Antihypertensive drugs- classify ,moa ,adverse effect ,precaution, Management of hypertensive emergencies and urgencies - describe; Thiazide diuretics - MOA, Combination Therapy in Hypertension 2 mbbs pharmacology

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Antihypertensive Drugs - Complete 2nd MBBS Pharmacology Notes

Source: Lippincott Illustrated Reviews Pharmacology

CLASSIFICATION OF BLOOD PRESSURE (JNC 8 / ACC/AHA 2017)

Category	Systolic (mmHg)		Diastolic (mmHg)
Normal	<120	and	<80
Elevated	120-129	or	<80
Stage 1 HTN	130-139	or	80-89
Stage 2 HTN	≥140	or	≥90

CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS

I. Diuretics

Thiazides: Hydrochlorothiazide (HCTZ), Chlorthalidone, Indapamide, Metolazone
Loop diuretics: Furosemide, Torsemide
K+-sparing: Spironolactone, Eplerenone, Amiloride, Triamterene

II. Renin-Angiotensin-Aldosterone System (RAAS) Blockers

ACE Inhibitors: Captopril, Enalapril, Lisinopril, Ramipril
Angiotensin Receptor Blockers (ARBs): Losartan, Valsartan, Candesartan, Olmesartan
Direct Renin Inhibitor: Aliskiren

III. Calcium Channel Blockers (CCBs)

Dihydropyridines (DHP): Amlodipine, Nifedipine, Nicardipine, Felodipine, Clevidipine
Non-DHP: Verapamil (phenylalkylamine), Diltiazem (benzothiazepine)

IV. Beta-Blockers (β-Blockers)

Non-selective: Propranolol, Nadolol, Carvedilol (α+β blocker)
Cardioselective (β1): Metoprolol, Atenolol, Bisoprolol
With ISA: Pindolol, Acebutolol
Combined α+β: Labetalol (used IV in emergencies)

V. Alpha-Blockers

α1-selective: Prazosin, Doxazosin, Terazosin
Non-selective α: Phentolamine (used in pheochromocytoma crisis)

VI. Central Sympatholytics

α2 agonists (central): Clonidine, Methyldopa (drug of choice in pregnancy)
Imidazoline receptor agonist: Moxonidine

VII. Direct Vasodilators

Arteriolar: Hydralazine, Minoxidil
Arteriolar + Venodilator: Sodium Nitroprusside (nitric oxide donor)

VIII. Dopamine Agonist

D1 agonist: Fenoldopam (used in hypertensive emergencies with renal impairment)

MECHANISM OF ACTION

1. Diuretics

Thiazides reduce preload by Na+/Cl- cotransporter inhibition in the distal convoluted tubule; long-term effect is reduced peripheral vascular resistance.
Loop diuretics inhibit Na+/K+/2Cl- cotransporter in the thick ascending limb of Henle.
Spironolactone blocks aldosterone receptors; amiloride/triamterene block epithelial Na+ channels in collecting duct.

2. ACE Inhibitors

Block angiotensin-converting enzyme (ACE), preventing conversion of angiotensin I to angiotensin II (a potent vasoconstrictor). They also prevent degradation of bradykinin (which accumulates and causes cough). Result: vasodilation of arterioles and veins, decreased aldosterone secretion, reduced Na+ retention.

3. ARBs

Competitively block AT1 receptors for angiotensin II, causing vasodilation similar to ACE inhibitors but WITHOUT bradykinin accumulation - hence no cough. All beneficial effects without the dry cough.

4. Calcium Channel Blockers

DHPs (amlodipine, nifedipine): Block L-type voltage-gated Ca2+ channels in vascular smooth muscle > heart. Cause arteriolar vasodilation, reducing peripheral resistance.
Non-DHPs (verapamil, diltiazem): Block L-type channels in cardiac tissue > vasculature. Reduce heart rate and cardiac contractility (negative chronotropy + inotropy), thus reducing cardiac output.

5. Beta-Blockers

Block β1 receptors in the heart → reduced heart rate and cardiac contractility → decreased cardiac output.
Block β1 receptors on juxtaglomerular cells → decreased renin release → decreased angiotensin II and aldosterone.
Central β-blockers also reduce sympathetic outflow.

6. Alpha-1 Blockers (Prazosin, Doxazosin)

Block postsynaptic α1 adrenoceptors on vascular smooth muscle → vasodilation of arterioles and veins → reduced peripheral resistance. Cause "first-dose hypotension."

7. Central Sympatholytics

Clonidine: Stimulates α2 receptors (and imidazoline I1 receptors) in the brainstem → decreases sympathetic outflow → reduces cardiac output and peripheral vascular resistance.
Methyldopa: Converted to α-methylnorepinephrine in CNS → stimulates central α2 receptors → reduces sympathetic outflow. Preferred in pregnancy.

