Pharmacology of Antihypertensive Drugs

1. Introduction/Overview

Hypertension represents a major global public health challenge, constituting a primary modifiable risk factor for cardiovascular disease, stroke, renal failure, and mortality. The pharmacological management of elevated blood pressure is a cornerstone of preventive cardiology and internal medicine. Antihypertensive pharmacotherapy aims to reduce long-term morbidity and mortality by achieving and maintaining blood pressure below established target thresholds. The selection of an appropriate agent is guided by the drug’s mechanism of action, pharmacokinetic profile, evidence from clinical outcome trials, patient comorbidities, and potential adverse effects. This chapter provides a systematic examination of the major drug classes used in the treatment of hypertension.

Learning Objectives

• Classify the major categories of antihypertensive medications based on their primary mechanism of action and therapeutic targets.
• Explain the detailed pharmacodynamic mechanisms by which each drug class lowers systemic vascular resistance, cardiac output, or both.
• Analyze the pharmacokinetic properties, including absorption, distribution, metabolism, and excretion, that influence the dosing and selection of antihypertensive agents.
• Evaluate the clinical applications, major adverse effect profiles, and significant drug interactions associated with each antihypertensive class.
• Apply knowledge of pharmacology to develop rational therapeutic strategies for special populations, including patients with renal impairment, hepatic disease, or those who are pregnant.

2. Classification

Antihypertensive drugs are categorized primarily by their mechanism of action. A functional classification system is most clinically relevant, though chemical subclasses exist within these broader categories. The major classes include agents that affect the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, vascular smooth muscle tone, and renal sodium handling.

Major Therapeutic Classes

• Diuretics
  • Thiazide and Thiazide-like Diuretics (e.g., hydrochlorothiazide, chlorthalidone)
  • Loop Diuretics (e.g., furosemide, bumetanide)
  • Potassium-Sparing Diuretics (e.g., spironolactone, amiloride)
• Drugs Acting on the Renin-Angiotensin-Aldosterone System (RAAS)
  • Angiotensin-Converting Enzyme (ACE) Inhibitors (e.g., lisinopril, enalapril)
  • Angiotensin II Receptor Blockers (ARBs) (e.g., losartan, valsartan)
  • Direct Renin Inhibitors (e.g., aliskiren)
• Calcium Channel Blockers (CCBs)
  • Dihydropyridines (e.g., amlodipine, nifedipine)
  • Non-dihydropyridines (e.g., verapamil, diltiazem)
• Sympatholytic Agents
  • Beta-Adrenergic Receptor Antagonists (Beta-Blockers) (e.g., metoprolol, atenolol)
  • Alpha-1 Adrenergic Receptor Antagonists (e.g., doxazosin, prazosin)
  • Centrally Acting Alpha-2 Agonists (e.g., clonidine, methyldopa)
• Vasodilators
  • Direct Arterial Vasodilators (e.g., hydralazine, minoxidil)
  • Nitrodilators (e.g., sodium nitroprusside)

3. Mechanism of Action

The ultimate goal of antihypertensive therapy is the reduction of systemic blood pressure, defined as the product of cardiac output and systemic vascular resistance (BP = CO × SVR). Each drug class intervenes at distinct physiological control points to lower one or both of these determinants.

Diuretics

Diuretics lower blood pressure primarily through sodium and water excretion, which reduces plasma volume and cardiac preload, thereby decreasing cardiac output. With chronic administration, thiazide diuretics are believed to induce a reduction in peripheral vascular resistance, possibly through direct vascular effects or depletion of intracellular sodium in vascular smooth muscle cells, which reduces responsiveness to vasoconstrictors. Loop diuretics inhibit the Na⁺-K⁺-2Cl^– cotransporter in the thick ascending limb of the loop of Henle, producing a potent natriuresis. Potassium-sparing diuretics act either as aldosterone receptor antagonists (spironolactone, eplerenone) or as direct inhibitors of epithelial sodium channels (ENaC) in the distal nephron (amiloride, triamterene).

ACE Inhibitors and ARBs

These agents antagonize the RAAS, a critical regulator of blood pressure, fluid balance, and vascular remodeling. ACE inhibitors (e.g., lisinopril) competitively inhibit angiotensin-converting enzyme, preventing the conversion of angiotensin I to the potent vasoconstrictor angiotensin II. This inhibition also decreases the degradation of vasodilatory kinins like bradykinin. The reduction in angiotensin II leads to decreased vasoconstriction, reduced aldosterone secretion (promoting sodium and water excretion), and diminished sympathetic outflow. ARBs (e.g., losartan) selectively block the angiotensin II type 1 (AT₁) receptor, preventing the downstream effects of angiotensin II regardless of its source, while leaving the AT₂ receptor unopposed, which may confer additional protective effects. Unlike ACE inhibitors, ARBs do not affect kinin metabolism.

