module 3: points to ponder

Question 1

what type of drugs is acetaminophen considered to be?

Answer 1

analgesic and antipyretic

Question 2

what symptoms does acetaminophen reduce?

Answer 2

pain and fevers

Question 3

which phase does acetaminophen undergoes?

Answer 3

II

Question 4

what are the two pathways acetaminophen is metabolized after it undergoes phase II reaction?

Answer 4

1. glucuronidated by glucuronosyltransferase
2. sulfated by sulfotransferase

Question 5

when acetaminophen undergoes phase II reactions, what does this allow for?

Answer 5

it can enter the plasma or bile

Question 6

a small amount of acetaminophen undergoes phase I reaction by CYP450 to form what?

Answer 6

N-acetyl-p-benzoquinone imine (NAPQI)

Question 7

what is NAPQI?

Answer 7

reactive oxygen species (free radical) that’s toxic to hepatocytes and is a strong oxidizer

Question 8

what does it mean to oxidize something?

Answer 8

take an electron away

Question 9

what antioxidant is present in high concentration in hepatocytes?

Answer 9

glutathione

Question 10

what groups does NAPQI react with?

Answer 10

thiol

Question 11

what enzyme adds glutathione to NAPQI to produce a harmless metabolite?

Answer 11

glutathione S- transferase

Question 12

true or false: the typical amount of NAPQI produced after taking an appropriate dose of acetaminophen is easily neutralized by glutathione

Answer 12

true

Question 13

what happens if you take too much acetaminophen?

Answer 13

Phase II reactions get overwhelmed leading to more Phase I reactions and a higher concentration of NAPQI in the liver.

Question 14

what happens if enough NAPQI is formed to let glutathione be depleted?

Answer 14

it leaves NAPQI free to oxidize other compounds

Question 15

how can NAPQI lead to hepatocellular necrosis and potentially liver failure?

Answer 15

by forming covalent bonds with sulfated molecules like cellular proteins

Question 16

what is the cough suppressant that replaced codeine?

Answer 16

dextromethorphan

Question 17

why can codeine and alcohol be dangerous?

Answer 17

codeine is an opioid and overdose can lead to respiratory depression, respiratory failure, and death

Question 18

how is 70% of codeine converted to codeine-6-glucuronide?

Answer 18

hepatic enzyme UGT2B7

Question 19

what group does UGT2B7 transfer to codeine?

Answer 19

glucuronosyl

Question 20

what specific opioid receptor does codeine-6-glucuronide bind to?

Answer 20

mu

Question 21

what happens to the 30% of codeine that’s not glucuronidated?

Answer 21

about half is N-demethylated by CYP3A4 to form norcodeine and the other half results in the formation of morphine

Question 22

where does the oxidation occur when CYP3A4 demethylates codeine to form norcodeine?

Answer 22

during the demethylation process, enzymes oxidize N-methyl groups to remove them from the compound and norcodeine weakly binds to mu with similar weak physiological effects

Question 23

how does morphine form from the metabolism of codeine?

Answer 23

CYP2D6 uses an O-demethylation reaction that removes a methyl group from an oxygen atom

Question 24

what happens to the body when morphine is formed?

Answer 24

opioid that binds very well to mu in the brain and causes euphoria, pain relief, and respiratory depression

Question 25

what is the primary active ingredient in alcohol?

Answer 25

ethanol

Question 26

what is ethanol metabolized to once in the liver?

Answer 26

acetaldehyde

Question 27

the metabolism of ethanol involved what phase reaction and what enzyme?

Answer 27

- phase I - alcohol dehydrogenase (non-cytochrome P450)

Question 28

what does alcohol dehydrogenase do?

Answer 28

removes H+ and e- from alcohol and pairs this with the reduction of NAD+ to NADH

Question 29

what is the end result of the oxidation of ethanol via alcohol dehydrogenase?

Answer 29

acetaldehyde

Question 30

what is CYP2E1?

Answer 30

located in smooth ER and works through microsomal oxidation when excessive amounts of alcohol (ethanol) is ingested

Question 31

describe microsomal oxidation with ethanol

Answer 31

ethanol is directly oxidized by molecular oxygen to acetaldehyde, so ethanol loses an electron to oxygen and reduces oxygen

Question 32

why can reduced oxygen be dangerous?

Answer 32

it becomes a free radical that damages protein and cell walls which then interferes with normal cellular function and viability

Question 33

when is CYP2E1 needed?

Answer 33

ONLY when alcohol dehydrogenase can't keep up with alcohol consumption

Question 34

how is NADPH involved in microsomal oxidation?

Answer 34

gets oxidized to NADP+, losing an electron and H+ in the process

Question 35

what is acetaldehyde converted to by acetaldehyde dehydrogenase?

Answer 35

acetate

Question 36

what are the two reasons that the faster acetaldehyde is metabolized to acetate the better?

Answer 36

1. acetaldehyde is a carcinogen 2. it's the reason you feel terrible after you've had too much to drink

Question 37

what is the major contributor to hangovers that causes headaches, tachycardia, flushing of skin from vasodilation, nausea, and vomiting?

Answer 37

acetaldehyde

Question 38

why kind of people are less likely to become alcholics?

Answer 38

people with increased alcohol dehydrogenase activity or decreased acetaldehyde dehydrogenase activity

Question 39

Many people from countries in _____ have an inactive version of acetaldehyde dehydrogenase-2 (ALDH2) in their liver.

Answer 39

Asia

Question 40

why is ALDH2 inactive?

Answer 40

due to a mutation that results in glutamate being replaced by lysine as the enzyme is synthesized

Question 41

the change in amino acids of ALDH2 _______ metabolism of acetaldehyde

Answer 41

slows

Question 42

what results from ALDH2 slowing the metabolism of acetaldehyde?

Answer 42

concentration of acetaldehyde in the blood increases drastically within a few minutes of consuming alcohol

Question 43

what drug is used to block active ALDH2 and why is it used to stop alcoholism?

Answer 43

Antabuse (disulfiram) - causes inducible and dramatic increase in blood concentrations of acetaldehyde accompanied by serious hangover symptoms