Pharmacology of Antihypertensive agents

Antihypertensive agents form a diverse class of drugs that reduce elevated blood pressure and thereby diminish the risk of major cardiovascular morbidity and mortality, such as stroke, myocardial infarction, heart failure, and chronic kidney disease. Their rational use requires understanding pathophysiology, mechanisms of action, pharmacokinetics and dynamics, clinical indications, adverse events, and individualized selection based on comorbidities and target-organ protection. This chapter draws exclusively from established medical pharmacology textbooks, principally Goodman & Gilman, Katzung, and Rang & Dale.​

I. INTRODUCTION AND OVERVIEW

• Hypertension (HTN) is a chronic disorder, attributed to complex interactions of genetic, environmental, and neurohumoral factors. It encompasses primary (essential) and secondary forms, with >90% falling under the former.​
• The disease is defined as persistently elevated arterial blood pressure (typically ≥140/90 mmHg, though thresholds evolve based on guidelines).
• Lowering BP is proven to reduce risk of stroke, heart failure, coronary events, and renal failure.​

II. PRINCIPLES IN ANTIHYPERTENSIVE THERAPY

Goals:

• Achieve and maintain a target BP (<140/90 mmHg for most; lower for some with diabetes, kidney disease, or high risk).
• Prevent organ damage while minimizing drug-related adverse effects.

General Mechanisms:

• Reduction of cardiac output
• Reduction of systemic vascular resistance
• Modulation of intravascular volume or neurohumoral drive

III. CLASSIFICATION OF ANTIHYPERTENSIVE AGENTS

A. Diuretics

• Thiazide diuretics (hydrochlorothiazide, chlorthalidone)
• Loop diuretics (furosemide, torsemide)
• Potassium-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene)
• Carbonic anhydrase inhibitors (acetazolamide; not routine for HTN)

B. Sympatholytics (antiadrenergic agents)

• Beta-adrenergic blockers (propranolol, metoprolol, atenolol, bisoprolol, nebivolol, carvedilol)
• Alpha-adrenergic blockers (prazosin, doxazosin, terazosin)
• Central sympatholytics (clonidine, methyldopa, guanfacine, moxonidine)
• Presynaptic adrenergic neuron blockers (reserpine, guanethidine; rarely used now)

C. Vasodilators

• Direct-acting vasodilators (hydralazine, minoxidil, sodium nitroprusside: emergency/critical care)
• Calcium channel blockers (dihydropyridines: amlodipine, nifedipine, felodipine; non-dihydropyridines: verapamil, diltiazem)
• Potassium channel openers (minoxidil)

D. Drugs interfering with the Renin–Angiotensin–Aldosterone System (RAAS)

• ACE inhibitors (enalapril, lisinopril, ramipril, perindopril, captopril)
• Angiotensin II receptor blockers (ARBs) (losartan, candesartan, valsartan, olmesartan)
• Direct renin inhibitors (aliskiren)
• Aldosterone antagonists (spironolactone, eplerenone)

E. Others

• Endothelin receptor blockers (experimental)
• Drugs targeting natriuretic peptide clearance
• Combined antihypertensive agents (e.g., ACE inhibitor + diuretic)
• SGLT2 inhibitors: not first-line for BP, but relevant in diabetes patients

IV. PHARMACOLOGICAL CHARACTERISTICS (MECHANISMS)

A. DIURETICS

Thiazides: Inhibit Na⁺Cl⁻ cotransport in distal convoluted tubules, increase excretion of sodium and water, cause volume depletion, decrease cardiac output and after several weeks lower peripheral resistance. First-line agents for uncomplicated hypertension.​

Loops: Inhibit Na⁺K⁺2Cl⁻ cotransport in ascending limb of loop of Henle. Used mainly in heart failure, CKD, or volume overload conditions.

Potassium-sparing: Block aldosterone or ENaC. Useful as adjuncts for patients with hypokalemia risk.

B. SYMPATHOLYTICS

Beta-blockers: Block beta-adrenergic receptors (predominantly β1 in the heart), decrease cardiac output, renin secretion, and central sympathetic outflow. Indicated for angina, post-MI, and heart failure.​

Alpha-blockers: Block α1-adrenergic receptors in vascular smooth muscle, reduce resistance. Not recommended as monotherapy due to increased risk of heart failure and stroke.​

Central agents: Clonidine, methyldopa act as agonists at central α2-adrenergic receptors, decrease sympathetic outflow, with sedation and dry mouth as typical adverse effects.​

C. CALCIUM CHANNEL BLOCKERS (CCBs)

Inhibit L-type calcium channels in vascular smooth muscle and myocardium.

• Dihydropyridines mainly reduce systemic vascular resistance
• Non-dihydropyridines (verapamil, diltiazem) decrease heart rate and contractility​

Adverse effects: ankle edema, flushing, headache, possible conduction blocks (non-dihydropyridines).

D. VASODILATORS

Hydralazine: Direct arteriolar dilator via nitric oxide, increase HR and renin via reflex, commonly used for severe hypertension in pregnancy. Adverse: lupus-like syndrome at high doses.​

Minoxidil: Opens K+ channels causing relaxation; potent, used for resistant hypertension with diuretic/beta-blocker.​

Sodium Nitroprusside: IV only; liberates NO; used for hypertensive emergencies. May cause cyanide toxicity with prolonged use.​

E. RAAS INTERFERING DRUGS

ACEi: Inhibit angiotensin-converting enzyme; lower Ang II, reduce vasoconstriction, and aldosterone; increase bradykinin (vasodilator).

