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MedChem Final > Nicolic > Flashcards

Nicolic Flashcards

1
Q

Factors that affect metabolism:

Inter-Individual Factors

A

Constant during an organism’s life-time

Animal Species

Genetics = genetic polymorphism

Sex

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2
Q

Dexmethazone

Carbamezapine

A

3A4 INDUCER

  • Reduce efficacy of 3A4 substrates
    • Estradiol (birth control)
      • –> pregnancy
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3
Q

Celecoxib

Fluvastatin

Sulfamethazole

A

2C9

Substrate

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4
Q

Phase 1 Metabolism:

Enzymes

A

CYP450

Epoxide Hydrolase

Glutathione S-Transferase

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5
Q

Clozapine

Imipramine

Tacrine

Theophylline

CAFFEINE

A

1A2

Substrate

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6
Q

Which p450 enzymes are known to be

Genetically Polymorphic

A

2C19

2D6

  • 2D6 is polymorphic but not inducible
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7
Q

P450 General Rxn

A

Incorporate 1 atom of OXYGEN into substrate

Monooxygenase

  • electron donor is NADPH
    • nicotinamide adenine dinucleotide phosphate
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8
Q

Oxybutynin

Carbamazepine

A

3A4 Substrates

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9
Q
A
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10
Q

Riluzole

Tacrine

Mexillitine

Clozapine

A

1A2

Substrate

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11
Q

Clopidogrel (prodrug)

+ Omeprazole

A

Clopidogrel (prodrug) = 2C19 Substrate

+

Omeprazole = 2C19 INHIBITOR

= Less active metabolite of clopidogrel

–> Increase risk of heart attacks

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12
Q

Tamoxifen (Prodrug)

+

Antidepressants

or BLACK COHOSH

A

Nearly 1/3rd of patients on Tamoxifen are on

Antidepressants = 2D6 Inhibitors

  • Antidepressants reduce hot flashes caused by tamoxifen
    • Hot flashes is a side effect (meaning Tamoxifen is WORKING)
    • –> REDUCES EFFICACY OF TAMOXIFEN
      • since Tamoxifen is a prodrug its metabolites are active
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13
Q

CYP450

Info / Naming

A

Most important P1 enzyme

Highest concentration in Liver

Found in ER

MW = 45-60k

450nm in absorption spectrum

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14
Q

Which isoforms are INDUCIBLE?

A

Almost ALL are inducible to extent

  • 2D6 (nitrogen one)*
  • has NO MEANINGFUL XENOBIOTIC INDUCER KNOWN*
  • BUT inducible in PREGNANCY*
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15
Q

Consequences of enzyme INHIBITION

for drug metabolism

A

Begins with the FIRST DOSE of the inhibitor

–> can lead to TOXICITY

Increase serum conc of second drug

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16
Q

Beta blockers

Metoprolol

Penbutolol

Propranolol

Timolol

A

2D6 Substrates

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17
Q

Phase 1 Reactions

A

Involve small structural change in the drug molecules

Functionalization

  • Oxidation
    • ​Introduces polar groups
  • Reductions
    • Exposes polar groups
  • Hydrolysis
    • Modifies group to be more polar
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18
Q

Debrisoquiline

Sparteine

A

2D6 Substrates

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19
Q

Cyclosporin

A

3A4 Substrates

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20
Q

Acetaminophen

Ethanol

A

2E1 Substrates

Ethanol = also an INDUCER, both

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21
Q

CYP450 Superfamily

Info

A
  • Many subfamilies / isoforms
    • only 15 are involved in drug metabolism
    • ​​many involved in metabolism of endogenous compounds (bile/steroids)
  • Only family 1/2/3 are responsible for metabolism of drugs
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22
Q

Phase 1 Metabolism:

Pharmacological Consequenses

A
  1. Activity is LOST
    1. termination of pharmacological activity
  2. Activity remains
    1. ​active metabolites
    2. Activity of metabolism can be weaker or stronger
  3. Metabolic Activation = Therapeutic
    1. PRODRUGS
  4. Metabolic Activation = Toxic
    1. Toxic metabolites (acetaminophen)
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23
Q

