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

lecture 5 part 1 Flashcards

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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
true or false all phase 2 metabolites are inactive
FALSE most, but an exception is morphine glucuronide metabolite of morphine is a more potent analgesic than the parent
26
explain what happens to HIGH MOLECULAR WEIGHT conjugates
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
27
name some high molecular weight drugs that may go through enterohepatic circulation
morphine and tetracyclines
28
what is the principal organ for biotransformation? name 5 others
LIVER GI tract lungs skin kidney brain
29
_____ is responsible for 1st pass effects
metabolism
30
give 2 examples of "first pass" when a drug is given orally
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) 2. 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
31
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
meperidine** morphine isoproterenol pentazocine
32
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
cyclosporine clonazepam midazolam (50%) chlorpromazine
33
give an example of a drug that is UNSTABLE IN GASTRIC ACID what does this contribute to
penicillin contributes to overall 1st pass effects
34
give an example of a drug that is metabolized by digestive enzymes and why. what does this contribute to
insulin - that's why given SUBQ. bc it is a peptide it is metabolized by digestive enzymes contributes to overall 1st pass effetcs
35
what kind of drugs are metabolized by intestinal wall enzymes
sympathomimetic and catecholamines
36
which route of administration has the highest bioavailability
IV
37
why is the bioavailability of oral drugs so limited
bc of 1st pass effects
38
true or false the intestinal flora may metabolize drugs and this could contribute to overall 1st pass effects
true
39
the bioavailability of oral drugs is so limited that.......
sometimes alternative routes of administration must be used (ie: lidocaine)
40
name the cytochrome p450 dependent oxidation reactions
aromatic hydroxylations aliphatic hydroxylations epoxidation O-dealkylation (N,O,S) N-oxidation S-oxidation Deamination desulfurization dechlorination
41
what are the cytochrome p450 INDENDENT oxidations
flavin monoxygenase (Ziegler's enzyme)
42
name 3 kinds of reductions
azo reductions nitro reductions carbonyl reductions
43
name 2 structures that undergo phase 1 hydrolysis
esters amides
44
what does FMO stand for
Flavin containing monooxygenases -superfamily of phase 1 in drug metabolism. CYTOCHROME P450 INDEPENDENT
45
Where are FMOs expressed in high levels
in the liver, bound to the ER
46
how many families of FMO are there? which is most abundant
6 families FMO3 is MOST ABUNDANT in human liver
47
what happens if someone has a genetic deficiency of FMO
fish odor syndrome lack of TMAO (tri methylamine N-oxide) metabolism to TMA (tri methyl amine) leads to its accumulation in the body
48
what does TMAO stand for and what is it
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
where is TMAO found in high concentrations
in murine animals (rodents -up to 15% of their body weight!
50
TRUE OR FALSE CYPs are not induced or inhibited by any clinically used drugs, while FMO is.
FALSE CYPs ARE induced/inhibited by clinically used drufs FMO is NOT
51
name some drugs that FMO3 metabolizes
nicotine H2 receptor antagonists (cimetidine and ranitidine) antpsychotics antiemetics
52
name a hydrolytic enzyme
the epoxide hydrolases --- sEH (soluble epoxide hydrolases) in the cytosol mEH (microsomal epoxide hydrolases) in the ER
53
what produces epoxide hydrolases ? (sEH and mEH)
CYPs
54
what are epoxides
highly reactive electrophiles that bind to nucleophiles found in protein, RNA, and DNA (dangerous!)
55
what is the function of epoxide hydrolases
the deactivate potentially toxic metabolites that are generated by CYPs (like epoxides)
56
give a specific example of epoxide hydrolases in action
carbamazepine (prodrug - antiepileptic) gets metabolizes to carbamazepine 10,11-EPOXIDE by a CYP. this gets HYDROLYZED to a Dihydrodiol by mEH.
57
Give the "rhyme" for metabolism
active to inactive active to reactive (toxic) active to active inactive to active LIVER MICROSOMAL SYSTEM
58
give an example of when an active drug is metabolized to an inactive, polar metabolite
