module 3: clinical scenario metabolism Flashcards
why are drugs coated with enteric coatings?
to prevent them from breaking down while they are in an acidic environment, low surface area, and poor absorption from the stomach
what cells line the small intestines?
enterocytes
what is the purpose of villi and microvilli?
dramatically increase the surface area of the small intestine and aid in the absorption of food
what is the first barrier for a drug that enters your system?
enterocytes
what is the most prominent drug metabolizing enzyme in the enterocytes?
CYP3A4
list the three fractions a single dose of medication follows once swallowed?
- one fraction failed to make it into the enterocytes
- one fraction metabolized by CYP3A4 in the enterocytes
- remaining fraction made it through the enterocytes unscathed
what is the main function of the liver?
metabolize molecules for their removal from the body via kidneys
true or false: drugs can be directly removed in bile
true
true or false: for most drugs, liver metabolism typically activates them and makes them more soluble for their removal
false: inactivates
what comprises the hepatic portal network?
intestinal capillary network and portal vein
true or false: small amounts of the drug that weren’t metabolized in the enterocytes can still be metabolized as they circulate because enzymes like CYP3A4 are everywhere
true
define bioavailability
amount of a drug that’s available to the biological tissues of the body
what is the bioavailability of a drug administered IV and why?
100% because it enters the systemic circulation
what is the bioavailability of a drug administered orally: For example, if 60% of a drug makes it through the enterocytes without being metabolized, but 50% of that is metabolized by CYP3A4 in the liver.
30%
what are first pass effects?
very little reaches the systemic circulation
what is the most common way to bypass first pass effects?
administering drugs IV
how does administering drugs IM minimize first pass effects?
enters the circulation via lymphatic system
how does administering drugs sublingual minimize first pass effects?
enter the systemic system circulation through sublingual vessels
how can drugs be inhaled and enter the systemic circulation?
via pulmonary capillaries that are closely associated with alveoli in the lungs
what is the pathway of drugs once it reaches the systemic circulation?
vena cava -> heart -> aorta -> liver via hepatic artery
what is the portal triad?
how drugs enter the liver through the portal vein and hepatic artery in a bundle with the bile duct region
what is the functional unit of the liver?
liver acinus
where does metabolism of hydrophilic drugs occur?
cytosol
where do hydrophobic drugs metabolize?
smooth ER
what are phase I drug metabolizing enzymes?
enzymes that oxidize and/or reduce drugs
what are phase II drug metabolizing enzymes?
enzymes that add other groups to drugs
true or false: phase I and II designations reflect the order that drugs are metabolized
false
what are the enzymes of phase I?
cytochrome P450 identified with designation CYP
how is CYP denoted?
family
subfamily
isoform
describe the isoform CYP2C9
phase I
- narrower range of substrates including the anticoagulant warfarin and ibuprofen
what is the overall purpose of CYP?
oxidizing enzymes that involve the removal of electrons in the process of transferring oxygen containing species like hydroxyl groups to drugs
phase II uses conjugation, what is that?
enzymes that most often add a molecule to a drug to make it more soluble in water
why do we want to make drugs more water soluble?
so it can be excreted in the urine
when is a drug considered to be metabolized?
after is has become altered by one or both sets of reactions
what does 450 mean in cytochrome P450
spectrophotometric peak occurs at 450 nm under a particular set of conditions
why are the CYP enzymes called oxidase?
they transfer oxygen to the drugs they metabolize
how do CYP enzymes transfer oxygen?
electrons have to be removed from the drug and from the oxygen-containing functional groups to form a covalent bond between the drug and the oxygen species.
why are some CYP enzymes considered reductases?
both reduction and oxidation occur (redox reactions)
why is cytochrome P450 considered heme containing enzymes?
the heme groups in the enzymes bind oxygen
the heme group in the CYP enzymes is covalently linked to the amino acid _________ and contains an _______ atom that plays a critical role in these reactions.
cysteine
Fe
what is cysteine important for in CYP enzymes?
transfer of the oxygen-containing functional groups to the drugs
The Fe atom oscillates between being in what three oxidation states depending on the what is happening in the redox reactions?
Fe2+, Fe3+ , and Fe4+
the reduced heme group in cytochrome P450 enzymes strongly bind to what?
carbon monoxide
how did cytochrome P450 get its name?
they contain a heme group that binds carbon monoxide and maximally absorbs light at the specific wavelength of 450 nm.
what happens when a drug binds near the heme of the CYP enzyme in the presence of oxygen?
the drug covalently binds one of the oxygen atoms in O2, the other O2 combines with two H+ to form water
how does NADP+ become NADPH
when it becomes reduced it can hold onto H+ to form NADPH
where and how does H+ come together to form water?
they can donate H+ to O2
how many NAPHs are needed to complete the reaction of water formation?
2 because water has 2 H+
when can NADPH donate its H+?
becomes oxidized and loses an electron
what enzyme is needed to oxidize NADPH?
oxidase, CYP450 enzymes
what is the result of the phase I reaction?
- drug with a polar group and creation of water molecule
- 2 NADPH2 oxidized to NADP+ and ready to be reduced again whenever electrons become available
it is extremely important that NADP+ and NADPH are available to gain or donate an __________
electron
what kind of enzymes are involved in the phase II drugs?
transferases
what are the molecules that can be transferred?
acetyl
sulfur
glucuronosyl
methyl groups
which of the transferred groups is hydrophobic?
methyl group
what is a conjugation reaction?
when a molecule gets transferred to a drug
what is the most prominent reaction handled by conjugative phase II enzymes?
glucuronidation
how is the compound of bilirubin formed?
in the liver when heme groups are extracted from red blood cells being removed at the end of their normal lifespan
what groups are transferred to bilirubin via a transferase enzyme?
glucuronosyl
where does the glucuronosyl group come from?
UDP
In the presence of the UGT enzyme, where is bilirubin conjugated and secreted into?
the bile and eventually released into the lumen of the small intestine.
While in the small intestine, the glucuronidated bilirubin can be metabolized further by bacterial enzymes to form either ________ or _________.
stercobilin
urobilinogen
Some of the urobilinogen is reabsorbed in the ______________, excreted by the ______, and forms urobilin when exposed to the air.
small intestines
kidneys
what is stercobilin?
breakdown product of bilirubin that leaves through the gastrointestinal tract and is the compound that causes feces to be brown.
- a biomarker used to document fecal contamination in rivers
what gives urine its yellow color?
urobilinogen
What happens if the UGT enzyme isn’t present?
bilirubin can’t be properly conjugated and metabolized
what are some symptoms of Gilbert’s syndrome?
- yellow tinge of skin and whites of eyes
- tired and weak
- abdominal pain
explain the bloodwork results of someone with Gilbert’s syndrome
they are unable to transfer glucuronate moiety to bilirubin (unconjugated bilirubin) so the bloodwork would reveal a high concentration of bilirubin (hyperbilirubinemia) lacking the glucuronosyl group
what does isoniazid become when it is metabolized?
acetylisoniazid
how does acetyl get added to isoniazid?
acetyl CoA
what is the main function of acetyl CoA?
- deliver an acetyl group to oxaloacetate to form citric acid in the citric acid cycle
- vital for cellular metabolism
- helps in many phase II reactions involving transfer of acetyl group