Omeprazole

Lansoprazole

Pantoprazole

A

2C19 Substrates

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24
Q

Statins

A

3A4 Substrates

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25
Q

Naproxen

A

2C9 & 1A2

Substrate

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26
Q

Cimetidine

Protease Inhibitors

A

3A4 INHIBITORS

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27
Q

Grapefruit Juice

Furanocoumarines

A

3A4 INHIBITOR

  • Increase BV of 3A4 substrates
    • benzodiazepines
    • statins
    • antihistamines
    • CCB’s (felodipine)
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28
Q

Clomipramine

Cyclophosphamide

Progestrone

A

2C19

Substrate

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29
Q

Factors that affect metabolism:

INTRA-individual factors

A

Variable during organism’s life time

Enzyme INDUCTION / INHIBITION

Age

Diseases (liver specifically)

Pregnancy / Stress

Nutrition (obesity/dietary supplements)

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30
Q

Calcium Channel Blockers

Nifedipine

A

3A4 Substrate

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31
Q

P450 Active Site

A

Heme (iron protoporphyrin IX)

in hydrophobic pocket

  • Iron in the middle of 4 pyrrole rings
    • 5th ligand is thiolate anion
    • from cysteine residue of apoprotein
32
Q

Benzodiazepines

Alprazolam

Diazepam

Midazolam

A

3A4 Substrates

33
Q

Warfarin

Tamoxifen

Tolbutamide

Torsemide

A

2C9

Substrate

34
Q

Barbiturates

Rifampicin

A

INDUCERS OF:

3A4

2C19

2C9

35
Q

Ethanol

Isoniazid

A

2E1 INDUCERS

Ethanol is also a Substrate of 2E1

36
Q

Chronic Alcoholism

A

Ethanol INDUCES 2E1

–> Acetaminophen Liver Toxicity

  • Alcoholism –> MORE 2E1
    • Acetaminophen gets more conversion to bad substrate
    • –>toxicity
37
Q

St. John’s Wort

(Hyperforin)

A

3A4 INDUCER

Activates pregnane X receptor, regulates transcription of CYP3A4

  • Herb to improve Mood
  • Reduces efficacy/BioAvailability of 3A4 substrates
    • Cyclosporin (prodrug)
    • Antidepressants
    • Birth control
    • HIV (indinavir drugs)
    • Cancer Drugs
    • Warfarin
38
Q

Enzyme Induction

A

May increase Metabolism of drug

–> reduce drug activity

  • Effects of induction can be seen within 2 days
    • can takes more than a week for new enzymes to be synthesized (max effect)
    • = TOLERANCE
  • Typically Reversible
39
Q

Opiates

Fentanyl / Methadone / Alfentanil

A

3A4 Substrates

40
Q

Diazepam

Amitriptyline

A

2C19

Substrate

41
Q

Cigarette Smoke

A

1A2 INDUCER

  • Reduce Fxn of 1A2 substrates
    • Theophylline + SMoke
      • –> asthma attack
    • CAFFEINE
42
Q

Erythromycin

A

3A4 Substrates & INHIBITOR

43
Q

Estradiol

Sildenafil

A

3A4 Substrates

44
Q

7-15% of Caucasians

are genetically DEFICIENT in….

A

DEFICIENT in CYP2D6

Due to genetics

  • POOR METABOLIZERS (PM) of
    • Antidepressants / Antipsychotics
    • Beta Blockers
    • Narcotics
    • DM / Atomoxetine
  • INCREASE Bioavailability of these drugs
45
Q

Order of Reactivity for

P450 oxidation

A

Most Stable Radical = Most Reactive

Ease of Nonbonded e- abstraction

  • tendency for oxidation follows the stability of the radicals that are formed
  • Carbon radical of benzyl carbon iis more stable than radical of aliphatic carbon
46
Q

Carbamezapine

(tegretol)

A

3A4

Substrate & INDUCER

both!

