1. Basic & Clinical Pharmacology Influence of liver impairment in the action of sodium thiopental

2. Overview

3. Absorption: pH, stomach and intestinal,physical character of drug. Distribution: Protein binding, selective tissue, regional blood flow, ect Elimination: -Metabolism: enzyme (inhibitor or inducer) -Excretion:Function of kidney Pharmacokinetics(ADME)what the body does to the drug Overview

4. Drug Metabolism and the Liver The liver is the main organ for drug metabolism ; Other tissues that display considerable activity include GI tract, skin, lungs, and kidneys

5. Significance of drug metabolism (1) Drug inactivation: Drugs are often inactivated after biotransformation. (2) Drug activation: some biotransformation products have enhanced activity or toxic properties. Examples: cortisonehydrocortisone prednisone prednisolone Drug Metabolism and the Liver

6. Lipid-soluble agents are metabolized by the liver using two general sets of reactions Phase Ⅰ reactions Frequently involved the P-450 system,a microsomal mixed function oxidase system. Phase Ⅱ reactions Conjugation, mostly with glucuronide. Drug Metabolism and the Liver

7. Drug Following Phase Ⅰ,the drug may be activated, unchanged, or most often, inactivated Phase Ⅰ : Oxidation Reduction and / or hydrolysis Phase Ⅱ : Conjugation Conjugated drug is usually inactive Some drugs directly enter Phase Ⅱ reactions Drug Metabolism and the Liver

8. Most of phase Ⅰ reactions are catalized by the microsomal P-450 enzymes (cytochrome P-450,CYP). CYP3A4 plays role in the metabolism of about 35% of the drugs that are currently prescribed. Drug Metabolism and the Liver

9. Phase Ⅰ reactions 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 Phenytoin,carbamazepine,phenobarbital enhance the acitivity of CYP3A4  pharmacological activity of other drugs ￬ Terfenadine, cimitidine and ranitidine inhibit the acitivity of CYP3A4  pharmacological activity of other drugs ￪ Drug Metabolism and the Liver

10. Effect and Metabolism of thiopental (1)Classfication of barbiturates According to their action duration, barbiturates are classified into : BarbituratesExamplesDuration of action Long actingphenobarbital1-2 days Short actingpentobarbital, secbarbital and amobarbital 3-8 hours Ultra-short- acting thiopental20 minutes

11. With the doses increase from small to large, the effects of barbiturates differ: Action of barbiturates

12. Characteristics of thiopental 1. Very lipid-soluble, penetrating brain tissue rapidly following intravenous administration used for induction of the anesthetic state. 2. Rapidly redistribute in the body from brain to skeletal muscle, and finally to adipose tissue  short duration of anesthetic action quick recovery from anesthesia.

13. Metabolism of thiopental Very lipid-soluble The majority of the drug binds plasma proteins and is not easily infiltrate from glomerular. Easily absorbed from renal tubule Very few original thiopental is eliminated from kidney. Thiopental must be biotransformated by the liver, and eliminated by the kidney liver damage will affect the biotransformation of thiopental and prolong the anesthetic duration.

14. 1) Chemical liver injury 2) Liver injury followed viral infection Carbon tetrachloride Acetaminophen galactosamine (D-GalN) Thioacetamide (TAA) 3) Liver injury induced by Ischemia / reperfusion Liver injury model

15. Carbon tetrachloride is a hepatotoxic chemical and used to build liver injury model and hepatic fibrosis model

16. Objective: To observe the influence of liver impairment in the anesthetic action of thiopental sodium Materials 1.Animals:20 ICR mice, weight 25-30 g,2 mice each group. 2. Drugs: 10% carbon tetrachloride, 0.5% thiopental sodium, normal saline. 3. Instruments: balance, surgical scissors, syringe (1 ml ), stopwatch. Protocol

17. Step 1(done by the lab stuff 24hr before the experiment) Mice are divided randomly into 2 groups and marked. 1.Liver injury group-10% carbon tetrachloride (0.2 ml/10 g) is subcutaneously injected to create the model of liver impairment. 2.Control group-saline is injected as control 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)

18. 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) Protocol

19. Groups Thiopental sodium (mg/kg ) Number of cases Anesthetic action (min) Appearance of livers Latent period Anesthetic duration Healthy control _ Liver injuried Table 1 Influence of liver impairment on the action of thiopental sodium Notes: Data are expressed as means  SD. Protocol

20. Experiment report 1.Title 2.Materials and methods 3.Results(Data are expressed as means  SD) 4.Discussion 1)What happens to the anesthesia action duration of thiopental sodium when the liver function is impaired? 2)What is the clinical significance of the results gained from the experiment ?