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Pharmacology Midterm (edit) > lecture 5 part 1 > Flashcards

lecture 5 part 1 Flashcards

1
Q

name the things that can happen to a drug after it is metabolized

A

active drug can become:

-a less toxic metabolite
-toxic metabolite
-inactive

an inactive drug (prodrug) can get activated after metabolism

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2
Q

metabolism consists of …

A

anabolism + catabolism

anabolism = synthesize

catabolism = destroy

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3
Q

biotransformation mostly has GOOD effects.

give 4 exceptions

A

-drug-drug interactions
-metabolic activation of toxic and carcinogenic derivatives
-variations in humans to metabolize drugs
-use of animal models is limited bc different species express different metabolic enzymes

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4
Q

true or false

some rectal drugs get absorbed and some dont

A

true

enema does not

a pediatric drug probably would

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5
Q

what kind of molecules are easily eliminated through the renal route

A

polar, hydrophilic molecules

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6
Q

true or false

very few drugs are polar and ionized

A

TRUE

most are lipophilic and unionized in physiological conditions

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7
Q

many ____ compounds are bound to plasma proteins and thus cannot……..

A

lipophilic

cannot pass glomerular filtration

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8
Q

_______ is an obstacle to drug excretion

A

LIPOPHILICITY

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9
Q

TRUE OR FALSE

metabolism always produces drugs that are more hydrophilic and less toxic

A

FALSE

sometimes they can retain their biological activity and even be toxic

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10
Q

the renal excretion of unchanged drug contributes _______ to elimination.
explain

A

only slightly, because the unchanged, lipophilic drug can be easily reabsorbed back into the body through the renal tubular membranes

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11
Q

true or false

metabolism can turn an active drug into a different active drug

A

true

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12
Q

drug biotransformation mechanisms are described as….

A

either phase 1 or phase 2

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13
Q

explain (in general) what happens in phase 1 metabolism

A

the parent drug is altered by introducing or exposing a functional group

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14
Q

name 3 functional groups that can be introduced/exposed in phase 1 metabolism

A

OH
SH
NH2

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15
Q

inactive prodrugs can be metabolized into biologically active metabolites

is this done through phase 1 or phase 2

A

phase 1

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16
Q

classify types of prodrugs

A

they can either have an intracellular or extracellular site of conversion

intracellular - subtypes A and B

A - location of conversion is the therapeutic TARGET tissues/cells

B - location of conversion is METABOLIC tissues such as liver, GI mucosal cell, lung, etc

extracellular - subtypes A, B, C

A - location of conversion is GI fluids

B - location of conversion is systemic circulation and other extracellular fluid compartments

C - location of conversion is THERAPEUTIC target tissues/cells

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17
Q

explain the potential fates of phase 1 reaction products

A

-directly excreted in the urine

or

-react with endogenous compounds to form more water soluble conjugates (AKA go through phase 2)

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18
Q

explain the characteristics of phase 2 metabolic reactions

A

the drug participates in CONJUGATION reactions that forms a COVALENT BOND between the parent functional group and potential endogenous substances

glucuronate
sulfate
glutathione
amino acids
acetate

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19
Q

name the enzyme involved in adding glucuronate in phase 2

A

UDP glucuronosyltransferase

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20
Q

name the enzyme involved in adding sulfate in phase 2

A

sulfotransferase

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21
Q

name the enzyme involved in adding glutathione in phase 2

A

glutathione-s-transferase

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22
Q

name an enzyme involved in adding amino acids in phase 2

A

acyl-coa glycinetransferase

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23
Q

name the enzyme involved in adding acetate in phase 2

A

n-acetyltransferase

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24
Q

explain the conjugates of phase 2 and any exceptions

A

highly polar
rapidly excreted in the urine
GENERALLY inactive

exception - the glucuronide metabolite of morphine is A MORE POTENT ANALGESIC than the parent compound

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25
Q

true or false

all phase 2 metabolites are inactive

A

FALSE

most, but an exception is morphine

glucuronide metabolite of morphine is a more potent analgesic than the parent

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26
Q

explain what happens to HIGH MOLECULAR WEIGHT conjugates

A

they are excreted in the bile (feces)

may go through enterohepatic circulation
-the conjugate bond may be cleaved my the intestinal flora and the parent drug may be released BACK into systemic circulation

this leads to delayed elimination of the parent drug and prolongation of drug effect

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27
Q

name some high molecular weight drugs that may go through enterohepatic circulation

A

morphine and tetracyclines

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28
Q

what is the principal organ for biotransformation?

name 5 others

A

LIVER

GI tract
lungs
skin
kidney
brain

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29
Q

_____ is responsible for 1st pass effects

A

metabolism

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30
Q

give 2 examples of “first pass” when a drug is given orally

A
  1. drug is administered orally and absorbed intact through the small intestine
  • the drug is transported to the liver portal system
    —extensive metabolism here (1st pass)
  1. a drig is administered orally and is absorbed intact through the small intestine

-the drug may undergo extensove INTESTINAL metabolism which will contribute to the overall 1st pass effect

