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Relationship of Pharmacokinetic and Pharmacodynamic Properties of the Organic Nitrates

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  • Pharmacokinetk-Pharmacodynamic Relationships
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Summary

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% bio-available 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.

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  1. Oklahoma University Health Sciences Center, P.O. Box 26901 - Cardiology, Oklahoma City, OK, 73190, USA

    Udho Thadani (Professor of Medicine) & Thomas Whitsett

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Thadani, U., Whitsett, T. Relationship of Pharmacokinetic and Pharmacodynamic Properties of the Organic Nitrates. Clin-Pharmacokinet 15, 32–43 (1988). https://doi.org/10.2165/00003088-198815010-00003

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