module 4 Flashcards
what is metabolism?
-enzyme-mediated alteration of drugsdrugs structure
what is metabolism also known as?
biotransformation
what are the sites of drug metabolism?
-liver
-intestine
-stomach (alcohol)
-kidney (contains enzymes)
-intestinal baacteria
why do we need metabolism?
to get rid of toxins etc
what are exogenous things?
-things that we put in our body that are naturally there to begin with
-potential to be toxic & this is why our body has enzymes to rid of it
-wine
-cigarettes
-steak
-vegetables
-coffee
what are endogonous things?
- same family of enzymes that is responsible from metabolizing drugs is also important in terms of endogenously regulated processes
- vit D synthesis, bilirubin, steroid hormones, bile acid
what happens to a drug after its been metabolized?
- increase water solubility to promote excretion
(lipophilic to hydrophilic)
-inactivate drugs
(active to inactive)
-increase drug effectiveness
(active to more active)
-activate prodrugs
(prodrugs are inactive until metabolized)
- increase drug toxicity
(non toxic to toxic)
what is first order kinetics?
MOST CLINICAL SITUATIONS
-the concentration of a drug is much lower than the
metabolic capacity of the body
-drug metabolism is directly proportional to the
the concentration of the free drug
-there is a constant FRACTION of the drug that it metabolized per unit time
- high drug concentration = high rate of metabolism
what is zero order kinetics?
-plasma concentration is much higher than the
metabolic capacity of the body
-drug metabolism is constant over time (this means that regardless of the concentration, the rate of drug metabolism doesn’t change)
-ethanol
what is first pass metabolism?
- PO drugs may undergo significant metabolism prior
to entering ciruclation
Where does first-pass metabolism occur?
hepatocytes
enterocytes
stomach
intestinal bacteria
what is the result of 1st pass metabolism?
decreased amount of parent drug that enters system circulation
degree of first pass metabolism can have a great degree on a drug action (if the drug is extensively metabolized in the liver, almost none of it will reach the systemic circulation and be available to act within the body)
what is the meaning of extraction ratio ?
the amount of metabolism on the first pass through the liver that determines a drugs bioavailibility
what are the characteristics of a drug with a high extraction ratio
-means there is a low bioavailability because liver
metabolizes alot of the drug on first pass
-PO dose must be higher than IV
-small changes in hepatic enzymes will produce large changes in bioavailability
-very susceptible to drug drug interactions
what characteristics does a drug with low ER have?
- high bioavailability (over 80)
- PO doses are similar to IV
-not suspectible to drug drug interactions
-takes many passes through the liver for the drug to be metabolized
-changes in hepatic enzyme will not have a big effect on bioavailability
when does first pass metabolism occur?
only with PO drugs!
drugs that are IV have 100% bioavailability and remained unchanged because they are already in the blood and do not need to pass through the liver to reach the systemic circulation
what happens in phase 1 of drug metabolism
-convert lipophilic to polar molecules
-involves oxidation, reduction and hydrolysis
-mediated by cytochrome p450
-metabolites formed can be more active, less active or
equally as active as the parent drug
what happens in phase 2 metabolism?
-increase the polarity by conjugation reactions
-addition of large water molecule
-conjugates include glucuronic acid, sulfate, acetyl
group or amino acids
-metabolites are less active than the parent drugs
types of drug metabolism
phase 1 - elimination
phase 1 - phase 2 - elimination
phase 2 - elimination
where does phase 1 metabolism occur
smooth endoplasmic recticulum
where does phase 2 metabolism occur
cytosol
EXCEPTION GLUCURONIDATION OCCURS IN THE SMOOTH ER
what are CYP enzymes
- used in phase 1 metabolism
-adds oxygen and water is a byproduct
-majority of metabolism is performed by CYP hepatic
-CYP is a large family of metabolizing enzymes
how many families of CYPs are there and how many are involved with the majority of drug metabolism?
-12 families
-3 major involvement
what decreases CYP activity?
-malnourisment
- deficiencies in iron, folic acid, protein and zinc
which cyp enzyme metabolizes the largest fraction of drug?
CYP3A4
what are the characteristics of UDP -glucuronosyltransferases?
- smooth ER
-phase 2 metabolism
-add glucuronic acid to a drug
-these drugs are more polar and will be excreted easier
-there are 19 human UGT enzymes
what are the characteristics of sulfotransferases
-in the cytosol
-phase 2 metabolism
-more polar and therefore more easily excreted
-11 sult enzymes
-drug+sulfate = drug-sulfate
what are the characteristics of glutathione s-transferases (GST)
-phase 2
-in the cytosol
-adds glutathione molecule
-is an antioxidant - makes metabolite less toxic
-over 20 human gst
NATS - N-Acetyltranferases
-cytosol & phase 2
-adding acetyl CoA to drug
-subject to polymorphisms (major variability in drug response)
- 2 human NAT enzyme - NAT1/2
TPMT - Thiopurine Methyltransferase
-cystol and phase 2
- add s-adenosylmethionine to drug
-subject to polymorphisms (dramatic factor on drug safety)
what factors affect drug metabolism?
-age
-disease
-polypmorphism
-disease
which population has the least hepatic function?
-almost no hepatic function under 6 months
- from 6 months to 2 years the function increase
-hepatic function worsens with age
what is enzyme induction?
a process where a cell synthesizes an enzyme in response to a drug or other chemical
what is the consequence of CYP induction
increased drug metabolism
what are the consequences of increased drug metabolism
decreased plasma concentration
decreased drug activity (if metabolite is inactive)
increased drug activity (if the metabolite is active)
how does smoking effect drug metabolism?
increase drug metabolism
what is enzyme inhibition?
some drugs can inhint cyps
what is the effect of enzyme inhibition?
decreased drug metabolism that leads to:
-higher plasma drug concentration
-increased therapeutic effect
-increased toxicity
what diseases decrease CYP actvity?
liver disease
kidney disease
inflammatory disease
infection
what is a SNP
single nucleotide polymorphism
it is a change of a single nucleotide
why does it matter if you have a SNP
SNPs affect protein (ezyme) that is produced
causes differences in response to drugs
CYP2C9 SNP
metabolizes warfarin
results in decreased enzymatic activity
may require a lower dose
may experience extensive bleeding if dose isnt adjusted
CYP2D6 SNP
purpose is to metabolize codeine to morphine
has many different SNP that can result in 4 different outcomes
-ultra rapid metabolizer - posess multiple copies of the gene
-extentsive metabolizer - normal
-intermediate metabolizer - reduced activity
-poor metabolizer - no actiivity
UGT1a1 SNP
-glucuronidates the anticancer compound SN38
- decrease its activity
- at increased risk for diarrhea and bone marrow suppression
NAT2 SNP
-acetylates (used to treat TB), caffeine adn various cancer causing chemicals
-over 23 SNPs in this gene
-either rapid or slow based on their geneotype
-slow acetylators are susceptible to toxicity
-slow acetylators have a higher risk for develping certain types of cancer
