Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. At high doses, nitrates can decrease afterload and may be used in hypertensive crises. The main adverse effects include headache, hypotension, and reflex tachycardia. Repeated use of nitrates leads to tolerance. Contraindications include concomitant therapy with PDE5 inhibitors, hypertrophic cardiomyopathy, and suspected right ventricular infarction.

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Chemistry and Pharmacodynamics


  • Nitrates are salts or esters of nitric acid.
  • Nitroglycerine is the prototype of this drug class.
Nitroglycerine chemical structure Nitrates

Nitroglycerine chemical structure

Image: “Skeletal formula of zwitterionic nitroglycerin” by BartVL71. License: Public Domain

Mechanism of action

Exogenously administered nitrates are converted to NO after entering the cell:

  • NO is converted into S-nitrosothiols → stimulates guanylyl cyclase
  • Guanylyl cyclase converts cellular guanosine-5′-triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP) → relaxation of vascular smooth muscle cells: 
    • Primarily venous dilation 
    • Secondarily arterial dilation
Mechanism of action for nitrates

Mechanism of action for nitrates:
Stimulation of guanylyl cyclase induces the conversion of guanosine-5′-triphosphate (GTP) to cGMP, resulting in vascular smooth muscle relaxation and vasodilation.

GMP: guanosine monophosphate
Image by Lecturio. License: CC BY-NC-SA 4.0

Physiologic effects

  • Preload reduction:
    • Primary mechanism to ↓ myocardial O2 demand
    • Nitrates relax vascular smooth muscle → venodilation → ↓ cardiac preload:
      • ↓ Myocardial wall stress
      • ↓ Myocardial O2 demand
      • ↓ BP
      • Can produce reflex tachycardia due to ↓ BP
    • Indirectly improves subendocardial blood flow:
      • ↓ Left end-diastolic pressure as a result of systemic venodilation
      • Epicardium to endocardium blood flow ↑
  • Afterload reduction:
    • Secondary mechanism to ↓ myocardial O2 demand
    • Higher doses have arteriodilatory effects:
      • ↓ Afterload
      • ↓ Myocardial wall stress due to lowered resistance
      • ↓ O2 consumption
  • Effect of higher doses:
    • Opens myocardial vascular bed:
      • Due to smooth muscle relaxation of the coronary artery
      • Large coronary arteries are dilated primarily.
      • Benefits the ischemic zone the most
    • Enhances collateral coronary artery blood flow
    • Beneficial in coronary artery vasospasm:
      • Relaxes or prevents coronary artery spasm
      • ↑ O2 supply
      • Does not ↓ O2 demand
  • Antiplatelet properties:
    • Antithrombotic effects
    • Stimulation of platelet guanylyl cyclase 
    • Inhibits binding of fibrinogen to platelet IIb and IIIa receptors, which are essential components of platelet aggregation



  • Oral:
    • Sublingual:
      • Tablet
      • Onset of action: 1‒3 minutes
      • Peak effect: 4‒8 minutes
      • Duration: 30‒60 minutes
    • Translingual:
      • Spray
      • Onset of action: 2 minutes
      • Peak effect: 4‒10 minutes
      • Duration: 30‒60 minutes
    • Buccal:
      • Tablet
      • Onset of action: 2‒5 minutes
      • Peak effect: 4‒10 minutes
      • Duration: 2 hours
    • Sustained release:
      • Tablet
      • Onset of action: 20‒45 minutes
      • Peak effect: 45‒120 minutes
      • Duration: 4‒8 hours
  • Topical:
    • Ointment
    • Onset: 15‒60 minutes
    • Peak effect: 30‒120 minutes
    • Duration: 2‒12 hours
  • Transdermal:
    • Patch
    • Onset: 40‒60 minutes
    • Peak effect: 60‒180 minutes
    • Duration: 18‒24 hours
  • IV:
    • Infusion
    • Onset: immediate
    • Peak effect: immediate
    • Duration: 3‒5 minutes


  • The volume of distribution following IV administration is 3.3 L/kg.
  • Plasma drug concentrations range between 50 and 500 ng/mL:
    • Binding of nitroglycerin to plasma proteins is approximately 60%.
    • Binding of 1,2-dinitroglycerin to plasma proteins is 60%.
    • Binding of 1,3-dinitroglycerin to plasma proteins is 30%.
  • Highly water soluble


  • Hepatic organic nitrate reductase is the primary enzyme responsible for the metabolism of nitroglycerin:
    • Cleaves nitrate groups from the parent molecule → glycerol di- and mononitrate metabolites → ultimately to glycerol and organic nitrate
    • Drugs with a 1st-pass effect (e.g., oral nitroglycerin and isosorbide dinitrate) exhibit lower potency.
    • Drugs without a 1st-pass effect (e.g., sublingual forms):
      • Higher potency
      • Therapeutic drug levels in the blood are achieved faster.
  • 1,2-dinitroglycerin and 1,3-dinitroglycerin are the 2 major metabolites found in plasma.
  • Glycerol mononitrate metabolites are biologically inactive.


