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201 Cards in this Set
- Front
- Back
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A drug-drug interation occurs when the response of one drug is
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alter by the concomitant adminstiration of another
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What are 3 reasons why we care about drug-drug interactions
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1. May result in increase toxcity
2. May result in decreased efficacy 3. The effect may be desirable |
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What are risk factors for drug-drug interactions
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MMAN PP
mutiple prescribers mutiple drugs advancing age narrow therapetic window Poor compliance predisposing illnesses (diabetes) |
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What are some environmental factors that may interact with drugs
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food, chemicals and cigarette smoke
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Smoking increases the metabolism of
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Theophylline (substrate)
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What is pharmacokinetics
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what the body does to the drug
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What are some pharmacokinetic mechanisms of drug-drug interactions
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Altered absortion
Altered distribution Altered metabolism Altered excretion |
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What is pharmacodynamics
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what the drug does to the body
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What are some pharacodynatmic mechanism of drug-durg interactions
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similar or additive drug actions, or antagonistic drug actions
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What are antagonistic drug actions
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taking an antihypertensive agent, and fludocortisone
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What is the enzyme responsible for catalyzing the metabolism of many drugs and endogenous compounds
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CYP 450
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CYPS are heme-containing enzymes embedded in
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the lipid bilayer of the Smooth ER
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Where are relatively high conecntions of CYP enzymes located
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in liver and small intestine
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Where are lower conections of CYP
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in other tissues such as kidney and lung
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Many drug-drug interaction result from
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inhibiation or induction of CYP 450
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What is the most abundant CYP 450
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CYP34
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Where is CYP3A located
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30% in liver
70% gut |
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What is more prevalent CYP3A4 or CYP3A5
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CYP3A4---CYP3A5 only present in 20-30% of caucasians
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Where is CYP2C located
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20% of liver
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What are important isoforms of CYP2C
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CYP2C9, CYP2C8 and CYP2C19
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Where is CYP2D6
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5% of liver
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CYP2D6 is only responsible for 5% of liver, why still important
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responsible for 20% of clinical drugs (depressants and antipsychotics)
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Where is CYP1A2
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10% of liver
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What is a substrate
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a compound that is metabolized by a given enzyme
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Warfarin is a substrate that is metabolized by
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CYP2C9 and also lesser extent by CYP3A4, and CYP1A2
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Theophylline is a substrate that is metabolized by
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CYP1A2
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What are most antidepressants metabolized by
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CYP2D6
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What is an inhibitor of drug metabolism
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is a compound taht slows down the metabolism of a stubstrate through a particular enzyme
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What does Ketoconazole inhibit
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CYP3A4
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Inhibition of drug metabolism may result in
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decreased metabolism of substrate
decreased clearance of substrate and increased levels of substrate drug in systemic circulation |
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What is an inducer of drug metabolism
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a compound that speeds up the metabolism of a substrate by a given enzyme
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What is an example of inducer
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Rifampin
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What does Rifampin INDUCE
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CYP2C9
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Should I always check for drug interactions with Rifampin
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YES
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Induction of durg metabolism may result in
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Increased metabolism of substrate, increased clearance of substrate, and decreased levels of teh substrate drug in the systemic circulation
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Inducers simply put
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REV of metabolism of a substrate
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What are the 3 types of enzyme inhibition
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reversible, competitive
reversible, non competive Irreverstible (suicidal) |
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What is most common type of inhibition
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Reversible Competivie inhbition
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What is reversible competivive inbhitior drug MOA
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competes with the substrate drug for occupancy of the CYP active site, and binds preventing binding of the substrate to active site of enzyme
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The most effective reversible competitive inhibtiors bind
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to BOTH the lipophillic region of the active site, adn the heme component at the SAME time
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What are 3 characteristic of a reversible competitive inhibitor
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1. binding affinity for enzyme
2. inibitor conc to compete 3. lipophilic and high MW |
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When is the onset of CYP inhibition following the administration of an reversible competitive inhibitor
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rapid--following 1st dose
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Normal metabolic functions of the CYP (enzyme) generally return
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when the inhbitor drugs is discontinued, and has been elminated from the body
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How long does it typically take to elminate the drug from the body
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4-5 half lives
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What is MOA of reversible non-competitive inhibition
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when the metabolite intermeidate of an inhbitor froms a stable complex with the CYP enzyme--making inactive
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May the impairment of metabolism be long-lived in reversible non-competitived inhibition
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YES
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What is irreversible inhibition AKA
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suicidal inhibition
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What is MOA of irreversible inhibtion
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the drug is oxidized by CPY450, generating a reactive species that binds irreversible to CPY heme or protein
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Are there clinically relevant drugs that are suicide inhbitiors
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FEW
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What are charctersitcs of enzyme inhibition
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Decrease metabolism of substrate
Decrease clearance Increase plasma drug levels |
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What effects does enzyme inhibtion have on drug half-life, rate of metabolite production, and pharmacoligc effect if parent drug is active
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Increase drug half-life
Decreased rate of metabolite production increase pharamcologic effect if parent drug is active |
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What is MOA of inducer drug
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has an influence on the transcription of CYP increasing its gene expression, resulting in more CYP
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Is induction of CYP the result of an interaction between the drug and the protein
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NO!!!!
