Influence of liver impairment in the action of sodium thiopental 1 what the body does to the drug 1.1 Absorption: pH, stomach and intestinal,physical character of drug. 1.2 Distribution: Protein binding, selective tissue, regional blood flow, ect 1.3 Elimination: -Metabolism: enzyme (inhibitor or inducer) -Excretion:Function of kidney The liver is the main organ for drug metabolism ; Other tissues that display considerable activity include GI tract, skin, lungs, and kidneys 2 Significance of drug metabolism 2.1 Drug inactivation: Drugs are often inactivated after biotransformation. 2.2 Drug activation: some biotransformation products have enhanced activity or toxic properties. Examples: cortisone 3 Biotransformation 3.1 Phase Ⅰreactions Frequently involved the P-450 system,a microsomal mixed function oxidase system. 3.2 Phase Ⅱreactions Conjugation, mostly with glucuronide. 3.3 Microsomal P-450 enzymes 3.3.1 Most of phase Ⅰreactions are catalized by the microsomal P-450 enzymes (cytochrome P-450,CYP). 3.3.2 CYP3A4 plays role in the metabolism of about 35% of the drugs that are currently prescribed. 3.3.3 Phase Ⅰreactions are the basis of one mechanism of drug interaction. Enhancement or inhibition of CYP3A4 by one drug will affect the levels of any other drug that is also metabolized by CYP3A4. Examples logical activity of other drugs↓ of other drugs↑ 4 Animal models of liver impairment Carbon tetrachloride is a hepatotoxic chemical and used to build liver injury model and hepatic fibrosis model 5 Objective: To observe the influence of liver impairment in the anesthetic action of thiopental sodium 6 Protocol 6.1 Materials 6.1.1 Animals:20 ICR mice, weight 25-30 g ,2 mice each group. 6.1.2 Drugs: 10% carbon tetrachloride, 0.5% thiopental sodium , normal saline. 6.1.3 Instruments: balance, surgical scissors, syringe (1 ml ), stopwatch. 6.2 Methods 6.2.1 Step 1(done by the lab stuff 24hr before the experiment) Mice are divided randomly into 2 groups and marked. Liver injury group-10% carbon tetrachloride (0.2 ml/10 g) is subcutaneously injected to create the model of liver impairment. Control group-saline is injected as control 6.2.2 Step 2 24 hours after carbon tetrachloride administration, 0.5% thiopental sodium (0.1 ml/10 g) is intraperitoneally injected for mice in both 2 groups. Observe the response of mice. Record the time of disappearance and recovery of righting reflex, respectively.(Note:loss of righting reflex is an indication of the anesthetic state caused by thiopental) 6.2.3 Step 3 Execute mice by dislocation of the cervical vertebra; Open the abdomen to take out the livers and compare the appearance between them. (note the livers of mice injected with carbon tetrachloride will be different with the healthy mice in size, color and granular texture) 6.3 Discussion 6.3.1 What happens to the anesthesia action duration of thiopental sodium when the liver function is impaired? 6.3.2 What is the clinical significance of the results gained from the experiment ?