Elimination & Detox 2: Drug Metabolism Flashcards
CYTOCHROME P450…
= what/where is it & what does it do? (overall & 2)
the TYPE of reaction CYTOCHROME P450 does depends on…
= ENZYME IN CELL MEMBRANE OF ER of HEPATOCYTES that converts drugs into more POLAR & WATER-SOLUBLE compounds, so that they can be…
1. excreted by KIDNEY INTO URINE
2. liver can PERFORM CONJUGATION REACTIONS
the TYPE of reaction CYTOCHROME P450 does depends on the DRUG IT ACTS ON
5 POSSIBLE REACTIONS via of CYTOCHROME P450?
- HYDROXYLATION = (+) –OH
- DEMETHYLATION = (-) –CH4
- OXIDATION
- DEAMINATION = (-) –NH3
- DEHALOGENATION = removal of fluorine, chlorine, bromine, iodine
what is the MOST COMMON phase I reaction?
OXIDATION
what are the 2 MOST COMMON phase II reactions?
- GLUCURONIDATION
- ACETYLATION
PHASE I vs. PHASE II reactions?
we can have NEITHER phases to have drug ELIMINATED BY KIDNEY, BOTH OR JUST ONE
TRUE/FALSE
cytochrome p450 IS LIVER-SPECIFIC
FALSE, found in MANY ORGANS but MOSTLY IN LIVER BC THAT’S WHERE MOST OF METABOLSIM OCCURS
what do drugs have to do to get enacted on by CYTOCHROME P450? (2 steps)
- must GET INTO HEPATOCYTES
- BIND TO IRON on the HEME
CYTOCHROME P450 requires ___ & ___ ___ to ____
COFACTORS, NADPH REDUCTASE, WORK
CONJUGATION REACTIONS are PHASE ___ REACTIONS
II
ACETYLATION…
what phase is this?
what KIND of reaction is this?
facilitated by WHAT ENZYME? where is it mostly found?
what happens in it?
PHASE II
CONJUGATION REACTION
facilitated by ACETYL TRANSFERASE, mostly found in LIVER
adding ACETYL COA
FIRST PASS EFFECT…
= definition
LOW extraction drugs? (3, definition, how it relates to first pass effect & bioavailability)
HIGH extraction drugs?
(3, definition, how it relates to first pass effect & bioavailability)
= when ORAL drugs come into GI LUMEN and METABOLIZED, enter PORTAL VEIN; how much the INITIAL LIVER METABOLISM affects them
LOW extraction drugs
1. NOT MUCH metabolism of that drug occurs IN LIVER, can EASILY GET TO THE REST OF THE BODY
2. DOES NOT HAVE SIGNIFICANT FIRST PASS EFFECT
3. HIGH BIOAVAILABILITY
HIGH extraction drugs
1. a LOT of metabolism of the drug OCCURS IN THE LIVER, DOES NOT EASILY GET TO THE REST OF THE BODY
2. HAS SIGNIFICANT FIRST PASS EFFECT
3. LOW BIOAVAILABILITY
ENTEROHEPATIC RECYCLING…
requires the substance being recycled to…
4 steps?
requires the substance being recycled to BE EXCRETED IN THE BILE
steps?
1. substance EXCRETED IN BILE as GLUCURONIDATED METABOLITES
- bile enters the DUODENUM
- MICROBIOTA in SI REMOVES the GLUCURONIC ACID to RESTORE DRUG TO PARENT DRUG
- PARENT DRUG can be ABSORBED AGAIN
generation & excretion of BILE helps with the ____ of ____
3 numerical parameters for whether a drug is EXCRETED IN BILE or URINARY SYSTEM?
drugs excreted into the BILE must have a ___ ____ ___, making them often ___ substances
ABSORPTION, FATS
3 parameters?
1. <300 DALTONS = URINARY
2. 300-500 DALTONS = EITHER ONE
3. >500 DALTONS = BILE
DRUGS EXCRETED INTO THE BILE MUST HAVE A STRONG POLAR GROUP, MAKING THEM OFTEN AMPHIPATHIC SUBSTANCES
how does GLUCURONIDATION affect how a drug is EXCRETED?
INCREASES likelihood of EXCRETION INTO BILE by INCREASING MOLECULAR WEIGHT & POLARITY
if an animal has RENAL DZ, we should choose drugs that have WHAT 2 TRAITS & why?
choose drugs that are LARGER IN MOLECULAR WEIGHT & HAVE STRONG POLAR GROUPS so that they’re MORE LIKELY TO BE EXCRETED IN BILE since urinary system is likely compromised
what species DO NOT have a gallbladder? (4)
this usually DOES NOT have…
- HORSES
- CERVIDS
- RATS
- SEVERAL BIRDS (pigeons & psittacines)
usually DOES NOT HAVE A CLINICAL EFFECT
if a drug IS NOT METABOLIZED, what happens to it?
it is DIRECTLY EXCRETED
PHARMACOGENOMICS…
= definition
= the STUDY OF GENES that INFLUENCE the ABSORPTION, DISTRIBUTION, METABOLISM & EXCRETION of drugs within an individual
differences in PHASE I CYP450 in… (+ 1 overall effect!)