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31
Q

give 4 examples of drugs that….

are administered orally, absorbed intact through SI, and then are carried to the liver portal system where they undergo 1st pass

A

meperidine**
morphine
isoproterenol
pentazocine

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32
Q

give 4 examples of drugs that….

are administered orally and absorbed intact through the SI, then undergo extensive INTESTINAL METABOLISM that contributes to overall 1st pass

A

cyclosporine
clonazepam
midazolam (50%)
chlorpromazine

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33
Q

give an example of a drug that is UNSTABLE IN GASTRIC ACID

what does this contribute to

A

penicillin

contributes to overall 1st pass effects

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34
Q

give an example of a drug that is metabolized by digestive enzymes and why.

what does this contribute to

A

insulin - that’s why given SUBQ.
bc it is a peptide it is metabolized by digestive enzymes

contributes to overall 1st pass effetcs

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35
Q

what kind of drugs are metabolized by intestinal wall enzymes

A

sympathomimetic and catecholamines

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36
Q

which route of administration has the highest bioavailability

A

IV

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37
Q

why is the bioavailability of oral drugs so limited

A

bc of 1st pass effects

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38
Q

true or false

the intestinal flora may metabolize drugs and this could contribute to overall 1st pass effects

A

true

39
Q

the bioavailability of oral drugs is so limited that…….

A

sometimes alternative routes of administration must be used (ie: lidocaine)

40
Q

name the cytochrome p450 dependent oxidation reactions

A

aromatic hydroxylations
aliphatic hydroxylations
epoxidation
O-dealkylation (N,O,S)
N-oxidation
S-oxidation
Deamination
desulfurization
dechlorination

41
Q

what are the cytochrome p450 INDENDENT oxidations

A

flavin monoxygenase (Ziegler’s enzyme)

42
Q

name 3 kinds of reductions

A

azo reductions
nitro reductions
carbonyl reductions

43
Q

name 2 structures that undergo phase 1 hydrolysis

A

esters
amides

44
Q

what does FMO stand for

A

Flavin containing monooxygenases

-superfamily of phase 1 in drug metabolism. CYTOCHROME P450 INDEPENDENT

45
Q

Where are FMOs expressed in high levels

A

in the liver, bound to the ER

46
Q

how many families of FMO are there? which is most abundant

A

6 families

FMO3 is MOST ABUNDANT in human liver

47
Q

what happens if someone has a genetic deficiency of FMO

A

fish odor syndrome

lack of TMAO (tri methylamine N-oxide) metabolism to TMA (tri methyl amine) leads to its accumulation in the body

48
Q

what does TMAO stand for and what is it

A

trimethyl amine N-oxide

it’s supposed to get metabolized by FMO system (cytp450 independent) to TMA (trimethylamine), but when a person is genetically deficient in FMO, they get FISH ODOR SYNDROME because TMAO builds up in the body

49
Q

where is TMAO found in high concentrations

A

in murine animals (rodents
-up to 15% of their body weight!

50
Q

TRUE OR FALSE

CYPs are not induced or inhibited by any clinically used drugs, while FMO is.

A

FALSE

CYPs ARE induced/inhibited by clinically used drufs

FMO is NOT

51
Q

name some drugs that FMO3 metabolizes

A

nicotine
H2 receptor antagonists (cimetidine and ranitidine)
antpsychotics
antiemetics

52
Q

name a hydrolytic enzyme

A

the epoxide hydrolases —

sEH (soluble epoxide hydrolases) in the cytosol

mEH (microsomal epoxide hydrolases) in the ER

53
Q

what produces epoxide hydrolases ? (sEH and mEH)

A

CYPs

54
Q

what are epoxides

A

highly reactive electrophiles that bind to nucleophiles found in protein, RNA, and DNA (dangerous!)

55
Q

what is the function of epoxide hydrolases

A

the deactivate potentially toxic metabolites that are generated by CYPs (like epoxides)

56
Q

give a specific example of epoxide hydrolases in action

A

carbamazepine (prodrug - antiepileptic)

gets metabolizes to carbamazepine 10,11-EPOXIDE by a CYP.

this gets HYDROLYZED to a Dihydrodiol by mEH.

57
Q

Give the “rhyme” for metabolism

A

active to inactive
active to reactive (toxic)
active to active
inactive to active

LIVER MICROSOMAL SYSTEM

58
Q

give an example of when an active drug is metabolized to an inactive, polar metabolite

A

phenobarbital is converted to barbituric acid by CYP2c19 isoform.

barbituric acid is INACTIVE and further undergoes phase 2 glucuronidation or sulfation (sulfuric acid) and is excreted in the urine

59
Q

phenobarbital has the potential to induce what enzymes

A

CYP2CP and CYP3A4

60
Q

give a specific example of an inactive drug getting metabolized to an active metabolite

A

this is the case for prodrugs

-purine and pyrimidine chemotherapy drugs

-terfenadine -> fexofenadine (inadvertant)

-L-dopa –> dopamine

61
Q

give a specific example of an active drug getting metabolized to a reactive/toxic metabolite

A

acetaminophen (when glucuronidation and sulfation are saturated)

becomes NAPQI

62
Q

give a specific example of an active drug getting metabolized to a different active drug

A

digitoxin metabolized to digoxin
-has same pharmacological activity

the metabolite is still active and working

63
Q

more than ______ individual CYPs have been identified in humans.

what are the categories based on?

