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36 Cards in this Set
- Front
- Back
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1. What does the liver do to a drug
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a. Makes it more water soluble
b. Detoxifies |
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2. Review: describe first pass effect
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a. Put in drug
i. Goes to heart 1. Goes to body and gut a. Moves to liver i. Metabolized 1. Whatever is left over is the bioavailability |
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3. Why is metabolism important for filtration of drugs?
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a. Makes nonpolar drugs more polar, making them more easily excreted
i. metabolism that decrease LS can be essential for eliminating a drug from the body |
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4. Describe the 'prodrug' concept and explain its potential clinical utility
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a. Drug put in body in the INACTIVE form
i. Metabolism may activate a drug 1. This is the prodrug concept |
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8. Discuss the role of metabolism in acetaminophen toxicity.
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8. Discuss the role of metabolism in acetaminophen toxicity.
b. Minor pathway i. CYP450 will metabolize it into reactive toxic intermediates 1. Typically this is not an issue because you have glutathione or other oxidases that can change the toxic intermediates into non-toxic metabolites c. With overdose i. You overuse the major pathway, so the minor pathway takes over 1. You use up the glutathione a. Now you have free radicals reacting with proteins and killing the hepatocytes i. Leading to liver failure |
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a. Phase I
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i. P450s
ii. Makes drug more water soluble iii. Most phase I products not eliminated rapidly iv. Redox reactions v. Basically adding small polar groups |
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b. Phase II
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i. Glutathiones
ii. Conjugation (putting to big molecules together) iii. Endogenous substrate added to drug by acetylation, glucuronidation or sulfation iv. Usually forms a highly polar, inactive metabolite that is renally excreted v. Phase I may or may not be required |
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What are the types of phase II reactions (5)
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Glucuronidation
Acetylation Glutathione conjugation Glycine conjugation Methylation GAGGMe! |
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11. Where is the principle site of biotransformation
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a. Liver
i. Other tissues may have some metabolism capacity (which may be important for a specific drug) |
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12. Describe the general characteristics of the microsomal mixed function oxidase enzyme system. (what type of rxn is most common, what 2 things does it require)
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Note that this is a Phase I reaction...
a. Oxidations most common b. Enzymes are membrane bound i. Take place in the endoplasmic reticulum (microsomes) c. Requires NADPH and O2 i. One atom of oxygen goes into forming H2O and the other goes into the drug |
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13. What metabolizes about half of the clinically used drugs?
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a. CYP3A4, part of phase I metabolism (the P450 family)
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14. Discuss CPY3A4 (how much of it there is, specificity, susceptibility to inhibition/induction)
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a. Predominant CYP in liver and intestine (~30% of hepatic, up to 60 in some)
b. Most clinically significant enzyme in drug metabolism c. Broadest specificity i. Thus susceptible to metabolic drug-drug interaction d. Very susceptible to induction and inhibition i. Inducers include rifampin, St. John’s Wort, phenobarbital, glucocorticoids, carbamazepine ii. Inhibitors include macrolide antibiotics, some antifungals, and many others |
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15. If an enzyme that’s role is to metabolize something, what will an inducer do to that enzyme?
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a. Increase its metabolic activity
b. Thus it will decrease the lvls of whatever the enzyme metabolizes |
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16. What effect does grapefruit juice have on the body?
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a. Inhibits intestinal CYP3A4
b. Can decrease enzyme activity by 50% c. Can affect antiarrythimics, calcium channel blockers, statins, immunosuppressants, protease inhibitors d. Effect can persist for up to 72 hours |
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17. What is the importance of CYP2D6
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a. Metabolizes 30% of drugs
b. Has considerable polymorphism (this is important) i. Slow metabolizers ii. Efficacy vs. toxicity c. More than 20 mutant alleles and considerable racial diversity in frequency |
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18. What are the CYP2D6 polymorphic subpopulations?
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a. Poor metabolizers
b. Intermediate metabolizers c. Extensive d. Ultra-rapid e. The 1st and last are the important ones to note |
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19. What are some of the key things CYP2D6 metabolizes?
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a. Antipsychotic medications
b. B-blockers c. Antiarrythmics d. Opiates (converts codeine to morphine, necessary for codeine’s effect, poor metabolizers have no effect) Always bring awesome opiates |
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22. What does phase I often provide for phase II?
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a. A site on the drug molecule for a phase II rxn to occur
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23. What kind of reactions are phase II?
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a. Conjugation reactions
i. Attaches a large water soluble molecule to the drug ii. Greatly increases water solubility of drug that enhances excretion of LS drug |
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25. What is most frequent form of a phase II rxn?
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a. glucuronidation
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26. What enzyme is involved in Glucuronidation? What does it do?
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a. Uridine diphosphate (UDP) glucuronosyl transferase (aka UGT)
i. catalyzes transfer of glucuronic acid from UDP-glucuronic acid (co-factor) to a drug |
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27. After glucuronidation, what are most drugs excreted as
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a. glucuronides
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28. What type of functional groups does glucuronic acid attach to?
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a. NH2, SH, COOH, OH
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29. What does glucuronidation do?
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a. Increases polarity and H2O solubility
b. Helps lead to rapid elimination by the kidneys |
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30. What does glutathione do?
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a. Plays important role in protecting cells against toxic injury ... especially oxidative damage
i. protects against free radicals, electrophiles, reactive metabolites |
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31. What does induction do (for example to CYP p450s)?
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a. Increased enzyme level (eg CYP P450)
i. greatly increases the rate of metabolism of many drugs |
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32. What is a classic example of an inducer?
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phenobarbital
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33. Are all P450 isozymes induced the same way?
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a. No
b. one inducer (drug) may increase the level of one isozyme but not others |
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34. What phase II process can be affected by induction?
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a. UGT systems (glucuronidation)
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35. What is an autoinducer?
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1. An inducer that increases the rate of its OWN metabolism
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36. What is tolerance?
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a. Classic ex: Barbiturates stimulate synthesis of enzymes that increases metabolism of itself
b. Have to keep increasing dose to maintain effect |
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37. What are drug interactions
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a. increase or decrease therapeutic effects & /or toxicity
b. Effect on drug plasma concentration, first pass, bioavailability? i. May need to increase dose to maintain effect |
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38. Induction uses what type of synthesis? What does this mean?
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a. De novo synthesis
b. Induction requires hours to days to manifest c. Can take days (or longer) for metabolic activity to return to normal levels |
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39. What is a significant inhibitor of P450?
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a. cimetidine (Tagamet)
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40. Is phase I (P450) or phase II (conjugation) metabolism more affected by age and liver disease?
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a. Phase I
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What is a typical inducer besides phenobarbital (one that old people like to use like crazy)
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St. John's Wort
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