ANGIOTENSIN CONVERTING ENZYME/ACE inhibitors
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This document provides an overview of angiotensin-converting enzyme (ACE) inhibitors, including their indications, mechanisms of action, and evidence of effectiveness. ACE inhibitors are used to treat hypertension, congestive heart failure, myocardial infarction, diabetes, proteinuria, and other conditions. They work by inhibiting the conversion of angiotensin I to angiotensin II in the renin-angiotensin-aldosterone system. Clinical trials have shown that ACE inhibitors reduce blood pressure, prevent complications of heart failure and diabetes, and slow the progression of kidney disease. Common ACE inhibitors discussed include captopril, enalapril, lisinopril, and fosinopril.
ANGIOTENSIN CONVERTING ENZYME/ACE inhibitors
- 2. Objectives • Overview of ACEI • Indications and Uses • Effectiveness and • The Evidence
- 3. Renin-Angiotensin-Aldosterone System • Juxtaglomerular apparatus secretes renin. • Renin acts on angiotensinogen (gamma globulin from the liver) giving angiotensin I • Angiotensin converting enzyme (ACE) acts on angiotensin I giving angiotensin II
- 4. • Renin: 1. It is secreted by the juxtaglomerular cells in Kidney 2. Changes in secretion is in response to changes in renal arterial pressure, sympathetic nervous system signals and some hormones 3. Its substrate is angiotensinogen
- 5. • Angiotensinogen It is a glycoprotein synthesized and secreted into the bloodstream by the liver Angiotensinogen Renin angiotensin ACE Angiotensin III Angiotensin II
- 6. Renin-Angiotensin-Aldosterone System • Angiotensin converting enzyme (ACE) is also known as kinanase II • It converts angiotensin I to II (vasoconstrictor) and inactivates bradykinin (vasodilator) • The principal site of its action is vascular epithelium • It is inhibited by synthetically produced Captopril drug
- 7. Effects of Angiotensin IIEffects of Angiotensin II
- 8. • Aldosterone: It is a mineralocorticoid produced in the adrenal cortex Increases cortical collecting tubule reabsorption of Na+ and secretion of K+ and H+
- 9. Regulation of Aldosterone • Angiotensin II and III stimulate aldosterone release • Changes in volume ( long Negative feedback loop) • Inhibition of renin secretion by angiotensin II (short negative feedback loop) • Endothelin and vasopressin stimulate aldosterone secretion • ANP is a potent inhibitor, dopamine also inhibits it.
- 10. ACE Inhibitor Groups A. Sulfhydryl-containing agents: – Captopril , the first ACE inhibitor B. Dicarboxylate-containing agents: – Enalapril – Ramipril – Quinapril – Perindopril – Lisinopril – Benazepril C. Phosphonate-containing agents: – Fosinopril – Trandolapril
- 11. ACE inhibitors • Captopril, lisinopril., enalapril, ramipril and fosinopril etc.
- 12. Clinical Indications for ACEI • Hypertension • CHF • Post MI • Diabetes Mellitus • Proteinuria • Vascular Disease • Post - transplant
- 13. ACE inhibitors in Hypertension Captopril • Sulfhydryl containing dipeptide and abolishes pressor action of Angiotensin-I and not Angiotensin-II and does not block AT receptors • Pharmacokinetics: – Available only orally, 70% - 75% is absorbed – Partly absorbed and partly excreted unchanged in urine – Food interferes with its absorption – Half life: 2 Hrs, but action stays for 6-12 Hrs
- 14. Captopril – Pharmacological actions 1. In Normal: – Depends on Na+ status – lowers BP marginally on single dose – When Na+ depletion – marked lowering of BP 2. In hypertensive: – Lowers PVR and thereby mean, systolic and diastolic BP – RAS is overactive in 80% of hypertensive cases and contributes to the maintenance of vascular tone – inhibition causes lowering of BP
- 15. – Initially correlates with renin-angiotensin status but chronic administration is independent of renin activity – Captopril decreases t.p.r on long term – arterioles dilate – fall in systolic and diastolic BP – No effect on Cardiac output – Postural hypotension is not a problem - reflex sympathetic stimulation does not occur – Renal blood flow is maintained – greater dilatation of vessels
- 16. DOSE OF Captopril-- Hypertension : • Start: 12.5 to 25 mg 2-3 times/day; may increase by 12.5 to 25 mg/dose at 1- to 2- week intervals up to 50 mg 3 times/day
- 17. Dose of captopril • CHF: Start 6.25 to 12.5 mg three times daily. Initial dose depends upon patient's fluid/electrolyte status. Target: 50 mg 3 times/day. Prevention of LV dysfunction following MI: Oral: Initial: 6.25 mg; followed by 12.5 mg 3 times/day; increase to 25 mg 3 times/day over the next few days; following by gradual increase to a goal of 50 mg tid.
- 18. Dose of captopril • Renal Dose Adjustments • CrCl 10 to 50 mL/min: 75% of the normal dose is recommended. CrCl less than 10 mL/min: 50% of the normal dose is recommended.