A

more than 50

categories based on protein sequence homology

64
Q

true or false

CYPs cannot metabolize a single compound at different positions on the molecule

A

FALSE - they can

65
Q

most of the DRUG-METABOLIZING enzymes are in what CYP families?

A

CYP 1,2,3

66
Q

What is the range of MW of CYPs

A

45-60kDa

67
Q

____ is VERY COMMON to the metabolism of many drugs.
explain

A

CYP3A4

its presence in the GI tract is responsible for the poor oral availability of many drugs

68
Q

what is responsible for the poor oral availabiltiy of many drugs

A

CYP3A4 presence in the GI TRAT

69
Q

true or false

CYPs have redundant and broad substrate specificiy

A

true

frequently, 2 or more enzymes can catalyze the same type of ocidation

70
Q

how many putative functional genes are in the mouse/human?

what about pseudogenes

A

human:
-57 putative functional genes
-58 pseduogenes

mouse:
-102 putative functional genes
-88 pseudogenes

71
Q

explain the nomenclature of CYPs

A

CYP3A4

3 = family (arabic number)
A = subfamily
4=additional number when more than 1 subfamily is identified

if 4 was in ITALICS – it would indicate the gene

if NOT in italics = enzyme

72
Q

give the formula for the CYP reactions

A

NADPH + H+ + drug -> NADP+ + H20 + oxidized drug

73
Q

what is the cofactor in the CYP reactions

A

NADPH

74
Q

what is the origin of the enzyme family name of CYP

A

carbon monoxide binds to the reduced Fe(II) heme at 450nm

75
Q

___________ is the major catalyst of drugs and endogenous compound oxidations in the liver, kidney, GI, skin, and lungs

A

CYP monooxygenase enzyme family

76
Q

name 5 things that oxidation reactions require

A

CYP heme protein
reductase
NADPH
phosphatidylcholine
molecular Oxygen

77
Q

where are CYPs? what are they with close association with and in what ratio?

A

in smooth ER

Close association with NADPH-CYP reductase in 10:1 ratio

78
Q

NADPH cytochrome P450 reductase serves as…….

A

the source of electrons for the oxidative reaction cycle

79
Q

what is another name for the heme portion of CYP

A

Iron-protoprophyrin IX

80
Q

go back to CYP cycle

A

go back

81
Q

majority of drugs are metabolized by what CYP isoforms

A

CYP3A4

CYP2C9

CYP2D6

ALSO…..

CYP2C19
CYP1A2
CYP2A6

82
Q

TRUE OR FALSE

in addition to metabolizing exogenous substances like drugs, CYP isoforms also metabolize many endogenous substances including prostaglandins, lipids, fatty acids, and steroid hormones

A

TRUE

83
Q

ethanol induces what CYP isoform?*****

A

CYP2E1

84
Q

isosafrole induces what CYP isoform

A

CYP1A2

85
Q

what is “induction mechanism 2” of CYP

A

p450 enzymes may be induced by substrate stabilization (decreased degradation)

such is the case for ethanol induces CYP2E1

86
Q

troleandomycin and clotrimazole induce what cytochrome isoform

A

CYP3A enzymes

87
Q

true or false

some drugs inhibit CYTp450s

A

true

88
Q

give examples of drugs that are COMPETITIVE INHIBITORS of CYT P450 enzymes***

A

they bind to the cytochrome component (thus competitive inhibitors)

cimetidine – CYP3A4 and CYP2D6 (anti ulcer H2 receptor blocker)

ketoconazole – CYP3A4 and CYP2D6 (antifungal)

89
Q

besides cimetadine and ketokonazole, give another example of a drug that is a CYP inhibitor and explain how it works

A

chloramphenicol (antibiotic) is metabolized (by CYP2B1) TO AN ALKYLATING METABOLITE THAT INACTIVATES THAT CYP ISOFORM

90
Q

If you take a drug that is a substrate for CYP3A4 and a drug that is an inducer of CYP3A4, what will happen?

what is you take an inhibitor?

A

the drug will be metabolized extremely quickly

with inhibitor – drug will not be metabolized nearly as fast and will remain the body longer - potential toxicity

91
Q

5-10% of caucasians are poor metabolizers of…….

A

substrates for CYP2D6

92
Q

explain the poor metabolizers of CYP2C19 drugs

A

about 20% of asian populations are poor metabolizers of drugs that are substrates for CYP2C19

but only about 4% in caucasian populations

93
Q

true or false

water conjugation is a type of phase 2 biotransformation

A

TRUE – enzyme is epoxide hydrolases in cytosol or microsomes (mEH or sEH)

94
Q
A

Pharmacology Midterm (edit) (12 decks)

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