Management of Hypertension - Conceptual Overview

1. What Is the Goal?

• General population: < 130/80 mmHg
• CKD patients (KDIGO 2020): SBP < 120 mmHg
• Elderly >80 years (NICE): < 150/90 mmHg
• Diabetes (ADA): < 140/90, or < 130/80 in high ASCVD risk

2. Non-Pharmacologic (Lifestyle) Interventions - First Line

• Braunwald's Heart Disease, p. 2945

3. When to Start Drugs and How Many?

• Stage 1 hypertension (130-139/80-89): lifestyle first; add drug if cardiovascular risk is high or lifestyle fails after 3 months.
• Stage 2 hypertension (≥140/90): start drug therapy alongside lifestyle.
• If SBP > 20 mmHg above goal or DBP > 10 mmHg above goal: start with two drugs simultaneously rather than monotherapy.
• Approximately two-thirds of patients with hypertension will require two or more drugs to reach target BP.

• Lippincott Illustrated Reviews: Pharmacology, p. 294

4. The Four First-Line Drug Classes

A. Thiazide Diuretics

• Mechanism: Initially reduce intravascular volume via Na+/water excretion; long-term effect is decreased peripheral vascular resistance.
• Key advantage: Inexpensive, proven mortality reduction.
• Avoid if: eGFR < 30 mL/min (use loop diuretics instead; metolazone is an exception).
• Adverse effects: Hypokalemia, hyperuricemia, hyperglycemia.

B. ACE Inhibitors (ACEi)

• Mechanism: Block conversion of angiotensin I to angiotensin II → decrease vasoconstriction and aldosterone release → lower BP + reduce cardiac/renal afterload.
• Special benefit: Slow CKD progression (beyond BP lowering - reduce intraglomerular hyperfiltration), reduce albuminuria, improve outcomes post-MI and in heart failure with reduced EF.
• Key adverse effects: Dry cough (up to 10% - due to bradykinin accumulation), angioedema (rare but serious), hyperkalemia, teratogenicity (absolutely contraindicated in pregnancy).
• A rise in serum creatinine of up to 30% after starting ACEi is acceptable and does not require stopping the drug.

C. Angiotensin Receptor Blockers (ARBs)

• Mechanism: Block AT1 receptors directly → similar hemodynamic effects to ACEi, but do NOT increase bradykinin - so no cough.
• Use: All indications of ACEi, preferred when ACEi is not tolerated (cough). Do NOT combine ACEi + ARB (no added benefit, increased harm).

D. Calcium Channel Blockers (CCBs)

• Mechanism: Block L-type Ca2+ channels in vascular smooth muscle and (for non-DHP) myocardium → vasodilation and reduced cardiac output.
• Dihydropyridines (amlodipine): Primarily vascular - preferred in hypertension; used in Black patients, elderly, stable angina.
• Non-dihydropyridines (diltiazem, verapamil): Also slow AV conduction - useful in AF with hypertension; avoid in HFrEF.
• Lippincott Illustrated Reviews: Pharmacology, p. 296-305

5. Drug Selection by Comorbidity (Compelling Indications)

6. Step-Up Approach (Sequential Intensification)

Step 1: Lifestyle modification alone (mild HTN)
        ↓ (if not at goal in 3 months)
Step 2: Single first-line drug (thiazide OR ACEi/ARB OR CCB)
        ↓ (if not at goal)
Step 3: Add a second drug from a different class
        Preferred combos: ACEi/ARB + CCB, or ACEi/ARB + Thiazide
        ↓ (if not at goal on two drugs at optimal doses)
Step 4: Add a third drug (triple therapy)
        ↓ (if still not at goal on 3 drugs including a diuretic)
Step 5: Resistant hypertension workup + add-on agents
        (spironolactone, alpha-blockers, beta-blockers, direct vasodilators)

• ACEi/ARB + CCB (best tolerated, cardioprotective)
• ACEi/ARB + thiazide diuretic
• CCB + thiazide diuretic

7. Resistant Hypertension

• Poor adherence ("pseudoresistance")
• White-coat hypertension
• Secondary causes (primary aldosteronism, renal artery stenosis, OSA, pheochromocytoma, Cushing's)
• Drug interactions (NSAIDs, sympathomimetics, oral contraceptives, licorice)

• Fuster and Hurst's The Heart, 15th Edition

8. Special Populations

CKD

• ACEi/ARB are first-line - they reduce intraglomerular pressure beyond their systemic BP effect.
• SGLT2 inhibitors (gliflozins) are now gaining a role in cardiorenal protection.
• A modest GFR dip (<30% of baseline) after starting ACEi/ARB is acceptable - it may reflect reduced hyperfiltration.
• Avoid ACEi + ARB combination; monitor potassium carefully.
• Harrison's Principles of Internal Medicine 22E, p. 295-299

Elderly

• Start low, go slow - age-related changes in drug metabolism.
• Check both seated and standing BP (orthostatic hypotension risk).
• Two or more drugs commonly needed.

Pregnancy

• ACEi and ARBs are absolutely contraindicated (fetal renal malformations).
• Safe options: Methyldopa, labetalol, nifedipine.

9. Key Conceptual Principles (Summary)

1. Treat the patient, not just the number - comorbidities dictate drug choice.
2. Most patients need 2+ drugs - combination therapy is the rule, not the exception.
3. RAS blockade (ACEi/ARB) is cornerstone in CKD, heart failure, diabetes, and post-MI.
4. CCBs and thiazides are especially effective in Black patients and the elderly.
5. Non-pharmacologic measures are always part of management - never optional.
6. Avoid dual RAS blockade (ACEi + ARB) - same class should not be combined.
7. Resistant hypertension requires secondary cause workup before escalating drugs.