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Wednesday, July 30, 2025

Vasodilators


Vasodilators are a diverse class of pharmacologic agents that induce dilation of blood vessels, thereby reducing vascular resistance, lowering blood pressure, and improving blood flow to various tissues. These agents exert their effects either by acting directly on vascular smooth muscle cells or by modulating neurohormonal mechanisms that influence vascular tone. Vasodilators are integral in the management of hypertension, angina pectoris, heart failure, pulmonary hypertension, hypertensive emergencies, and peripheral vascular diseases.

Based on the site and mechanism of action, vasodilators are classified as:

  • Arterial vasodilators: Reduce afterload by dilating arteries

  • Venous vasodilators: Reduce preload by dilating veins

  • Balanced vasodilators: Affect both arteries and veins

Mechanisms of Action

  1. Direct smooth muscle relaxation: Some agents activate potassium channels or inhibit calcium influx, leading to hyperpolarization and relaxation of vascular smooth muscle.

  2. Nitric oxide (NO) donors: Convert to NO in the body, which activates guanylate cyclase and increases cyclic GMP → vasodilation.

  3. Calcium channel blockade: Prevents calcium influx into smooth muscle, reducing contraction.

  4. Alpha-adrenergic antagonism: Inhibits sympathetic vasoconstriction.

  5. RAAS modulation: Includes ACE inhibitors and ARBs that indirectly promote vasodilation via bradykinin and angiotensin II pathways.

  6. Phosphodiesterase inhibition: Increases intracellular cGMP/cAMP, leading to vasodilation.

Classification of Vasodilators by Type

1. Direct-acting Vasodilators

  • Act directly on vascular smooth muscle

  • Examples: Hydralazine, Minoxidil, Diazoxide

2. Nitrates and Nitrites (NO Donors)

  • Release nitric oxide, promoting venodilation (and some arterial)

  • Examples: Nitroglycerin, Isosorbide dinitrate, Sodium nitroprusside

3. Calcium Channel Blockers (CCBs)

  • Block L-type calcium channels in vascular smooth muscle

  • Examples: Amlodipine, Nifedipine, Nicardipine

4. Alpha-Adrenergic Blockers

  • Block α1 receptors causing vasodilation

  • Examples: Prazosin, Doxazosin

5. ACE Inhibitors / ARBs

  • Inhibit RAAS pathway, reduce vasoconstriction and aldosterone

  • Examples: Lisinopril, Losartan

6. Phosphodiesterase Inhibitors

  • Increase cGMP (PDE5 inhibitors) or cAMP (PDE3 inhibitors)

  • Examples: Sildenafil, Milrinone

7. Endothelin Receptor Antagonists (ERAs)

  • Block vasoconstrictive effects of endothelin-1

  • Examples: Bosentan, Ambrisentan

Generic Names of Common Vasodilators

Direct Vasodilators

  • Hydralazine

  • Minoxidil

  • Diazoxide

  • Fenoldopam (dopamine receptor agonist)

Nitrates and Nitrites

  • Nitroglycerin

  • Isosorbide dinitrate

  • Isosorbide mononitrate

  • Sodium nitroprusside

Calcium Channel Blockers

  • Amlodipine

  • Nifedipine

  • Nicardipine

  • Clevidipine

  • Felodipine

Alpha-Adrenergic Blockers

  • Prazosin

  • Doxazosin

  • Terazosin

ACE Inhibitors

  • Enalapril

  • Lisinopril

  • Ramipril

Angiotensin II Receptor Blockers (ARBs)

  • Losartan

  • Valsartan

  • Candesartan

Phosphodiesterase Inhibitors

  • Sildenafil (PDE5)

  • Tadalafil (PDE5)

  • Milrinone (PDE3)

  • Cilostazol

Endothelin Receptor Antagonists

  • Bosentan

  • Ambrisentan

  • Macitentan

Therapeutic Uses

ConditionPreferred Vasodilators
HypertensionHydralazine, Minoxidil, CCBs, ACEIs, ARBs, α-blockers
Hypertensive emergencySodium nitroprusside, Nicardipine, Labetalol, Fenoldopam
Angina pectorisNitrates (e.g., nitroglycerin), CCBs
Heart failureHydralazine + nitrates, ACEIs, ARBs, ARNi
Pulmonary hypertensionERAs (e.g., Bosentan), PDE5 inhibitors (Sildenafil), Prostacyclins
Peripheral artery diseaseCilostazol, Pentoxifylline
Erectile dysfunctionSildenafil, Tadalafil
Raynaud's phenomenonCCBs (Nifedipine), α-blockers
Hair loss (topical)Minoxidil topical solution



