Medicines for Hypertension

First-Line Drug Classes

1. ACE Inhibitors (ACEi)

• Mechanism: Block angiotensin-converting enzyme, preventing conversion of angiotensin I to angiotensin II. This reduces vasoconstriction, lowers aldosterone secretion, and decreases sodium/water retention.
• Key benefits: Renoprotective (especially in diabetic nephropathy), reduce proteinuria, beneficial post-MI and in heart failure.
• Side effects: Dry cough (most common, due to bradykinin accumulation), hyperkalemia, first-dose hypotension, angioedema (rare but serious). Contraindicated in pregnancy.
• Goodman & Gilman's Pharmacological Basis of Therapeutics

2. Angiotensin II Receptor Blockers (ARBs)

• Mechanism: Block AT₁ receptors directly, preventing angiotensin II from causing vasoconstriction and aldosterone release. Unlike ACEi, they do not raise bradykinin.
• Key benefits: Same organ-protective benefits as ACEi; preferred when ACEi cough is intolerable.
• Side effects: Hyperkalemia (less frequent than ACEi), rarely angioedema. Contraindicated in pregnancy. Do not combine with ACEi (increases risk without benefit).
• Lippincott Illustrated Reviews: Pharmacology, p. 294

3. Calcium Channel Blockers (CCBs)

• Mechanism: Block L-type voltage-gated Ca²⁺ channels. DHPs act mainly on vascular smooth muscle causing vasodilation; non-DHPs also slow SA/AV nodal conduction and reduce heart rate.
• Key benefits: DHPs are effective in elderly, Black patients, and isolated systolic hypertension. Independent of dietary sodium intake - effective even in high-sodium diets.
• Side effects: DHPs - pedal edema, flushing, headache. Non-DHPs - constipation (verapamil), bradycardia, AV block.
• Goldman-Cecil Medicine, Comprehensive Clinical Nephrology

4. Diuretics

• Mechanism: Inhibit NaCl reabsorption in the distal convoluted tubule, reducing plasma volume. With long-term use, also cause direct arterial vasodilation.
• Key benefits: Chlorthalidone and indapamide have superior evidence for cardiovascular outcomes vs. HCTZ.
• Side effects: Hypokalemia, hyperuricemia (gout), hyperglycemia, hyperlipidemia, sexual dysfunction.

• Lippincott Illustrated Reviews: Pharmacology, p. 286-288

5. Beta-Blockers (β-Blockers)

• Mechanism: Block β₁ adrenergic receptors, reducing heart rate and cardiac output. Also reduce renin secretion.
• Key benefits: Especially useful in patients with coexisting angina, heart failure with reduced EF, post-MI, or tachyarrhythmias.
• Carvedilol/Nebivolol also vasodilate via α-blockade/NO release.
• Side effects: Fatigue, cold extremities, bradycardia, bronchospasm (avoid in asthma), hyperglycemia, masking of hypoglycemia, sexual dysfunction. Avoid abrupt withdrawal.
• Lippincott Illustrated Reviews: Pharmacology

Other Drug Classes (Second-line / Specific Indications)

• Lippincott Illustrated Reviews: Pharmacology, p. 286-310; Comprehensive Clinical Nephrology, 7th Ed.

Sites of Action (Summary)

Drug Selection by Comorbidity

• Goodman & Gilman's; Comprehensive Clinical Nephrology, 7th Ed., Selection of Drug Therapy

Current Guidelines (2024-2025)

• Start with combination therapy (ACEi/ARB + CCB + thiazide) for most patients with Stage 1-2 hypertension
• Single-pill combinations improve adherence
• Target BP <130/80 mmHg for most patients

• Lifestyle modification (DASH diet, sodium restriction, exercise, weight loss) alongside pharmacotherapy
• First-line: ACEi/ARB, CCB, thiazide-type diuretics
• β-blockers remain first-line when specific indications exist (CHF, post-MI, angina)

