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Foundations 2 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

xenobiotics

A

foreign substances to biological systems, not natural and can reach toxic levels

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2
Q

cometabolism

A

enzymes that are present to metabolize endogenous agents also metabolize xenobiotics

ex. epinephrine is metabolized by monoamine oxidase (MAO) and exogenous amines such as tyramine are also metabolized by MAO

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3
Q

four characteristics that describe drug function

A

ADME - Absorption, Distribution, Metabolism, and Excretion

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4
Q

Phase I drug metabolism

A

place an alluring functional group on the drug to make it more polar and provide a reactive center for phase II reactions

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5
Q

Phase II drug metabolism

A

covalently conjugate the drug at the reactive center provided by Phase I reactions and also usually make drugs more polar

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6
Q

Phase I reactions

A

HOR - Hydrolysis, Oxidation, Reduction

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7
Q

Phase II reactions

A

SAGGMeth - Sulfation, Acetylation, Glucuronidation, Glutathione, Methylation

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8
Q

most common Phase I reaction

A

oxidation reactions are by far the most common

carried out by cytochrone P450 monooxygenases known as CYPs

CYP3A4 is the most common

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9
Q

most common Phase II reaction

A

glucuronidation

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10
Q

use and mechanism of action of midazolam

A

use - sedative/hypnotic used frequently as premedication prior to surgery or outpatient procedures

mechanism of action - a benzodiazepine, all benzodiazepines work on GABA(A) receptors, receptor channels open more frequently in the presence of benzodiazepine, increasing synaptic inhibition

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11
Q

generic benzodiazepine structure

A

7 membered ring with 2 nitrogens and 2 benzene groups attached

either _zolam or _zepam as suffixes

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12
Q

metabolism of medazolam

A

CYP34A hydroxylation in phase I followed by addition of glucuronide in phase II

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13
Q

oxidations

A

Phase I reaction, includes hydroxylations and oxidative dealkylations

reactions are carried out mostly by cytochrome P450 monooxygenases known as CYPs

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14
Q

what is the most prevalent CYP?

A

CYP3A

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15
Q

Where are CCYP enzymes found?

A

in liver and intestinal cells in the ER membrane

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16
Q

Describe the hydroxylation oxidation cycle.

A

key players are oxidase and reductase

two electrons and two protons are donated to form water and attach the OH group

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17
Q

therapeutic use and mechanism of action for propranolol

A

use - antihypertensive, anti-anginal, anti-arrhythmic, stage fright, etc.

mechanism of action - blocks beta1 adrenoreceptors (mediate increases in heart rate and cardiac contraction)

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18
Q

H2 histamine receptors

A

found in parietal cells, responds to histamine release from paracrine cells and promtoes HCl excretion

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19
Q

therapeutic use and mechanism of action for cimetidine (tagamet)

A

use - suppresses acid secrtion, wonder drug of the 1980s and early 1990s to treat ulcerative conditions, still frequently used for heartburn

mechanism of action - competitive inhibitor of histamine at H2 receptor

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20
Q

metabolism of cimetidine

A

undergoes S-Oxidation

inhibits a bunch of CYPs (CYP1A2, CYP2E1, CYP3A, CYP2D6, CYP2C) except for CYP2E1

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21
Q

therapeutic use and mechanism of action for diphenhydramine (Benadryl)

A

use - to treat mild allergic reactions

mechanism of action - competitive inhibitor of histamine at H1 receptors (H1 receptors are responsible for mild allergic reactions produced by histamine release from mast cells)

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22
Q

metabolism of diphenhydramine

A

N-oxidation

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23
Q

therapeutic use and mechanism of action for diazepam (valium)

A

use - to treat seizures, anxiety, muscle spasms and other disorders in which enhancing GABA(A) function would prove helpful

