module 3: clinical scenario metabolism

Question 1

why are drugs coated with enteric coatings?

Answer 1

to prevent them from breaking down while they are in an acidic environment, low surface area, and poor absorption from the stomach

Question 2

what cells line the small intestines?

Answer 2

enterocytes

Question 3

what is the purpose of villi and microvilli?

Answer 3

dramatically increase the surface area of the small intestine and aid in the absorption of food

Question 4

what is the first barrier for a drug that enters your system?

Answer 4

enterocytes

Question 5

what is the most prominent drug metabolizing enzyme in the enterocytes?

Answer 5

CYP3A4

Question 6

list the three fractions a single dose of medication follows once swallowed?

Answer 6

1. one fraction failed to make it into the enterocytes
2. one fraction metabolized by CYP3A4 in the enterocytes
3. remaining fraction made it through the enterocytes unscathed

Question 7

what is the main function of the liver?

Answer 7

metabolize molecules for their removal from the body via kidneys

Question 8

true or false: drugs can be directly removed in bile

Answer 8

true

Question 9

true or false: for most drugs, liver metabolism typically activates them and makes them more soluble for their removal

Answer 9

false: inactivates

Question 10

what comprises the hepatic portal network?

Answer 10

intestinal capillary network and portal vein

Question 11

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

Answer 11

true

Question 12

define bioavailability

Answer 12

amount of a drug that’s available to the biological tissues of the body

Question 13

what is the bioavailability of a drug administered IV and why?

Answer 13

100% because it enters the systemic circulation

Question 14

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.

Answer 14

30%

Question 15

what are first pass effects?

Answer 15

very little reaches the systemic circulation

Question 16

what is the most common way to bypass first pass effects?

Answer 16

administering drugs IV

Question 17

how does administering drugs IM minimize first pass effects?

Answer 17

enters the circulation via lymphatic system

Question 18

how does administering drugs sublingual minimize first pass effects?

Answer 18

enter the systemic system circulation through sublingual vessels

Question 19

how can drugs be inhaled and enter the systemic circulation?

Answer 19

via pulmonary capillaries that are closely associated with alveoli in the lungs

Question 20

what is the pathway of drugs once it reaches the systemic circulation?

Answer 20

vena cava -> heart -> aorta -> liver via hepatic artery

Question 21

what is the portal triad?

Answer 21

how drugs enter the liver through the portal vein and hepatic artery in a bundle with the bile duct region

Question 22

what is the functional unit of the liver?

Answer 22

liver acinus

Question 23

where does metabolism of hydrophilic drugs occur?

Answer 23

cytosol

Question 24

where do hydrophobic drugs metabolize?

Answer 24

smooth ER

Question 25

what are phase I drug metabolizing enzymes?

Answer 25

enzymes that oxidize and/or reduce drugs

Question 26

what are phase II drug metabolizing enzymes?

Answer 26

enzymes that add other groups to drugs

Question 27

true or false: phase I and II designations reflect the order that drugs are metabolized

Answer 27

false

Question 28

what are the enzymes of phase I?

Answer 28

cytochrome P450 identified with designation CYP

Question 29

how is CYP denoted?

Answer 29

family subfamily isoform

Question 30

describe the isoform CYP2C9

Answer 30

phase I - narrower range of substrates including the anticoagulant warfarin and ibuprofen

Question 31

what is the overall purpose of CYP?

Answer 31

oxidizing enzymes that involve the removal of electrons in the process of transferring oxygen containing species like hydroxyl groups to drugs

Question 32

phase II uses conjugation, what is that?

Answer 32

enzymes that most often add a molecule to a drug to make it more soluble in water

Question 33

why do we want to make drugs more water soluble?

Answer 33

so it can be excreted in the urine

Question 34

when is a drug considered to be metabolized?

Answer 34

after is has become altered by one or both sets of reactions

Question 35

what does 450 mean in cytochrome P450

Answer 35

spectrophotometric peak occurs at 450 nm under a particular set of conditions

Question 36

why are the CYP enzymes called oxidase?