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Are most CYP genes inducible
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YES
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Can some drugs induce more the one CYP isozyme
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YES
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Some drugs are metabolized by CYP to reactive intereidate or active metabolites, what would happen with CYP induction
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may be assoicated with increased toxciity
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When does CYP induction take place after taking the inducer drug
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may take anwerhe from 1 day to several weeks for maximul induction
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What are main consequences of Enzyme induction
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Increased metabolism
Increased clearance Decrease Plasma Drug levels |
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What effect does Enzyme induction have on metabolite production
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increases rate of metabolite production
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What effect does Enzyme induction have on drug half life
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Decrease
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What effect does Enzyme induction have on metabolites that are inactive vs active
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increase pharmacoligic effects on active metabolic
DECREASE pharmacoligc effects if metabolites are inactive |
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What is a CYP1A2 inducer
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hydrocarbons found in cigarette smoke, and chemical in charbroiled meats
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Choronic use of ethanol induces
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CYP2E1
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Can an inhibitor drug be a substrate for the enzyme it inhibts
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YES erthromyscin can inhibit CYP3A4, but also be metabolized by it
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Can a drug be an inhibitor of one isozyme, but a stubstrate for a different
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YES--Quinidine inhibit CYP2D6, but can be metabolized by CYP3A4
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Can some drug inhibit many different isoenzymes
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YES
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Can an inducer drug be a stubstrate for the enzyme it induces, and name
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YES, autoinduction
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What does it mean when an inducer drug is a subsrate for the enzyme it induces
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it induces its own metabolism
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What is an example of autoinduction
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Carbamazepine incduces CYP3A4, but it is also a substrate for CYP3A4
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The inital half-life of carbamzepine ranges from 25-65 hours, however after stable dosing, the half-life of caramazepine becomes
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12-17 hours--b/c of autoinduction
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What are drugs I should pay attention to with Narrow Therapeutic Windows
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Cyclosporine
Antiarrhytmics Theophylline Tricycle Antidepressants (amitrityline) Warfarin |
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What are the 4 main questions you ask when evaluating DRUG-DRUG interactions
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1. What is the substrate drug
2. Is substrate metabolized by CYP? 3.Is substrate given concureently with a CYP inhbitor 4. Is substrate given concurrently with a CYP enzyme inducer |
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What does it mean to have a narrow therapetic index
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great risk for toxic side effects or being partially ineffective or ineffective
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What drugs are in the protease inhibitor Kalertra
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1. Lopinavir (met CYP 34A)
2. Ritonavir (inhibit CYp 34A) |
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What are the 2 medications given simulatneous
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Lopinar has poor bioavilabile
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What is benefit of Ritonavir
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POTENT inhibiot of CYP 3A4 in LIVER and GUT, preveent Lopinavar metabolism, increases its bioavailablity and levels
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Kalteta is an intentional drug-drug interation AKA
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BOOSTING
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Can the consituents of herbral products vary, therefore
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the herb-drug interactions may not be consists
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Who are particular concern for Herb-drug interactions
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individuals on drugs with narrow therapuetic range
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A patient is taking Cyclosporine, asks if it is ok to also take St. John Wort--why not--mechanism
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St. John's induces the metabolism of cyclosporine by CYP 3A4, increased metabolism of cyclosponrine in gut AND liver, resulting in decrease plasma conc
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What does Grapefruit juice inbhit and where
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CYP3A4 in the intestine, increases ORAL bioavailibty of drugs primarily metabolized by INTESTINAL CYP 3A4
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What are the active components of grapefruit juice
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favonoids, and furanocoumarin
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When is CYP3A4 inhbitino in the intestine evident
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1st glass of grapefruit juice--and persis for 24 hrs or MORE
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What does daily ingestion of grapefruit juice cause
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loss of CYP3A4 expression in the GUT
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Grapefruit juice is most likely to affect CYP3A4 substrates with
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LOW bioavailabilty
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Why is grapefruit juice not used at drug booster
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not consistant
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Can drug interactions occur that have NOTHING to do with metaboism
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YES
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What is order of metabolism of oral drugs
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1. enters GI
2. absorbed through gut Wall metabolism can occur here 3. enters Portal circulation 4. enter Liver (metabolsim) 5. then systemic circulation |
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What are factors that contribute to variability in drug distribution and response
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GDDSSK
1. Genetic makeup 2. Diet 3. Drug-Drug interactions 4. Social Habits 5. Sex, weight, race 6. Kidney/Liver disease |
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What was the purpose of teh Human genone project