  • Metabolites are primarily excreted in the urine.
  • Plasma drug concentration decreases rapidly.
  • Average elimination half-life: 2–3 minutes


Table: Comparison of nitrates
MedicationsCommon formulationsIndicationsClinical pearls
  • Sublingual
  • Oral
  • Transdermal
  • IV
  • Angina
  • Acute MI (unless a right ventricular or inferior infarct)
  • Congestive heart failure
  • Variant angina
  • Hypertensive emergency (off label)
  • Can dose sublingual nitroglycerin every 5 minutes, up to 3 doses
  • Can use IV nitroglycerin for angina
Isosorbide dinitrateOral
  • Angina
  • Congestive heart failure
  • Achalasia (off label)
  • Slower onset but longer duration of action than nitroglycerin
  • Good for chronic stable angina prophylaxis
Isosorbide mononitrateOral
  • Angina
  • Congestive heart failure
Active metabolite of isosorbide dinitrate (better bioavailability)
Sodium nitroprussideIV
  • Hypertensive emergency
  • Congestive heart failure
Combines with hemoglobin to produce cyanide and cyanmethemoglobin
Amyl nitriteInhalation
  • Cyanide poisoning
  • Angina
  • Oxidizes hemoglobin to methemoglobin
  • Methemoglobin binds with cyanide to form cyanmethemoglobin.
  • As a drug of abuse, “poppers” produces euphoria.
Sodium nitriteIVCyanide poisoningSimilar mechanism as that of amyl nitrite

Adverse Effects and Contraindications

Adverse effects

  • Common side effects:
    • Headache (cerebral vasodilation)
    • Hypotension (systemic vasodilation)
    • Tachycardia (reflex sympathetic activity)
    • Flushing (cutaneous vasodilation)
  • High blood concentrations may induce methemoglobinemia:
    • Nitrates oxidize ferrous (Fe2+) iron to ferric (Fe3+) iron.
    • Inducing methemoglobinemia may be used therapeutically to treat cyanide poisoning: Methemoglobin has a high binding affinity for cyanides.
  • Long-term infusion of sodium nitroprusside may lead to cyanide toxicity.

Tachyphylaxis and tolerance

  • Tachyphylaxis (↓ effect with rapid, repeated administration) 
  • Tolerance (requiring ↑ doses over time to achieve the same effect)
    • Major problem resulting from the chronic use of nitrates
    • With continued administration:
      • ↓ Hemodynamic and antianginal effects
      • Side effects also ↓
    • Incompletely understood
    • 3 proposed mechanisms:
      • ↓ Formation of NO as a result of impaired nitroglycerin conversion to 1,2-glyceryl dinitrate
      • Reduction in NO bioactivity
      • Vasoconstrictor activation of the sympathetic nervous system and RAAS due to nitrate-induced vasodilation
    • Prevention:
      • Most effective: intermittent therapy with a nitrate-free interval of 8‒10 hours
      • Rebound angina can occur in the nitrate-free interval.

Drug interactions

PDE5 inhibitors

  • Can be fatal due to:
    • Hypotension: due to increased vasodilation
    • Inhibition of PDE5, which is responsible for the breakdown of cGMP to GMP
    • ↑ cGMP levels resulting from prevention of its breakdown
  • Examples:
    • Sildenafil (ViagraⓇ)
    • Vardenafil (LevitraⓇ)
    • Tadalafil (CialisⓇ)


  • Hypertrophic cardiomyopathy: may induce or enhance outflow tract obstruction
  • Severe aortic stenosis: potential severe hypotension
  • Volume depletion:
    • ↑ Risk of severe and uncontrollable hypotension
    • Due to loss of compensatory mechanisms 
  • Increased intracranial pressure: 
    • Nitrates induce cerebral vasodilation.
    • ↑ Cerebral blood flow
    • Compromises intracranial perfusion
  • Right-sided (ventricular) MI: 
    • Patients with right ventricular dysfunction are preload dependent.
    • Nitrates cause venous pooling and ↓ preload
  • Hypotension


  1. Fung, H. (1992). Do nitrates differ? British Journal of Clinical Pharmacology, 34, 5S-9S.
  2. Parker, J. (1989). Nitrate tolerance in angina pectoris. Cardiovascular Drugs and Therapy, 2(6): 823-829.
  3. Kannam, J., Gersh, B. (2021). Nitrates in the management of chronic coronary syndrome. In Kaski, J. (Ed.), UpToDate. Retrieved June 6, 2021, from
  4. Reeder, G. (2021). Nitrates in the management of acute coronary syndrome. In Kaski, J. (Ed.), UpToDate. Retrieved June 6, 2021, from
  5. Parker, J.D., Parker, J.O. (1998). Nitrate therapy for stable angina pectoris. N Engl J Med; 338:520.
  6. Fihn, S.D., Gardin, J.M., Abrams, J., et al. (2012). ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation; 126:3097.
  7. Katzung, B.G. (2012). Vasodilators & the treatment of angina pectoris. In Katzung, B.G., Masters., and Trevor, A.J. (Eds). Basic & Clinical Pharmacology, 12th edition. (pp. 195-201). McGraw-Hill Companies, Inc.

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