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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
Q

O-dealkylation

A

codeine (weak agonist) to morphine (full agonist)

also hydrocodone to hydromorphone

done by CYP2D6

26
Q

P450 independent oxidations

A

dehydrogenases such as alcohol dehydrogenase

amine oxidases such as monoamine oxidase

27
Q

sulfate conjugation

A

occurs via sulfotransferases (13 isozymes)

cytosolic enzymes that require activated sulfate - 3’-phosphoadenosine-5’-phosphosulfate (PAPS)

28
Q

therapeutic use and mechanism of action for acetaminophen

A

use - analgesic and antipyretic

mechanism of action - inhibits cyclooxygenase (COX)

29
Q

metabolism of acetaminophen

A

sulfation

also inactivated by glucuronidation

actually prfers glucuronidation over sulfation

30
Q

glucuronidation

A

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
Q

lorazepam (ativan) metabolism

A

a benzodiazepine with no active intermeidates

undergoes clucoronide conjugation

all benzodiazepines are inactivated by glucuronide conjugation

32
Q

glutathione

A

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
Q

glutathione S-transferase (GST)

A

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
Q

NAPQI

A

the resultant molecule when high doses of acetamenophen is processed by CYPE1 or CYP3A4

may be neutralized by GSH

35
Q

possible antidote for acetominophen overdose

A

N-acetylcysteine

36
Q

CYP2D6 polymorphisms

A

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
Q

CYP2C19 polymorphisms

A

poor metabolizers in 15-25% of Asians

3-5% of caucasians

4-6% of African Americans

38
Q

CYP2C19 substrates

A

diazepam and other zepam benzos

proton pump inhibitors such as omeprazole and other prazoles

NSAIDs

39
Q

CYP2D6 poor metabolizers

A

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
Q

CYP2D6 ultraextensive metabolizers

A

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
Q

Why is diazepam (valium) metabolism slower in Asians as compared to Caucasians?

A

CYP2C19 - poor metabolizers

15-25% of Asians have mutant alleles

in poor metabolizers, the t1/2 can be >4x longer than normal

42
Q

therapeutic use and mechanism of action for omeprazole

A

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
Q

N-acetyltransferase (NAT) polymorphisms

A

fast and slow acetylators, bimodal distribution

related to how much enzyme is synthesized, slow acetylators have less NAT

44
Q

slow acetylator phenotype

A

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
Q

GST and glutathione null genotypes

A

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
Q

Why does CYP3A4 have such broad substrate specificity?

A

large active site and ligand promiscuity

others such as CYP1A2 have small active sites and ligand specificity

47
Q

CYPE21 functions

A

processes ethanol at higher doses

creates toxic NAPQI from acetaminophen

48
Q

ethanol and acetaminophen toxicity

A

induces CYP2E1 and helps create reactive toxic intermediate NAPQI

reduces GSH and prevents rescue from NAPQI

49
Q

other factors that may affect the CYPs

A

environmental pollutants

picnics

herbal remedies

50
Q

environmental pollutants and CYPs

A

induce CYP1A, responsibly for generating toxicity and carcinogenesis

pollutants include cigarette smoke which contain benzo(a)pyrines, polychlorinated biphenyls, and dioxin

51
Q

other inducers of CYP1A (food products)

A

charbroiled foods and cruciferous vegetables

52
Q

Gingko and CYPs

A

induces CYP2C19, 2C9, and 3A4

53
Q

St. John’s Wort and CYPs

A

induces CYP3A4, 2C9, and 2E1

enhances the metabolism of oral contraceptives

54
Q

echnacea

A

inhibits CYP1A2 and induces CYP3A4

55
Q

What happens if two co-administered substrate drugs use the same CYP?

A

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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