Pharmacology of Antihypertensive Drugs

1. Introduction/Overview

Hypertension represents a major modifiable risk factor for cardiovascular, cerebrovascular, and renal diseases, contributing significantly to global morbidity and mortality. The pharmacological management of elevated blood pressure is a cornerstone of preventive cardiology and internal medicine. Antihypertensive pharmacotherapy aims to reduce the long-term complications associated with sustained high blood pressure, including stroke, myocardial infarction, heart failure, and chronic kidney disease. The selection of an appropriate agent is guided by the underlying pathophysiology, patient comorbidities, demographic factors, and the drug’s pharmacological profile. This chapter provides a systematic examination of the major classes of antihypertensive medications, detailing their mechanisms, clinical applications, and relevant safety considerations.

Learning Objectives

• Classify the major drug categories used in the treatment of hypertension according to their primary mechanism of action.
• Explain the molecular and physiological mechanisms by which each drug class lowers blood pressure.
• Analyze the pharmacokinetic properties of key agents within each class and their implications for dosing and therapeutic monitoring.
• Evaluate the clinical indications, major adverse effects, and significant drug interactions for common antihypertensive drugs.
• Apply knowledge of pharmacology to select appropriate antihypertensive therapy for specific patient populations, including those with renal impairment or compelling comorbidities.

2. Classification

Antihypertensive drugs are categorized primarily by their mechanism of action. A functional classification system is most clinically relevant, though chemical subdivisions exist within several classes. The major categories include agents that reduce cardiac output, decrease peripheral vascular resistance, or diminish intravascular volume.

Major Pharmacological Classes

• Diuretics
  • Thiazide and Thiazide-like Diuretics (e.g., Hydrochlorothiazide, Chlorthalidone, Indapamide)
  • Loop Diuretics (e.g., Furosemide, Bumetanide, Torsemide)
  • Potassium-Sparing Diuretics (e.g., Spironolactone, Eplerenone, Amiloride, Triamterene)
  • Carbonic Anhydrase Inhibitors (e.g., Acetazolamide – rarely used primarily for hypertension)
• Agents Affecting the Renin-Angiotensin-Aldosterone System (RAAS)
  • Angiotensin-Converting Enzyme (ACE) Inhibitors (e.g., Lisinopril, Enalapril, Ramipril)
  • Angiotensin II Receptor Blockers (ARBs) (e.g., Losartan, Valsartan, Candesartan)
  • Direct Renin Inhibitors (e.g., Aliskiren)
  • Mineralocorticoid Receptor Antagonists (MRAs) (e.g., Spironolactone, Eplerenone)
• Calcium Channel Blockers (CCBs)
  • Dihydropyridines (e.g., Amlodipine, Nifedipine, Felodipine)
  • Non-Dihydropyridines (e.g., Verapamil, Diltiazem)
• Sympatholytic Agents
  • Beta-Adrenergic Receptor Antagonists (Beta-Blockers) (e.g., Metoprolol, Atenolol, Bisoprolol, Carvedilol)
  • Alpha-1 Adrenergic Receptor Antagonists (e.g., Doxazosin, Prazosin, Terazosin)
  • Centrally Acting Alpha-2 Agonists (e.g., Clonidine, Methyldopa)
• Vasodilators
  • Direct Arterial Vasodilators (e.g., Hydralazine, Minoxidil)
  • Nitrates (e.g., Isosorbide dinitrate/mononitrate – used in specific combinations)

3. Mechanism of Action

The ultimate goal of antihypertensive therapy is to reduce systemic vascular resistance and/or cardiac output. Each class achieves this through distinct molecular pathways, often targeting specific components of physiological blood pressure regulation, including the RAAS, sympathetic nervous system, vascular smooth muscle tone, and renal sodium handling.

Diuretics

Diuretics lower blood pressure initially by promoting natriuresis and diuresis, reducing plasma volume and cardiac preload. The chronic antihypertensive effect is more closely associated with a reduction in peripheral vascular resistance, possibly mediated by sodium depletion from vascular smooth muscle cells, which decreases their responsiveness to vasoconstrictors. Thiazide diuretics inhibit the Na⁺-Cl^– symporter in the distal convoluted tubule. Loop diuretics block the Na⁺-K⁺-2Cl^– cotransporter in the thick ascending limb of the loop of Henle, producing a more potent but shorter-lived diuresis. Potassium-sparing diuretics act either as aldosterone antagonists (spironolactone, eplerenone) at the mineralocorticoid receptor in the collecting duct or as direct epithelial sodium channel (ENaC) inhibitors (amiloride, triamterene).