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
phenobarbital has the potential to induce what enzymes
CYP2CP and CYP3A4
60
give a specific example of an inactive drug getting metabolized to an active metabolite
this is the case for prodrugs -purine and pyrimidine chemotherapy drugs -terfenadine -> fexofenadine (inadvertant) -L-dopa --> dopamine
61
give a specific example of an active drug getting metabolized to a reactive/toxic metabolite
acetaminophen (when glucuronidation and sulfation are saturated) becomes NAPQI
62
give a specific example of an active drug getting metabolized to a different active drug
digitoxin metabolized to digoxin -has same pharmacological activity the metabolite is still active and working
63
more than ______ individual CYPs have been identified in humans. what are the categories based on?
more than 50 categories based on protein sequence homology
64
true or false CYPs cannot metabolize a single compound at different positions on the molecule
FALSE - they can
65
most of the DRUG-METABOLIZING enzymes are in what CYP families?
CYP 1,2,3
66
What is the range of MW of CYPs
45-60kDa
67
____ is VERY COMMON to the metabolism of many drugs. explain
CYP3A4 its presence in the GI tract is responsible for the poor oral availability of many drugs
68
what is responsible for the poor oral availabiltiy of many drugs
CYP3A4 presence in the GI TRAT
69
true or false CYPs have redundant and broad substrate specificiy
true frequently, 2 or more enzymes can catalyze the same type of ocidation
70
how many putative functional genes are in the mouse/human? what about pseudogenes
human: -57 putative functional genes -58 pseduogenes mouse: -102 putative functional genes -88 pseudogenes
71
explain the nomenclature of CYPs
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
give the formula for the CYP reactions
NADPH + H+ + drug -> NADP+ + H20 + oxidized drug
73
what is the cofactor in the CYP reactions
NADPH
74
what is the origin of the enzyme family name of CYP
carbon monoxide binds to the reduced Fe(II) heme at 450nm
75
___________ is the major catalyst of drugs and endogenous compound oxidations in the liver, kidney, GI, skin, and lungs
CYP monooxygenase enzyme family
76
name 5 things that oxidation reactions require
CYP heme protein reductase NADPH phosphatidylcholine molecular Oxygen
77
where are CYPs? what are they with close association with and in what ratio?
in smooth ER Close association with NADPH-CYP reductase in 10:1 ratio
78
NADPH cytochrome P450 reductase serves as.......
the source of electrons for the oxidative reaction cycle
79
what is another name for the heme portion of CYP
Iron-protoprophyrin IX
80
go back to CYP cycle
go back
81
majority of drugs are metabolized by what CYP isoforms
CYP3A4 CYP2C9 CYP2D6 ALSO..... CYP2C19 CYP1A2 CYP2A6
82
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
TRUE
83
ethanol induces what CYP isoform?*****
CYP2E1
84
isosafrole induces what CYP isoform
CYP1A2
85
what is "induction mechanism 2" of CYP
p450 enzymes may be induced by substrate stabilization (decreased degradation) such is the case for ethanol induces CYP2E1
86
troleandomycin and clotrimazole induce what cytochrome isoform
CYP3A enzymes
87
true or false some drugs inhibit CYTp450s
true
88
give examples of drugs that are COMPETITIVE INHIBITORS of CYT P450 enzymes***
they bind to the cytochrome component (thus competitive inhibitors) cimetidine -- CYP3A4 and CYP2D6 (anti ulcer H2 receptor blocker) ketoconazole -- CYP3A4 and CYP2D6 (antifungal)
89
besides cimetadine and ketokonazole, give another example of a drug that is a CYP inhibitor and explain how it works
chloramphenicol (antibiotic) is metabolized (by CYP2B1) TO AN ALKYLATING METABOLITE THAT INACTIVATES THAT CYP ISOFORM
90
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?
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
5-10% of caucasians are poor metabolizers of.......
substrates for CYP2D6
92
explain the poor metabolizers of CYP2C19 drugs
about 20% of asian populations are poor metabolizers of drugs that are substrates for CYP2C19 but only about 4% in caucasian populations
93
true or false water conjugation is a type of phase 2 biotransformation
TRUE -- enzyme is epoxide hydrolases in cytosol or microsomes (mEH or sEH)
94

Pharmacology Midterm (edit) (12 decks)

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