lecture 5 part 2

Question 1

name the transferase (enzyme) and endogenous reactant for glucuronidation

name where the enzyme is located as well

Answer 1

endogenous reactant = UDP glucuronic acid

transferase = UDP glucuronosyltransferase (microsomes)

Question 2

phase 2 enzymes are…..

Answer 2

transferases

Question 3

name the endogenous reactant for acetylation and the enzyme and where it’s located

Answer 3

endogenous reactant = acetyl-coA

enzyme = N-acetyltransferase (cytosol)

Question 4

name the endogenous reactant for GSH conjugation and the enzyme and where it’s located

Answer 4

endogenous reactant = GSH (glutathione)

transferase = GSH-S-transferase, located in the cytosol and microsomes

Question 5

name the endogenous reactant for glycine conjugation as well as the trasnferase and where it’s located

Answer 5

endogenous reactant = glycine

enzyme = acyl-coa glycinetransferase– located in the mitochondria

Question 6

name the endogenous reactant for sulfation, the enzyme, and where it’s located

Answer 6

endogenous reactant = phosphoadenosyl phosphosulfate (PAPS)

enzyme = sulfotransferase, in the cytosol

Question 7

name the endogenous reactant for methylation, the enzyme and where it’s located

Answer 7

endogenous reactant = SAM (S-adenosyl methionine)

enzyme = transmethylases in the cytosol

Question 8

name the endogenous reactant for water conjugation, the enzyme, and where it’s located

Answer 8

endogenous reactant = water

enzyme = epoxide hydrolases, either in microsomes or cytosol (sEH and mEH)

Question 9

______ enzymes catalyze all conjugation reactions EXCEPT ______-

Answer 9

non microsomal

glucuronidation

Question 10

what is the location of phase 2 reactions

Answer 10

primarily in the liver, but also the plasma and GI tract

Question 11

conjugation reactions can also be called….. why?

Answer 11

detoxification reactions bc their metabolites are more polar, easily excreted, and typically inactive

Question 12

what enzymes hydrolyze drugs that contain ester linkages?

give a specific example

Answer 12

nonspecific esterases in the liver, plasma, and GI tract

succinylcholine (anectine) is hydrolzyed by these enzymes

Question 13

acetaminophin can cause ____ toxicity outside of therapeutic dosing

Answer 13

hepato

Question 14

explain what happens with the metabolism of acetaminophen within therapeutic dosing and when OD happens

Answer 14

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

Question 15

***** what is the antidote to acetaminophen OD

Answer 15

N-acetylcysteine – it is the precursor to glutathione and can conjugate the toxic metabolite to a mercapturate (Ac-SG) that is excreted and harmless

Question 16

with age, there is a variation in drug responses.

this is usually due to what?

Answer 16

diminished cardiac output.

this reduces hepatic perfusion (deliver of drug to liver to be metabolized) which PROLONGS THE DURATION OF THE DRUG

Question 17

TRUE OR FALSE

elderly patients have increased body fat and this has an effect on drug metabolism

Answer 17

TRUE

high body fat increases Vd

promotes the accumulation of highly lipid soluble agents such as diazepam and thiopental (pentothal

Question 18

explain how neonates and elderly patients have different drug metabolism abilites

Answer 18

neonates have reduced hepatic metabolism bc of organ immaturity

elderly pts have differences in absorption, clearance, vd, hepatic metabolism

Question 19

name a potent inhibitor of CYP3A4

where is CYP3A4 localized?

Answer 19

grapefruit juice

in the intestinal wall mucosa

Question 20

what is the issue with some drugs + cruciferous vegetables?
name some cruciferous vegetables

Answer 20

they can INDUCE CYP1A2

brussel srpouts
cabbage
cauliflower
hydrocarbons in charcoal broiled meats

Question 21

explain the issue with calcium + some drugs

Answer 21

calcium in some dairy products can chelate drugs like

TETRACYCLINES AND FLUOROQUINOLONE antibiotics

–will chelate and be inactivated

Question 22

what is the issue with cigarette smokers when they taken drugs

Answer 22

some smokers metabolize drugs more rapidly than nonsmokers bc of ENZYME INDUCTION

Question 23

true or false

smokers tend to inhibit enzymes more than nonsmokers

Answer 23

FALSE - INDUCE
thus metabolize the drugs more rapidly

Question 24

explain the issue with industrial workers taking drugs

Answer 24

they may be exposed to pesticides and metabolize some drugs more rapidly than normal ppl

Question 25

define a drug interaction

Answer 25

when one drug affects the pharmacological response of a second drug given at the same time

Question 26

drug interactions may be due to…….

Answer 26

pharmacokinetic effects
pharmacodynamic effects

Question 27

what is a DIRECT drug interaction?
explain and give example

Answer 27

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)

Question 28

what is an INDIRECT drug interaction

Answer 28

Drug A alters (increases or decreases) the levels of an endogenous substance that thus affects the actions of Drug B

Question 29

give 3 examples of indirect drug interactions

Answer 29

-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

Question 30

what are in vitro drug-drug interactions

Answer 30

one of both or the drugs are inactivated.

there are NO pharmacological principles involved - just chemistry

Question 31

give 2 examples of in vitro drug-drug interactions

Answer 31

thiopentone + suxamethonium form a complex (so can’t be mixed in same syringe)

heparin is highly (-) charged and interacts with lot of basic drugs

Question 32

GI absorption is slowed by….

Answer 32

drugs tha tinhibit gastric emptying

Question 33

give 2 examples of drugs that inhibit gastric emptying and thus slow down GI absorption

Answer 33

atropine and opiates

Question 34

what drug accelerates GI absorption

Answer 34

metoclopramide

Question 35

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

Answer 35

FALSE - increased clearance

Question 36

name the main mechanisms in which 1 drug can affect the rate of renal excretion of the other

Answer 36

-inhibiting tubular secretion
-altering urine flow and pH
-by altering protein binding (and hence filtration)

Question 37

give an example of a drug that inhibits tubular secretion and thus affects excretion

Answer 37

probenecid inhibits penicillin tubular secretion and thus prolongs its action

(also inhibits secretion of other drugs like AZT)

Question 38

explain how urine flow and pH are altered to affect excretion

Answer 38

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

Question 39

___ and __ form an insoluble complex with tetracyclines and thus decrease its»»

Answer 39

calcium and iron

absorption

Question 40

_______ binds several drugs like warfarin and digoxin. this prevents their ____if they are administered at the same time

Answer 40

cholestyramine (bile acid reducing resin used to treat hypercholesterolemia)
prevents absorption

Question 41

explain how epinephrine can affect absorption

Answer 41

when adding epinephrine to local anesthetic injections, causes vasoconstriction and thus slows the absorption of the anasthetic and provides a LONGER LOCAL EFFECT

Question 42

When a drug is displaced from binding sites in plasma or tissues by another drug, this does what?

Answer 42

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.

Question 43

name some protein-bound drugs that are given in large enough dosage to act as “displacing agents’

Answer 43

aspirin
sulphonamides
chloral hydrate (its metabolites is trichloracetic acid which binds very strongly to albumin)