mechanism of action - increases the frequency of opening of GABA(A) receptors

24
Q

metabolism of diazepam

A

N-dealkylation produces a very long acting metabolite

two active intermediates are nordazepam and oxazepam

25
O-dealkylation
codeine (weak agonist) to morphine (full agonist) also hydrocodone to hydromorphone done by CYP2D6
26
P450 independent oxidations
dehydrogenases such as alcohol dehydrogenase amine oxidases such as monoamine oxidase
27
sulfate conjugation
occurs via sulfotransferases (13 isozymes) cytosolic enzymes that require activated sulfate - 3'-phosphoadenosine-5'-phosphosulfate (PAPS)
28
therapeutic use and mechanism of action for acetaminophen
use - analgesic and antipyretic mechanism of action - inhibits cyclooxygenase (COX)
29
metabolism of acetaminophen
sulfation also inactivated by glucuronidation actually prfers glucuronidation over sulfation
30
glucuronidation
occurs via glucuronyl transferases and is th emost common phase II reaction the enzymes are in the smooth ER and require UDP (uridine 5'-diphosphate) glucuronic acid
31
lorazepam (ativan) metabolism
a benzodiazepine with no active intermeidates undergoes clucoronide conjugation **all benzodiazepines are inactivated by glucuronide conjugation**
32
glutathione
structurally a gamma-glutamyl-cysteinyl-glycine site of reaction with electrophiles is the HS group transferred to toxic electrophiles via glutathione-S transferase (GST)
33
glutathione S-transferase (GST)
approximately 20 human GSTs, extremely important to protect against toxic metabolites GST is one of th emost common liver enzymes (comprises of 5% of the liver) if impaired, increased risk of developing cancers such as CML implicated in the development of resistance to chemotherapeutic agents
34
NAPQI
the resultant molecule when high doses of acetamenophen is processed by CYPE1 or CYP3A4 may be neutralized by GSH
35
possible antidote for acetominophen overdose
N-acetylcysteine
36
CYP2D6 polymorphisms
by far the most common polymorphisms has a trimodal distribution with poor metabolizers, wild type, and ultraextensive metabolizers as peaks substrates include beta blockers such as metoprolol, opioids, and tricyclic antidepressants
37
CYP2C19 polymorphisms
poor metabolizers in 15-25% of Asians 3-5% of caucasians 4-6% of African Americans
38
CYP2C19 substrates
diazepam and other zepam benzos proton pump inhibitors such as omeprazole and other prazoles NSAIDs
39
CYP2D6 poor metabolizers
inheritance of two mutant CYP2D6 alleles no or very poor enzyme activity, impaired metabolism of substrates high plasma drug leve, may need to lower the dose caucasians 8-10% of population African Americans 1-3% Japanese/Chinese \<1%
40
CYP2D6 ultraextensive metabolizers
duplication or amplification (up to 13 functional cpies) excessive expression of enzyme, high metabolic capacity Swedish 2% of population Ethiopan and Saudi Arabian 30%
41
Why is diazepam (valium) metabolism slower in Asians as compared to Caucasians?
CYP2C19 - poor metabolizers 15-25% of Asians have mutant alleles in poor metabolizers, the t1/2 can be \>4x longer than normal
42
therapeutic use and mechanism of action for omeprazole
use - this drug and other prazoles are the proton pump inhibitors (PPIs), these are the current drugs of choice to treat disorders associated with excessive acid secretion mechanism of action - irreversibly blocks the proton pump
43
N-acetyltransferase (NAT) polymorphisms
fast and slow acetylators, bimodal distribution related to how much enzyme is synthesized, slow acetylators have less NAT
44
slow acetylator phenotype
in ~50% of blacks and whites associated with higher incidence of drug induced autoimmune disease and some bladder cancers toxic effects of isoniazid and other NAT substrates
45
GST and glutathione null genotypes
mu genotype (GST deficiency) expressed in 50% of caucasian population, linked to lung, colon, and bladder malignancies in humans theta genotype (glutathione deficiency) as high as 60% in Chinese and Koreans, null activity associated with toxicity and adverse side effects with cancer chemotherapeutic drugs, cannot be cleared by glutathione conjugation increased risk of CML
46
Why does CYP3A4 have such broad substrate specificity?
large active site and ligand promiscuity others such as CYP1A2 have small active sites and ligand specificity
47
CYPE21 functions
processes ethanol at higher doses creates toxic NAPQI from acetaminophen
48
ethanol and acetaminophen toxicity
induces CYP2E1 and helps create reactive toxic intermediate NAPQI reduces GSH and prevents rescue from NAPQI
49
other factors that may affect the CYPs
environmental pollutants picnics herbal remedies
50
environmental pollutants and CYPs
induce CYP1A, responsibly for generating toxicity and carcinogenesis pollutants include cigarette smoke which contain benzo(a)pyrines, polychlorinated biphenyls, and dioxin
51
other inducers of CYP1A (food products)
charbroiled foods and cruciferous vegetables
52
Gingko and CYPs
induces CYP2C19, 2C9, and 3A4
53
St. John's Wort and CYPs
induces CYP3A4, 2C9, and 2E1 enhances the metabolism of oral contraceptives
54
echnacea
inhibits CYP1A2 and induces CYP3A4
55
What happens if two co-administered substrate drugs use the same CYP?
if residual levels of one drug remains at the active site, then it may inhibit the metabolism of the other drug

Foundations 2 (33 decks)

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