GREYHOUNDS?
CATS?
HORSES?
MINI/MICROPIGS?
GREYHOUNDS = have LOWER CYP2B11 ACTIVITY than other dogs
–> likely the reason they have PROLONGED RECOVERY FROM PROPOFOL (anesthesia)
CATS = DO NOT HAVE CYP2B6 in LIVER
–> might contribute to HEPATIC NECROSIS W/ DIAZEPAM
HORSES = have LOW CYP2D ACTIVITY
–> contributes to MONENSIN TOXICITY (from cattle feed)
MINI/MICROPIGS = have INCREASED CYP activity IN GENERAL
–> NEED HIGHER DOSES OF EVERYTHING
differences in PHASE II CYP450 in… (+ 1 overall effect!)
CATS? (1 effect)
DOGS? (3 effects)
CATS = CANNOT GLUCURONIDATE because they LACK THE ENZYME
- this is why they have LOW ASPIRIN CLEARANCE & ACETAMINOPHEN TOXICITY
DOGS = DO NOT HAVE N-ACETYLTRANSFERASE, so CANNOT ADD ACETYL CoA TO DRUGS
- SULFONAMIDE ADMINISTRATION can cause HYPERSENSITIVITY
- PROCAINAMIDE is NOT METABOLIZED TO ACTIVE METABOLITE but IS STILL EFFECTIVE
- HYDRALAZINE (vasodilator) has MUCH LONGER HALFLIFE IN DOGS > HUMANS
THIOPURINE METHYLTRANSFERASE has VARIABLE activity depending on ___ of ____
what PHASE is this involved in?
BREED, DOG
PHASE II REACTION
what DRUG are GIANT SCHNAUZERS susceptible to HYPERSENSITIVITY to? why?
what PHASE is this involved in?
GIANT SCHNAUZERS are prone to TOXICITY with AZATHIOPRINE because CANNOT METABOLIZE drugs ACTIVE –> INACTIVE metabolites due to THIOPURINE METHYLTRANSFERASE DEFICIENCY
PHASE II REACTION
PIGS DO NOT HAVE ____ ____, and this is a PHASE ___ reaction
unsure of the….
SULFATE CONJUGATION, II
unsure of the CLINICAL SIGNIFICANCE
BIRDS & REPTILES HAVE DIFFERENT TYPES OF ____ ____ ____
AMINO ACID CONJUGATION
unsure of the CLINICAL SIGNIFICANCE
in OLDER PEOPLE, what trends do we tend to see with…
PHASE I METABOLISM?
PHASE II METABOLISM?
FIRST PASS METABOLISM?
PHASE I = PROLONGED
PHASE II = NO CHANGE
FIRST PASS = REDUCED 1% PER YEAR OF AGE
how do the TWO PREGNANCY HORMONES affect METABOLISM?
- PROGESTERONE = can INCREASE or DECREASE certain CYP450 activity
- ESTROGEN = can DECREASE BILE ACID SECRETION
ST. JOHN’S WORT..
what does it do?
INHIBITS CYP3A4 and CP2D6, so CAN HAVE SIGNIFICANT EFFECT ON METABOLISM
effect of PHENOBARBITAL & KETOCONAZOLE on CYP450?
PHENOBARIBITAL = INCREASES the activity of CYP450
KETOCONAZOLE = DECREASES the activity of CYP450
THERAPEUTIC DRUG MONITORING…
= definition
in order for this to work the PLASMA CONCENTRATION must…
2 purposes?
= measurement of PLASMA/SERUM CONCENTRATION of a drug we’re administering at PEAK (maximum concentration) or TROUGH (right before next dose)
in order for this to work the PLASMA CONCENTRATION must CORRELATE TO THE OBSERVED CLINICAL EFFECT
purpose?
1. to ASSESS LIKELIHOOD OF EFFICACY/RISK OF TOXICITY of a drug
2. to DIFFERENTIATE between DISEASE PROGRESSION & DRUG FAILURE
what 4 categories (& give one example of a drug) do we use THERAPEUTIC DRUG MONITORING?
- EPILEPSY/SEIZURES
–> ex = PHENOBARBITAL - IMMUNOMODULATION
–> ex = CYCLOSPORINE - ANTIMICROBIALS
–> ex = AMINOGLYCOSIDES bc they can cause RENAL TOXICITY if too HIGH - CARDIOVASCULAR drugs
–> ex = QUINIDINE
THERAPEUTIC DRUG MONITORING…
4 main steps/what they mean
- START UP = need a BASELINE to know WHAT’S WORKING
- FOLLOW-UP = +/- depending on PATIENT STATUS/OWNER FINANCES
- CHECK-UP = are patients STILL HEALTHY?
- WHAT’S UP? = when there’s a problem; is it the concentration, type of drug, or do we need another drug?
how do we SUBMIT SAMPLES for THERAPEUTIC DRUG MONITORING?
on AUBURN UNIVERSITY PHARM LAB
