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1) Classify drugs used in treatment of hypertension. Write mechanism of action and adverse effects of Angiotensin-Converting Enzyme Inhibitors. (5+5)

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Q.1 Classification of Antihypertensive Drugs + MOA & Adverse Effects of ACE Inhibitors

PART A: CLASSIFICATION OF DRUGS USED IN HYPERTENSION (5 marks)

1. Diuretics

Thiazide diuretics - Hydrochlorothiazide, Chlorthalidone, Indapamide
Loop diuretics - Furosemide, Torsemide
Potassium-sparing diuretics - Spironolactone, Eplerenone, Amiloride

2. Drugs Acting on the Renin-Angiotensin-Aldosterone System (RAAS)

ACE Inhibitors - Captopril, Enalapril, Lisinopril, Ramipril, Benazepril, Fosinopril, Quinapril, Perindopril, Trandolapril
Angiotensin Receptor Blockers (ARBs) - Losartan, Valsartan, Candesartan, Telmisartan, Olmesartan, Irbesartan, Azilsartan
Renin Inhibitors - Aliskiren
ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - Sacubitril + Valsartan

3. Sympatholytic Drugs

Beta-blockers (β1-selective) - Atenolol, Metoprolol, Bisoprolol, Nebivolol
Non-selective beta-blockers - Propranolol, Nadolol
Alpha + Beta blockers - Labetalol, Carvedilol
Alpha-1 blockers - Prazosin, Doxazosin, Terazosin
Central sympatholytics - Clonidine (α2 agonist), Methyldopa

4. Calcium Channel Blockers (CCBs)

Dihydropyridines - Amlodipine, Nifedipine, Nicardipine, Felodipine
Non-dihydropyridines - Verapamil, Diltiazem

5. Direct Vasodilators

Oral - Hydralazine, Minoxidil
Parenteral - Sodium Nitroprusside, Fenoldopam

PART B: MECHANISM OF ACTION AND ADVERSE EFFECTS OF ACE INHIBITORS (5 marks)

Mechanism of Action

Step 1 - The Normal RAAS Pathway:

Renin (released from kidney) → acts on Angiotensinogen → Angiotensin I → ACE (endothelial enzyme) → Angiotensin II → vasoconstriction + aldosterone release → ↑ BP

ACE (angiotensin-converting enzyme) is a peptidyl dipeptidase enzyme with a dual role:

It converts Angiotensin I → Angiotensin II (a potent vasoconstrictor)
It inactivates Bradykinin (a potent vasodilator) under the name "plasma kininase"

Step 2 - Action of ACE Inhibitors: ACE inhibitors (e.g., Captopril) competitively block this enzyme, leading to:

Effect	Result
↓ Angiotensin II formation	↓ Peripheral vascular resistance (vasodilation)
↓ Aldosterone secretion	↓ Sodium and water retention → ↓ Blood volume
↑ Bradykinin levels	Further vasodilation via nitric oxide and prostacyclin release
↓ Intraglomerular pressure	Renoprotective effect, reduces proteinuria

Key points:

Lower BP primarily by decreasing peripheral vascular resistance
Cardiac output and heart rate are not significantly changed - no reflex tachycardia (due to resetting of baroreceptors and enhanced parasympathetic activity)
Most are prodrugs (e.g., Enalapril → Enalaprilat in liver); exception is Captopril and Lisinopril which are active drugs
Effective even in low-renin hypertensive states

(Source: Katzung's Basic and Clinical Pharmacology, 16th Edition)

Adverse Effects

Adverse Effect	Mechanism / Notes
Dry, persistent cough	Most common (~10-15% patients). Due to ↑ bradykinin and substance P accumulation in the airways. Nonproductive; resolves on stopping the drug. Reason to switch to ARB.
Angioedema	Rare (0.1-0.5%) but potentially life-threatening. Due to ↑ bradykinin causing submucosal edema of face, lips, tongue, larynx. Absolute contraindication to restarting drug.
First-dose hypotension	Severe hypotension after initial dose, especially in hypovolemic patients (on diuretics, sodium-restricted diet, or with GI fluid loss).
Hyperkalemia	Due to reduced aldosterone levels → ↓ renal potassium excretion. Risk increased in renal insufficiency and diabetes.
Acute renal failure	Particularly in patients with bilateral renal artery stenosis or stenosis of renal artery of a solitary kidney (ACE inhibitors dilate efferent arteriole → ↓ GFR → renal failure).
Teratogenicity	Contraindicated in 2nd and 3rd trimesters of pregnancy - causes fetal hypotension, anuria, renal failure, fetal malformations, or death. Recent evidence also suggests 1st trimester risk.
Neutropenia/Proteinuria	Mainly with Captopril, especially in high doses in patients with renal insufficiency.
Minor effects	Altered taste (dysgeusia), allergic skin rashes, drug fever - occur in up to 10% of patients.

Important Drug Interactions:

Potassium supplements / K+-sparing diuretics - additive hyperkalemia risk
NSAIDs - reduce hypotensive effect by blocking bradykinin-mediated vasodilation (which is prostaglandin-mediated)

(Source: Katzung's Basic and Clinical Pharmacology, 16th Edition; Goodman & Gilman's Pharmacological Basis of Therapeutics)

Exam Tip: Remember the mnemonic CAPTOPRIL for ACE inhibitor adverse effects: Cough, Angioedema, Proteinuria, Teratogenicity, Orthostatic hypotension (first dose), Potassium increase (hyperkalemia), Rash/taste alteration, Inhibits renal function (in RAS), Leukopenia (neutropenia).

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