Pharmacodynamic models of nitroglycerin-induced hemodynamic tolerance in experimental heart failure.
Pharmacodynamic tolerance during continuous nitroglycerin (NTG) infusion is a significant limitation of nitrate therapy. The mechanism of this phenomenon is not well-understood but may involve physiologic compensation which involves vasoconstriction. We have obtained pharmacodynamic data on NTG-induced hemodynamic tolerance in a rat model of congestive heart failure (CHF), which we have shown to mimic human behavior toward NTG in vivo. In this report, we developed two mechanism-based pharmacokinetic/pharmacodynamic models to describe the time-dependent effects of NTG infusion on left ventricular end-diastolic pressures (LVEDP) in CHF rats and compared their abilities to describe the observed hemodynamic data. Both mathematical models introduced a counter-regulatory vasoconstrictive effect as a result of NTG-induced vasodilation and assumed the magnitude of this effect to be driven by the extent of the initial hemodynamic effect produced by NTG. The decay of this counter-regulatory effect was described by a first-order process in both models. A model that assumed vasoconstriction to develop via two sequential first-order processes was statistically superior in describing the data, when compared to one that assumed a single first-order process and a lag phase. Both models provided similar estimates of the half-life for the disappearance of the vasoconstriction (t1/2 of vasoconstriction: 128min vs. 182min, respectively), and both predicted rebound elevation of LVEDP after abrupt NTG withdrawal. These results are consistent with a counter-regulatory mechanism of NTG-induced hemodynamic tolerance and suggest that such an approach may be useful for modeling other tolerance phenomena as well.
Bauer
J A
JA
Department of Pharmaceutics, State University of New York at Buffalo 14260.
Fung
H L
HL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004361:Drug Tolerance; D006207:Half-Life; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008954:Models, Biological; D005996:Nitroglycerin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D005996:Nitroglycerin