Nitroglycerin plasma concentrations

Lefebvre RA, Bogaert MG, Teirlynck O, Sioufi A, Dubois JP. Influence of exercise on nitroglycerin plasma concentrations after transdermal application. Br J Clin Pharmacol 1990 30(2) 292-6. 

Tolerance to nitrates is defined as the reduction in hemodynamic effect or the requirement for higher doses to achieve a persistent effect with continuous use in the face of constant plasma concentrations [15]. Nitrate tolerance was first described for nitroglycerin in 1888 [36] it occurs with all organic nitrates, albeit to different extents. For reasons that are not understood, PETN appears to be the least susceptible to the development of tolerance. No, or much less, tolerance is observed with nitrite esters, such as amyl nitrite [37], molsidomine, and sodium nitroprusside. Earlier investigations suggested that a depletion of intracellular thiols is involved in tolerance development [17], but this has not been substantiated in later studies [38, 39]. As with organic nitrate bioactivation, the precise mechanism(s) involved in nitrate tolerance remain(s) unknown, but it is likely to be complex and multifactorial. Two principal... 

Figure 8.6 Plasma concentration versus time profiles obtained following administration of different transdermal nitroglycerin systems for 24 hours (Modified from Transdermal Delivery Systems A Medical Rationale. Cleary, G.W. In Topical Drug Bioavailability, Bioequivalence, and Penetration. Shah, V.P. and Maibach, H.I. Eds. Plenum Press, New York, 1993, pp 17-68)...

If absorption is slow, and the apparent absorption half-life is much longer than the elimination half-life, then the dose regimen can be based on the apparent half-life of the absorption phase. Changing the formulation is a relatively common approach that is taken for short-acting drugs to extend the duration of absorption. The elimination half-life of nitroglycerin is approximately 2 min. However, nitroglycerin from a transdermal formulation is slowly released, and therapeutic plasma concentrations can be maintained for 24 h. 

Fig. 6 Cross-sectional view of a unit of Transderm-Nitro system, showing various structural components, and plasma concentration profiles of nitroglycerin in 14 human volunteers, each receiving one unit of Transderm-Nitro system (20 cm, with a delivery rate of lOmg/day) for 24h. (From RefsJ l)...

D Rifampin significantly reduces the plasma concentrations of the calcium channel blockers verapamil, diltiazem, and nifedipine. Diltiazem is a substrate of Gi P3A4 and rifampin is an inducer of CYP3A4. Rifampin does not interact with metoprolol, aspirin, pravastatin, or nitroglycerin. However, if the patient had been on another HMG-CoA reductase inhibitor such as atorvastatin, lova-statin, or simvastatin instead of pravastatin, rifampin would have reduced the plasma concentrations of these agents since they are also metabolized via CYP3A4. 

Nitroglycerin is only marketed for the prevention of angina pectoris in humans and the US Food and Drug Administration did not approve its use for the treatment of CHF. If therapeutic plasma concentrations can be achieved in horses, nitroglycerin would be useful for reducing venous return and preload in horses with acute CHF. However, there are no data to support its use in CHF in any veterinary species. 

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