Pharmacology of Antihypertensive Drugs

Introduction and Overview

Hypertension remains a leading contributor to cardiovascular morbidity and mortality worldwide. Effective management of elevated blood pressure necessitates a nuanced understanding of the pharmacological agents available, their mechanisms of action, and the clinical contexts in which they are employed. The selection of an antihypertensive regimen should be guided by evidence-based principles, patient-specific factors, and the pharmacodynamic and pharmacokinetic properties of each drug class.

Learning objectives for this monograph include:

• Identify the major classes of antihypertensive agents and their distinguishing chemical features.
• Explain the pharmacodynamic pathways that underlie blood pressure reduction for each drug class.
• Describe the absorption, distribution, metabolism, and excretion characteristics that influence dosing strategies.
• Recognize the approved indications and common off‑label uses associated with each class.

<li. Evaluate potential adverse effects, drug interactions, and special population considerations to inform clinical decision‑making.

Classification of Antihypertensive Agents

1. Renin–Angiotensin–Aldosterone System (RAAS) Modulators

• ACE inhibitors (e.g., lisinopril, enalapril)
• Angiotensin II receptor blockers (ARBs; e.g., losartan, valsartan)
• Direct renin inhibitors (e.g., aliskiren)
• Aldosterone antagonists (e.g., spironolactone, eplerenone)

2. Calcium Channel Blockers (CCBs)

• Dihydropyridines (e.g., amlodipine, nifedipine)
• Non‑dihydropyridines (e.g., verapamil, diltiazem)

3. Beta‑Adrenergic Blockers

• Non‑selective (e.g., propranolol, nadolol)
• Selective (β₁‑selective) (e.g., metoprolol, atenolol)
• Thiazolidinedione‑like agents (e.g., carvedilol)

4. Diuretics

• Thiazide and thiazide‑like (e.g., hydrochlorothiazide, chlorthalidone)
• Loop diuretics (e.g., furosemide, bumetanide)
• Potassium‑sparing diuretics (e.g., amiloride, triamterene)

5. Vasodilators

• Direct vasodilators (e.g., hydralazine, minoxidil)
• Endothelin antagonists (e.g., bosentan)
• Phosphodiesterase‑5 inhibitors (e.g., sildenafil, primarily for pulmonary hypertension)

6. Other Agents

• Central alpha‑2 agonists (e.g., clonidine, methyldopa)
• Angiotensin receptor neprilysin inhibitors (ARNIs; e.g., sacubitril/valsartan)
• Selective Rho‑kinase inhibitors (e.g., ripasudil, under investigation)

Mechanism of Action

Blood pressure regulation is achieved through modulation of vascular tone, cardiac output, and renal fluid handling. Each antihypertensive class exerts its effect through distinct pharmacodynamic pathways, often intersecting at common downstream targets.

RAAS Modulators

ACE inhibitors block the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction and aldosterone secretion. ARBs competitively inhibit angiotensin II binding to AT₁ receptors, achieving similar downstream effects. Direct renin inhibitors diminish the catalytic activity of renin, preventing the formation of angiotensin I. Aldosterone antagonists inhibit mineralocorticoid receptors in the distal nephron, promoting sodium excretion and potassium retention.

Calcium Channel Blockers

Dihydropyridines preferentially dilate arterial smooth muscle by blocking L‑type calcium channels, leading to decreased peripheral resistance. Non‑dihydropyridines also inhibit calcium influx in cardiac tissue, reducing heart rate and contractility. The net effect is a reduction in mean arterial pressure via both vasodilatory and chronotropic mechanisms.

Beta‑Adrenergic Blockers

Beta blockers antagonize β‑adrenergic receptors, attenuating sympathetic stimulation of cardiac β₁ receptors and decreasing heart rate and myocardial contractility. Selective β₁ blockers spare β₂ receptors, reducing bronchoconstriction risk. Some agents (e.g., carvedilol) possess additional α₁ antagonism and antioxidant properties, contributing to vasodilatory effects.

