THE LIVER AS A STORAGE COMPARTMENT FOR MUSCLE RELAXANTS DETERMINING THEIR DURATION OF ACTION: ~CHANISMS FOR HEPATIC ACCUMULATION

t 227 W.E.M. Mol, Ch. Hollen~a, A. Bencini %,is. Agoston , D.K.F. Meijer, Department of

Pharmacology and Pharmacotherapeutics, Department of Pharmacology and Clinical Pharmacology, University of Groningen, The Netherlands.

Rapid uptake and accumulation in the liver terminates the muscle relaxing effect of vecu- ronium in animals and man resulting in a very short duration of action. In contrast, the structurally related pancuronium (N-methyl-vecuronium) shows a minimal net liver uptake and a much longer duration of action. The curare-llke agent vecuronium contains a single quater- nary nitrogen as well as a tertiary amine group (pKa=8.5), whereas, pancuronium possesses two quaternary ammonium groups. Initial clearance by rat liver of vecuronium and pancuronium was 29+4 and 0.3+0. i ml/min respectively. Pharmacokinetic analysis of the clearance profiles ob- taTned in isolated perfused rat livers suggests that the small net hepatic uptake of pancu- ronium is caused by a very efficient efflux from the liver to the plasma. We studied this as- pect of the hepatic transport mechanism in more detail to check differences in the primary up- take mechanism or in intrahepatic distribution and/or hepatic efflux. Vecuronium but not pan- curonium was rapidly excreted into bile in the form of unchanged compound and the deacetylated 3-hydroxy derivative (both about 30% of the dose). Chromatographic studies showed that predo- minantly the non-active 3-OH metabolite was transported from liver back into the perfusate. K-Strophanthoside, a potent inhibitor of hepatic accumulation of curare-like agents markedly increased the efflux of the 3-OH-vecuronium to the perfusate but only slightly affected prima- ry uptake and intracellular binding of vecuronium. It largely affected hepatic accumulation of preformed 3-OH-vecuronium added to the perfusion medium. It is concluded that the large dif- ference in hepatic net uptake of these muscle relaxants occurs at the hepatic efflux level, a plasmamembrane-transport step that is somehow largely affected by cardiac glycosides. A better insight in this aspect of net uptake will increase our understanding of liver storage function in relation to duration of effects as well as potential hepatic release into the general cir- culation of muscle relaxants.

THE EFFECT OF DIFFERENT ANAESTHETIC AGENTS ON CARDIOVASCULAR RESPONSIVENESS TO VARIOUS VASOACTIVE AGENTS IN BILE DUCT LIGATED DOGS.

228 I. Monies-Chass*, L. Kamenet~, B. Pinhassi and A. Bomzon**

*Department of Anaesthesia, Rambam Medical Center, Haifa, and **Department of Pharmacology, Faculty of Medicine and Rappaport Family Inst i tute for Medical Research, Technlon, Haifa, Israel.

Anaesthetic agents can a l te r blood pressure (BP) and i ts ref lex control by influencing car- diac output, peripheral resistance or its centra] control. Conscious bi le duct l igated dogs (BDL) have attenuated pressor responses to noradrenaline (NA) and angiotensin II (A l l ) , and this blunted response is thought to be important in the development of post-operative shock in patients with obstructive jaundice. The effect of the combination of anaesthesia and BDL on the cardlovascuIar responsiveness is not known. Hence, the study has investigated the effects of ha]othane, fentanyl and pentobarbitone anaesthesia on the cardiovascular responses to NA, All and isoprena]ine (ISUP) in BDL and sham-operated (SO) dogs and compared to the responses observed in conscious BDL and SO dogs. BDL, as anticipated in the conscious dogs, caused a tendency towards hypotension, a reduction in heart rate (HR), reduced pressor responsiveness to intravenous infusions of NA and A l l , as well as an attenuated tachycardiac response to IUSP without reducing BP. Anaesthesia, prior to BDL and irrespective of the agent used, reduced BP, increased HR, reduced pressor response to A l l , but not to NA, and attenuated the tachycardiac response but potentiated the fa l l in BP following ISUP infusion. When the same responses weFe measured under anaesthesia in the BDL dogs, we observed a lowered BP, enhanced responsiveness to A l l , NE and ISUP. These changes were not observed in the 4 SO sogs. In conclusion, we have demonstrated that anaesthesia in jaundice potentiates the responsiveness of the cardio- vascular system indicating that anaesthesia may "protect" the patient from shock during surg- ery.

$292