Notable Agents and Their Profiles

Hydralazine

  • Mechanism: Direct arteriolar dilation via smooth muscle relaxation

  • Indications: Hypertension, heart failure (with isosorbide dinitrate)

  • Route: Oral, IV

  • Adverse Effects: Reflex tachycardia, lupus-like syndrome, headache

Minoxidil

  • Mechanism: Potassium channel opener, strong arteriolar dilator

  • Indications: Severe/resistant hypertension, alopecia (topical)

  • Route: Oral (systemic), topical

  • Adverse Effects: Fluid retention, pericardial effusion, hypertrichosis

Nitroglycerin

  • Mechanism: NO donor → venous > arterial dilation

  • Indications: Angina, acute coronary syndrome, pulmonary edema

  • Route: Sublingual, IV, transdermal, oral

  • Adverse Effects: Headache, hypotension, tolerance (nitrate-free interval required)

Sodium Nitroprusside

  • Mechanism: Balanced vasodilator (arterial and venous)

  • Indications: Hypertensive crisis, acute heart failure

  • Route: IV infusion

  • Adverse Effects: Cyanide toxicity with prolonged use or high doses

Sildenafil

  • Mechanism: PDE5 inhibitor → ↑ cGMP → vasodilation in pulmonary and penile vasculature

  • Indications: Erectile dysfunction, pulmonary hypertension

  • Route: Oral

  • Adverse Effects: Hypotension, vision disturbances, headache

Bosentan

  • Mechanism: Dual endothelin receptor antagonist

  • Indications: Pulmonary arterial hypertension (PAH)

  • Route: Oral

  • Adverse Effects: Hepatotoxicity, teratogenicity, anemia

Contraindications

  • Nitrates + PDE5 inhibitors: Risk of profound hypotension and cardiac arrest

  • Severe aortic stenosis: Vasodilators may worsen perfusion

  • Pregnancy (some agents): Bosentan, ACEIs, ARBs are teratogenic

  • Volume depletion: Can exacerbate hypotension

Precautions and Monitoring

  • Blood pressure: Monitor closely to prevent hypotension

  • Renal function: Especially with RAAS-modifying agents

  • Liver enzymes: With Bosentan, Macitentan

  • Electrolytes: Watch for hyperkalemia with ACEIs/ARBs

  • Drug interactions: Especially with nitrates, PDE5 inhibitors, and CYP3A4 substrates

Adverse Effects

SystemCommon Reactions
CardiovascularHypotension, tachycardia, flushing
NeurologicalHeadache, dizziness, syncope
GastrointestinalNausea, vomiting (some with nitrates or PDE5 inhibitors)
HematologicAnemia (ERAs)
DermatologicRash (minoxidil)
MetabolicSodium/water retention (hydralazine, minoxidil)



Drug Interactions

  • PDE5 inhibitors + nitrates: Severe hypotension, contraindicated

  • CYP3A4 inhibitors/inducers: Affect metabolism of CCBs, Bosentan

  • NSAIDs + ACEIs/ARBs: Risk of renal impairment

  • Diuretics + Vasodilators: Additive hypotension

  • Alcohol: Potentiates hypotensive effect

Clinical Use in Combination Therapy

  • Hydralazine + Isosorbide Dinitrate: Approved for heart failure in African-American patients

  • ACEI/ARB + CCB or diuretic: Standard approach in hypertension

  • Nitrates + β-blockers: Angina management (nitrates decrease preload, β-blockers reduce afterload and O₂ demand)

Formulations and Routes of Administration

  • Oral: Amlodipine, Hydralazine, Minoxidil, Nitrates, Sildenafil

  • Sublingual: Nitroglycerin for rapid angina relief

  • Topical: Minoxidil for hair growth

  • IV Infusion: Sodium nitroprusside, Nicardipine, Hydralazine (in hypertensive emergencies)

  • Transdermal patch: Nitroglycerin

Emerging and Investigational Agents

  • Riociguat: Soluble guanylate cyclase stimulator for PAH

  • Rodatristat: Serotonin synthesis inhibitor under study for PAH

  • CRF-PEP agents: In development for pulmonary vasodilation




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