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Title: Hydralazine : the interaction with lipophilic beta-adrenoceptor antagonists and the relative anti-vasoconstrictor activity of its hydrazones in vitro
Author: Spalding, D. J. M.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1986
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The mechanism of the hydralazine/propranolol pharmacokinetic interaction was investigated using the rat as an animal model. Hydralazine infused intraportally, either 15 minutes prior to, or concurrently with propranolol, caused a 2-fold and 4-fold increase in the area under the blood concentration-time curve for propranolol respectively. The extent of the interaction in the rat is thus greater than that in man, where a 2-fold increase is seen. In contrast, the calcium antagonist nifedipine had no significant effect upon the kinetics of propranolol. The interaction could be explained by an increase in propranolol protein binding, a decrease in propranolol hepatic metabolism or a transient increase in hepatic blood flow. Hydralazine caused a 15% and 22% reduction in the metabolism by rat liver microsomes in vitro, of aminopyrine and propranolol respectively, although the effect on propranolol metabolism was not statistically significant. In addition, although hydralazine caused small dose-dependent increases in hepatic blood flow, whilst nifedipine caused small reductions in flow, there was no statistically significant effect of either drug. Furthermore, rather than causing an increase in the binding of propranolol, hydralazine and its pyruvate hydrazone caused a significant decrease in propranolol binding to rat serum. The data suggest that an effect of hydralazine on the intra-sinusoidal shunting of blood, rather than an effect upon total hepatic blood flow, could contribute to this interaction and merits investigation. The human radial artery obtained post mortem was used to evaluate the hypotensive effects of hydralazine and its hydrazones. Hydralazine and its acetone hydrazone were equipotent in antagonising potassium- and noradrenaline-induced contractures, whilst the pyruvate and α-ketoglutarate hydrazones had no significant activity. The data indicate that levels of 'apparent' hydralazine, which consist mainly of the pyruvate hydrazone, are a poor indicator of the pharmacodynamic effects of hydralazine.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available