---

Antihypertensive Drugs - Comprehensive Notes (KDT-Based)

---

CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS

1. Diuretics

2. Sympatholytics (Adrenergic Inhibitors)

• Alpha-2 agonists: Clonidine, Methyldopa, Moxonidine, Rilmenidine
• Imidazoline receptor agonists: Moxonidine

• Ganglion blockers: Trimethaphan (obsolete)
• Adrenergic neuron blockers: Guanethidine, Reserpine

• Beta-blockers (non-selective): Propranolol, Nadolol
• Beta-1 selective (cardioselective): Atenolol, Metoprolol, Bisoprolol
• Beta-blockers with intrinsic sympathomimetic activity (ISA): Pindolol, Acebutolol
• Combined alpha + beta blockers: Labetalol, Carvedilol
• Alpha-1 blockers: Prazosin, Doxazosin, Terazosin

3. Calcium Channel Blockers (CCBs)

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

5. Vasodilators

• Hydralazine, Minoxidil, Diazoxide

• Sodium nitroprusside

• Fenoldopam

---

MECHANISMS OF ACTION (MOA)

Thiazide Diuretics

• Inhibit the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT)
• Initial: reduce plasma volume and cardiac output
• Long-term: decrease total peripheral resistance (TPR) - the principal sustained mechanism
• Also may have a direct vasodilatory effect (open K+ channels in vascular smooth muscle)
• Chlorthalidone has a longer half-life (>24 h) vs. HCTZ (several hours), giving more stable BP control; meta-analyses confirm superiority of chlorthalidone

Beta-Blockers

• Block beta-1 adrenoceptors -> reduce heart rate and cardiac output
• Reduce renin secretion from the juxtaglomerular apparatus
• Central action: reduce sympathetic outflow
• Carvedilol/labetalol: additional alpha-1 blockade -> vasodilation

ACE Inhibitors

• Block ACE (kininase II) -> reduce conversion of Ang I to Ang II
• Decrease vasoconstriction (Ang II-mediated)
• Decrease aldosterone secretion -> reduce Na+ and water retention
• Increase bradykinin levels -> additional vasodilation (also responsible for cough)
• Reduce afterload and preload -> beneficial in heart failure

ARBs

• Selectively block AT1 receptors for Ang II
• Similar effects to ACEIs but do NOT increase bradykinin (no cough)
• Ang II is redirected to AT2 receptors -> additional vasodilation and antiproliferative effects

Calcium Channel Blockers

• Block L-type voltage-gated Ca2+ channels
• DHP type (amlodipine, nifedipine): act primarily on vascular smooth muscle -> vasodilation -> reduce TPR
• Non-DHP (verapamil, diltiazem): also act on cardiac tissue -> reduce heart rate and cardiac contractility

Centrally Acting Agents

• Clonidine, Methyldopa: stimulate alpha-2 receptors (and imidazoline receptors) in the brainstem nucleus tractus solitarius -> reduce sympathetic outflow -> decrease HR, cardiac output, TPR
• Methyldopa is converted to alpha-methylnorepinephrine, which is the active agonist

Alpha-1 Blockers

• Block post-synaptic alpha-1 adrenoceptors in arterioles -> decrease TPR
• Prazosin: cause reflex tachycardia and first-dose orthostatic hypotension

Direct Vasodilators

• Hydralazine: opens K+ channels or activates NO pathway in arteriolar smooth muscle -> arteriolar dilation; reflex tachycardia and fluid retention occur (give with beta-blocker + diuretic)
• Minoxidil: opens ATP-sensitive K+ channels -> hyperpolarization -> arteriolar dilation; causes severe fluid retention and reflex tachycardia
• Sodium nitroprusside: releases NO -> activates guanylate cyclase -> increases cGMP -> dilates arteries AND veins

---

THERAPEUTIC USES

---

ADVERSE EFFECTS & PRECAUTIONS

Thiazide Diuretics

Beta-Blockers

ACE Inhibitors

ARBs

• Similar to ACEIs but no cough and lower risk of angioedema
• Hyperkalemia, fetal toxicity (same precautions as ACEIs)
• Avoid combining ACEI + ARB (increased adverse effects without added benefit)

Calcium Channel Blockers

Centrally Acting (Clonidine)

• Sedation, dry mouth, sexual dysfunction
• Rebound hypertension on abrupt withdrawal (taper slowly)
• Avoid in patients with bradycardia or heart block

Alpha-1 Blockers (Prazosin, Doxazosin)

• First-dose orthostatic hypotension (give at bedtime with first dose)
• Reflex tachycardia, edema, headache
• ALLHAT trial: doxazosin arm stopped due to increased heart failure risk

Hydralazine

• Reflex tachycardia, fluid retention (give with beta-blocker and diuretic)
• Drug-induced lupus (slow acetylators, doses >200 mg/day)
• Headache, flushing, palpitations

Minoxidil

• Severe fluid retention, reflex tachycardia (must combine with diuretic + beta-blocker)
• Hypertrichosis (hair growth - used topically)
• Pericardial effusion

---

MANAGEMENT OF HYPERTENSIVE EMERGENCIES AND URGENCIES

Definitions

Target Organ Damage in Emergencies

• Hypertensive encephalopathy
• Acute ischemic or hemorrhagic stroke
• Acute MI / unstable angina
• Acute left ventricular failure with pulmonary edema
• Aortic dissection
• Eclampsia / severe pre-eclampsia
• Acute kidney injury (AKI)
• Retinal hemorrhages / papilledema

Goals of Treatment

Drugs Used in Hypertensive Emergencies (IV)

Sodium Nitroprusside is the most potent and titratable agent. However, prolonged use (>48-72 h) or high doses in renal impairment can cause cyanide and thiocyanate toxicity (monitor blood thiocyanate levels).