Agents Affecting the Renin-Angiotensin-Aldosterone System

ACE Inhibitors competitively inhibit angiotensin-converting enzyme, which is responsible for the conversion of angiotensin I to the potent vasoconstrictor angiotensin II. This inhibition also decreases the degradation of vasodilatory bradykinin. The net effects include vasodilation, reduced aldosterone secretion (leading to sodium and water excretion), and decreased sympathetic outflow. Angiotensin II Receptor Blockers (ARBs) selectively block the angiotensin II type 1 (AT₁) receptor, preventing the vasoconstrictor, aldosterone-secreting, and proliferative effects of angiotensin II while leaving the AT₂ receptor potentially unopposed. Direct Renin Inhibitors (e.g., aliskiren) bind competitively to the active site of renin, preventing the conversion of angiotensinogen to angiotensin I, thus inhibiting the RAAS at its initial rate-limiting step. Mineralocorticoid Receptor Antagonists block the effects of aldosterone, promoting sodium excretion and potassium retention in the distal nephron and exerting additional anti-fibrotic and anti-inflammatory effects.

Calcium Channel Blockers

CCBs reduce calcium influx into vascular smooth muscle and cardiac myocytes by blocking L-type voltage-gated calcium channels. Dihydropyridines (e.g., amlodipine) exhibit relative vascular selectivity, causing arterial vasodilation and reducing peripheral resistance with minimal direct cardiac effects at standard doses. Non-Dihydropyridines (verapamil, diltiazem) have more balanced cardiac and vascular effects, reducing sinoatrial node automaticity and atrioventricular node conduction velocity in addition to causing vasodilation.

Sympatholytic Agents

Beta-Blockers competitively antagonize catecholamine binding at β-adrenergic receptors. Cardioselective (β₁) agents primarily reduce heart rate, myocardial contractility, and renin release. Non-selective agents (β₁ and β₂) also cause bronchoconstriction and peripheral vasoconstriction. Some beta-blockers (e.g., carvedilol, labetalol) also possess α₁-adrenergic blocking activity, contributing to vasodilation. Alpha-1 Blockers (e.g., doxazosin) inhibit postsynaptic α₁-adrenergic receptors on vascular smooth muscle, leading to arterial and venous dilation. Centrally Acting Agents like clonidine and methyldopa stimulate α₂-adrenergic receptors in the central nervous system, particularly in the rostral ventrolateral medulla, reducing sympathetic outflow from the CNS to the periphery.

Direct Vasodilators

Hydralazine directly relaxes arterial smooth muscle, likely through the opening of potassium channels and subsequent hyperpolarization, and possibly via nitric oxide-mediated mechanisms. Minoxidil is a prodrug activated by sulfotransferase; its active metabolite opens ATP-sensitive potassium channels (K_ATP) in vascular smooth muscle, causing hyperpolarization and profound arteriolar dilation.

4. Pharmacokinetics

The pharmacokinetic profiles of antihypertensive drugs significantly influence their dosing frequency, onset and duration of action, and suitability for patients with organ dysfunction.

Diuretics

Most thiazide diuretics are orally absorbed, with hydrochlorothiazide having a bioavailability of approximately 60-80%. They are not extensively metabolized and are primarily excreted renally. The half-life varies: hydrochlorothiazide (6-15 hours) supports once-daily dosing, while chlorthalidone has a much longer half-life (40-60 hours). Loop diuretics like furosemide have variable oral bioavailability (10-100%) and a short half-life (1-2 hours), often necessitating multiple daily doses for continuous effect. Spironolactone is extensively metabolized to active metabolites (e.g., canrenone), contributing to its long duration of action (half-life 10-35 hours).

ACE Inhibitors and ARBs

ACE inhibitors vary in their pharmacokinetic properties. Some are prodrugs (e.g., enalapril, ramipril) requiring hepatic esterification for activation, while others are active (e.g., lisinopril, captopril). Most are primarily renally excreted, necessitating dose adjustment in renal impairment. Their half-lives generally support once- or twice-daily dosing (e.g., lisinopril t_1/2 ≈ 12 hours). ARBs, such as losartan (prodrug) and valsartan (active), are generally well-absorbed, highly protein-bound, and undergo hepatic metabolism via cytochrome P450 enzymes (primarily CYP2C9). Their elimination half-lives are sufficiently long for once-daily administration (e.g., losartan metabolite 6-9 hours, valsartan 6-9 hours, candesartan 9-12 hours).