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1. Identifying all genes in DNA
2. determining the sequence of 3 billion NT's that make up DNA 3. Charactiring variability in genome |
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What is meant by the Genomic Medicine
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1. Use gentic info to importve teh prediction of drug efficacy and toxicty, and diagnosis of disease
2. Using gnetic infor for eariler detection of genetic predispostions to disease |
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What is pharmacoGENETICS
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study of how genetic differance in a SINGLE gene influence variablity in drug efficacy and toxcity
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What is pharmcoGENOMICS
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study of how genetic differances in multiple genes influences varability in drug efficacy and toxicity
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What are nucleotides
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they are the building blocks of DNA consits of AG TC
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The nucleotides make up the sequence of DNA, and variation of this sequence account for
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basis of genetic variation, leading to differance in drug dispostion and response
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What is a codon
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3 NT that code for an amino acid
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What are exons and introns
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INTERVENTING intron non coding
exons are the coding |
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Genes are hundreds and thousands of NT's, what does a gene do
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protein building instructions with exons, introns and promoter)
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What is a chromsome
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single DNA molecule that has many genes
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How is a gene transcribed into protein
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Gene to mRNA by transcription, and mRNA translation into protein
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What is an allele
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different DNA sequences at a particular locus
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What is a genotype
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a pair of alleels a person has at a specifc region in DNA
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What is an example of phenotype
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poor metabolism, or poor response to an antihypertensive
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What is a mutation
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differance int eh DNA code that occurs in LESS than 1% of the population
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Mutations are often assciated with
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rare diseases
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What is polymorphsism
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differance in the DNA code that occur in MORE than 1% of teh population
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Is a single polymorphism less liekyl to be the main cause of a disease
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YES
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The majority of the observed sequence variation between people appear to be the result of
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SNP (single NT polymorhpism) which is a single base pair substitution G instead of T
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How many SNP are their in the human genone
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10 million
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In what regions can SNP occur
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coding regions, non-coding regions,
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What is a synonymous SNP
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SNP that does not resullt in an AA change (silent), no functional consequence
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What is a non-snyonymous SNP
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SNP that DOES result in an amino acid change
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What is the functional conseqenuce of Non-synonymous SNP
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may affect protein furnction or quantity or premature stop codon
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In what cases might intronic SNP be important
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a different sequence in intronic DNA may promote of inhibit mRNA splicing can result in less exons or introns not being removed
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How might SNP in protmoter affect gene function
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it can influence gene transcription by altering the binding sites for transcription factors that turn a gene on/off
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What are other types of polymorphisms besides SNP in introns and promoters
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insertion/edeltion, NT repeats, gene duplication
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What are insertion/deletion polymorphisms
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cetrain number of NT are either inserted or deleted from DNA sequence
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What are nucleotide repeats
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certain # of NT are repeated in the DNA sequence
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What is homozygous and heterozygous
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homozygous- 2 identical alleles
heterozygous is 2 different alleles |
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Wild-type
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most common allele @ at locus in a given population
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The C/T at nucleotide position 430 in exon 3, what are the 2 possible alleles
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C T
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What are the possible genotype for C/T, and C is more common
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CC HOMO-WILDTYPE, CT HETEROZYGOUS, TT Homo Variant
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SNPs and genotype cna be reffered to by
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nucletodie position, and amino acid designation
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There is a SNP in codon 49 of the Beta-1 receptor gene, it results in an amino acid change from serine to glycine, what are the 3 possible genotypes
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Ser/Ser, Gly/Gly and Ser/Gly
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What is linkage
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measure of proximity of 2 or more polymorhisms on a single chromosome
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Polymorphisms in close proximity tend to be co-inheriteated, these regions of linked polymorphisms are knowns as
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haplotypes
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Regions of linked polmorphisms are haplotypes, and how are they arranged
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a linear arrangement of alles on a SINGLE chormsome (only from mom)
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What are Possible Hapotype sequences for C(T/C)GT(AG)
