Relationship of Pharmacokinetic and Pharmacodynamic Properties of the Organic Nitrates

Abstract

Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate are, in various formulations, available for clinical use. The pharmacokinetics of glyceryl trinitrate are complex and only 1% of the drug administered orally can be detected in the plasma due to a pronounced arteriovenous concentration gradient, hydrolysis in the blood, and rapid denitration in the liver. There is a poor and usually transient correlation between plasma concentrations and therapeutic effects, due in part to the complex pharmacokinetics of glyceryl trinitrate, but primarily due to development of tolerance during continuous administration, either via the intravenous or cutaneous route. Isosorbide dinitrate kinetics are complicated by its extensive metabolism into 2- and 5-mononitrates, which are pharmacologically active, and which also accumulate more than the parent drug during long term treatment. These facts, combined with development of tolerance during long term therapy, preclude the establishment of a concentration-response relationship. Isosorbide-5-mononitrate has ideal and dose-linear kinetics and is nearly 100% bioavailable after oral administration. However, tolerance develops during long term therapy, and therefore a relationship between plasma concentrations and clinical effects cannot be established. On the basis of available data, plasma concentrations of various nitrates do not reliably predict clinical effects.

A Study to Determine the Nitroglycerin Ointment Dose and Dosing Interval That Best Promote the Healing of Chronic Anal Fissures

“…The clinical pharmacology and pharma- 26,27 NTG is metabolized by cells to yield NO. NTG has been administered to humans by oral, sublingual, intravenous, and transdermal routes.…”

Nitroglycerin is superior to diltiazem as a coronary bypass conduit vasodilator

“…Vessel segments were then exposed to increasing doses of nitroglycerin or diltiazem (10 -9 -10 -5 mol/L), and dose-response curves were recorded. The ability to prevent radial artery spasm was assessed by dose-response curves to U46619 in baths containing PSS alone (control) or physiologic concentrations of nitroglycerin (0.1 µmol/L) 14 or diltiazem (1 µmol/L). 9 In vivo radial artery vasodilatory studies.…”

Cardiolipin-cytochromeccomplex: Switching cytochromecfrom an electron-transfer shuttle to a myoglobin- and a peroxidase-like heme-protein

“…Accounting for in vitro kinetic, thermodynamic, and catalytic parameters of CL–cyt c listed in Table , therapeutic levels of NO could affect only cyt c (II) reactivity. In fact, although a direct relationship between plasma nitrate and nitrite concentrations (generally taken as precursors and end‐products of NO metabolism) and clinical effects of NO‐donors cannot be firmly established, plasma NO levels in the micromolar range may be reached after drug administration .…”