Calcium Channel Blockers

Dihydropyridines like amlodipine are well-absorbed orally, have high bioavailability, are highly protein-bound, and are extensively metabolized by the liver to inactive metabolites. Amlodipine has a very long half-life (30-50 hours), allowing for once-daily dosing and providing a stable 24-hour effect. Non-dihydropyridines: Verapamil undergoes significant first-pass metabolism, resulting in low bioavailability (20-35%), and is metabolized by CYP3A4. Diltiazem also undergoes extensive first-pass metabolism and is a substrate for CYP3A4. Their half-lives (verapamil 3-7 hours, diltiazem 3-4.5 hours) often require multiple daily doses, though extended-release formulations are available.

Beta-Blockers

Pharmacokinetics vary widely. Propranolol is highly lipid-soluble, undergoes extensive first-pass metabolism, and is a substrate for CYP2D6 and CYP1A2. Atenolol is hydrophilic, is not extensively metabolized, and is primarily renally excreted. Metoprolol is metabolized primarily by CYP2D6, exhibiting significant genetic polymorphism in its metabolism. The half-lives range from short (propranolol 3-6 hours) to long (atenolol 6-9 hours, extended-release metoprolol up to 24 hours).

5. Therapeutic Uses/Clinical Applications

While all classes are effective for lowering blood pressure, specific agents are often preferred based on compelling indications from comorbid conditions, as outlined by major clinical guidelines.

Primary Hypertension

Thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers are all considered first-line options for uncomplicated hypertension. The choice is often guided by patient age, race, and tolerability.

Hypertension with Comorbidities

• Heart Failure with Reduced Ejection Fraction (HFrEF): ACE inhibitors/ARBs/ARNIs, beta-blockers (bisoprolol, carvedilol, metoprolol succinate), MRAs (spironolactone, eplerenone), and loop diuretics (for volume management) are cornerstone therapies.
• Post-Myocardial Infarction: Beta-blockers and ACE inhibitors (or ARBs if intolerant) are indicated to reduce mortality and prevent remodeling.
• Chronic Kidney Disease (CKD), especially with proteinuria: ACE inhibitors or ARBs are first-line due to their renoprotective effects, independent of blood pressure lowering.
• Diabetes Mellitus: ACE inhibitors or ARBs are preferred due to benefits in delaying nephropathy. Thiazide-like diuretics (e.g., chlorthalidone) and CCBs are also effective.
• Benign Prostatic Hyperplasia: Alpha-1 blockers (e.g., doxazosin) can manage both conditions.
• Angina Pectoris: Beta-blockers and non-dihydropyridine CCBs (verapamil, diltiazem) are used for their anti-anginal and antihypertensive effects.
• Atrial Fibrillation (rate control): Beta-blockers and non-dihydropyridine CCBs are employed.
• Migraine Prophylaxis: Beta-blockers (e.g., propranolol, metoprolol) and possibly CCBs like verapamil.

Hypertensive Crises

Parenteral agents such as sodium nitroprusside, labetalol, nicardipine, and clevidipine are used in hypertensive emergencies. Oral loading with agents like captopril, clonidine, or labetalol may be appropriate for urgent, non-emergency situations.

6. Adverse Effects

The adverse effect profile is a critical determinant in drug selection and often correlates with the drug’s primary mechanism of action.

Diuretics

• Thiazides: Hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia, hyperuricemia (may precipitate gout), hyperglycemia (insulin resistance), dyslipidemia (mild increases in LDL and triglycerides), sexual dysfunction, and photosensitivity.
• Loop Diuretics: Similar electrolyte disturbances but with greater potential for hypokalemia and hypomagnesemia. Ototoxicity (dose-related, especially with rapid IV administration, more common with ethacrynic acid) and nephrotoxicity with concurrent other nephrotoxins.
• Potassium-Sparing Diuretics: Hyperkalemia (risk increased with renal impairment, diabetes, or concomitant ACEi/ARB/NSAID use). Spironolactone can cause gynecomastia, menstrual irregularities, and antiandrogenic effects due to progestational and antiandrogenic activity; eplerenone is more selective and has lower risk of these endocrine effects.

ACE Inhibitors

• Dry Cough: Occurs in 5-20% of patients, attributed to increased bradykinin and substance P. It is a class effect, though incidence may vary.
• Angioedema: A potentially life-threatening swelling of the face, lips, tongue, or larynx, also linked to bradykinin accumulation. More common in African American patients.
• Hyperkalemia: Due to reduced aldosterone secretion.
• Acute Kidney Injury: Risk is heightened in patients with bilateral renal artery stenosis or stenosis in a solitary kidney, as glomerular filtration rate (GFR) maintenance depends on angiotensin II-mediated efferent arteriolar constriction.
• Teratogenicity: Contraindicated in pregnancy due to risk of fetal renal damage, oligohydramnios, and fetal hypocalvaria.
• Other: Rash, dysgeusia (especially with captopril), and neutropenia (rare, dose-related with captopril).