8. Direct Vasodilators

Hydralazine: Dilates arterioles preferentially; exact mechanism not fully established but involves K+ channel opening. Causes compensatory reflex tachycardia and Na+ retention (must be combined with a β-blocker and diuretic).
Minoxidil: Opens ATP-sensitive K+ channels in smooth muscle → hyperpolarization → arteriolar dilation. Very potent; causes severe Na+ retention and reflex tachycardia. Also causes hypertrichosis (used topically as Rogaine for hair loss).
Sodium Nitroprusside: Releases NO → activates guanylyl cyclase → increased cGMP → vasodilation of arterioles AND veins. Ultra-short acting; metabolized to cyanide (thiocyanate toxicity with prolonged use).

ADVERSE EFFECTS

Drug Class	Key Adverse Effects
Thiazides	Hypokalemia, hyponatremia, hyperuricemia (gout), hyperglycemia, hyperlipidemia, hypercalcemia, impotence
Loop diuretics	Hypokalemia, hyponatremia, hypocalcemia, ototoxicity (at high doses), hyperuricemia
Spironolactone	Hyperkalemia, gynecomastia, menstrual irregularities (anti-androgen effect)
ACE Inhibitors	Dry cough (bradykinin accumulation), angioedema (rare but dangerous), hyperkalemia, acute kidney injury in bilateral renal artery stenosis, teratogenic (contraindicated in pregnancy)
ARBs	Hyperkalemia, AKI in bilateral RAS, teratogenic; NO cough (no bradykinin effect)
DHP-CCBs	Peripheral edema (ankle), reflex tachycardia (esp. nifedipine), flushing, headache
Non-DHP CCBs	Bradycardia, AV block, heart failure exacerbation, constipation (verapamil > diltiazem)
Beta-Blockers	Bradycardia, bronchospasm (contraindicated in asthma), fatigue, sexual dysfunction, masking of hypoglycemia in diabetics, cold extremities, rebound hypertension on abrupt withdrawal
Alpha-1 Blockers	First-dose orthostatic hypotension (most with prazosin), reflex tachycardia, edema
Clonidine	Sedation, dry mouth, rebound hypertension on abrupt withdrawal, constipation
Methyldopa	Sedation, positive Coombs test (hemolytic anemia), hepatotoxicity, lupus-like syndrome
Hydralazine	Reflex tachycardia, Na+ retention, lupus-like syndrome (with high doses, >200mg/day), headache, palpitations, angina
Minoxidil	Severe Na+ retention, reflex tachycardia, hypertrichosis (hair growth), pericardial effusion
Nitroprusside	Cyanide/thiocyanate toxicity (prolonged use), severe hypotension
Aliskiren	Hyperkalemia, diarrhea; contraindicated with ACE inhibitors/ARBs in diabetics

PRECAUTIONS / CONTRAINDICATIONS

Drug	Contraindications / Precautions
ACE inhibitors & ARBs	Pregnancy (all trimesters), bilateral renal artery stenosis, hyperkalemia, avoid combination with each other (or aliskiren in diabetics)
Beta-Blockers	Asthma/COPD (non-selective), sick sinus syndrome, 2nd/3rd degree AV block, decompensated heart failure (acute), peripheral arterial disease, diabetes prone to hypoglycemia
Verapamil	Do NOT combine with β-blockers (complete AV block risk), WPW syndrome
Thiazides	Gout (raise uric acid), severe renal impairment (GFR <30 - become ineffective)
Loop diuretics	Electrolyte monitoring essential; ototoxicity risk increases with aminoglycosides
Spironolactone	Hyperkalemia, avoid with ACE-I/ARB in patients with renal impairment
Clonidine	Never stop abruptly - causes rebound hypertensive crisis; use with caution with β-blockers
Hydralazine	Avoid in lupus-prone patients; must combine with β-blocker + diuretic to counteract reflex tachycardia and Na+ retention
Minoxidil	Must be given with loop diuretic + β-blocker; not for mild-moderate hypertension
Nitroprusside	Monitor thiocyanate levels; limit infusion duration; protect from light; use sodium thiosulfate as antidote for cyanide toxicity

THIAZIDE DIURETICS - MOA IN DETAIL

Drugs

Chlorothiazide (first thiazide, oral), Hydrochlorothiazide (HCTZ - most commonly used), Chlorthalidone (preferred - 2x potency, 50-60 hr half-life), Indapamide, Metolazone (thiazide-LIKE, but work at similar site)

Mechanism of Action

Primary site: Distal convoluted tubule (DCT)
Target: Inhibit the Na+/Cl- cotransporter (NCC) on the luminal membrane of DCT cells
This blocks Na+ and Cl- reabsorption → increased Na+, Cl- in tubular fluid → osmotic diuresis
Thiazides must be secreted into the tubular lumen via organic acid secretion mechanism at the proximal tubule to reach their site of action