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TA, TG, CA, CG
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For speicfic locations in the genome a small number of haplotypes patterns can account for
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80-90% of the population
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What is the international HapMap project
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identifying common haplotypes in 4 poputions from different parts of the world, and "TAGGIN" SNP that unuqely identify these haplotypes
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Where can DNA be obtained to determine a patient's genotype
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all cells except RBC and platelts
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What are most common site fro DNA collection
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Blood lymphocytes (blood draws)
Buccal cells (mouthwash sable or cheek swab |
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What are 3 things pharmacogenomics takes in account for varriability in efficacy/ toxciity
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1. Drug metabolizing enzymes
2. Drug transporters 3. Drug targets |
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Does pharmacognemoics incorportate both parhacokinetics and pharmacodyamics
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YES
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How for does literature date bakc to for Drug metabolism pharmacogenomics
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1950 with Succinylcholines why 1 in 3,000 are completely knocked out from drug and don't recover as quickly
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How do we first identify varaiblity in drug metabolism
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Phenotypes (regcognize differances, then look to genotypes)
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What is monogenic
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Polymorphisms in a single gene have a large impact on phenotype
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What type of phenotype distributions exists with Drug metabolism pharacogenomics
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Bimodal and trimodal phenotype distrubtions
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Polymorphisms in drug metabolizing enzymes genes may affect metabolism phenotype in the following ways
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Decrease metabolizing enzyme efficeny, acity or affinity for substrate resulting in an inactive enzyme
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What are results of a drecreased metabolizing enzyme
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metabolism decrease, clearance decreases, and increased plasma levels
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Not as common, some polymorphisms can result in multiple copies of the gene (gene duplications) which is
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making more metabolizing enzymes
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What happens when polymorphisms result in gene duplications
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metabolism increases, drug clearance increases, and plasma levels decrease
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What are the 3 distinct phenotypes for CYP2D6
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poor metabolizers
extensive metabolizers ultrarapid metabolizers |
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What are the normal group of CYP2D6
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extensive metabolizers
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15% of CYP2D6 poor metabolizers phenotype is due to
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a gene deletion
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What is the cause for the ultrarapid metbolizer phenotype for CYP2D6
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gene duplication
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What are the effets on metabolism, plasma conc and effets on drug response for ultrapid metabolizers
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increase metabolism, decrease plasma conc, and NO or little drug response
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What are the effects of extensive metbolizers on metabolism, plasma conc, and drug response
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NORMAL
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What are effects of poor metabolizer for CYP2D6 on metabolism, plasma conc, and drug response
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decrease metabolism, increase plasma conc, and increased drug response
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What are poor metabolziers at risk for
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concentration depend toxcities
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Who should be given the largest doses ultrarapid, extensive or poor metabolizer
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ULTRArapid metabolizers should be given the largest doses
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Codeine is a pro-drug is metabolized to and by
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metabolized by CYP2D6 to morphine
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What are the effects of codine on poor metabolizers
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cannot metabolize codeine to morphine, and poteint for lack of therapeutic efficacy
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What is the Roche AmpliChip CYP450 Test
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identify a patients CYP2D6 and CYP2C19 genotype from genomic DNA extracted from whole blood sampppple
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Why is information about CYP2D^ and CYP2C19 genotype important for clinicans
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determine treatment doses for drugs metabolized by these enzymes
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SNPS in CYP2C9 generally results in what
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decreased affinity for substrate
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How do SNP affect CYP2C9 drug metabolism, clearance, plasma, and risk of toxicities
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decrease metabolism, decrease clearance, increase plasma, and increase risk of toxcity
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CYP2C9 has many polymorphisms, what is the wild type called
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*1
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What are the most studied CYP2C9 polymorphisms, and what do they result in
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*2 and *3 alleles, both result in decreased affinity of the enzyme for the substrate
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Having a SNP in CYP2C9, can have what effects on warfarin/phentoyin, what genotype is worst
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decreased metabolism, decreased clearance, and increase plasma concentrations, *3/*3 allele is worst
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If *3/*3 genotype is the worst, what kind of doseages of a drug should be given
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the lowest
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What is substrate metabolized by CYP 2C19
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PPI and phenytoin
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Polymorphisms in CYP2C19 result in 3 main phenotypes
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rapid metabolizers
intermediate metabolizers poor metabolizers |