Hypotension

Types of Hypotension

1. Acute / Shock States

2. Orthostatic (Postural) Hypotension

3. Neurally Mediated (Vasovagal)

4. Postprandial Hypotension

Treatment by Type

A. Hypovolemic Shock (Hemorrhagic)

1. Ensure adequate ventilation and oxygenation
2. Control hemorrhage (direct pressure, tourniquet, REBOA for uncontrolled bleeding)
3. IV isotonic crystalloid (10-20 mL/kg) - judicious infusion
4. If poor organ perfusion: packed RBC transfusion (5-10 mL/kg)
5. Massive hemorrhage: balanced transfusion of PRBCs + fresh frozen plasma + platelets

• Rosen's Emergency Medicine

B. Septic Shock (Distributive)

1. Fluids: IV crystalloid bolus (30 mL/kg within 3 hours per Surviving Sepsis guidelines)
2. Antibiotics: Primary treatment - early broad-spectrum antibiotics
3. Vasopressors (when fluids insufficient to maintain MAP ≥65 mmHg):
   • Norepinephrine - first-line vasopressor (dual α- and β-adrenergic effects: peripheral vasoconstriction + cardiac inotropy). Dose: 0.5-30 mcg/min
   • Vasopressin - add as second agent (0.03-0.04 units/min) when norepinephrine requirements are high
   • Epinephrine - second-tier; increases MAP but may cause acidosis and dysrhythmias
   • Dopamine - NOT recommended as first-line in distributive shock (increased dysrhythmia risk)
   • Phenylephrine - NOT first-line in septic shock (associated with higher in-hospital mortality)

"Norepinephrine is the preferred first-line vasopressor in septic shock." - Goldman-Cecil Medicine; Harrison's Principles of Internal Medicine 22E; Tintinalli's Emergency Medicine

C. Cardiogenic Shock

1. Oxygen + PEEP for pulmonary edema
2. Norepinephrine (0.5 mcg/min) + Dobutamine (2-20 mcg/kg/min) - mainstay combination
   • Dobutamine alone if SBP ≥90 mmHg (inotrope - increases contractility)
   • Norepinephrine preferred over dopamine if SBP <70 mmHg
   • Milrinone (0.5 mcg/kg/min): alternative inotrope if patient is on a β-blocker
3. Avoid ACE inhibitors and other vasodilators
4. Treat underlying cause (reperfusion for MI)

• Tintinalli's Emergency Medicine

D. Anaphylactic Shock

• Epinephrine (adrenaline) IM - first and most important treatment (0.3-0.5 mg IM into anterolateral thigh, repeat every 5-15 min as needed)
• IV fluids for volume expansion
• Antihistamines (diphenhydramine) and corticosteroids are adjuncts only

E. Neurogenic Shock (Spinal Cord Injury)

• IV fluids
• Norepinephrine or phenylephrine (α-agonists) to restore vascular tone
• Atropine for bradycardia
• Goodman & Gilman's

Orthostatic Hypotension - Management

Non-pharmacologic (first-line):

• Rise slowly; briefly sit before standing
• Increase fluid intake (2-2.5 L/day)
• Increase dietary salt (add 1-2 teaspoons/day; salt tablets 0.5 g with meals)
• Eat smaller, low-carbohydrate, more frequent meals
• Avoid hot/humid environments
• Avoid or limit alcohol
• Compression stockings/abdominal binders
• Exercise in seated/supine position or in a pool
• Elevate head of bed 10-20 degrees at night

Pharmacologic:

Key principle: fludrocortisone is preferred for volume-depleted patients; midodrine is ideal when vasoconstriction is needed. Treatment of orthostatic hypotension often worsens supine hypertension, requiring careful titration. - Goldman-Cecil Medicine; Adams and Victor's Principles of Neurology; Harrison's Principles of Internal Medicine 22E

Vasovagal (Neurocardiogenic) Hypotension

• Acute: Lay the patient flat, elevate legs, loosen clothing, cool environment
• Long-term prevention: Increased fluid/salt intake, counter-pressure maneuvers (leg crossing, squatting), compression stockings
• Medications (refractory cases): Fludrocortisone, midodrine, beta-blockers (in selected patients with high-adrenergic forms), SSRIs

Key Drug Reference - Vasopressors/Inotropes