Calcium Channel Blockers

CCBs inhibit the influx of extracellular calcium ions through voltage-gated L-type calcium channels in vascular smooth muscle and cardiac cells. In vascular smooth muscle, this inhibition decreases intracellular calcium concentration, leading to relaxation of arterial smooth muscle and a reduction in systemic vascular resistance. Dihydropyridine CCBs (e.g., amlodipine) exhibit relative vascular selectivity, causing pronounced arterial vasodilation with minimal direct cardiac effects. Non-dihydropyridine CCBs (verapamil, diltiazem) have more balanced effects on cardiac and vascular tissues, reducing sinoatrial node automaticity and atrioventricular node conduction velocity in addition to causing vasodilation.

Beta-Adrenergic Receptor Antagonists

The antihypertensive mechanism of beta-blockers is multifactorial and varies among agents. Primary mechanisms include a reduction in cardiac output via negative chronotropic and inotropic effects mediated by blockade of cardiac β₁-adrenoceptors. Chronic administration may also lead to inhibition of renin release from the juxtaglomerular cells, reduction of central sympathetic outflow, and potentially resetting of baroreceptor sensitivity. Some beta-blockers with additional vasodilatory properties (e.g., carvedilol, nebivolol) achieve blood pressure reduction through combined β-blockade and α₁-blockade or nitric oxide-mediated vasodilation.

Other Sympatholytic Agents

Alpha-1 adrenergic receptor antagonists (e.g., doxazosin) produce competitive blockade of postsynaptic α₁-receptors on vascular smooth muscle, inhibiting the vasoconstrictive effect of endogenous catecholamines and leading to arteriolar and venous dilation. Centrally acting α₂-adrenoceptor agonists (clonidine, methyldopa) stimulate presynaptic α₂-receptors in the brainstem, reducing sympathetic outflow from the central nervous system to the periphery.

Direct Vasodilators

These agents act directly on vascular smooth muscle independent of autonomic receptors. Hydralazine is believed to activate guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) and causing vasodilation, preferentially in arterioles over veins. Minoxidil is a prodrug metabolized to minoxidil sulfate, which opens ATP-sensitive potassium (K_ATP) channels in vascular smooth muscle, leading to hyperpolarization and relaxation.

4. Pharmacokinetics

The pharmacokinetic profiles of antihypertensive drugs significantly influence their dosing frequency, onset and duration of action, and suitability for specific patient populations.

Diuretics

Thiazide diuretics like hydrochlorothiazide are generally well absorbed orally, with bioavailability exceeding 60%. They are not extensively metabolized and are primarily excreted unchanged by the kidneys via active tubular secretion. Their elimination half-life varies; hydrochlorothiazide has a half-life of 6-15 hours, while chlorthalidone has a much longer half-life of 40-60 hours, supporting once-daily dosing. Loop diuretics such as 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 in the liver to active metabolites, including canrenone, which have long half-lives (10-35 hours).

ACE Inhibitors

ACE inhibitors vary in their pharmacokinetic properties, particularly in their route of elimination and prodrug status. Lisinopril is not a prodrug, is absorbed slowly, and is excreted unchanged in the urine, with a half-life of 12 hours. Prodrugs like enalapril and ramipril are hydrolyzed in the liver to their active forms (enalaprilat, ramiprilat). Most ACE inhibitors are primarily renally excreted, necessitating dose adjustment in renal impairment. The presence of food may impair the absorption of some agents like captopril.

Angiotensin II Receptor Blockers

ARBs are generally well absorbed orally, but many undergo significant first-pass metabolism. Losartan is metabolized by cytochrome P450 enzymes (primarily CYP2C9 and CYP3A4) to an active metabolite (E-3174) that is more potent than the parent drug. Valsartan and irbesartan are excreted largely unchanged, with valsartan undergoing biliary excretion. The half-lives of ARBs range from approximately 6-9 hours for losartan (and 6-9 hours for its active metabolite) to over 24 hours for telmisartan, which allows for once-daily dosing.

