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40 Cards in this Set
- Front
- Back
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What are the 2 most common types of drug metabolism interactions?
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-Enzyme induction
-Enzyme inhibition |
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What is enzyme induction?
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Upregulation of an enzyme amount or activity due to exposure to its substrate drug or an environmental chemical
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What are drugs or environmental chemicals that upregulate an enzyme called?
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Inducing agents
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Which metabolism enzymes are inducible?
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Both Phase I and II
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What is usually the cause of the upregulated enzyme amt or activity?
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Increased transcription
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How does increasing the steady state concentration of an enzyme accelerate metabolism?
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By increasing the Vmax
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Upregulation of which cytochrome P450 will affect the most drug metabolisms? How much?
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Cyp 3A - 50%
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What mechanism of induction will result in slow enzyme induction? Which will result in fast?
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Slow = transcriptional increases
Fast = Translational or protein stabilization |
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How can enzyme induction effect a drug substrate?
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EITHER
-Inactivate a drug -Activate a prodrug |
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Does an inducer have to be a substrate of the enzyme it induces?
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No not necessarily
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Are 2 inducers of the same drug always quantitatively equal?
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no, some are stronger than others
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How long does Transcriptional induction take to see max effects?
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1-2 days
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What else can drugs and environmental chemicals do to enzymes?
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Inhibit them
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What is usually the mechanism by which enzymes are inhibited by drugs?
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By activity decreases - not decreases in gene expression
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What will inhibiting an enzyme that normally inactives a drug result in?
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Less inactive drug, and possible toxicity
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What will inhibiting an enzyme that normally activates a prodrug result in?
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Less active drug, so decreased effectiveness.
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2 types of enzyme inhibition:
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-Competitive
-Noncompetitive |
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What enzymes are especially inhibited by Competition?
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P450 enzymes
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How do non-competitive enzyme inhibitors work?
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By compromising the enzyme function - change conformation
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What is a suicide inhibitor?
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An irreversible noncompetitive inhibitor
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What is the only way to overcome a suicide inhibitor?
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Make new enzyme
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Which type of inhibitors are the major cause of CYP-related drug interactions?
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Competitive inhibitors
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What is an example of noncompetitive inhibition?
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Binding of CYP heme to disrupt its catalytic activity
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How long does enzyme Inhibition generally take?
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Immediate (if its due to interaction with the enzyme itself)
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What does Grapefruit juice inhibit and what is its effect?
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Cyp3A in the intestine
-Greatly increases absorption of active drug |
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What is Cyp3A inhibition by grapefruit juice analogous to?
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MAOIs inhibiting the metabolism of Tyramine in the gut which causes hypertensive crisis
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For how many drugs will be absorption be enhanced by grapefruit inhibition of CYP3A?
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50%
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What drugs are subject to less drug interactions by enzyme induction and inhibition?
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FMOs
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how does Age affect drug metabolism?
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-Very young and old have altered drug responses
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What are some disease states that affect drug metabolism?
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-Liver disease
-Cancer -Infections |
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How do infections affect drug metabolism activity?
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Cytokines decrease some P450 expression
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How can gender influence drug metabolism?
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By variation in sex hormone metabolism
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What P450 is responsible for Acetaminophen metabolism?
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CYP2E1
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What is Acetaminophen the most common cause of in the USA? What is it the 2nd most common cause of?
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1. Acute Hepatic Failure
2. Liver failure needing transplant |
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What happens to Tylenol in normal people?
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1. UGT (most) converts to inactive metabolites
2. SULT (some) does the same 3. CYP2E1 (least) converts it to toxic Nap1Q |
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What prevents NAP1Q from causing hepatotoxicity in normal people?
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GST (glutathione s transferase) conjugates NAP1Q to an inactive metabolite
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What happens when someone has a tylenol overdose? why?
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It overwhelms the ability of GST to convert NAPIQ to nontoxic metabolite - GST is low capacity
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What else can increase NAPQ1 other than overdose on tylenol?
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Ethanol
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Why does Ethanol increase NAP1Q?
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It upregulates CYP2E1 so even if you take a normal amount of Tylenol, more gets shuttled thru this route and results in much more NAP1Q - saturates GST
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So the 2 ways that Tylenol can cause acute liver failure:
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-Acetaminophen overdose
-Alcohol binge |
