GLYCERYL TRINITRATE

  • Need to understand PK and PD.
Structure Nitric and nitrous acid of alcohols
Pharmacodynamics
  1. Taken up by vascular smooth muscle cells (and not cardiac, or skeletal muscle)
  2. Denitrited by glutathione-S-transferase
  3. Nitric oxide is then released. NO activates cGMP and reduces intracellular Ca2+.
  4. This leads to vasodilation.
  5. Organ system effects
    • Vasodilation – low dose leads to vasodilation first. Larger dose causes arteriolar dilation, leading to reduced BP and reduced afterload à this reduces myocardial oxygen demand.
    • Also causes a redistribution of blood flow in ischaemic cardiac tissues, leading to relief of angina symptoms.
Absorption/administration
  1. Multiple routes – S/L, I/V, Buccal, Nasal, Patch, oral (for example, isosorbide mononitrate)
Distribution
Metabolism
  1. The liver contains a high capacity organic nitrate reductase à this ultimately inactivates the drug (extensive first pass)
Excretion
  1. Via kidneys
Indications
  1. Angina of effort
  2. Variant/Prinzmetal’s angina (coronary vasospasm)
  3. Unstable angina
    • Mainly important because GTN reduces preload, and therefore reduces cardiac well tension and therefore, myocardial oxygen demand.
Contraindications
Interactions
Special precautions
  1. Hypotensive patients
  2. Those patients with inferior/posterior MI
  3. Patients which cannot increase cardiac output to compensate (e.g. severe AS, tamponade)
  4. AVOID DRUG IN RICP
  5. Significant tachycardia/bradycardia
Adverse effects
  1. Tachycardia and hypotension
  2. Headache (note that the drug is safe in raised intra-ocular pressure)
  3. Lightheadedness and dry mouth
  4. Lightheadedness and dry mouth
  5. Tachyphylaxis
    • This is probably due to a decrease in tissue sulfhydryl groups and can be partially prevented/reversed with a sulfhydryl-regenerating agent.
  6. Methaemaglobinemia
    • Nitrite groups react with haemoglobin to form methaemaglobin (but remember that in adults, this tends to be insignificant)
Dosing/administration
Toxicology
Withdrawal syndrome