+.

Step 1: renin release

Renin is a proteolytic enzyme that converts angiotensinogen to angiotensin I. It is released from juxtaglomerular (JG) cells in response to three stimuli:

  1. Sympathetic stimulation of renal β1 adrenergic receptors.
  2. Low Na+ concentration in the distal tubule.
  3. Low renal blood pressure.

The juxtaglomerular apparatus comprises the distal tubule, macula densa, afferent and efferent arterioles, JG cells, glomerulus and glomerular capillary, extraglomerular matrix of mesangial cells and intraglomerular mesangium.

The three release mechanisms, stated as the slide sets them out:

  • Baroreceptor mechanism: increased pressure in the afferent arteriole inhibits renin release from JG cells; decreased pressure promotes it.
  • Sympathetic nerve mechanism: β1-adrenergic nerves stimulate renin release.
  • Macula densa mechanism: increased NaCl in the distal nephron inhibits renin release; a decreased load promotes it.

Stimulation versus inhibition of the whole cascade:

  • Stimulation: ↓blood pressure, ↓fluid volume, ↑β1-sympathetic activity → ↑angiotensinogen, ↑renin, ↑angiotensin I, ↑ACE, ↑angiotensin II → vasoconstriction; and ↓NaCl/H2O reabsorption in the kidney → ↑aldosterone.
  • Inhibition: ↑blood pressure, ↑fluid volume, ↓β1-sympathetic activity, ANP → ↓angiotensinogen, ↓renin, ↓angiotensin I, ↓ACE, ↓angiotensin II → ↓vasoconstriction; and ↑NaCl/H2O reabsorption → ↓aldosterone.

Step 2: ACE and the two forms of the enzyme

ACE is a kinase that cleaves angiotensin I to angiotensin II. It is a proteolytic enzyme on the surface of endothelial cells, and it is also responsible for the breakdown of bradykinin. Two forms exist:

  • Extrinsic: ACE present on the vascular endothelial surface, converting local angiotensin I to angiotensin II following renin release from the kidney.
  • Intrinsic: a soluble form expressed along with renin, angiotensinogen and angiotensin I in the cytosol of kidney, heart and brain tissue.

Angiotensin II can also be generated independently of ACE. Angiotensinogen may be converted to angiotensin I by renin or, by a non-renin dependent route, by tonin/cathepsin G. Angiotensin I may be converted to angiotensin II by ACE or, ACE-independently, by chymase. This matters therapeutically: ACE inhibitors block only the ACE-dependent route, whereas ARBs block the AT1 receptor regardless of how angiotensin II was generated.

Angiotensin II receptors: AT1 versus AT2

Both are G-protein coupled receptors with seven transmembrane helices.

  • AT1R mediates the pathological hypertensive effects of angiotensin II: hypertension, fibrosis, hypertrophy, vasoconstriction. In the overview flow diagram, AT1 activation produces vasoconstriction, cell growth and fibrosis.
  • AT2R is considered beneficial: it inhibits cell proliferation (antihypertrophic), increases nitric oxide production, is anti-fibrotic and antihypertensive, and causes vasodilation. In the overview flow diagram, AT2 activation produces apoptosis, opposing the AT1 effects.

Effects of angiotensin II via AT1 receptors:

  • Powerful vasoconstrictor.
  • Promotes Na+ and fluid retention by the nephron.
  • Stimulates release of aldosterone from the adrenal cortex.
  • Enhances sympathetic activity, acting within the CNS and at sympathetic nerve endings; stimulates synaptic noradrenaline release and inhibits noradrenaline reuptake. It also acts within sympathetic ganglia to stimulate sympathetic activity, increasing β-receptor mediated renin release.
  • Stimulates cardiac and vascular hypertrophy.
  • Stimulates collagen deposition, promoting fibrosis (stiffening and scarring) and atherosclerosis.
  • Stimulates release of vasopressin (ADH) from the posterior pituitary.

At the sympathetic synapse, angiotensin II acts on presynaptic AT1 receptors to stimulate the synthesis pathway tyrosine → (via tyrosine hydroxylase) → DOPA → dopamine → noradrenaline, promoting noradrenaline release and inhibiting its reuptake, while α2 receptors provide inhibitory feedback on release. The net effect is raised noradrenaline in the synaptic cleft and increased sympathetic outflow to myocardium, kidney and vasculature.

Therapeutic targets in the RAAS

The system can be targeted by:

  • Reducing renin release or activity (for example a beta blocker, or a renin inhibitor).
  • Reducing angiotensin II production (ACE inhibitor).
  • Inhibiting AT1 receptors (ARB).
  • Decreasing aldosterone-mediated effects (mineralocorticoid receptor inhibitors, for example spironolactone, covered in the diuretics lecture).

The summary diagram places renin inhibitors at the angiotensinogen → angiotensin I step, ACE inhibitors at the angiotensin I → angiotensin II step, and AT1 blockers and AT2 blockers at their respective receptors, with feedback inhibition from the receptors back to renin. ACE (kinase II) also converts bradykinin to inactive peptides and, marked with a question mark, potentially to a further product acting on the BK receptor to produce nitric oxide.