Ionic Effects Summary

Ion	Effect
Na+, Cl-	Increased urinary excretion
K+	Increased excretion (hypokalemia)
Mg2+	Increased excretion
Ca2+	Decreased excretion (unique - promotes reabsorption in DCT via PTH-regulated channels)
Uric acid	Decreased excretion (hyperuricemia - competes with uric acid at secretion sites)
HCO3-	Mild increase in excretion

Antihypertensive Mechanism (Two Phases)

Acute: Reduces plasma volume and cardiac output via diuresis
Chronic: Blood volume returns to near-normal, but peripheral vascular resistance falls due to relaxation of arteriolar smooth muscle (mechanism not fully defined; may involve K+ channel hyperpolarization)

Unique Feature

Thiazides produce hyperosmolar (concentrated) urine - unique among diuretics. This makes them paradoxically useful in nephrogenic diabetes insipidus (by causing mild Na+ depletion which increases proximal tubule reabsorption and reduces urine volume).

Uses

Hypertension (first-line, alone or in combination)
Edema (mild-moderate - cardiac, hepatic, renal)
Nephrogenic diabetes insipidus (paradoxical effect)
Osteoporosis prevention (reduce urinary Ca2+ loss)
Idiopathic hypercalciuria and calcium kidney stones

Key Adverse Effects

Hypokalemia (most common) - causes metabolic alkalosis
Hyperuricemia - can precipitate gout
Hyperglycemia - reduce insulin secretion; worsen diabetes
Hyperlipidemia - raise LDL and triglycerides
Hypercalcemia (reduce Ca2+ excretion)
Hyponatremia - especially elderly women
Hypersensitivity - although sulfonamide derivatives, cross-reactivity with sulfonamide antibiotics is rare

HYPERTENSIVE EMERGENCIES AND URGENCIES

Definitions

Hypertensive Emergency

Severe BP elevation (SBP >180 mmHg OR DBP >120 mmHg) WITH evidence of progressive target organ damage (TOD)
TOD includes: hypertensive encephalopathy, intracranial hemorrhage, acute aortic dissection, acute MI/unstable angina, acute LV failure with pulmonary edema, acute kidney injury, eclampsia
Requires immediate IV treatment in ICU

Hypertensive Urgency

Severe BP elevation (same threshold: SBP >180 / DBP >120) WITHOUT evidence of target organ damage
Symptoms may include: severe headache, anxiety, shortness of breath, epistaxis
Does NOT require immediate IV therapy
Treatment: oral antihypertensives, gradual reduction over 24-48 hours, close follow-up within 24-48 hours

Management of Hypertensive Emergency

Goals of BP Reduction:

Initial goal: Reduce MAP by no more than 25% within the first hour
Next 2-6 hours: Reduce to 160/100-110 mmHg
Over 24-48 hours: Gradually normalize BP
Avoid rapid over-reduction - can cause cerebral, myocardial, or renal ischemia due to autoregulation failure

Exception to gradual reduction rule: Aortic dissection - reduce SBP to <120 mmHg within 20 minutes using IV labetalol + nitroprusside

IV Drugs Used in Hypertensive Emergency

Drug	Class	MOA	Onset	Key Use / Notes
Labetalol	α+β blocker	Blocks α1 + β1/β2	2-5 min	First-line in most emergencies, stroke, eclampsia, aortic dissection
Nicardipine	DHP-CCB	Ca2+ channel block	5-15 min	Stroke, encephalopathy, post-op hypertension
Clevidipine	DHP-CCB	Ca2+ channel block	2-4 min	Ultra-short acting; heart failure, post-op
Sodium Nitroprusside	NO donor	Arteriolar + venous dilation	Seconds	Most powerful; aortic dissection (with β-blocker); risk: cyanide toxicity
Nitroglycerin	NO donor	Venodilation > arteriolar	1-2 min	ACS, pulmonary edema, cardiac surgery
Esmolol	Cardioselective β1-blocker	Reduces HR + CO	1-2 min	Aortic dissection, peri-operative; ultra-short T½ (9 min)
Phentolamine	Non-selective α-blocker	α1 + α2 blockade	1-2 min	Pheochromocytoma crisis, MAO inhibitor crisis
Hydralazine	Direct vasodilator	Arteriolar dilation	10-20 min	Eclampsia/pregnancy (IV use)
Fenoldopam	D1 agonist	Renal vasodilation	5 min	Hypertensive emergency with renal impairment; increases renal perfusion
Enalaprilat	ACE inhibitor (IV)	Blocks ACE	15-30 min	Useful in heart failure-associated HTN emergency