Calcium Channel Blockers

Dihydropyridines like amlodipine have high oral bioavailability and are extensively metabolized in the liver by CYP3A4 to inactive metabolites. Amlodipine has a very long elimination half-life (30-50 hours), permitting once-daily administration and providing a smooth, sustained antihypertensive effect. Non-dihydropyridines also undergo extensive hepatic metabolism. Verapamil exhibits significant first-pass metabolism, resulting in low systemic bioavailability (20-35%), and its half-life increases with repeated dosing due to saturation of hepatic enzymes.

Beta-Blockers

Beta-blockers demonstrate considerable pharmacokinetic diversity. Propranolol is highly lipid-soluble, undergoes extensive hepatic metabolism via CYP2D6 and other enzymes, and has a short half-life (3-6 hours) requiring multiple daily doses, though long-acting formulations exist. Atenolol is hydrophilic, is not extensively metabolized, and is primarily excreted renally, with a half-life of 6-9 hours. Metoprolol is metabolized by CYP2D6, exhibiting significant interindividual variability due to genetic polymorphism. The clearance of renally excreted beta-blockers is reduced in patients with impaired kidney function.

5. Therapeutic Uses/Clinical Applications

While all major classes are effective for lowering blood pressure, specific indications and compelling comorbidities often guide drug selection based on evidence from large outcome trials.

Primary Hypertension

Thiazide diuretics, ACE inhibitors, ARBs, and CCBs are all considered first-line agents for uncomplicated hypertension. Beta-blockers are generally recommended as first-line only in patients with specific comorbidities such as ischemic heart disease or heart failure.

Hypertension with Comorbid Conditions

• Heart Failure with Reduced Ejection Fraction (HFrEF): ACE inhibitors, ARBs, beta-blockers (specifically carvedilol, metoprolol succinate, bisoprolol), and mineralocorticoid receptor antagonists (spironolactone, eplerenone) are cornerstone therapies that improve mortality. Loop diuretics are used for symptom management of volume overload.
• Coronary Artery Disease/Post-Myocardial Infarction: Beta-blockers and ACE inhibitors are indicated to reduce mortality and recurrent events.
• Chronic Kidney Disease (CKD), especially with Proteinuria: ACE inhibitors or ARBs are preferred due to their renoprotective effects, which are independent of blood pressure lowering. They reduce intraglomerular pressure and protein excretion.
• Diabetes Mellitus: ACE inhibitors or ARBs are recommended as first-line therapy due to their benefits in delaying the progression of diabetic nephropathy.

Other Approved Indications

Several antihypertensives have non-hypertensive indications. Beta-blockers are used for angina pectoris, arrhythmias, migraine prophylaxis, and essential tremor. CCBs are used for angina (especially vasospastic) and certain arrhythmias (non-dihydropyridines). Alpha-1 blockers are used for symptomatic benign prostatic hyperplasia. Spironolactone is used for primary hyperaldosteronism and in the management of edema associated with hepatic cirrhosis.

Off-Label Uses

Clonidine is sometimes used off-label for the management of opioid withdrawal symptoms, attention deficit hyperactivity disorder, and menopausal hot flashes. Propranolol is used for performance anxiety and essential tremor. Spironolactone is increasingly used off-label for the treatment of hormonal acne and hirsutism in women due to its anti-androgenic properties.

6. Adverse Effects

The adverse effect profiles of antihypertensive drugs are often directly related to their pharmacodynamic actions and can significantly impact patient adherence and drug selection.

Diuretics

Thiazide and loop diuretics commonly cause electrolyte disturbances: hypokalemia, hyponatremia, hypomagnesemia, and hypercalcemia (with thiazides). Metabolic alterations include hyperuricemia (which may precipitate gout) and impaired glucose tolerance or worsening of diabetes mellitus. Orthostatic hypotension and volume depletion may occur. Loop diuretics can cause ototoxicity, particularly at high intravenous doses or in combination with other ototoxic drugs. Spironolactone can cause hyperkalemia, particularly in patients with renal impairment or on concomitant ACE inhibitors/ARBs, and anti-androgenic effects such as gynecomastia, breast tenderness, and menstrual irregularities.

ACE Inhibitors

A dry, persistent cough is a class effect, occurring in up to 20% of patients, believed to be mediated by increased bradykinin and substance P. Angioedema, a potentially life-threatening swelling of the face, lips, tongue, or larynx, is a rare but serious adverse reaction also linked to bradykinin accumulation. Hypotension may occur, especially after the first dose in volume-depleted patients. Hyperkalemia can develop due to reduced aldosterone. A significant decline in glomerular filtration rate may be observed in patients with bilateral renal artery stenosis or stenosis in a solitary kidney, as the maintenance of glomerular filtration depends on angiotensin II-mediated efferent arteriolar constriction. ACE inhibitors are contraindicated in pregnancy due to fetotoxicity (oligohydramnios, fetal renal dysplasia, pulmonary hypoplasia).

