module 3: points to ponder Flashcards
what type of drugs is acetaminophen considered to be?
analgesic and antipyretic
what symptoms does acetaminophen reduce?
pain and fevers
which phase does acetaminophen undergoes?
II
what are the two pathways acetaminophen is metabolized after it undergoes phase II reaction?
- glucuronidated by glucuronosyltransferase
- sulfated by sulfotransferase
when acetaminophen undergoes phase II reactions, what does this allow for?
it can enter the plasma or bile
a small amount of acetaminophen undergoes phase I reaction by CYP450 to form what?
N-acetyl-p-benzoquinone imine (NAPQI)
what is NAPQI?
reactive oxygen species (free radical) that’s toxic to hepatocytes and is a strong oxidizer
what does it mean to oxidize something?
take an electron away
what antioxidant is present in high concentration in hepatocytes?
glutathione
what groups does NAPQI react with?
thiol
what enzyme adds glutathione to NAPQI to produce a harmless metabolite?
glutathione S- transferase
true or false: the typical amount of NAPQI produced after taking an appropriate dose of acetaminophen is easily neutralized by glutathione
true
what happens if you take too much acetaminophen?
Phase II reactions get overwhelmed leading to more Phase I reactions and a higher concentration of NAPQI in the liver.
what happens if enough NAPQI is formed to let glutathione be depleted?
it leaves NAPQI free to oxidize other compounds
how can NAPQI lead to hepatocellular necrosis and potentially liver failure?
by forming covalent bonds with sulfated molecules like cellular proteins
what is the cough suppressant that replaced codeine?
dextromethorphan
why can codeine and alcohol be dangerous?
codeine is an opioid and overdose can lead to respiratory depression, respiratory failure, and death
how is 70% of codeine converted to codeine-6-glucuronide?
hepatic enzyme UGT2B7
what group does UGT2B7 transfer to codeine?
glucuronosyl
what specific opioid receptor does codeine-6-glucuronide bind to?
mu
what happens to the 30% of codeine that’s not glucuronidated?
about half is N-demethylated by CYP3A4 to form norcodeine and the other half results in the formation of morphine
where does the oxidation occur when CYP3A4 demethylates codeine to form norcodeine?
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
how does morphine form from the metabolism of codeine?
CYP2D6 uses an O-demethylation reaction that removes a methyl group from an oxygen atom
what happens to the body when morphine is formed?
opioid that binds very well to mu in the brain and causes euphoria, pain relief, and respiratory depression
what is the primary active ingredient in alcohol?
ethanol
what is ethanol metabolized to once in the liver?
acetaldehyde
the metabolism of ethanol involved what phase reaction and what enzyme?
- phase I
- alcohol dehydrogenase (non-cytochrome P450)
what does alcohol dehydrogenase do?
removes H+ and e- from alcohol and pairs this with the reduction of NAD+ to NADH
what is the end result of the oxidation of ethanol via alcohol dehydrogenase?
acetaldehyde
what is CYP2E1?
located in smooth ER and works through microsomal oxidation when excessive amounts of alcohol (ethanol) is ingested
describe microsomal oxidation with ethanol
ethanol is directly oxidized by molecular oxygen to acetaldehyde, so ethanol loses an electron to oxygen and reduces oxygen
why can reduced oxygen be dangerous?
it becomes a free radical that damages protein and cell walls which then interferes with normal cellular function and viability
when is CYP2E1 needed?
ONLY when alcohol dehydrogenase can’t keep up with alcohol consumption
how is NADPH involved in microsomal oxidation?
gets oxidized to NADP+, losing an electron and H+ in the process
what is acetaldehyde converted to by acetaldehyde dehydrogenase?
acetate
what are the two reasons that the faster acetaldehyde is metabolized to acetate the better?
- acetaldehyde is a carcinogen
- it’s the reason you feel terrible after you’ve had too much to drink
what is the major contributor to hangovers that causes headaches, tachycardia, flushing of skin from vasodilation, nausea, and vomiting?
acetaldehyde
why kind of people are less likely to become alcholics?
people with increased alcohol dehydrogenase activity or decreased acetaldehyde dehydrogenase activity
Many people from countries in _____ have an inactive version of acetaldehyde dehydrogenase-2 (ALDH2) in their liver.
Asia
why is ALDH2 inactive?
due to a mutation that results in glutamate being replaced by lysine as the enzyme is synthesized
the change in amino acids of ALDH2 _______ metabolism of acetaldehyde
slows
what results from ALDH2 slowing the metabolism of acetaldehyde?
concentration of acetaldehyde in the blood increases drastically within a few minutes of consuming alcohol
what drug is used to block active ALDH2 and why is it used to stop alcoholism?
Antabuse (disulfiram)
- causes inducible and dramatic increase in blood concentrations of acetaldehyde accompanied by serious hangover symptoms
