Mzantsi Medics

Angiotensin-Converting Enzyme(ACE) Inhibitors

Drugs included in this group are captopril, enalapril maleate, perindopril tert-butylamine, quinapril, ramipril, trandolapril and Lisinopril. ACE inhibitors are divided into three drug classes.^1,2,3

ACE inhibitor Class	Pharmacokinetic distinctions	Examples
Class 1	Readily absorbed ACE inhibitor.	Captopril
Class 2	Inactive pro-drugs, requires liver metabolism for activation.	Enalapril Perindopril Quinapril Ramipril Trandolapril
Class 3	Active drug , does not require liver metabolism.	Lisinopril

…

Mechanism of action of ACE Inhibitors   

Angiotensinogen, also referred to as renin substrate, is produced by the liver, while renin is produced by the kidney. Renin converts angiotensinogen into angiotensin-1; angiotensin-converting enzyme (ACE), which is produced by the endothelium of the lung blood vessels, converts angiotensin-1 to angiotensin-2. Angiotensin-2 is a potent vasoconstrictor, which results in increased blood pressure. ^4,5,6,7 ACE inhibitors prevent the conversion of angiotensin-1 to angiotensin-2, therefore lowering the blood pressure.

…

ACE Inhibitors indications

• Hypertension
• Initiated early, within 24 hours, Post ST Elevation Myocardial Infarction (STEMI).^8,9,10
• Heart failure¹¹  
• Diabetes mellitus^12,13
• Proteinuria or nephrotic syndrome^14,15
• Chronic kidney disease^16,17

…

ACE Inhibitors contraindications

• Pregnancy^18,19
• History of angioedema.^20,21 
• Hyperkalemia^22,23
• Renal artery stenosis^24,25

ACE inhibitors and the black patient

Black patients have a higher incidence of low renin hypertension, and therefore ACE inhibitors are less effective in black patients. ^26,27,28 Angioedema is also more common in black patients. ^29,30,31

…

Pregnancy and ACE inhibitors

ACE inhibitors are contraindicated in pregnancy because of their possible teratogenic effects. The decision to stop ACE inhibitors during pregnancy should be taken in consultation with the treating obstetrician. ^32,33

…

Low-salt diet and ACE inhibitors

A low-salt diet enhances the effects of ACE inhibitors. ^34,35

…

ACE inhibitors side-effects ^36,37,38

• 1^st dose hypotension
• Dizziness
• Renal Impairment
• Hyperkalaemia
• Dry irritating cough due to the inhibition of bradykinin degradation
• Angioedema
• Hepatotoxicity
• Skin rashes
• Dysgeusia
• Teratogenic effects in pregnancy

