ACE Inhibitors – Mechanism of Action

Introduction

ACE inhibitors (Angiotensin-Converting Enzyme Inhibitors) are a foundational class of antihypertensive drugs. They are used to treat hypertension, heart failure, and various forms of renal and cardiovascular disease.

Common examples include:

• Enalapril
• Lisinopril
• Ramipril
• Captopril

These drugs are frequently tested in both clinical exams and licensure tests due to their dual impact on the cardiovascular and renal systems.

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Stepwise Mechanism of Action of ACE Inhibitors

1. Inhibition of Angiotensin-Converting Enzyme (ACE):
   ACE inhibitors block the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme, which is primarily located in the pulmonary endothelium.
2. Reduced Angiotensin II Levels:
   Angiotensin II is a potent vasoconstrictor and stimulates aldosterone secretion. Its reduction leads to:
   • Vasodilation
   • Decreased sodium and water retention
   • Reduced blood pressure
3. Decreased Aldosterone Secretion:
   With lower aldosterone, there is reduced sodium and water reabsorption in the distal nephron, promoting natriuresis and diuresis.
4. Increased Bradykinin Levels:
   ACE also degrades bradykinin, a vasodilator. ACE inhibition increases bradykinin, further contributing to vasodilation but also increasing the risk of dry cough and angioedema.
5. Overall Effects:
   • Decreased preload and afterload
   • Reduced systemic vascular resistance
   • Improved cardiac output in heart failure
   • Renoprotective in diabetic nephropathy

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Pharmacokinetic Parameters of ACE Inhibitors

Parameter	General Range
Bioavailability	25–75% (varies with each drug)
Onset of Action	1–2 hours (oral); peak in 4–6 hours
Half-life	2–40 hours depending on the drug
Protein Binding	90% for most ACEIs
Metabolism	Hepatic (most are prodrugs except lisinopril)
Excretion	Renal (dose adjustment needed in CKD)

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Clinical Uses of ACE Inhibitors

• Hypertension (first-line in patients with diabetes, CKD)
• Congestive heart failure
• Post-myocardial infarction
• Diabetic nephropathy
• Proteinuria with chronic kidney disease
• Left ventricular dysfunction

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Adverse Effects of ACE Inhibitors

• Dry cough (due to bradykinin accumulation)
• Hyperkalemia
• Hypotension, especially after first dose
• Angioedema (life-threatening in rare cases)
• Taste disturbances (metallic taste)
• Teratogenic – contraindicated in pregnancy
• Renal function deterioration in bilateral renal artery stenosis

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Comparative Analysis: ACE Inhibitors vs ARBs

Feature	ACE Inhibitors	ARBs (Angiotensin II Receptor Blockers)
Main Target	Inhibits ACE enzyme	Blocks angiotensin II receptor (AT1)
Bradykinin effect	Increases → cough, angioedema	No effect → fewer side effects
Use in dry cough	Avoid	Preferred
Potassium level	May cause hyperkalemia	May cause hyperkalemia
Fetal risk	Teratogenic	Teratogenic

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Practice MCQs

Q1. What is the primary enzyme inhibited by ACE inhibitors?
a. Renin
b. Angiotensinogenase
c. Angiotensin-converting enzyme ✅
d. Aldosterone synthase

Q2. Which substance increases as a result of ACE inhibition?
a. Aldosterone
b. Bradykinin ✅
c. Angiotensin II
d. Dopamine

Q3. Which of the following is a known side effect of ACE inhibitors?
a. Hypokalemia
b. Hypercalcemia
c. Dry cough ✅
d. Arrhythmia

Q4. ACE inhibitors are contraindicated in which of the following conditions?
a. Diabetes mellitus
b. Pregnancy ✅
c. Hypertension
d. Heart failure

Q5. Which of the following ACE inhibitors is not a prodrug?
a. Enalapril
b. Ramipril
c. Lisinopril ✅
d. Perindopril

Q6. The fall in blood pressure with ACE inhibitors is primarily due to:
a. Beta-blockade
b. Vasodilation via angiotensin II suppression ✅
c. Increased heart rate
d. Decreased blood volume only

Q7. Bradykinin accumulation leads to which adverse effect?
a. Rash
b. Hyperglycemia
c. Dry cough ✅
d. Hypokalemia

Q8. ACE inhibitors have renoprotective effects in:
a. Acute kidney injury
b. Nephrolithiasis
c. Diabetic nephropathy ✅
d. Glomerulonephritis

Q9. ACE inhibitors are especially useful in:
a. Asthma
b. Hyperthyroidism
c. Heart failure with reduced ejection fraction ✅
d. Acute MI with bradycardia

Q10. Which electrolyte abnormality is expected with ACE inhibitor use?
a. Hyperkalemia ✅
b. Hypokalemia
c. Hyponatremia
d. Hypermagnesemia

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FAQs

Q1: Can ACE inhibitors be used in pregnancy?
No, they are contraindicated due to teratogenic effects, especially in the second and third trimesters.

Q2: Why do ACE inhibitors cause a dry cough?
Due to bradykinin accumulation in the lungs, which irritates airway receptors.

Q3: Can ACE inhibitors be combined with ARBs?
Generally avoided due to increased risk of hyperkalemia and renal dysfunction.

Q4: Are ACE inhibitors safe in chronic kidney disease?
Yes, but they should be used cautiously, with monitoring of serum creatinine and potassium.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• American Heart Association Guidelines
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK538507/