lecture 5 part 2 Flashcards
name the transferase (enzyme) and endogenous reactant for glucuronidation
name where the enzyme is located as well
endogenous reactant = UDP glucuronic acid
transferase = UDP glucuronosyltransferase (microsomes)
phase 2 enzymes are…..
transferases
name the endogenous reactant for acetylation and the enzyme and where it’s located
endogenous reactant = acetyl-coA
enzyme = N-acetyltransferase (cytosol)
name the endogenous reactant for GSH conjugation and the enzyme and where it’s located
endogenous reactant = GSH (glutathione)
transferase = GSH-S-transferase, located in the cytosol and microsomes
name the endogenous reactant for glycine conjugation as well as the trasnferase and where it’s located
endogenous reactant = glycine
enzyme = acyl-coa glycinetransferase– located in the mitochondria
name the endogenous reactant for sulfation, the enzyme, and where it’s located
endogenous reactant = phosphoadenosyl phosphosulfate (PAPS)
enzyme = sulfotransferase, in the cytosol
name the endogenous reactant for methylation, the enzyme and where it’s located
endogenous reactant = SAM (S-adenosyl methionine)
enzyme = transmethylases in the cytosol
name the endogenous reactant for water conjugation, the enzyme, and where it’s located
endogenous reactant = water
enzyme = epoxide hydrolases, either in microsomes or cytosol (sEH and mEH)
______ enzymes catalyze all conjugation reactions EXCEPT ______-
non microsomal
glucuronidation
what is the location of phase 2 reactions
primarily in the liver, but also the plasma and GI tract
conjugation reactions can also be called….. why?
detoxification reactions bc their metabolites are more polar, easily excreted, and typically inactive
what enzymes hydrolyze drugs that contain ester linkages?
give a specific example
nonspecific esterases in the liver, plasma, and GI tract
succinylcholine (anectine) is hydrolzyed by these enzymes
acetaminophin can cause ____ toxicity outside of therapeutic dosing
hepato
explain what happens with the metabolism of acetaminophen within therapeutic dosing and when OD happens
glucuronidation + sulfation – takes care of 95%
toxic metabolite goe through alternate CYTP450 depending GSH conjugation (CYP450 2E1) under stress — produces a mercapturate which is HARMLESS and is excreted
however, the toxic metabolite can alternatively bind to macromolecules in the liver and cause cell death of liver cells
***** what is the antidote to acetaminophen OD
N-acetylcysteine – it is the precursor to glutathione and can conjugate the toxic metabolite to a mercapturate (Ac-SG) that is excreted and harmless
with age, there is a variation in drug responses.
this is usually due to what?
diminished cardiac output.
this reduces hepatic perfusion (deliver of drug to liver to be metabolized) which PROLONGS THE DURATION OF THE DRUG
TRUE OR FALSE
elderly patients have increased body fat and this has an effect on drug metabolism
TRUE
high body fat increases Vd
promotes the accumulation of highly lipid soluble agents such as diazepam and thiopental (pentothal
explain how neonates and elderly patients have different drug metabolism abilites
neonates have reduced hepatic metabolism bc of organ immaturity
elderly pts have differences in absorption, clearance, vd, hepatic metabolism
name a potent inhibitor of CYP3A4
where is CYP3A4 localized?
grapefruit juice
in the intestinal wall mucosa
what is the issue with some drugs + cruciferous vegetables?
name some cruciferous vegetables
they can INDUCE CYP1A2
brussel srpouts
cabbage
cauliflower
hydrocarbons in charcoal broiled meats
explain the issue with calcium + some drugs
calcium in some dairy products can chelate drugs like
TETRACYCLINES AND FLUOROQUINOLONE antibiotics
–will chelate and be inactivated
what is the issue with cigarette smokers when they taken drugs
some smokers metabolize drugs more rapidly than nonsmokers bc of ENZYME INDUCTION
true or false
smokers tend to inhibit enzymes more than nonsmokers
FALSE - INDUCE
thus metabolize the drugs more rapidly
explain the issue with industrial workers taking drugs
they may be exposed to pesticides and metabolize some drugs more rapidly than normal ppl
define a drug interaction
when one drug affects the pharmacological response of a second drug given at the same time
drug interactions may be due to…….