47
Q

Nefazodone

Protease Inhibitors

Tacrolimus

Tolterodone

A

3A4 Substrates

48
Q

Phase 2 Metabolism:

A

Functional group masked by addition of conugate

Conjugation ->

(typically polar INACTIVE metabolites)

  • Glucuronidation
  • Conjugation:
    • ​Sulfate
    • Glutathione
    • Amino Acid
49
Q

Experimental steps in drug metabolism studies

A
  1. Isolation (often can be omitted)
    1. extrations/ion exchange
  2. Seperations
    1. HPLC / GC
  3. Identification
    1. ​NMR, mass spectrometry
  4. Quantification
    1. Radioactive labeling, GC/HPLC
50
Q

Disulfram

A

2E1 INHIBITOR

51
Q

Flavoprotein NADPH

-CYP450 REDUCTASE

A

Electron carrier

Delivers electron ONE AT A TIME

  • NADPH –> NADP
  • P450 can only handle 1 electron at a time
    • = stepwise manner
  • P450 reductase carries the other electron
52
Q

Azole Antifungals

Clarithromycin / Erythromycin

Ciprofloxacin

A

3A4 INHIBITORS

  • ​Cyclosporin + Ketoconazole (inhibitor of 3A4)
    • ​Increase Immune Supression
      • –> transplant rejection
53
Q

Antipsychotics

Haloperidol

Perphenazine

Risperidone

Thioridazine

A

2D6 Substrates

54
Q

OTC’s

Dextromethorphan (DM)

Cimetidine

Chlorpheniramine

Diphenahydramine

Brompheniramine

A

2D6 INHIBITORS

  • Prozac + DM
    • –> Increase Prozac antidepressant fxn
    • –> CNS DEPRESSION
55
Q

P450 Reaction Mechanism

A

2 steps

  • 1) Oxygen Activation
    • CARBON MONOXIDE IS POISON FOR THE RXN
      • blocks binding –> kills rxn
  • ​​2) Iron oxo complex Abstracts H atom
    • Oxygen rebound gives oxidized substrate
56
Q

Tricyclic Antidepressants:

Venlafaxine (effexor)

Fluoxetine

Paroxetine

A

2D6 Substrates

57
Q

EDG

Electron Donating Sustituent

A

Ortho / Para directing

Enhance Oxidation Rate

  • OH
  • CH3 (alkyl)
  • NR3 (amino)
58
Q

Methadone

Quinidine

Haloperidol

A

2D6 INHIBITORS

  • Reduce effectiveness of Codeine
    • Codeine is metabolized by 2D6 into morphine
      • morphine = active form
      • less morphine is metabolized due to less 2D6
59
Q

EWG

Electron Withdrawing Group

A

Meta Directing

Slow/prevent aromatic hydroxylation

-X (halogens)

  • NO2 (nitro)
  • Carbonyl groups
  • NH3+ (ammonium salt)
60
Q

CYP2D6

Role in hepatic drug metabolism

A
  • Only 2% found in liver
  • But metabolizes 23% of drugs
    • ​”PRE-SELECT” drugs that are substrates for this enzyme
    • ​Basic Nitrogens
  • Very specific
61
Q

CYP450 Superfamily

Family

A

>40% sequence homology

Labeled with #NUMBERS

62
Q

Phenytoin

A

2C19 & 2C9 Substrate

63
Q

SSRI’s

esp. Paxil / Prozac

A

2D6

Substrates & INHIBITOR

64
Q

CYP450 Superfamily

Subfamily

A

>55% sequence homology

Labeled with Letters

65
Q

FMOs

“mFMO”

