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47 Cards in this Set
- Front
- Back
Define metabolism/biotransformation |
enzyme mediated alteration of a drug's structure |
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Name 5 sites of drug metabolism |
1. Liver (Primary Site) 2. Intestine (Enterocytes can metabolize) 3. Stomach (especially alcohol) 4. Kidney (contains many drug metabolizing enzymes) 5. Intestinal bacteria (in the lumen) |
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What are two roles of drug metabolism? |
to protect us from environmental toxins, and synthesize essential endogenous molecules |
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T/F - the same family of enzymes that synthesize exogenous molecules, metabolize endogenous molecules |
False. - the same family of enzymes that metabolize exogenous molecules, synthesize endogenous molecules |
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Name 5 consequences of drug metabolism on the drug. |
1. The Water solubility of the drug may be increased to promote excretion. (This is the most important consequence of drug metabolism) 2. Drug Inactivation 3. Increase in drug effectiveness 4. Drug activation (prodrugs are inactive until metabolized) 5. Increase drug toxicity |
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Explain first order kinetics |
In situations where the amount of free drug is less than the metabolic capacity, first order kinetics is displayed. This is when the rate of metabolism is directly proportional to the concentration of the free drug, so a constant fraction of free drug is getting metabolized per unit time (i.e. 1% per second) |
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Is first order kinetic independent, or dependent of drug concentration? |
Dependent. Rate of metabolism is directly proportional to drug concentration. |
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Do most drugs exhibit first, or zero order kinetics? |
First! :) |
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Explain zero order kinetics |
In zero order kinetics, the concentration of the free drug is much higher than the metabolic capacity of the body. Rate of drug metabolism is constant over time. A constant amount of drug is metabolized per unit time. |
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Is zero order kinetics independent, or dependent of drug concentration? |
independent. A constant amount of drug is metabolized per unit of time. |
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What is a classic example of a drug that displays zero order kinetics? |
Alcohol |
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What are 4 areas of first pass metabolism? |
Hepatocytes, intestinal enterocytes, stomach, intestinal bacteria |
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What is the primary result of first pass metabolism |
a decreased amount of parent drug in the systemic circulation |
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name 4 characteristics of high ER drugs |
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Name 4 characteristics of low ER drugs |
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What is the function of phase 1 metabolism? |
To convert lipophilic drugs to more polar molecules, facilitating excretion, by introducing or unmasking polar functional groups such as hydroxyls or amines |
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What three reactions are involved in phase 1 metabolism? |
oxidation, reduction, hydrolysis |
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What is the function of phase II metabolism? |
To make lipophilic drugs more polar via conjugation reactions, that is, the addition of large, water soluble molecules |
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In which phase, 1 or 2, are the metabolites always less active than the parent drug? |
Phase 2. In phase 1, metabolites may be more, less, or equally as active as the parent drug |
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Name 4 examples of Phase II conjugates added to drugs |
glucuronic acid, sulfate, acetate, amino acids
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What is the only phase II metabolite that is more active than its parent drug |
Morphine 6-glucuronide. It is a more potent analgesic than morphine unmetabolized. |
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T/F some drugs can directly enter phase II metabolism |
True
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Where are phase I metabolic enzymes localized within cells? |
Smooth Endoplasmic Reticulum |
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Where are most Phase II metabolic enzymes localized within cells? What is an exception to this? |
Most phase II metabolic enzymes are localized within the cytosol. The exception to this is glucuronidation, which is localized to the smooth ER |
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CYPs are the predominant Phase ___ metabolizing enzyme. Majority of drug metabolism is performed by _______ CYP enzymes. |
CYPs are the predominant Phase I metabolizing enzyme. Majority of drug metabolism is performed by hepatic CYP enzymes.
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Describe the mechanism of action of CYP. |
CYPs oxidize drugs by inserting a molecule of oxygen onto the drug and producing water as a product |
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What condition can decrease CYP activity? |
Malnutrition |
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Which enzyme metabolizes that largest fraction of marketed drugs? Describe its nomenclature. |
CYP3A4. 3 is the family. A is the sub-family. 4 is the isozyme |
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Name the 5 Phase II drug metabolizing enzymes. |
1. UGTs 2. SULTs 3. NATs 4. GSTs 5. TPMT |
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Which Phase II metabolizing enzyme metabolizes the most drugs? |
Trick question. They're all relatively split in their metabolizing activity. |
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Describe the location and mechanism of action of UGTs. |
1. They are found in the smooth ER 2. They catalyze the transfer of a glucuronic acid to a drug, making it more polar, facilitating excretion |
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Describe the location and mechanism of action of SULTs. |
1. They are found in the cytosol of cells 2. Catalyze the transfer of a sulfate group to the hydroxyl group of drugs. This makes the drug more polar, facilitating excretion |
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Describe the location and mechanism of action of NATs. |
1. Found in the cytosol 2. Catalyze the transfer of an acetyl group from acetyl CoA to a drug |
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Describe the location and mechanism of action of GSTs. |
1. Found either in the cytosol or microsomes 2. Catalyze the transfer of a glutathione molecule to a drug, an intracellular anti-oxidant, rendering the metabolite less toxic. |
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Describe the location and mechanism of action of TPMT. |
1. Found in the cytosol 2. catalyze the transfer of a methyl group to a drug. |
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What are the 4 factors that affect drug metabolism? |
1. Age 2. Drug Interactions (enzyme induction and inhibition) 3. Disease State 4. Genetic Polymorphisms
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By what age do humans reach adult-levels of drug metabolizing enzymes? |
2 years old |
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________ can induce CYP enzymes |
Smoking |
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Name 3 consequences of enzyme induction/increased drug metabolism |
1. Decreased drug plasma concentration 2. decreased drug activity (if metabolite is inactive) 3. increased drug activity (if metabolite is active) |
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Name 3 consequences of enzyme inhibition/decreased drug metabolism |
1. higher drug plasma concentration 2. increased therapeutic effects of drugs 3. Increased toxicity of drugs |
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Name 4 diseases that decrease CYP activity |
1. Liver Disease 2. Kidney Disease 3. Inflammatory Disease 4. Infection
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Name the two enzymes affected by phase I SNPs |
1. CYP2C9 2. CYP2D6 |
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Name the effect of SNPs on CYP2C9 |
CYP2C9 metabolizes the anticoagulant Warfarin. Polymorphisms decrease CYP2C9 activity. If Warfarin dose is not lowered, then patients may experience extensive bleeding |
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Name the effects of SNPs on CYP2D6 |
This enzyme metabolizes codeine to morphine, which is a more potent analgesic. 4 phenotypes can arise from the polymorphisms.
1. Poor metabolizer. No analgesic effect. 2. Intermediate metabolizer. Reduced metabolic activity 3. Extensive metabolizer. Normal metabolic activity. 4. Ultra-rapid metabolizer. Significantly higher metabolic activity. More potent analgesic effects, but more susceptible to side effects. |
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Name 2 Phase II enzymes SNPs can affect |
1. UGT1A1 2. NAT2
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Describe the effect of SNPs on UGT1A1 |
UGT1A1 glucuronidates the anti-cancer drug SN 38. Polymorphisms decrease enzyme activity, causing the patient to experience possible side effects of the drug, that is diarrhea and bone marrow suppression |
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Describe the effect of SNPs on NAT2 |
Polymorphisms can cause individuals to become rapid acetylators or slow acetylators to isoniazid. Slow acetylators are susceptible to increased drug toxicity, and certain cancers. |