pharmacokinetic effects
pharmacodynamic effects
what is a DIRECT drug interaction?
explain and give example
Drug A blocks the TARGET SITE (like receptor/enzyme/transporter/dna/ribosome/etc) of Drug B
thereby diminishing or antagonizing the effect of Drug B
adrenoceptor antagonists diminish the effectiveness of receptor agonists (like terbutaline or salbutamol)
what is an INDIRECT drug interaction
Drug A alters (increases or decreases) the levels of an endogenous substance that thus affects the actions of Drug B
give 3 examples of indirect drug interactions
-some diuretics decrease plasma K concentration (bc you’re peeing it out) which can ENHANCE the actions of digoxin and predispose you to glycoside toxicity (needs K to work)
-MAO I (monoamine oxidase inhibitors) inhibit NE metabolism which INCREASE NE levels. this produces interactions with drugs that work by releasing stored norepinephrine (like ephedrine or tyramine)
-H1 receptor antagonists (mepyramine) cause drowsiness as unwanted effect. it’s worse if drug is taken with alcohol - may lead to accidents
what are in vitro drug-drug interactions
one of both or the drugs are inactivated.
there are NO pharmacological principles involved - just chemistry
give 2 examples of in vitro drug-drug interactions
thiopentone + suxamethonium form a complex (so can’t be mixed in same syringe)
heparin is highly (-) charged and interacts with lot of basic drugs
GI absorption is slowed by….
drugs tha tinhibit gastric emptying
give 2 examples of drugs that inhibit gastric emptying and thus slow down GI absorption
atropine and opiates
what drug accelerates GI absorption
metoclopramide
true or false
Drug A is a substrate for CYP450 1A2
Drug B is an inducer for this same enzyme
the effect would be decreased clearance of Drug A
FALSE - increased clearance
name the main mechanisms in which 1 drug can affect the rate of renal excretion of the other
-inhibiting tubular secretion
-altering urine flow and pH
-by altering protein binding (and hence filtration)
give an example of a drug that inhibits tubular secretion and thus affects excretion
probenecid inhibits penicillin tubular secretion and thus prolongs its action
(also inhibits secretion of other drugs like AZT)
explain how urine flow and pH are altered to affect excretion
loop and thiazide diretics increase tubular reabsorption of Li+ — can cayse Li+ toxicity in pts treated with lithium carbonate for mood disorders
urinary pH’s effect on the excretion of weak acids and bases is out to use in the treatment of poisioning, but NOT accidental interactions
___ and __ form an insoluble complex with tetracyclines and thus decrease its»»
calcium and iron
absorption
_______ binds several drugs like warfarin and digoxin. this prevents their ____if they are administered at the same time
cholestyramine (bile acid reducing resin used to treat hypercholesterolemia)
prevents absorption
explain how epinephrine can affect absorption
when adding epinephrine to local anesthetic injections, causes vasoconstriction and thus slows the absorption of the anasthetic and provides a LONGER LOCAL EFFECT
When a drug is displaced from binding sites in plasma or tissues by another drug, this does what?
increases the concentration of free (unbound) drug — thus an increased elimination.
this produces a new steady state where the total drug concentration in the plasma is decreased, BUT the free drug conc is similar to that before the introduction of the “displacing” drug
the increase in conc of free drug before the steady state was reached could cause toxicity.
name some protein-bound drugs that are given in large enough dosage to act as “displacing agents’
aspirin
sulphonamides
chloral hydrate (its metabolites is trichloracetic acid which binds very strongly to albumin)