Drugs Used in Hypertensive Urgencies (Oral)

Special Situations

• Aortic dissection: Esmolol (or labetalol) + nitroprusside - target SBP <120 mmHg rapidly
• Eclampsia: IV labetalol or hydralazine; IV magnesium sulfate for seizures; definitive = delivery
• Acute pulmonary edema: IV nitroglycerine + furosemide
• Cocaine-induced: Benzodiazepines first; avoid beta-blockers alone (unopposed alpha)
• Pheochromocytoma: Phentolamine (alpha-blocker first), then beta-blocker

---

THIAZIDE DIURETICS - MOA (Detailed)

Site of Action

Mechanism in Detail

1. Acute mechanism: Inhibit NCC -> reduce Na+ reabsorption -> natriuresis and diuresis -> decrease plasma volume and cardiac output -> lower BP
2. Chronic/sustained mechanism: Plasma volume is partially restored by compensatory mechanisms, but total peripheral resistance (TPR) decreases - this is the main long-term antihypertensive effect. The exact mechanism of TPR reduction is not fully established but may involve:
   • Direct vasodilation via opening of vascular smooth muscle K+ channels
   • Reduced intracellular Na+ and Ca2+ in vascular smooth muscle
   • Reduced sensitivity to catecholamines
3. Xipamide exception: Can access NCC from the blood side (not tubular lumen), retaining efficacy when GFR is low
4. Thiazides also have residual carbonic anhydrase-inhibiting activity (reduce proximal Na+ reabsorption); increase Na+ delivery to macula densa -> tubuloglomerular feedback -> slight reduction in GFR

Pharmacokinetic Differences

• Chlorthalidone: t1/2 >24 hours; greater sustained BP reduction, especially nocturnal; meta-analyses confirm superiority over HCTZ for cardiovascular outcomes; underutilized
• HCTZ: t1/2 several hours; more widely prescribed despite less evidence
• Indapamide: Sulfonamide diuretic with both diuretic and direct vasodilator properties

Dosing for Antihypertensive Effect

• Start with 12.5 mg chlorthalidone or HCTZ; maximum 25 mg/day for antihypertensive effect
• Higher doses give more diuresis but NOT more antihypertensive effect in normal renal function
• High doses increase adverse effects (hypokalemia, arrhythmias, sudden death)
• If 25 mg/day is inadequate -> add a second drug, not increase the thiazide dose
• Thiazides INEFFECTIVE when GFR <30 mL/min (use loop diuretics instead; exception: metolazone, xipamide)

---

COMBINATION THERAPY IN HYPERTENSION

Rationale

1. Attack multiple pathways: Drugs acting on different systems produce additive/synergistic BP reduction
2. Counter compensatory responses: CCBs activate SNS and RAAS -> RAAS blockers blunt this. RAAS blockers deplete volume -> diuretics enhance this
3. Reduce adverse effects: Two drugs at half-dose have fewer side effects than one drug at full dose
4. Reduce pill burden: Fixed-dose combinations (FDCs) improve adherence
5. Reduce BP variability: CCBs and diuretics reduce visit-to-visit BP variability; beta-blockers increase it

Key Evidence

• The extra BP reduction from combining two drugs from different classes is approximately 5x greater than doubling the dose of a single drug
• At low doses: thiazides cause side effects in only 2%, CCBs in 1.6%, vs. 9.9% and 8.3% at standard doses
• Most patients with BP >20/10 mmHg above target will need 2 or more drugs
• ALLHAT: Only 1/3 of patients achieved target BP with monotherapy after 5 years

Preferred Combinations

Combinations to AVOID

• ACEI + ARB: No additional benefit; increase adverse effects (hyperkalemia, AKI) - discouraged by JNC 8 and ESC
• Non-DHP CCB + Beta-blocker: Risk of severe bradycardia and heart block (verapamil/diltiazem + beta-blocker)
• Beta-blocker + Alpha-2 agonist (clonidine): Both reduce HR, risk of severe bradycardia
• Two RAAS blockers (ACEI + aliskiren in diabetes/CKD): Contraindicated

Triple Therapy

• ACEI/ARB + CCB + Thiazide is the most common triple combination
• TRIUMPH trial: Triple-pill FDC (telmisartan + amlodipine + chlorthalidone) significantly improved BP control vs. usual care

Step-Care Approach (KDT principle)

• Step 1: Lifestyle modification (weight, salt restriction, exercise, alcohol)
• Step 2: Monotherapy - thiazide diuretic, ACEI/ARB, or CCB (all first-line)
• Step 3: Two-drug combination
• Step 4: Three-drug combination (add third agent from different class)
• Resistant HTN (BP uncontrolled on 3 drugs including a diuretic): Add spironolactone (25-50 mg/day) - most effective 4th agent

---

Note: KD Tripathi's "Essentials of Medical Pharmacology" is not in the available textbook library, but all content above follows the same classification, drug groupings, and clinical approach used in KDT, cross-referenced with Goodman & Gilman and Katzung.