ACE inhibitors: mechanism

ACE inhibitors are the “pril” drugs: enalapril, perindopril, ramipril, lisinopril, fosinopril. They inhibit ACE production of angiotensin II.

Inhibition of vascular ACE:

  • Decreases levels of angiotensin II released, reducing angiotensin II induced arterial vasoconstriction and so systemic vascular resistance (reduced ventricular afterload), and increasing venous vasodilation (reduced ventricular preload).
  • Increases levels of bradykinin (a vasodilator) by preventing ACE-induced breakdown of kinins, contributing to the vasodilator effect. The same enzyme inhibition therefore blocks both angiotensin II formation and bradykinin degradation.
  • Downregulates angiotensin II provoked sympathetic activity, helping promote vasodilation.

By reducing angiotensin II effects in the kidney and reducing aldosterone release from the adrenal cortex, ACE inhibitors additionally:

  • Promote Na+ excretion (natriuresis) and water excretion (diuresis), reducing plasma volume (volume unloading), which reduces blood pressure.
  • Reduce aldosterone production, which is linked to K+ retention in plasma.
  • Inhibit cardiac and vascular remodelling (cell swelling and proliferation) and fibrosis associated with chronic hypertension, MI and heart failure.
  • Block angiotensin II effects on renal function.

Preload and afterload

  • Preload: all of the factors contributing to passive ventricular wall stress (or tension) at the end of diastole. It is the stretch on sarcomeres before systole, that is end diastolic volume; it relates to the veins and pulmonary system, and to venous return from the upper body via the superior vena cava and from the lower body via the inferior vena cava.
  • Afterload: all of the factors contributing to total myocardial wall stress (or tension) during systolic ejection. It is the stress generated by the left ventricle during ejection, that is resistance to outflow, depending on the state of the blood vessels; contraction/dilation changes total resistance (end systolic pressure). It relates to arteries and arterioles, to resistance to flow in the aorta and arteries (peripheral vascular resistance), and to the work required to open the aortic valve.

and , so the load on the ventricles can be reduced by reducing either preload or afterload.

Enalapril pharmacokinetics

  • Route: per oral.
  • Good oral absorption; bioavailability approximately 40 to 60%.
  • Enalapril is a pharmacologically inactive prodrug, hepatically metabolised by first-pass metabolism (esterases) to the active drug enalaprilat.
  • Clearance is renal, mostly as the active metabolite. Hepatic impairment affects enalaprilat formation but not its clearance. Renal impairment (30 mL/min) reduces clearance, raising plasma concentrations of enalaprilat.
  • Enalapril peak plasma level (Cmax) approximately 1 h; Cmax of the active moiety enalaprilat occurs at three to four hours post dosing.
  • Enalaprilat plasma half-life 11 to 14 h; effective for 24 to 36 h. High volume of distribution.

ACE inhibitors: therapeutic uses

Cardiovascular indications are hypertension, chronic heart failure and renal injury.

Primary/essential and renovascular hypertension. Enalapril and all ACE inhibitors reduce angiotensin II and aldosterone release, giving:

  • Cardiovascular effects: arterial and venous dilation; reduced arterial and venous pressures (↓preload and ↓afterload).
  • Renal effects: natriuresis and diuresis, decreasing blood volume and so lowering blood pressure.

Further value in hypertension: while ACE inhibitors are effective in hyper-reninemic hypertension, they will still reduce blood pressure in patients with low-to-normal circulating renin levels, possibly by potentiating the vasodilatory effects of bradykinin. Inhibition of angiotensin II production is also crucial in reducing the pro-inflammatory and pro-fibrotic consequences of hypertension.

Chronic heart failure:

  • Reduced afterload enhances ventricular stroke volume and improves ejection fraction, and reduces arterial vascular resistance.
  • Reduced preload decreases pulmonary capillary wedge pressure (left atrial pressure) and systemic oedema.
  • The decreased afterload/preload improves the O2 supply/demand ratio.
  • Reduced sympathetic activation.
  • Prevents angiotensin II triggering deleterious cardiac remodelling.
  • Useful post MI; can be used with diuretics.
  • Initiated at low dose and increased to the lowest maintenance dose based on renal and hepatic function.

Also used in renal disease, diabetes, post MI and stroke prophylaxis, which the lecture defers to third year.

ACE inhibitors: adverse effects and contraindications

  • Bradykinin related ADRs: persistent dry cough, and rarely angioedema.
  • Initial hypotension.
  • Rash.
  • Dysgeusia (disturbed sense of taste).
  • Foetal abnormalities.
  • Renal issues: decrease the dose in renal impairment, and use caution with concomitant NSAIDs and diuretics.

Contraindicated in patients with evidence of hypersensitivity, or with a history of angioedema related to previous treatment, and in idiopathic and hereditary angioedema.

Important

Angioedema secondary to ACE inhibitor use may occur many years after therapy is initiated. Up to 25% of reported cases of angioedema appear to result from ACE inhibitor therapy, with incidence variably reported at 0.1 to 0.7% of patients on ACE inhibitors. It is believed to arise from defective degradation of bradykinin or substance P, and presents clinically as marked facial, neck or lip swelling with erythema.