Management of Hypertensive Urgency

No IV therapy required
Oral options: Clonidine (0.1-0.2 mg, repeat q1h), captopril (25 mg sublingual/oral), labetalol (200-400 mg oral), amlodipine
Restart/optimize existing antihypertensive regimen
Do NOT lower BP too rapidly - risk of ischemia
Follow-up within 24-48 hours is mandatory

Specific Hypertensive Emergencies - Drug of Choice

Condition	Preferred Agents	Avoid
Hypertensive encephalopathy	Labetalol, nicardipine	Nitroprusside (increases ICP)
Ischemic stroke	Labetalol, nicardipine (only if SBP >220 mmHg)	Aggressive lowering before thrombolysis
Hemorrhagic stroke	Nicardipine, labetalol
Aortic dissection	Esmolol + nitroprusside / labetalol	Vasodilators alone (reflex tachycardia increases shear force)
Acute MI / ACS	Nitroglycerin, labetalol	Hydralazine, nifedipine (reflex tachycardia)
Acute LV failure / pulmonary edema	Nitroglycerin, nicardipine, enalaprilat	Beta-blockers (worsen HF acutely)
Eclampsia / Pre-eclampsia	Hydralazine (IV), labetalol (IV), nifedipine (oral)	ACE inhibitors (teratogenic), ARBs
Pheochromocytoma	Phentolamine (IV) + β-blocker AFTER alpha block	Beta-blocker FIRST (causes paradoxical HTN)
Renal crisis	ACE inhibitor, fenoldopam

COMBINATION THERAPY IN HYPERTENSION

Why Combination Therapy?

Most hypertensive patients require 2 or more drugs for adequate control
Combining drugs with different mechanisms is synergistic
Allows lower doses of each drug (fewer side effects)
Addresses multiple pathophysiological mechanisms simultaneously

Preferred Combinations (Rational)

1. ACE inhibitor/ARB + CCB (DHP)

ACCOMPLISH trial showed ACE inhibitor + amlodipine superior to ACE inhibitor + HCTZ in reducing cardiovascular events
Rationale: CCB-induced ankle edema is reduced by ACE inhibitor (which reduces arteriolar dilation-driven capillary pressure)
Example: Enalapril + Amlodipine, Ramipril + Amlodipine

2. ACE inhibitor/ARB + Thiazide diuretic

Diuretic activates RAAS (raising angiotensin II) → ACE inhibitor/ARB blunts this counter-regulatory response
ACE inhibitor reduces diuretic-induced hypokalemia
Example: Ramipril + HCTZ, Losartan + HCTZ

3. Beta-Blocker + Thiazide

Beta-blocker counters reflex tachycardia from diuretic; both reduce cardiac output
Metabolic downside: both raise glucose and lipids - avoid in metabolic syndrome
Example: Atenolol + HCTZ

4. CCB + Beta-Blocker

DHP-CCBs cause reflex tachycardia; β-blockers prevent this
Avoid verapamil/diltiazem + beta-blocker (excessive cardiac depression → AV block)
Example: Amlodipine + Metoprolol

5. Alpha-Blocker + Beta-Blocker

Labetalol alone covers both; or prazosin + β-blocker used in resistant HTN
Rationale: alpha blockade reduces peripheral resistance; β-blocker prevents reflex tachycardia

Combinations to AVOID

Combination	Reason
ACE inhibitor + ARB	Dual RAAS blockade - excess hyperkalemia, AKI - not recommended
ACE inhibitor/ARB + Aliskiren in diabetics	Same - dual RAAS blockade prohibited
Non-DHP CCB (verapamil/diltiazem) + Beta-blocker	Complete heart block, severe bradycardia
Two β-blockers	Additive cardiac depression, no benefit

Initial Therapy Strategy (JNC 8 / ACC-AHA 2017)

General population: Start with one of four classes: thiazide, ACE inhibitor, ARB, or DHP-CCB
If SBP >20 mmHg or DBP >10 mmHg above goal: Start with two-drug combination initially
Black patients: Thiazide + CCB preferred (ACE inhibitors less effective as monotherapy)
CKD: ACE inhibitor or ARB preferred (nephroprotective)
Diabetes + hypertension: ACE inhibitor or ARB (reduce diabetic nephropathy)
Heart failure with reduced EF: ACE inhibitor/ARB + β-blocker + spironolactone (+ diuretic if needed)
Post-MI: Beta-blocker + ACE inhibitor

Fixed-Dose Combination Products Available

Amlodipine + Benazepril (Lotrel)
Losartan + HCTZ (Hyzaar)
Olmesartan + Amlodipine + HCTZ (Tribenzor) - triple pill
Valsartan + HCTZ (Diovan HCT)

Sources: Lippincott Illustrated Reviews Pharmacology; Comprehensive Clinical Nephrology 7th Ed.; Goldman-Cecil Medicine; Symptom to Diagnosis 4th Ed.

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