Diuretics

Thiazide diuretics inhibit Na⁺/Cl⁻ cotransporters in the distal tubule, reducing sodium reabsorption and promoting natriuresis. Loop diuretics block the Na⁺-K⁺-2Cl⁻ symporter in the thick ascending limb, causing robust diuresis and decreasing intravascular volume. Potassium‑sparing agents antagonize epithelial sodium channels (ENaC) or aldosterone receptors, mitigating potassium loss.

Vasodilators

Direct vasodilators such as hydralazine increase cyclic GMP via nitric oxide pathways, relaxing vascular smooth muscle. Minoxidil opens ATP‑sensitive potassium channels, leading to hyperpolarization and vasodilation. Endothelin antagonists block endothelin‑1 receptors, counteracting potent vasoconstriction.

Other Agents

Central α‑2 agonists stimulate presynaptic receptors, reducing norepinephrine release and sympathetic tone. Angiotensin receptor neprilysin inhibitors combine ARB activity with neprilysin inhibition, enhancing natriuretic peptide levels and promoting vasodilation.

Pharmacokinetics

Drug absorption, distribution, metabolism, and excretion (ADME) parameters inform dosing intervals, therapeutic monitoring, and potential drug interactions.

Absorption

• ACE inhibitors and ARBs exhibit good oral bioavailability (>70% for most agents). Thiazide diuretics are well absorbed but may require food to enhance uptake. Loop diuretics demonstrate variable absorption; furosemide is poorly absorbed (≈5–10% of oral dose). Calcium channel blockers are highly lipophilic, enabling rapid absorption (T_max 1–3 h).

Distribution

• High protein binding (>90%) is common among ACE inhibitors and ARBs. Lipophilic agents such as dihydropyridines cross the blood–brain barrier, potentially contributing to central side effects. Volume of distribution (V_d) varies: hydralazine (≈2 L/kg), spironolactone (≈4 L/kg).

Metabolism

• Cytochrome P450 enzymes (CYP2D6, CYP3A4, CYP2C9) metabolize many beta blockers and ARBs. ACE inhibitors undergo hydrolysis or conjugation. Hepatic impairment may reduce clearance, necessitating dose adjustment.

Excretion

• Renal clearance predominates for most diuretics and ACE inhibitors; loop diuretics are eliminated primarily via the kidneys. Hydralazine undergoes hepatic metabolism and excretion via bile and urine. The half‑life (t_1/2) ranges from 8 h for lisinopril to 27 h for chlorthalidone.

Dosing Considerations

• Initiation of therapy typically employs low doses to mitigate hypotension. Titration is guided by trough blood pressure monitoring. Steady‑state concentrations are achieved after approximately five half‑lives. For drugs with narrow therapeutic indices (e.g., hydralazine), therapeutic drug monitoring may be advantageous.

Therapeutic Uses and Clinical Applications

Beyond primary hypertension, many antihypertensive agents serve secondary indications, often leveraging their pharmacologic properties in adjunct or monotherapy.

Primary Hypertension

• First‑line therapy often includes thiazide diuretics, ACE inhibitors, ARBs, or calcium channel blockers, depending on patient comorbidities and ethnicity.

Secondary Hypertension

• Aldosterone antagonists are indicated for hyperaldosteronism. Loop diuretics treat volume overload associated with congestive heart failure (CHF).

Cardiovascular Disease Prevention

• ACE inhibitors and ARBs reduce the risk of myocardial infarction and stroke in high‑risk populations. Beta blockers are favored post‑myocardial infarction and in heart failure with reduced ejection fraction.

Heart Failure

• Combination of ACE inhibitors or ARBs with beta blockers and mineralocorticoid receptor antagonists forms the backbone of guideline‑directed medical therapy.

Pulmonary Hypertension

• Minoxidil and endothelin antagonists are employed in severe cases, often in conjunction with phosphodiesterase‑5 inhibitors.

Other Off‑Label Uses

• Clonidine is used to manage withdrawal from opioids and stimulants. Hydralazine can be combined with methyldopa for refractory hypertension in pregnancy.

Adverse Effects

Adverse events vary considerably across drug classes, reflecting their pharmacologic targets and systemic exposure.

