Individual variation in response to thiopentone

The purpose of this study was twofold. The first one was to quantify differences in dose requirements for thiopentone in different patient groups and the second one was to point out and elucidate possible explanations for the observed differences. Pharmacodynamic aspects were studied by comparisons of doses and serum concentrations associated with the achievement of obtundance of the eyelash reflex. Also the effect of thiopentone on cardiovascular system was studied in vivo and in vitro. For the study of the in vitro effect rings of the rabbit pulmonary artery were used in vivo the cardiac effect of thiopentone was assessed by impedance cardiography. Classical compartmental analysis of serum concentration/time relationship after administration of anaesthetic doses of thiopentone was performed to establish comparable pharmacokinetic data. Furthermore unbound and protein-bound levels of thiopentone were measured and assessed. The analysis of thiopentone was based on high pressure liquid chromatography and separation between bound and unbound drug was done by ultrafiltration as well as equilibrium dialysis. The binding of thiopentone in human serum and in a physiological saline solution (PSS) with 45 g albumin per litre was 85% and remarkably constant over the concentration range between 4 and 80 micrograms/ml. At lower drug concentration the binding increases and was 87% at 0.4 micrograms/ml. The increase was more pronounced at pH 6 and 6.8 than at pH 7.4 while no increase was observed at pH 9.0. The percentage binding increases with increasing pH from approximate 75% at pH 6.0 to a maximum value of 95% at pH 9.0. This increase in binding with increasing pH might be explained by the simultaneous transition of N-albumin to B-albumin. The albumin binding was at a higher level after reduction of the temperature from 37 degrees C to 2 degrees C. The partition coefficient between olivaoil and PSS also showed an increase by this change in temperature. The very moderate changes in binding over long ranges of drug concentration made it difficult to obtain reliable expressions for thermodynamic parameters which could characterize the nature of the binding. It was suggested that the nature of the protein binding could be characterized best as a solution of the drug in hydrophobic areas of the albumin molecule. The average percentual binding on serum has been shown reduced in patients with deteriorated kidney and liver function and also in elderly subjects, in pregnant women and in newborns. The reduced binding may explain the increased values for total body clearance and for volumes of distribution found in patients with kidney failure.(ABSTRACT TRUNCATED AT 400 WORDS)