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