Basic & Clinical Pharmacology

Influence of liver impairment in the action of sodium thiopental

Overview

•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

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

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: cortisonehydrocortisone prednisone prednisolone

Drug Metabolism and the Liver

Lipid-soluble agents are metabolized by the liver using two general sets of reactions

Phase Ⅰreactions

•Frequently involved the P-450 system,a microsomal mixed function oxidase system.

Phase Ⅱreactions

•Conjugation, mostly with glucuronide.

Drug Metabolism and the Liver

Drug

Following Phase ,the drug may Ⅰbe activated, unchanged, or most

often, inactivated

Phase : Ⅰ Oxidation Reduction and / or hydrolysis

Phase :ⅡConjugation

Conjugated drug is usually inactive

Some drugs directly enter Phase reactionsⅡ

Drug Metabolism and the Liver

• Most of phase reactions are catalized by Ⅰ 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

• Phase reactions are the basis of one mechanism of Ⅰdrug 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

Effect and Metabolism of thiopental

(1)Classfication of barbiturates According to their action duration, barbiturates are classified into :

Barbiturates Examples Duration of action

Long acting phenobarbital 1-2 days

Short acting pentobarbital, secbarbital and amobarbital

3-8 hours

Ultra-short-acting

thiopental 20 minutes

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

Action of barbiturates

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.

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.

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

Liver injury model

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

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

Protocol

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)

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

GroupsThiopental

sodium (mg/kg )

Number of

cases

Anesthetic action(min)

Appearanceof liversLatent

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

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 ?