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33 Cards in this Set
- Front
- Back
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What is the major mech for drug elimination?
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biotransformation
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What teminates the pharm activity of most drugs?
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Metabolism (metabolites can be more active [eg prodrugs])
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Which cells have the greatest capacity for metabolism
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liver hepatocytes
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What factors can affect biotrans?
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Prior drug admin, drug co-admin, physiological status, age, gender, genetic diff form isozymes, metabolizing organ fcn
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What are some possible outcomes of biotrans?
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*Inactive, inc or dec potency, w/ diff pharm actions, toxic metabolites, or activated prodrugs
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How many steps are there in drug metabolism?
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In biphasic
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Describe phase I of metabolism.
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The cellular enzymes introduce reactive groups into the drug
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Describe phase II of drug metabolism.
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The cell performs an conjugation rxn using the active group from phase 1 & conjugating agents form the cell
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What optimizes metabolism?
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Both phase I & II coupled tightly & balanced
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What can lead to accumulation of active metabolites?
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Interference w/ phase II conjugation
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What are the 2 general categories of drugs? How are they eliminated?
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Polar/hydrophilic(elimin in urine) & Nonpolar/hydrophobic (need to be converted to more soluble form)
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What category are most thereuptic drugs?
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Nonpolar/hydrophobic (most act in cell membranes & CNS)
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What can enhance elimin?
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Introduction of ionizable groups (b/c they are more soluble)
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What enzymes catalyze phase I?
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Cyto P-450, aldehyde/alcohol dehydrogenase, deaminase, esterase, amidase, epoxyhydrolases
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What enzymes catalyze phase II?
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Glucuronyl transferase, sulfotransferase, transacylase, acetylase, methylase, **glutathione transferase
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Where are phase I & II enzymes located? Which are inducible by drugs?
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Cytosol, mito, **SER (inducible)
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What are the general charac of Cyto P-450?
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Large family, specificity w/ overlap,catalyzes numerous interaction, freq phase I rxns
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What is the overall rxn scheme of cytoP-450?
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Drug +O2+NADPH+H -> Drug-OH + NADP +H2O
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Where is cyto-p450 located?
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Liver has higher concen but located in many tissues. In lipid membrane of SER (aids in meta of lipid-soluble drugs)
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Describe induction of cyto p-450.
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Amt inc by drugs or endogenous substances, involves de novo mRNA/protein synthesis
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Why is induction clinically important?
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A drug may induce its own metabolism (dec t1/2 & inc clearance) or meta of other drugs. ***major cause of drug interactions
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What may cause a reduction in rate of metabolism?
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When biotransformation is so rapid that hepatic blood flow is the rate limiting step
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What can dec hepatic blood flow?
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The drug itself, co-admin drug, disease process, hepatotoxic agents, covalent binding of reactive meta intermed destroy enzyme fcn
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What are the general features of glucuronyl transferase?
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most common in phase II, located in ER & inducible by some drugs, serious drug interaction if cofactors for conjugation are depleted by other drugs
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What is the fcn of glucuronyl transferase?
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Catalyzes conjugation of glucuronic acid to a variety fcnal groups (OH, COOH, SH, NH2- all from phase II)
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What is the mech of action of glucuronyl transferase?
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UTP+glucose 1-phosphate -> UDP-glucuronic acid. Then glucuronyl transferase catalyzes conjugation to active center of the drug
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What is clearance?
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The loss of drug across an organ of elimin primarily through metabolism
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What determines the degree of clearance?
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Depends on the physical-chemical properties of the drug & liver enzyme sys involved
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What is the extraction ratio?
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ER= (Ca -Cv)/Ca {ranges from 0 to 1)
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What is hepatic clearance?
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Cl= Q x ER
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How is clearance affected by high extraction ratio?
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Clearance will = liver blood flow
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How does low extraction ratio affect clearance?
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Not affected by blood flow. But affected by changes in blood protein binding & changes in metabolic enzyme activity
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What factors affect drug metabolism in clinical situations?
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Induction, inhibitors, poor health, nutrition, genetic polymorphisms, age, gender
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