Angiotensin II Receptor Blockers

ARBs share the hyperkalemia and renal risk profiles of ACE inhibitors in patients with renal artery stenosis. However, they are not associated with cough or angioedema (incidence is much lower than with ACE inhibitors), as they do not affect kinin metabolism. Dizziness and headache are among the most commonly reported side effects.

Calcium Channel Blockers

Dihydropyridines frequently cause peripheral edema and reflex tachycardia due to potent arteriolar dilation. Headache, flushing, and dizziness are also common. Gingival hyperplasia is a less common but notable side effect. Non-dihydropyridines can cause constipation (particularly verapamil), bradycardia, and heart block due to their cardiac depressant effects.

Beta-Blockers

Adverse effects stem from excessive β-adrenoceptor blockade. Cardiovascular effects include bradycardia, heart block, and exacerbation of heart failure in susceptible patients. Bronchoconstriction can occur due to blockade of β₂-receptors in the airways, making non-selective beta-blockers relatively contraindicated in asthma. Metabolic effects include masking of hypoglycemic symptoms in diabetics and potentially worsening of lipid profiles (increased triglycerides, decreased HDL cholesterol). Central nervous system effects such as fatigue, depression, sleep disturbances, and vivid dreams are reported. Abrupt discontinuation can precipitate a withdrawal syndrome characterized by rebound hypertension, tachycardia, and angina.

Other Agents

Alpha-1 blockers are associated with a high incidence of “first-dose syncope” due to severe orthostatic hypotension, requiring careful dose initiation. Centrally acting agents like clonidine cause sedation, dry mouth, and rebound hypertension upon rapid withdrawal. Direct vasodilators like hydralazine can cause a drug-induced lupus-like syndrome with chronic use at higher doses, while minoxidil frequently causes hirsutism and profound fluid retention requiring concomitant diuretic therapy.

7. Drug Interactions

Antihypertensive drugs are frequently used in combination and with other medications, creating a significant potential for pharmacokinetic and pharmacodynamic interactions.

Pharmacodynamic Interactions

• Additive Hypotension: Concurrent use of multiple antihypertensive agents from different classes predictably increases the risk of symptomatic hypotension. This is particularly notable with the combination of ACE inhibitors/ARBs, diuretics, and alpha-blockers.
• Hyperkalemia: The combination of ACE inhibitors, ARBs, potassium-sparing diuretics (spironolactone, amiloride), and potassium supplements or salt substitutes significantly elevates the risk of dangerous hyperkalemia.
• Bradycardia and Heart Block: The combination of beta-blockers with non-dihydropyridine CCBs (verapamil, diltiazem) can produce synergistic depression of sinoatrial and atrioventricular node function, leading to severe bradycardia or complete heart block.
• Lithium Toxicity: Thiazide and loop diuretics reduce renal clearance of lithium, potentially leading to lithium toxicity. This interaction requires close monitoring of lithium serum levels.

Pharmacokinetic Interactions

• Enzyme Induction/Inhibition: Many CCBs (metabolized by CYP3A4) interact with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir), leading to increased plasma concentrations and toxicity risk. Conversely, CYP3A4 inducers (e.g., rifampin, carbamazepine) can reduce CCB efficacy.
• NSAIDs: Nonsteroidal anti-inflammatory drugs can antagonize the antihypertensive effect of most classes, particularly diuretics, ACE inhibitors, and ARBs, by inhibiting renal prostaglandin synthesis, leading to sodium retention and reduced renal blood flow. NSAIDs also increase the risk of hyperkalemia and acute kidney injury when combined with RAAS inhibitors.
• Digoxin: Verapamil increases serum digoxin concentrations by reducing its renal and non-renal clearance, increasing the risk of digoxin toxicity.

8. Special Considerations

The selection and dosing of antihypertensive agents must be carefully adjusted in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or unique risks.