ARBs: mechanism and comparison with ACE inhibitors

ARBs are the “sartan” drugs: candesartan, losartan, valsartan. They are orally active, potent, selective AT1 receptor antagonists.

  • Block all angiotensin II effects at AT1 receptors, irrespective of how angiotensin II was produced.
  • Prevent angiotensin II effects on vascular smooth muscle contraction and pressor responses, aldosterone secretion, sympathetic activation, and profibrotic pathways.
  • Do not cause kinin accumulation, so there is a reduced incidence of cough.

Theoretical benefits over ACE inhibitors:

  • Bypass ACE to inhibit angiotensin II action at AT1 directly, blocking its effect regardless of how it is formed (ACE versus chymase and other routes).
  • Effect limited to AT1 receptor inhibition, so angiotensin II may still act on the beneficial AT2 receptors.
  • No major effect on bradykinin levels. This is a mixed benefit: there is no bradykinin-mediated vasodilation, but a reduced incidence of bradykinin related cough and angioedema.

Candesartan pharmacokinetics

  • Given per oral as candesartan cilexetil, which must be metabolised by esterases in the GI tract to release the active metabolite candesartan (rapid conversion).
  • Low oral bioavailability, 15 to 40%, formulation dependent and because of incomplete absorption.
  • Peak plasma levels approximately 3 to 4 h; plasma half-life approximately 9 h. Protein binding greater than 99%.
  • Clearance by renal and biliary routes: candesartan is excreted mostly unchanged in urine, by both glomerular filtration and active tubular secretion, and in bile. Hepatic metabolism (CYP2C9) plays only a minor role, and no substantial interactions are indicated at CYP2C9 or CYP3A4.
  • Special populations: hepatic impairment increases the AUC of candesartan; decreased renal function can affect candesartan clearance, with Cmax and AUC increasing.

ARBs: indications and adverse effects

Indications are the same as for ACE inhibitors, and ARBs are generally used when the patient cannot tolerate an ACE inhibitor because of adverse effects: hypertension, heart failure (congestive heart failure), renal injury.

Adverse effects, generally well tolerated, with fewer bradykinin related events than ACE inhibitors but an otherwise similar profile:

  • Hypotension, dizziness, headache.
  • Rash.
  • GI effects: nausea, vomiting, diarrhoea.
  • Cough, but not usually.
  • Hyperkalaemia (elevated K+), due to inhibited aldosterone formation, since aldosterone causes K+ excretion.
  • Renal issues again if bilateral renal artery stenosis is present.
  • Teratogenic.

Glossary

  • Ang I: angiotensin I
  • Ang II: angiotensin II
  • BK: bradykinin
  • AT1R: angiotensin subtype 1 receptor
  • AT2R: angiotensin subtype 2 receptor
  • ACE: angiotensin converting enzyme
  • ACE-Is: angiotensin converting enzyme inhibitors
  • ARB: angiotensin receptor blocker
  • MR: mineralocorticoid receptor

Self-test

  1. Describe the steps of the RAAS cascade in order, from angiotensinogen to renal sodium retention.
  2. List the three stimuli for renin release from juxtaglomerular cells.
  3. Explain the baroreceptor and macula densa mechanisms of renin release, stating the direction of the effect in each.
  4. Distinguish the extrinsic from the intrinsic form of ACE.
  5. Distinguish the effects mediated by AT1 receptors from those mediated by AT2 receptors.
  6. List the effects of angiotensin II acting at AT1 receptors.
  7. Explain how angiotensin II increases noradrenaline in the sympathetic synaptic cleft.
  8. Explain why inhibiting ACE raises bradykinin levels, and name the two adverse effects this causes.
  9. Define preload and afterload, and state which vessels each is associated with.
  10. Describe how ACE inhibitors reduce both preload and afterload.
  11. Describe the renal actions of ACE inhibitors and their effect on plasma potassium.
  12. Describe the pharmacokinetics of enalapril, including its prodrug status, bioavailability, half-life and route of clearance.
  13. Predict what happens to plasma enalaprilat concentrations in a patient with renal impairment, and explain why.
  14. Explain why ACE inhibitors still lower blood pressure in patients with low-to-normal circulating renin.
  15. List the benefits of ACE inhibitors in chronic heart failure.
  16. List the adverse effects of ACE inhibitors and state the contraindications.
  17. Describe the clinical features and reported incidence of ACE inhibitor associated angioedema, and its proposed mechanism.
  18. Describe the pharmacokinetics of candesartan, including its prodrug form, bioavailability, half-life and elimination.
  19. Explain the theoretical advantages of ARBs over ACE inhibitors.
  20. Explain why ARBs cause hyperkalaemia.
  21. List the four pharmacological targets within the RAAS cascade and name a drug class acting at each.
  22. A patient on enalapril for hypertension develops a persistent dry cough. Explain the mechanism, predict what change of therapy is appropriate, and state what is gained and what is lost by that change.

Answers

Graph View

Backlinks