Common Side Effects

• ACE inhibitors: cough (≈10–20%), hyperkalemia, angioedema.
• ARBs: dizziness, hyperkalemia, hypotension.
• Beta blockers: fatigue, bradycardia, bronchospasm (particularly non‑selective agents).
• Calcium channel blockers: peripheral edema (dihydropyridines), constipation (verapamil).
• Diuretics: electrolyte disturbances (hypokalemia, hyponatremia), dehydration, gout exacerbation.
• Hydralazine: lupus‑like syndrome, headache, tachycardia.

Serious or Rare Reactions

• Angioedema with ACE inhibitors and ARBs, often requiring immediate cessation.
• Severe hyperkalemia in patients with renal insufficiency or concomitant potassium‑sparing agents.
• Myocardial ischemia or arrhythmias precipitated by beta‑blocker withdrawal.
• Pulmonary edema with high‑dose hydralazine or minoxidil.

Black Box Warnings

• ACE inhibitors: risk of fetal injury when used during the second and third trimesters.
• Hydralazine: potential for serious cutaneous reactions and lupus‑like syndrome.
• Mineralocorticoid receptor antagonists: hyperkalemia and renal dysfunction.

Drug Interactions

Understanding pharmacokinetic and pharmacodynamic interactions is critical to avoid adverse outcomes.

Major Drug–Drug Interactions

• ACE inhibitors/ARBs with potassium‑sparing diuretics or potassium supplements → hyperkalemia.
• Beta blockers with calcium channel blockers (especially non‑dihydropyridines) → additive negative chronotropic effects.
• Loop diuretics with NSAIDs → reduced diuretic efficacy and increased risk of renal impairment.
• CYP3A4 inhibitors (e.g., ketoconazole) increase serum levels of certain ARBs and beta blockers.
• St. John’s wort decreases concentrations of several antihypertensives via CYP induction.

Contraindications

• ACE inhibitors in patients with a history of angioedema.
• Beta blockers in severe asthma or chronic obstructive pulmonary disease (COPD) due to bronchoconstriction risk.
• Thiazide diuretics in patients with glucose intolerance or hyperuricemia.
• Hydralazine in patients with severe left ventricular dysfunction due to reflex tachycardia.

Special Considerations

Pregnancy and Lactation

ACE inhibitors and ARBs are contraindicated in pregnancy due to teratogenicity. Calcium channel blockers (except verapamil) may be considered, though data are limited. Beta blockers pose a risk of neonatal bradycardia; selective agents are preferred. Loop diuretics are used cautiously to avoid fetal dehydration.

Pediatric Use

Beta blockers and ACE inhibitors are approved for pediatric hypertension in select indications. Thiazide diuretics are generally avoided due to growth concerns and electrolyte disturbances. Calcium channel blockers have limited pediatric data.

Geriatric Considerations

Older adults are more susceptible to orthostatic hypotension and electrolyte imbalances. Dose titration should proceed slowly, and monitoring for cognitive effects with beta blockers is advised.

Renal and Hepatic Impairment

ACE inhibitors and ARBs require dose adjustment in chronic kidney disease (CKD) to avoid hyperkalemia and further deterioration of renal function. Loop diuretics remain efficacious in severe CKD but may require higher doses. Hepatic impairment reduces clearance of metabolized agents, necessitating dose reductions or avoidance.

Summary and Key Points

• Antihypertensive therapy is guided by a balance between efficacy, safety profile, and patient comorbidities.
• RAAS modulators, calcium channel blockers, beta blockers, diuretics, and vasodilators constitute the primary pharmacologic arsenal.
• Pharmacokinetic properties—including absorption, distribution, metabolism, and excretion—must inform dosing and monitoring strategies.
• Adverse effect profiles, particularly for ACE inhibitors, beta blockers, and diuretics, require vigilant monitoring of electrolytes and renal function.
• Drug interactions, especially involving CYP enzymes and potassium‑sparing agents, can precipitate serious complications.
• Special populations (pregnant women, pediatrics, geriatrics, renal/hepatic impairment) demand individualized therapeutic approaches and close surveillance.

Clinicians should integrate these pharmacologic principles with patient‑centered care to optimize blood pressure control while minimizing adverse outcomes.

References

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