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Basic & Clinical Pharmacology Influence of liver impairment in the action of sodium thiopental 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: 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 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. 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 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 Due to its high lipid-solubility •The majority of thiopental binds plasma proteins and is not easily infiltrate from glomerular. •Easily absorbed from renal tubule Very few original thiopental is eliminated from kidney . Liver injury induced by carbon tetrachloride 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(prepared 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 Protocol 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 ?