What are the first and second line treatments for hypertension?

First-Line and Second-Line Treatment for Hypertension

1a. First-Line and Second-Line Treatments

First-line pharmacological therapy consists of four equally effective medication classes: thiazide or thiazide-like diuretics (e.g., chlorthalidone, hydrochlorothiazide), ACE inhibitors (e.g., enalapril), ARBs (e.g., candesartan), and calcium channel blockers (e.g., amlodipine). 1, 2, 3

First-Line Treatment Components:

Lifestyle Modifications (for ALL patients):

• Weight loss to achieve healthy BMI (20-25 kg/m²) if overweight 1, 2
• Sodium restriction to <2,300 mg/day (approximately 2g/day) 1, 2
• DASH or Mediterranean dietary pattern with increased potassium intake 1, 2
• At least 150 minutes of moderate-intensity aerobic exercise weekly plus resistance training 2-3 times/week 1, 2
• Alcohol limitation to <100g/week (ideally complete avoidance) 1, 2
• Smoking cessation 1, 2

First-Line Pharmacological Therapy:

• Thiazide/thiazide-like diuretics (chlorthalidone, hydrochlorothiazide) 1, 2, 3
• ACE inhibitors (enalapril, lisinopril) 1, 2, 3
• ARBs (candesartan, losartan) 1, 2, 3
• Calcium channel blockers (amlodipine, diltiazem) 1, 2, 3

Second-Line Treatment:

Second-line therapy involves combination therapy when monotherapy fails to achieve BP targets:

• Two-drug combination: RAS blocker (ACE inhibitor or ARB) + calcium channel blocker OR thiazide/thiazide-like diuretic 1, 2
• Three-drug combination: RAS blocker + calcium channel blocker + thiazide/thiazide-like diuretic 2
• Fixed-dose single-pill combinations are preferred to improve adherence 2

For resistant hypertension (requiring ≥3 drugs), additional agents include:

• Mineralocorticoid receptor antagonists (spironolactone) with mandatory monitoring of potassium and creatinine 1
• Beta-blockers when specific indications exist (coronary artery disease, heart failure) 2

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1b. Rationale for First-Line and Second-Line Designations

Why These Are First-Line Treatments:

The four medication classes are designated first-line because randomized clinical trials have definitively demonstrated they reduce cardiovascular morbidity and mortality, not just blood pressure numbers. 3, 4

Key Evidence Supporting First-Line Status:

• Mortality and morbidity reduction: A 10 mmHg reduction in systolic BP decreases cardiovascular events by 20-30% 3
• Equal efficacy: All four first-line classes demonstrate comparable effectiveness in reducing cardiovascular outcomes 1, 3
• Extensive safety data: Decades of clinical trial evidence establish favorable benefit-risk profiles 3, 4
• Guideline consensus: Both ACC/AHA and European Society of Cardiology designate these four classes as first-line based on robust evidence 5, 1, 2

Lifestyle modifications are universally first-line because:

• They reduce BP without medication side effects 3, 6
• Effects are partially additive with pharmacological therapy 3
• They address multiple cardiovascular risk factors simultaneously 6
• For stage 1 hypertension with low cardiovascular risk (<10% 10-year ASCVD risk), lifestyle modification alone for 3-6 months is appropriate before initiating medications 5, 1

Why Combination Therapy Is Second-Line:

Combination therapy is designated second-line (used after monotherapy) because:

• Stage 2 hypertension (≥140/90 mmHg) requires immediate two-drug combination therapy to achieve BP targets within 3 months 5, 1
• Monotherapy controls BP in only a minority of patients; most require ≥2 medications 2
• Combination therapy accelerates BP control and improves adherence when using fixed-dose combinations 2
• The treatment algorithm progresses systematically: monotherapy → two-drug combination → three-drug combination based on BP response 2

Special Population Considerations That Modify First-Line Selection:

These patient-specific factors determine which first-line agent to prioritize:

• Black patients: Calcium channel blockers or thiazide diuretics are more effective than ACE inhibitors/ARBs as monotherapy 1, 2
• Albuminuria (UACR ≥30 mg/g): ACE inhibitor or ARB is mandatory first-line because these reduce proteinuria and slow kidney disease progression 1, 2
• Coronary artery disease: ACE inhibitor or ARB should be selected first-line 1, 2
• Chronic kidney disease: RAS inhibitors (ACE inhibitors/ARBs) are first-line to slow CKD progression 1

Critical Treatment Algorithm:

For Stage 1 Hypertension (130-139/80-89 mmHg):

• Low cardiovascular risk (<10% 10-year ASCVD): Lifestyle modifications alone for 3-6 months 5, 1
• High cardiovascular risk (≥10% 10-year ASCVD, diabetes, CKD, established CVD): Immediate combination of lifestyle modifications + single first-line medication 5, 1

For Stage 2 Hypertension (≥140/90 mmHg):

• Immediate initiation of two first-line medications from different classes + lifestyle modifications 5, 1

For Hypertensive Crisis (≥180/110 mmHg):

• Prompt antihypertensive treatment within 1 week maximum, with rapidity dependent on target organ damage 5, 1

Common Pitfalls to Avoid:

• Never combine ACE inhibitor with ARB—this increases adverse effects without additional benefit and is potentially harmful 1, 2
• Monitor serum creatinine and potassium within 7-14 days when initiating ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists 1, 2
• ACE inhibitors and ARBs are absolutely contraindicated in pregnancy 1
• Do not delay pharmacological therapy in high-risk stage 1 hypertensive patients—immediate treatment prevents cardiovascular events 1
• Target BP <130/80 mmHg for most adults <65 years; systolic <130 mmHg for adults ≥65 years 1, 2