Indications
Modes of Action
  1. Increase oxygen extraction from blood
  2. Decrease oxygen requirement
Research Paper on the Physiological effect of Organic Nitrates on Cardiac function
Rank the sensitivity of tissues to Organic Nitrates
  1. Veins
  2. Arteries
  3. Arterioles
Mechanism of action
  • Stimulate release of Nitric Oxide, triggering the Guanylyl Cyclase cascade leading to relaxation of vascular smooth muscle
  • Does not generally trigger a compensitory Baroreflex response (no Chronotropy)
  • Tissue specificity provided by location of Guanylyl Cyclase
  • No effects on Ionotropy as the gas difuses into the cells and affects down stream enzymes
Therapeutic Actions
Use ER/transdermal dosage forms
  • Usually TID, BID, QD for prevention

    • Timing such that there is 8hr (12hr prefered) of no nitro in the system
    • Last dose TID ~3pm
    • Last dose BID ~noon
Sublingual
  • PRN for acute relief
  • Take every 5 minutes up to 3 tablets in 15 minutes, if no relief after first 5 minutes, call 911
  • May be taken 10 minutes before activity which may cause Angina attack
Side Effects
  • Headaches are very common due to vasodilation (see MOA of Migraine Headache
  • Dizziness
  • Tachycardia
  • Hypotension due to vasodilation

    • Potentiation of other vasodilators
    • Competes with Alcohol for Mitochondrial Aldehyde Dehydrogenase (mtALDH)
  • Tolerance
Cautions
Theories on Mechanism of Tolerance to Organic Nitrates
  1. Cannot sustain Nitric Oxide production

    • Damage to endothelial layer, resulting in lower enzyme concentrations
    • Loss of Bradykinin
  2. Compensatory increase in physiological antagonists (e.g. increase in Endothelin)
Compensation for Tolerance Take a Nitro vacation
Contraindications
Enzymes acting on Organic Nitrates
  • Mitochondrial Aldehyde Dehydrogenase (mtALDH)
  • Glutathione-Organic Nitrate Reductase (GONR)
Key Enzyme catalyzing bioactivation of Glyceryl Trinitrate Mitochondrial Aldehyde Dehydrogenase (mtALDH)

753NitricOxideProduction.GIF

Where does Glyceryl Trinitrate activation occur? Intercellular, it mtALDH right?
How is mtALDH regenerated
  • Glutamate complex reaction product could be reduced with the addition of one sulfenic acid, producing the active enzyme and an R-S-OH
  • The sulfide bridge could be reduced with the addition of two sulfinic acid molecules
Hepatic Metabolism of Organic Nitrates to produce Nitric Oxide
  1. Glutathione-Organic Nitrate Reductase (GONR) frees Nitrite (NO2-) from the Organic Nitrate using two molecules of Glutathione
  2. Nitrite is oxidized in the blood to Nitrate (NO3-)
  3. Nitrate undergoes Renal Elimination
  4. GONR repeats the reaction for each nitrite group of the compound

    • Subsequent reactions are slower than the first
Memorization Tip for Acute and Chronic Angina Tx
  • Odd Nitric Acid groups for acute
  • Even Nitric Acid groups for chronic

(not always true, but close)

Agents Structure Notes
Amyl nitrite (isopentyl Nitrite) C07457.gif
  • Volatile yellow liquid
  • Rapid onset (30-60 secs), short duration (1-2 mins)
Glyceryl Trinitrate C07455.gif
  • Synthesized by a dehydration reaction with Glycerol and three Nitric Acid molecules
  • Ind: Acute Angina
  • Volatile, stabilizted with PEG, lactose
  • Stored in glass because it can be absorbed by plastic
  • Rapid onset (2 mins), moderate duration (30 minutes)
  • Major (33%) urinary metabolite has a terminal Nitrite Group
Erythrityl Tetranitrate D04051.gif
  • Solid, crystalline substance
  • Moderate onset (15 mins)
  • Good duration 3-6 hours
  • Prophylaxis treatment of Angina
Pentaerythritol Tetranitrate D01721.gif per Erythrityl Tetranitrate
Isosorbide dinitrate D00516.gif
  • Solid
  • Oral or Sublingual
  • Onset (2-3 mins SL), (15-30 mins PO)
  • Duration (1-6 hrs) dep. on route
  • Prophylaxis OR acute (that's kinda handy)
  • Metabolized into Isosorbide 5-Mononitrate, as the 5-endo Nitrite is inaccessable to GONR, but is accessible to mtADH
  • Bioactivation is independent of mtALDH

picrender.fcgi?artid=1189320&blobname=zpq0340593140003.jpg

Isosorbide 5-Mononitrate D00630.gif
  • Metabolite of dinitrate
  • Longer Half-life than dinitrate
Molsidomine D01320.gif
  • Prodrug
  • Lower 'Nitrate Tolerance' than other drugs possibly due to different enzymatic activation pathway
  • Carcinogenicity and atherogenicity
  • Peroxynitrite formation
  • Not available in the US - used in Europe for Angina treatment
Molsidomine Metabolism
  1. Ester Hydrolysis
  2. Ring opening
  3. Radical Initiation with Molecular Oxygen

Nitric Oxide Release

753MolsidomineReaction.GIF

Dosage Forms
  • Immediate Release

    • Nitroglycerin (aka Glyceryl Trinitrate)
  • Extended Release

    • Isosorbide? di- or mono- nitrate
    • Erythrityl Tetranitrate
    • Pentaerythritol Tetranitrate
  • Transdermal Nitroglycerin (Transderm-nitro, Nitro-dur)
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