- 19. Captopril – Adverse effects • Cough – persistent brassy cough in 20% cases – inhibition of bradykinin and substanceP breakdown in lungs • Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level) • Hypotension – sharp fall may occur – 1st dose • Acute renal failure: CHF and bilateral renal artery stenosis
- 20. • Angioedema: swelling of lips, mouth, nose etc. • Dysgeusia: loss or alteration of taste • Rashes, urticaria etc • Foetopathic: hypoplasia of organs, growth retardation etc • Neutripenia • Contraindications: Pregnancy, bilateral renal artery stenosis, hypersensitivity and hyperkalaemia
- 21. • 1st line of Drug: –No postural hypotension or electrolyte imbalance (no fatigue or weakness) –Safe in asthmatics and diabetics –Prevention of secondary hyperaldosteronism and K+ loss –Renal perfusion well maintained Benefits of ACEI
- 22. – Reverse the ventricular hypertrophy and increase in lumen size of vessel – No No rebound hypertension – hyperuraecemia or deleterious effect on plasma lipid profile – Minimal worsening of quality of life – general wellbeing, sleep and work performance etc.
- 23. Additional Benefits of ACEI • Prevention of diabetes • Prevention of stroke recurrence • Prevention of atrial fibrillation
- 24. How ACEI is useful in hypertension? • ACE inhibitors block the conversion of angiotensin I to angiotensin II • Lower arteriolar and renovascular resistance • Increase venous capacity, • Increase cardiac output, cardiac index and stroke volume.
- 25. Fixed Drug Combination ► To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents.
- 26. Choice of antihypertensive agents When implementing blockade of the renin– angiotensin system start treatment with an ACE inhibitor first then move to an ARB if the ACE inhibitor is not tolerated.
- 27. Less effective Diuretics Beta Blockers ACEIs ARBs Calcium Channel Blockers 1-Receptor Blockers Particularly effective Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299–1313. Concomitant Use of Antihypertensive Drugs
- 28. The Moral of the Tale As long as we reach the objective BP below 140/90 (130/80), it doesn’t matter how we get there
- 29. ACEI and the Kidneys – Contd: • Decreases Proteinuria (DM and Non-DM) • Beneficial effect on permeability • Beneficial effect on size selectivity • Slow the Rate of GFR Decline
- 30. Pharmacotherapy –BP Control • In people without CKD aim to keep the systolic blood pressure below 140 mmHg (target range 120–139 mmHg) and the diastolic blood pressure below 90 mmHg. • In people with CKD and diabetes with urinary protein excretion 1 g/24 h or more) aim to keep the systolic blood pressure below 130 mmHg (target range 120–129 mmHg) and the diastolic blood pressure below 80 mmHg
- 31. ACEI and the Kidneys Clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure- lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure.
- 32. The Heart Matters – the effect of ACEI • Prevents cardiac hypertrophy • Limits infarct size • Improves cardiac function • Improves cardiac metabolism
- 33. ACEI in Heart Failure • ACE inhibitors are recommended to treat HF due to systolic dysfunction. • The benefit of ACE inhibitors has been demonstrated in all severities of symptomatic HF and in patients with asymptomatic left ventricular (LV) dysfunction.
- 34. ACE in Heart Failure: the evidence A meta-analysis evaluated five trials • Improvement in symptoms • A lower total mortality. • A lower rate of readmission for HF).
- 35. ACE Inhibitors for ‘Diastolic’ Heart Failure? • Guidelines for the management of heart failure focus on patients with left ventricular systolic dysfunction. • However, guidelines make no recommendation for their use in patients with heart failure and preserved left ventricular systolic function.
- 36. Type 2 diabetes Management of cardiovascular risk factors Lending our patients a hand
- 37. Can ACEI prevent Diabetes ? • Several recent studies indicate that ACE inhibitor therapy reduces the development of type 2 diabetes in persons with essential hypertension. • HOPE, CAPPP, SOLVD, and ALLHAT • DREAM & ONTARGET = more recent
- 38. Path physiology • Exact mechanism is not known • ACEI reduces oxidative stress • Increases insulin sensitivity in the liver • Reduces Insulin resistance in muscles • Helps in the preservation of islet cells of pancreas
- 39. Angiotensin Receptor Blockers e.g. Losartan • Block only the AT-1 subtype • Comparable effects to ACE Inhibitors in almost all situations. • Less decrease in GFR in volume depleted states • Less side effects especially cough, angioedema, rash • Block all AII effects and not dependent on particular pathway
- 40. • Theoretical superiority over ACEIs: – Cough is rare – no interference with bradykinin and other ACE substrates – Complete inhibition of AT1 – alternative remains with ACEs – Result in indirect activation of AT2 – vasodilatation (additional benefit) – Clinical benefit of ARBs over ACEIs – not known
- 41. • However, losartan decreases BP in hypertensive which is for long period (24 Hrs) – heart rate remains unchanged and cvs reflxes are not interfered – no significant effect in plasma lipid profile, insulin sensitivity and carbohydrate tolerance etc – Mild uricosuric effect
- 42. ACE inhibitors versus ARBs: comparison of practice guidelines and treatment selection • ACC/AHA Heart Failure guidelines 2005. ACE inhibitors should be prescribed to all patients with left ventricular systolic dysfunction HF (class IA recommendation). • They recommend ARBs as a "reasonable alternative" first-line therapy (class IIA recommendation).
- 43. ACE inhibitors versus ARBs: comparison of practice guidelines : Contd • ACEI more cost effective • ARB better tolerated than ACEI • Deciding factor may be largely patient- specific.
- 44. • The ACE inhibitor Enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure • Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.
- 45. THANK YOU
Editor's Notes
- #37: 31/08/2020