Angiotensin II Receptor Blockers

Generally better tolerated than ACE inhibitors, with a significantly lower incidence of cough and angioedema, as they do not affect bradykinin metabolism. They share the risks of hyperkalemia, acute kidney injury in renal artery stenosis, and teratogenicity. Dizziness and headache may occur.

Calcium Channel Blockers

• Dihydropyridines: Peripheral edema (due to precapillary dilation), headache, flushing, reflex tachycardia (with short-acting formulations), and gingival hyperplasia.
• Non-Dihydropyridines: Constipation (especially verapamil), bradycardia, heart block, and exacerbation of heart failure in patients with systolic dysfunction. Negative inotropy is more pronounced than with dihydropyridines.

Beta-Blockers

• Cardiovascular: Bradycardia, heart block, reduced exercise tolerance, and exacerbation of vasospastic (Prinzmetal’s) angina upon abrupt withdrawal.
• Metabolic: May mask hypoglycemic symptoms in diabetics (especially non-selective agents), worsen insulin resistance, and adversely affect lipid profile (increase triglycerides, decrease HDL).
• Respiratory: Bronchoconstriction, contraindicated in asthma (relative contraindication for cardioselective agents in mild disease).
• CNS: Fatigue, depression, sleep disturbances, nightmares.
• Peripheral Vasoconstriction: Cold extremities, Raynaud’s phenomenon.
• Abrupt Withdrawal Syndrome: Can precipitate rebound hypertension, tachycardia, and angina due to upregulation of beta-receptors.

Alpha-1 Blockers

First-dose hypotension (syncope), dizziness, headache, and orthostatic hypotension. A unique adverse effect is “floppy iris syndrome,” which can complicate cataract surgery.

Centrally Acting Agents

Clonidine causes dry mouth, sedation, constipation, and rebound hypertension upon abrupt discontinuation. Methyldopa can lead to sedation, dry mouth, hemolytic anemia (positive Coombs’ test), hepatitis, and drug fever.

Direct Vasodilators

Hydralazine can cause a drug-induced lupus-like syndrome (more common with slow acetylators and high doses), headache, tachycardia, fluid retention, and peripheral neuropathy (pyridoxine deficiency). Minoxidil frequently causes marked hirsutism, pericardial effusion, and severe fluid retention requiring concomitant diuretic therapy.

7. Drug Interactions

Antihypertensive drugs are commonly used in combination, and interactions can lead to loss of efficacy or increased toxicity.

Pharmacodynamic Interactions

• Additive Hypotension: Concomitant use of multiple antihypertensive agents, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil), antipsychotics, or tricyclic antidepressants.
• Additive Bradycardia/Heart Block: Beta-blockers combined with non-dihydropyridine CCBs (verapamil, diltiazem), digoxin, or ivabradine.
• Hyperkalemia: ACE inhibitors, ARBs, MRAs, and potassium-sparing diuretics used together or with potassium supplements, salt substitutes, or NSAIDs (which reduce renal potassium excretion).
• Lithium Toxicity: Thiazide and loop diuretics reduce renal clearance of lithium, increasing the risk of toxicity.
• Increased Risk of Renal Impairment: ACE inhibitors/ARBs combined with NSAIDs or diuretics in volume-depleted states.

Pharmacokinetic Interactions

• CYP450 Interactions: Verapamil and diltiazem are moderate CYP3A4 inhibitors and can increase levels of drugs like simvastatin, increasing myopathy risk. Many beta-blockers (metoprolol, propranolol) and losartan are metabolized by CYP2D6 and CYP2C9, respectively, and levels can be affected by inhibitors or inducers of these enzymes.
• Absorption Interactions: Bile acid sequestrants (e.g., cholestyramine) can bind to and reduce absorption of thiazides, digoxin, and warfarin.
• Protein Binding Displacement: Highly protein-bound drugs like warfarin and phenytoin can theoretically be displaced by other highly bound drugs (e.g., some ARBs), though this is rarely clinically significant.