Pregnancy and Lactation

ACE inhibitors and ARBs are absolutely contraindicated in all trimesters of pregnancy due to fetotoxicity, including fetal renal dysplasia, oligohydramnios, pulmonary hypoplasia, skull hypoplasia, and fetal death. Methyldopa is considered the first-line agent for chronic hypertension in pregnancy due to its long safety record. Labetalol and nifedipine are also commonly used. Diuretics are generally avoided as they can reduce plasma volume expansion, which is crucial for normal fetal development. Most antihypertensives are excreted in breast milk in small quantities; methyldopa, labetalol, and nifedipine are generally considered compatible with breastfeeding, while ACE inhibitors like enalapril and captopril may be used with caution.

Pediatric Population

Hypertension in children is often secondary to an underlying cause. When pharmacotherapy is required, ACE inhibitors, ARBs, CCBs, beta-blockers, and diuretics are used, with dosing adjusted carefully based on body weight or surface area. ACE inhibitors and ARBs are often preferred in children with proteinuric kidney disease or diabetes. Long-term effects on growth and development require ongoing monitoring.

Geriatric Population

Elderly patients often have isolated systolic hypertension due to reduced arterial compliance. They are more sensitive to volume depletion and sympathetic inhibition, increasing the risk of orthostatic hypotension, falls, and electrolyte disturbances. Low starting doses and slow titration are imperative. Thiazide diuretics and CCBs have strong evidence of benefit in this population. Beta-blockers may be less effective for isolated systolic hypertension. Renal and hepatic function must be assessed for appropriate dosing.

Renal Impairment

In chronic kidney disease, hypertension is both a cause and a consequence. Dose adjustment is required for drugs that are primarily renally excreted (e.g., most ACE inhibitors, atenolol, water-soluble beta-blockers, lithium). Thiazide diuretics lose efficacy when glomerular filtration rate falls below 30 mL/min/1.73m², at which point loop diuretics become the diuretic of choice. ACE inhibitors and ARBs are first-line for their renoprotective effects but require monitoring for hyperkalemia and an acute rise in serum creatinine (typically an increase up to 30% may be acceptable).

Hepatic Impairment

Drugs with extensive hepatic metabolism or high first-pass effect (e.g., propranolol, labetalol, most CCBs, losartan) may have significantly increased bioavailability and prolonged half-life in patients with cirrhosis or severe hepatic impairment, necessitating dose reduction. In patients with ascites and edema, diuretics must be used cautiously to avoid precipitating hepatic encephalopathy or electrolyte imbalances; spironolactone is often the preferred initial diuretic.

9. Summary/Key Points

• Antihypertensive drugs are classified by their primary mechanism of action, with major classes including diuretics, RAAS inhibitors (ACE inhibitors, ARBs), calcium channel blockers, beta-blockers, and vasodilators.
• The therapeutic goal is to reduce cardiac output, systemic vascular resistance, or both, thereby lowering blood pressure to mitigate long-term cardiovascular and renal risks.
• Pharmacokinetic properties, such as route of elimination and half-life, critically influence dosing regimens and guide selection in patients with renal or hepatic impairment.
• Drug selection is often guided by compelling indications (e.g., ACE inhibitors/ARBs in diabetic nephropathy, beta-blockers in heart failure) and contraindications (e.g., beta-blockers in asthma).
• Adverse effect profiles are class-specific: electrolyte disturbances with diuretics, cough with ACE inhibitors, edema with dihydropyridine CCBs, and bronchoconstriction with non-selective beta-blockers.
• Significant drug interactions include additive hypotension, hyperkalemia with combined RAAS inhibition, and pharmacokinetic interactions mediated by cytochrome P450 enzymes, particularly for calcium channel blockers.
• Special population considerations are paramount: ACE inhibitors and ARBs are contraindicated in pregnancy; low starting doses are essential in the elderly; and dose adjustment is required in renal and hepatic impairment.

Clinical Pearls

• The “first-dose hypotension” effect is most pronounced with alpha-1 blockers and ACE inhibitors; administer the first dose at bedtime.
• When combining a diuretic with an ACE inhibitor or ARB, monitor serum potassium and renal function closely within 1-2 weeks of initiation or dose change.
• Peripheral edema caused by dihydropyridine CCBs is due to precapillary dilation and is often resistant to diuretics; it may be managed by dose reduction, switching to a non-dihydropyridine, or adding an ACE inhibitor/ARB.
• Beta-blockers should not be abruptly discontinued; a taper over 1-2 weeks is recommended to avoid rebound hypertension and tachycardia.
• In hypertensive urgencies, oral agents with a relatively rapid onset (e.g., captopril, labetalol, clonidine) are preferred; reserve intravenous agents (e.g., nitroprusside, nicardipine) for true emergencies with acute end-organ damage.

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