ARBs: Block AT1 Ang II receptors; similar outcomes to ACEi but less cough/angioedema.​

Direct renin inhibitors: Aliskiren blocks conversion of angiotensinogen to Ang I.​

Aldosterone antagonists: Spironolactone and eplerenone block mineralocorticoid receptor, sparing potassium.​

V. CLINICAL INDICATIONS AND ALGORITHM

1. Uncomplicated hypertension: Begin with thiazide, ACEi/ARB, CCB mono- or combination therapy.​
2. Comorbid situations:
   • Diabetes nephropathy: ACEi/ARB preferred
   • Post-MI, heart failure: beta-blockers, ACEi/ARB, aldosterone antagonists
   • Pregnant: methyldopa, labetalol, hydralazine
   • African ancestry: CCB/thiazides more effective ​
   • Chronic kidney disease: ACEi/ARB slow progression
   • Elderly: CCBs, thiazides preferred

VI. ADVERSE EFFECTS, CAUTIONS, INTERACTIONS

• Thiazides: Hypokalemia, hyperuricemia, glucose intolerance, dyslipidemia
• Loops: Similar, but more pronounced diuresis and risk of hypokalemia
• Potassium–sparing: Hyperkalemia, especially when combined with ACEi/ARB
• Beta-blockers: Bradycardia, fatigue, bronchospasm, masking hypoglycemia
• Alpha-blockers: Orthostatic hypotension
• CCBs: Edema, headache, AV block with non-dihydropyridines
• ACEi: Cough, angioedema, hyperkalemia, renal dysfunction
• ARBs: Hyperkalemia, lower risk of cough/angioedema
• Central agents: Sedation, dry mouth, rebound hypertension with abrupt withdrawal
• Hydralazine: Tachycardia, lupus syndrome
• Minoxidil: Hirsutism, pericardial effusion

VII. ANTIHYPERTENSIVE COMBINATIONS AND FIXED DOSES

• Fixed-dose combo tablets improve adherence (e.g., ACEi + thiazide, ARB + CCB)
• Must combine drugs with complementary mechanisms and non-overlapping toxicities​

VIII. HYPERTENSIVE EMERGENCIES

Drugs: sodium nitroprusside, labetalol, esmolol, nicardipine, hydralazine, clevidipine, phentolamine.​

Indications: Severe hypertension with acute organ damage—stroke, dissection, acute kidney injury

IX. PHARMACOKINETICS AND INDIVIDUALIZATION

• Most agents (except IV forms) have oral bioavailability, varying metabolism and renal excretion.
• Genetics (CYP polymorphisms, ACE genotype), comorbidities, polypharmacy require careful dosing.
• Renal, hepatic dysfunction demand adjustment for many—especially beta-blockers, ACEi, ARBs, diuretics.​

X. SPECIAL TOPICS

• Resistant hypertension: Defined as uncontrolled BP despite three agents (including diuretic); causes include secondary hypertension, non-adherence, white coat effect.
• Pregnancy: Methyldopa, labetalol, hydralazine safely used; ACEi/ARB contraindicated.
• Pediatric use: Dosing, choice varies markedly; lifestyle modification is always first.

XI. TABLES (CLASSIFICATION AND MECHANISMS)

Class	Representative Drugs	Main Mechanism	Key Indications
Thiazide diuretics	Hydrochlorothiazide, chlorthalidone	Lower plasma volume, dilate arterioles	Uncomplicated HTN, elderly
Loop diuretics	Furosemide, torsemide	Strong volume reduction	Severe HTN, CKD, HF
Potassium-sparing diuretics	Spironolactone, amiloride	Retain potassium, block aldosterone	Adjunct
ACE inhibitors	Enalapril, lisinopril	Block Ang II generation	Diabetes, CKD, HF, MI
ARBs	Losartan, candesartan	Block Ang II receptor	Similar to ACEi
CCBs	Amlodipine, verapamil	Disrupt Ca2+ entry, relax vessels	Elderly, isolated systolic
Beta-blockers	Metoprolol, bisoprolol, nebivolol	Lower CO, renin, CNS outflow	Post-MI, HF, young adults
Alpha-blockers	Prazosin, doxazosin	Block vascular α1	Resistant/urinary symptoms
Central agents	Clonidine, methyldopa	Lower CNS outflow	Pregnancy, special cases
Direct vasodilators	Hydralazine, minoxidil	Relax arterioles via NO/K+	Severe/resistant HTN

Class	Main Mechanism	Best Use
Thiazides	↓ Blood volume, SVR	Elderly, Black adults, mild HTN
Loops	Potent natriuresis	Severe CKD, heart failure
ACEi/ARBs	RAAS block	Diabetics, post-MI, CKD, HF
Beta-blockers	↓ HR, CO, renin	Post-MI, heart failure
CCBs	Vasodilation, ±HR↓	Elderly, ISH, Black adults
Vasodilators	Arterial Direct relax	Severe/resistant hypertension
Aldosterone antags	MR blockade	Resistant HTN, HF, hyperaldosteronism
Central agents	↓ CNS outflow	Special cases (pregnancy, resistant)

XII. SUMMARY POINTS

• Choice of agent should consider age, comorbidities, indication, cost, and tolerance.
• Lifestyle modification is always first-line; pharmacologic therapy tailored, often using combinations for synergy.
• Therapy aims for target BP, protection from major CV outcomes, minimizing adverse effects and improving quality of life. The number of available agents enables precise choice for each clinical scenario.​

REFERENCES

1. Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill; 2017. Chapter: Antihypertensive Agents.
2. Katzung BG, Trevor AJ, eds. Basic & Clinical Pharmacology. 15–14th ed. New York: McGraw-Hill; 2023. Chapter: Antihypertensive Agents.
3. Ritter JM, Flower R, Henderson G, et al. Rang & Dale’s Pharmacology. 9th–10th ed. London: Elsevier; 2024. Chapter: Cardiovascular Drugs.