8. Special Considerations

Pregnancy and Lactation

ACE inhibitors and ARBs are absolutely contraindicated in all trimesters due to teratogenic risks (second and third trimester: oligohydramnios, fetal renal dysplasia, hypocalvaria; first trimester: possible increased risk of cardiovascular malformations). Methyldopa is considered first-line due to its long safety record. Labetalol and nifedipine are also commonly used alternatives. Diuretics are generally avoided as they can reduce placental perfusion. Most antihypertensive drugs are excreted in breast milk in small amounts; methyldopa, labetalol, and nifedipine are generally considered compatible with breastfeeding, while ACE inhibitors like enalapril and captopril may also be used cautiously.

Pediatric Considerations

Hypertension in children is often secondary. Dosing is weight-based. ACE inhibitors and ARBs are frequently used, especially in children with proteinuric kidney disease. Amlodipine is a commonly used CCB. Beta-blockers may be used but can affect school performance and exercise tolerance. Close monitoring of growth and development is necessary.

Geriatric Considerations

Elderly patients often have isolated systolic hypertension with increased arterial stiffness. They are more sensitive to volume depletion and sympathetic inhibition. Low-dose thiazide diuretics (e.g., chlorthalidone) and long-acting dihydropyridine CCBs (e.g., amlodipine) are particularly effective. Dosing should start low and be titrated slowly (“start low, go slow”) to avoid orthostatic hypotension, falls, and electrolyte disturbances. Renal and hepatic function must be assessed prior to and during therapy.

Renal Impairment

Renal function significantly impacts drug selection and dosing. Thiazide diuretics lose efficacy when GFR falls below 30 mL/min/1.73m²; loop diuretics become the diuretic of choice. ACE inhibitors and ARBs require careful monitoring of serum creatinine and potassium, especially upon initiation or dose escalation. They are often continued unless hyperkalemia or a significant rise in creatinine (e.g., >30%) occurs. Many drugs (e.g., atenolol, most ACE inhibitors, digoxin) are renally excreted and require dose reduction. Drugs that can further impair renal function (e.g., NSAIDs) should be avoided.

Hepatic Impairment

Drugs with extensive hepatic metabolism or high first-pass effect (e.g., propranolol, labetalol, verapamil, most ARBs) may have increased bioavailability and prolonged half-life in liver cirrhosis, necessitating dose reduction. Drugs that can cause or exacerbate hepatic injury (e.g., methyldopa, hydralazine, captopril) should be used with caution. Diuretics can precipitate or worsen hepatic encephalopathy in patients with advanced liver disease by causing hypokalemia and alkalosis, which favor ammonia production and entry into the brain.

9. Summary/Key Points

• Antihypertensive therapy is a fundamental strategy for reducing cardiovascular and renal morbidity and mortality associated with chronic hypertension.
• Major drug classes include diuretics, RAAS inhibitors (ACEi, ARBs, MRAs), calcium channel blockers, beta-blockers, and vasodilators, each with a distinct molecular mechanism targeting cardiac output, vascular resistance, or plasma volume.
• Pharmacokinetic properties, such as half-life, route of elimination, and need for metabolic activation, dictate dosing schedules and suitability for patients with renal or hepatic impairment.
• Drug selection is often guided by compelling indications (e.g., ACEi/ARB for CKD with proteinuria, beta-blockers for post-MI) and contraindications based on patient comorbidities.
• Adverse effect profiles are class-specific: electrolyte disturbances with diuretics, cough/angioedema with ACEi, peripheral edema with dihydropyridine CCBs, and metabolic/bronchoconstrictive effects with beta-blockers.
• Significant drug interactions are common, particularly additive effects on blood pressure, heart rate, potassium balance, and renal function, as well as pharmacokinetic interactions involving CYP450 enzymes.
• Special populations require tailored therapy: avoidance of ACEi/ARBs in pregnancy, cautious dosing in the elderly, adjustment for renal/hepatic function, and consideration of age-appropriate formulations in pediatrics.

Clinical Pearls

• The “DASH” (Dietary Approaches to Stop Hypertension) diet and lifestyle modifications remain the foundation of hypertension management and can enhance the efficacy of pharmacotherapy.
• Most patients require combination therapy to achieve blood pressure targets; rational combinations often pair drugs with complementary mechanisms (e.g., a diuretic with an ACE inhibitor or ARB).
• Adherence is a major challenge; once-daily dosing regimens, fixed-dose combination pills, and patient education improve long-term control.
• Home blood pressure monitoring and ambulatory blood pressure monitoring provide more accurate assessments of true blood pressure control than isolated office readings.
• For resistant hypertension, defined as uncontrolled blood pressure on three or more drugs including a diuretic, consider secondary causes, non-adherence, volume overload, and the potential addition of a mineralocorticoid receptor antagonist (e.g., spironolactone).

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