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What enthic group have SNPs that results in them being poor metabolizers
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asian persons
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Ulcer cure rate for H pylori infection using omeprazole and amoxicillin has best cure rate for what type of metabolizers and why
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Poor metabolizers, increases plamsa concenctions, and omeprazole has a wide theraptic rands, so don't have to worry about side effects
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Are there eithinc differences in Drug metabolism of enzymes due to polymorpisms
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YES
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What is TPMT
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Thiopurine-S-Methltransferase
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What type of metabolizing enzyme is TPMT
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Phase II metabolizing enzyme
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What is TPMT important for metabolizing
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INACTIVATING thiopurines in the body
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What are some examples of thiopurines
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azathioprine, and mercaptopruine
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What happens if thiopurines are not inactivated
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they can accumlate and cause serious toxicities
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What do SNPs in TPMT result in
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decreased TPMT enzyme activity, prediposes individuals to toxicites
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BA has lymphoblastic luekemia, which is treated with mercaptopurine, why do his vital signs plumment , and his not has severe bone marrow supression
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SNP in TMPT gene result in decreased TPMT enzyme activity
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What does decrease TPMT activity predisposes indivdiuals to
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serve bone marrow suppression from standard doses
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Is genetic resting for TPMT routine practice at some cancer centers
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YES
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Patients who are heterozygous for TPMT SNPs should generally receive what % of the standard dose
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65% (1 normal allele and 1 variant allele)
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Patient who are homozgous for TPMT SNP should receive only
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10% of the standard dose of thiopurine
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For a given disease the same drug or drug class does nto have the same efficacy rate in all people T/F
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True
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Where are polymorphisms in pharmaacodynamics
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in gene encoding drug targets may influence variability
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Why is Drug Target pharmacogenomics a difficult area to study
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POLYGENIC and---all proteins are encoded by genes with can have polymorphisms
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What are some alterations in drug receptros due to polymorhpisms
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altered binding of drug to receptor, altered receptor synthesis/processing, and communication with "downstsream proteins"
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What is an example of altered receptor communcation with "downstream" proteins
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singal transduction cascade
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What is albuterol
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Beta-2 receptor agonist use to treat asthma
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SNPs exist in the beta-2 receptor genes which results in
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albuterol not working as well
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What are the first line agents in treatment of HTN
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B-blockers
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Why do 30-60% of paitients fail to achieve adequate blood pressure lowering with BB
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common SNP in B1-receptor gene Codon 389 Arg-Gly, makes receptor less responsive
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What is the wild-type of B1-receptor
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Arg-Arg 389
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Drug Metabolism characteristics
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MD PS
monogenic, drug disposition, pharmacokinetics, phenotypes distinct phenotypes, and phenotypes easy to measure |
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What do SNP do to drug metabolizing enzymes
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often result in non-functional proteins
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What do SNP do to drug targets
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DONT result in non-functional proteins--more subtle effects
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What deals with pharmacokinetics
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drug metabolism
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What deals with pharcodynamics
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drug targets
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What are phenotypes like in drug targets
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Non-distinct, and are hard to measure (impresis and variable)
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What has to do with drug disposition vs Efficacy (drug response)
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drug dispostion-drug metabolism
efficacy has do with drug targets |
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Although cancer cells are human cells, there have undergone mutation during the patient's lifetime, are these mutation present in the genomic DNA
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NO
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Can we target drug base on tumor genetics or protein expression
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YES
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What is issue in tumor cells with HER2 gene
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HER2 gene amplicfication that causes an overexpression of HER2 protein
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20-25% of breast cancer are Her2 overexpresion is treated with
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Herceptin
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How can we moving PGX to clinical practive
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document Pgx superiority
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Why for the majority of drug a single SNP won't be able to explain all the variability in PK or PD
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we must also conisder numeous SNP in numerous genes, and non-genetic factors
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Should we develop algorithms that include the most important non-genetic and genetic favtors that explain the greatest amount of variaiblity in PK and PD of a drug
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YES
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