Pharmacy - Organic Nitrates

Indications	Angina Neonatal Hypoxia Dilation of the pulmonary system
Modes of Action	Increase oxygen extraction from blood Decrease oxygen requirement
Research Paper on the Physiological effect of Organic Nitrates on Cardiac function	Significantly Decreases Preload Decreases Afterload by inducing Vasodilation
Rank the sensitivity of tissues to Organic Nitrates	Veins Arteries Arterioles this is the reverse of most other agents, making Organic Nitrates uniquely suited for treatement of Angina
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	According to term papers: decrease Cardiac Load by reducing peripheral resistance Improve perfusion of coronary vasculature Both direct and indirect effects Block Platelet Aggregation via release of Nitric Oxide
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
Use	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	Bradycardia Tachycardia Hypotension Right Ventricular Infarction
Theories on Mechanism of Tolerance to Organic Nitrates	Cannot sustain Nitric Oxide production Damage to endothelial layer, resulting in lower enzyme concentrations Loss of Bradykinin Compensatory increase in physiological antagonists (e.g. increase in Endothelin)
Compensation for Tolerance	Take a Nitro vacation
Contraindications	Shock Hemmorage (due to blocking of Platelet Aggregation) Phosphodiesterase Type 5 Inhibitors (due to potentially fatal Vasodilation and Hypotension
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)

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	Glutathione-Organic Nitrate Reductase (GONR) frees Nitrite (NO2-) from the Organic Nitrate using two molecules of Glutathione Nitrite is oxidized in the blood to Nitrate (NO3-) Nitrate undergoes Renal Elimination 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)		Volatile yellow liquid Rapid onset (30-60 secs), short duration (1-2 mins)
Glyceryl Trinitrate		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		Solid, crystalline substance Moderate onset (15 mins) Good duration 3-6 hours Prophylaxis treatment of Angina
Pentaerythritol Tetranitrate		per Erythrityl Tetranitrate
Isosorbide dinitrate		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
Isosorbide 5-Mononitrate		Metabolite of dinitrate Longer Half-life than dinitrate
Molsidomine		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	Ester Hydrolysis Ring opening Radical Initiation with Molecular Oxygen Nitric Oxide Release

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)