Flavin Mono-oxygenases

P1 Enzyme

A

Oxidize Nucleophilic Atoms

N / S / P –> N-O / S-O / P-O

Found in liver / kidney / lung / intestine

  • DIFFERENT mechanism to heterocycle oxidation by CYP450
    • But end-product is similar
  • More specific to N- / S- oxidation
  • NOT INDUCED BY DRUGS OR POLLUTANTS
    • _​_less prone to drug interactions
  • Not dependent ton gender/age/smoking history
    • intra-individual factors
  • Narrower substrate specificity
66
Q

MAOs

Monoamine Oxidase

P1 Enzyme

A

Metabolism of Endogenous + Exogenous Amines

1* Amine –> Aldehyde

2* / 3* Amines –> Ketone

  • Same product as P450
    • but OXYGEN COMES FROM WATER
      • not air
    • ​oxygen is used for FAD –> h2o2
67
Q

EH

Epoxide Hydrolase

P1 Enzyme

A

Hydrolyses Epoxides –> DIOLS

Microsomal / soluble forms

TRANS PRODUCT

  • Double bond + P450 = Epoxide
  • Epoxide + EH = Trans Diol
  • EPOXIDE IS VERY REACTIVE
    • ​Can ATTACK NUCLEOPHILES
    • =TOXICITY
68
Q

MAO-A

P1 Enzyme

A

Primarily found in the CNS

also found in GI Tract / Liver / Placenta

outer membrane of mitochondria

Serotonin / Epinephrine / Norepinephrine

(endogenous fxn)

along with MAO-B also, dopamine/tyramine/tryptamine

69
Q

MAO-B

P1 enzyme

A

Primarily found in the CNS

also found in Platelets

outer membrane of mitochondria

Drugs: Phenethylamine, benzylamine

(EXOogenous fxn)

along with MAO-A also, dopamine/tyramine/tryptamine

70
Q

Disulfram

Antabuse

A

INHIBITOR of Aldehyde Dehydrogenase

Aldehyde -/-> Carboxylic Acid

Used for Alcoholism

Acytlaldehyde product is unpleasant

Carboxylic acid product is the happy feel

71
Q

Genetic Polymorphism in

Aldehyde Dehydrogenase

&

Alcohol Dehydrogenase

A

Point Mutation in Aldehyde Dehydrogenase

Glu787 - Lys487

Atypical Alcohol Dehydrogenase

= FLUSHING SYNDROME

  • FAST Alcohol dehydrogenase
    • Alcohol –> Aldehyde (negative effects)
  • SLOW Aldehyde dehydrogenase
    • Aldehyde –> Carboxylic acid (positive0
72
Q

Quinone Reductase

NAD(P)H-Quinone Oxidoreductase / DT-diaphorase

P1 Enzyme

A

ChemoPREVENTATIVE Enzyme

=DETOX enzyme

HIGHLY INDUCIBLE by weak electrophiles

Brocolli

Breaks down Quinones –> UGT substrates (excreted)

  • If quinone goes through P450 Reductase
    • ​–> SUPEROXIDE ANION RADICAL = ROS
      • ​Toxic, can cause oxidative stress
73
Q

Esterase

Hydrolytic P1 Reaction

A

R-COOR

Ester –> Carboxylic Acid + Alcohol

FASTER

Most succeptible to Hydrolysis

vs amides / carbamates (amidase)

ASPIRIN (prodrug)

Many prodrugs are Esters (also improve taste)

PROCAINE

74
Q

Amidase

Hydrolytic P1 Reaction

A

Amide –> Carboxylic Acid + Amine

  • SLOWER than esterase*
  • less succeptible to hydrolysis*

Procainamide

orally active, resistant to hydrolysis (slower)

75
Q

Order of Susceptibility to Hydrolysis

A

Ester > Thioester

Carbonate >

Amide > Carbamate >

Ureide

76
Q

Which Enzymes are known to be genetically polymorphic?

A

CYP2C19

CYP2C9

Alcohol Dehydrogenase / Aldehyde Dehydrogenase

77
Q

Which RXN does the OXYGEN come from WATER?

A

MAO

Oxygen comes from water unlike P450 (from the air)

MedChem Final (8 decks)

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