…

References

1. Rossiter D, Blockman M, Barnes KI. South African Medicines Formulary. 14^th edition. Cape town: SAMA Health and Medical Publishing Group; 2022. C09, Agents Acting On the Renin-Angiotensin System; p.171-136.
2. Drug Classes Angiotensin Converting Enzyme (ACE) Inhibitors [Internet]. Available from: https://bihsoc.org/wp-content/uploads/2017/11/Angiotensin-Converting-Enzyme-Final-2017.pdf
3. Brown NJ, Vaughan DE. Angiotensin-Converting Enzyme Inhibitors. Circulation [Internet]. 1998 Apr 14;97(14):1411–20. Available from: https://www.ahajournals.org/doi/full/10.1161/01.CIR.97.14.1411
4. Brenner GM, Stevens CW. Pharmacology. 4^th edition. Philadelphia: Elsevier-Saunders; 2013. Chapter 8, Antihypertensive drugs; p.88-101.
5. Guyton AC, Hall JE. Textbook of medical physiology. 11^th edition. Philadelphia: Elsevier-Saunders; 2006. Chapter 19, Dominant Role of the Kidney in Long-Term Regulation of Arterial Pressure and in Hypertension: The Integrated System for Pressure Control; p.224-226.
6. Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 23^rd edition. New York: McGraw-Hill Companies; 2010. CHAPTER 39, Regulation of Extracellular Fluid Composition & Volume; p669-672.
7. Anthony PK, Pharmacology Secrets. 1^st Edition. Philadelphia: Hanley & Belfus, Inc.; 2002. Chapter 14, The Therapy of Hypertension; p.113-114.
8. Kloeck GJ, Alekar S, Ariedien N. A guide to the management of common medical emergencies in adults. 11^th edition. Pretoria: University of the Wiwatersrand; 2017. Section 1, Cardio-respiratory emergencies; p.18.
9. UpToDate [Internet]. http://www.uptodate.com. Available from: https://www.uptodate.com/contents/angiotensin-converting-enzyme-inhibitors-and-receptor-blockers-in-acute-myocardial-infarction-clinical-trials
10. Indications for ACE Inhibitors in the Early Treatment of Acute Myocardial Infarction. Circulation. 1998 Jun 9;97(22):2202–12.
11. Herman L, Bashir K. Angiotensin Converting Enzyme Inhibitors (ACEI) [Internet]. Nih.gov. StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431051/
12. Dj C, P Z, S H. Role of ACE Inhibitors in Patients With Diabetes Mellitus [Internet]. Drugs. 2001. Available from: https://pubmed.ncbi.nlm.nih.gov/11708761/
13. Sadovsky R. Use of ACE Inhibitors in Patients with Type 2 Diabetes. American Family Physician [Internet]. 2000 May 1;61(9):2830–2. Available from: https://www.aafp.org/pubs/afp/issues/2000/0501/p2830.htm
14. https://www.ccjm.org/sites/default/files/additional-assets/PDFs/Current_Drug_Therapy_Example.pdf
15. Gansevoort RT, Zeeuw D, Jong PE. ACE inhibitors and proteinuria. Pharmacy World and Science. 1996;18(6):204–10.
16. Angiotensin-converting enzyme (ACE) inhibitors & angiotensin receptor blockers (ARBs) [Internet]. National Kidney Foundation. 2023. Available from: https://www.kidney.org/atoz/content/angiotensin-converting-enzyme-ace-inhibitors-angiotensin-receptor-blockers-arbs#:~:text=Over%20the%20long%2Dterm%2C%20people
17. Zhang Y, He D, Zhang W, Xing Y, Guo Y, Wang F, et al. ACE Inhibitor Benefit to Kidney and Cardiovascular Outcomes for Patients with Non-Dialysis Chronic Kidney Disease Stages 3–5: A Network Meta-Analysis of Randomised Clinical Trials. Drugs [Internet]. 2020 Apr 24;80(8):797–811. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242277/
18. Ray JG, Vermeulen MJ, Koren G. Taking ACE inhibitors during early pregnancy. Canadian Family Physician [Internet]. 2007 Sep 1;53(9):1439–40. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234619/#:~:text=It%20is%20well%20accepted%20that
19. ACE Inhibitors in Early Pregnancy [Internet]. medsafe.govt.nz.  Available from: https://medsafe.govt.nz/profs/puarticles/aceinhibitors.htm
20. ACE inhibitor-induced angioedema | DermNet NZ [Internet]. dermnetnz.org. Available from: https://dermnetnz.org/topics/ace-inhibitor-induced-angioedema
21. Rubin S, Tomaszewski M. Prediction and prevention of ACE-inhibitor-induced angioedema—an unmet clinical need in management of hypertension. Hypertension Research [Internet]. 2023 Nov 9;1–4. Available from: https://www.nature.com/articles/s41440-023-01491-9
22. Goyal A, Cusick AS, Thielemier B. ACE Inhibitors [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430896/#:~:text=Hyperkalemia%3A%20Hyperkalemia%20from%20ACE%20inhibitors
23. Raebel MA. Hyperkalemia Associated with Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers. Cardiovascular Therapeutics. 2011 Jan 26;30(3):e156–66.
24. Khosla S, Ahmed A, Siddiqui M, Trivedi A, Benatar D, Salem Y, et al. Safety of Angiotensin-Converting Enzyme Inhibitors in Patients with Bilateral Renal Artery Stenosis Following Successful Renal Artery Stent Revascularization. American Journal of Therapeutics. 2006 Jul;13(4):306–8
25. GP. ACE inhibitors and renal artery stenosis [Internet]. Gponline.com. GP; 2009. Available from: https://www.gponline.com/ace-inhibitors-renal-artery-stenosis/cardiovascular-system/article/914629
26. Warnock DG. Low-Renin and Nonmodulating Essential Hypertension. Hypertension. 1999 Sep;34(3):395–7.
27. Low-renin hypertension: Causes, symptoms, treatment, and more [Internet]. http://www.medicalnewstoday.com. 2023 [cited 2024 Mar 23]. Available from: https://www.medicalnewstoday.com/articles/low-renin-hypertension
28. Mulatero P, Verhovez A, Morello F, Veglio F. Diagnosis and treatment of low-renin hypertension. Clinical Endocrinology. 2007 Sep;67(3):324–34.
29. UpToDate [Internet]. http://www.uptodate.com. Available from: https://www.uptodate.com/contents/ace-inhibitor-induced-angioedema#:~:text=Angiotensin%2Dconverting%20enzyme%20(ACE)
30. Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature. The Journal of Clinical Hypertension. 2017 Oct 10;19(12):1377–82.
31. Erickson DL, Coop CA. Angiotensin-converting enzyme inhibitor–associated angioedema treated with c1-esterase inhibitor: A case report and review of the literature. Allergy & Rhinology [Internet]. 2016;7(3):e168–71. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244275/
32. NICE. Hypertension in pregnancy: diagnosis and management NICE guideline [Internet]. 2019 Jun. Available from: https://www.nice.org.uk/guidance/ng133/resources/hypertension-in-pregnancy-diagnosis-and-management-pdf-66141717671365
33. bumps – best use of medicine in pregnancy [Internet]. www.medicinesinpregnancy.org. Available from: https://www.medicinesinpregnancy.org/Medicine–pregnancy/ACE-Inhibitors/
34. Li SC, Jiang TM, Zhang JH, Zeng MY, Ma YX, Feng SY, et al. Salt Restriction and Angiotensin-Converting Enzyme Inhibitor Improve the Responsiveness of the Small Artery in Salt-Sensitive Hypertension. International Journal of Medical Sciences [Internet]. 2023 Mar 5;20(5):572–80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110468/
35. Slagman MCJ, Waanders F, Hemmelder MH, Woittiez AJ ., Janssen WMT, Lambers Heerspink HJ, et al. Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial. BMJ. 2011 Jul 26;343(jul26 2):d4366–6.
36. Alderman CP. Adverse Effects of the Angiotensin-Converting Enzyme Inhibitors. Annals of Pharmacotherapy. 1996 Jan;30(1):55–61.
37. Mayo Clinic. What do ACE inhibitors do for heart health? [Internet]. Mayo Clinic. Mayo Clinic; 2021.  Available from: https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480
38. 7 Side Effects of ACE Inhibitors to Be Aware of [Internet]. GoodRx.

Available from: https://www.goodrx.com/classes/ace-inhibitors/side-effects-of-ace-inhibitors