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