Answer 36

they transfer oxygen to the drugs they metabolize

Question 37

how do CYP enzymes transfer oxygen?

Answer 37

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.

Question 38

why are some CYP enzymes considered reductases?

Answer 38

both reduction and oxidation occur (redox reactions)

Question 39

why is cytochrome P450 considered heme containing enzymes?

Answer 39

the heme groups in the enzymes bind oxygen

Question 40

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.

Answer 40

cysteine Fe

Question 41

what is cysteine important for in CYP enzymes?

Answer 41

transfer of the oxygen-containing functional groups to the drugs

Question 42

The Fe atom oscillates between being in what three oxidation states depending on the what is happening in the redox reactions?

Answer 42

Fe2+, Fe3+ , and Fe4+

Question 43

the reduced heme group in cytochrome P450 enzymes strongly bind to what?

Answer 43

carbon monoxide

Question 44

how did cytochrome P450 get its name?

Answer 44

they contain a heme group that binds carbon monoxide and maximally absorbs light at the specific wavelength of 450 nm.

Question 45

what happens when a drug binds near the heme of the CYP enzyme in the presence of oxygen?

Answer 45

the drug covalently binds one of the oxygen atoms in O2, the other O2 combines with two H+ to form water

Question 46

how does NADP+ become NADPH

Answer 46

when it becomes reduced it can hold onto H+ to form NADPH

Question 47

where and how does H+ come together to form water?

Answer 47

they can donate H+ to O2

Question 48

how many NAPHs are needed to complete the reaction of water formation?

Answer 48

2 because water has 2 H+

Question 49

when can NADPH donate its H+?

Answer 49

becomes oxidized and loses an electron

Question 50

what enzyme is needed to oxidize NADPH?

Answer 50

oxidase, CYP450 enzymes

Question 51

what is the result of the phase I reaction?

Answer 51

- 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

Question 52

it is extremely important that NADP+ and NADPH are available to gain or donate an __________

Answer 52

electron

Question 53

what kind of enzymes are involved in the phase II drugs?

Answer 53

transferases

Question 54

what are the molecules that can be transferred?

Answer 54

acetyl sulfur glucuronosyl methyl groups

Question 55

which of the transferred groups is hydrophobic?

Answer 55

methyl group

Question 56

what is a conjugation reaction?

Answer 56

when a molecule gets transferred to a drug

Question 57

what is the most prominent reaction handled by conjugative phase II enzymes?

Answer 57

glucuronidation

Question 58

how is the compound of bilirubin formed?

Answer 58

in the liver when heme groups are extracted from red blood cells being removed at the end of their normal lifespan

Question 59

what groups are transferred to bilirubin via a transferase enzyme?

Answer 59

glucuronosyl

Question 60

where does the glucuronosyl group come from?

Answer 60

UDP

Question 61

In the presence of the UGT enzyme, where is bilirubin conjugated and secreted into?

Answer 61

the bile and eventually released into the lumen of the small intestine.

Question 62

While in the small intestine, the glucuronidated bilirubin can be metabolized further by bacterial enzymes to form either ________ or _________.

Answer 62

stercobilin urobilinogen

Question 63

Some of the urobilinogen is reabsorbed in the ______________, excreted by the ______, and forms urobilin when exposed to the air.

Answer 63

small intestines kidneys

Question 64

what is stercobilin?

Answer 64

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

Question 65

what gives urine its yellow color?

Answer 65

urobilinogen

Question 66

What happens if the UGT enzyme isn’t present?

Answer 66

bilirubin can’t be properly conjugated and metabolized

Question 67

what are some symptoms of Gilbert's syndrome?

Answer 67

- yellow tinge of skin and whites of eyes - tired and weak - abdominal pain

Question 68

explain the bloodwork results of someone with Gilbert's syndrome

Answer 68

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

Question 69

what does isoniazid become when it is metabolized?

Answer 69

acetylisoniazid

Question 70

how does acetyl get added to isoniazid?

Answer 70

acetyl CoA

Question 71

what is the main function of acetyl CoA?

Answer 71

- 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