Download Drug Metabolism and the Liver

Basic & Clinical Pharmacology
Influence of liver impairment in
the action of sodium thiopental
Overview
Overview
Pharmacokinetics(ADME)what the body does to the drug
•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
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
Drug Metabolism and the Liver
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
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
Phase Ⅰ:
Oxidation
Reduction and
/ or hydrolysis
Following Phase Ⅰ,the drug may
be activated, unchanged, or most
often, inactivated
Some drugs directly enter
Phase Ⅱreactions
Phase Ⅱ:
Conjugation
Conjugated
drug is
usually
inactive
Drug Metabolism and the Liver
• Most of phase Ⅰreactions 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
• 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
•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￪
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-shortacting
thiopental
20 minutes
Action of barbiturates
With the doses increase from small to large, the effects of
barbiturates differ:
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.
Liver injury model
1) Chemical liver injury
Carbon tetrachloride
galactosamine (D-GalN)
Thioacetamide (TAA)
Acetaminophen
2) Liver injury followed viral infection
3) Liver injury induced by Ischemia / reperfusion
Liver injury model
Carbon tetrachloride is a
hepatotoxic chemical and
used to build liver injury
model and hepatic fibrosis
model
Protocol
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
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)
Protocol
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
Table 1 Influence of liver impairment on the action of thiopental sodium
Groups
Healthy
control
Thiopental Number
sodium
of
(mg/kg )
cases
Anesthetic action
(min)
Latent
period
Anesthetic
duration
_
Liver
injuried
Notes: Data are expressed as means  SD.
Appearance
of livers
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 ?