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IDIT > Dr. Issar - Drug metabolism > Flashcards

Dr. Issar - Drug metabolism Flashcards

1
Q

What is the biggest site for metabolism

A

liver

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2
Q

metabolism is also called _____ or detoxification. It tries to convert drugs to metabolites (hydrophilic) and changes the polarity of the compounds to undergo easy elimination. It is a defense mechanism of the body. Its does this by _____ water solubility (polarity)

A

biotransformation; increasing

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3
Q

loss of pharmacological activity deals with:

A
  1. changing polarity: makes it more hydrophilic;

2. structural alteration

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4
Q

What are exceptions

A
  1. Pro drugs: doesn’t have action of its own; has to be metabolized in our body (liver) where it converts to active form which does the job. They are themselves pharmacologically inactive
  2. Metabolism = activation; drugs can be weakly active
    - Codeine gets metabolized to–> morphine
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5
Q

what are the phases of metabolism

A

Phase 0: transport of drug from blood to liver (sinusoidal uptake process)
Phase I: functionalization reactions; includes oxidation, reduction, and hydrolysis reactions. Includes the addition of hydrophilic moieties which get linked and removed from body.
Phase II: conjugation or synthetic reactions

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6
Q

what are the 4 types of reactions involved in drug metabolism

A
  1. oxidation
  2. reduction
  3. hydrolysis
  4. conjugation
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7
Q

Which enzyme is the most important oxidative enzyme

A

P450; heme containing monoxidases which are membrane bound. When they combine with CO they form ducts that absorb at diff wavelengths.

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8
Q

what are properties of oxidation reactions

A
  1. addition of oxygen/removal of H
  2. Cytochrome P450
  3. Mixed function oxidases
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9
Q

How is the naming process for enzymes done

A

3 represents family
A represents subfamily
4 represents 4th enzyme in that category

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10
Q

what are examples of oxidation by MFO

A
  1. Aromatic hydroxylation: gets added on ring
  2. Aliphatic hydroxylation: on side chain
  3. N-dealkylation: removal of an alkyl functional group attached to a nitrogen.
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11
Q

Other oxidation reactions that can happen are:

A
  1. O dealkylation
  2. S dealkylation
  3. Epoxidation
  4. Oxidative deamination
  5. sulfoxide formation
  6. desulfuration
  7. N oxidation and N hydroxylation
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12
Q

What do all oxidation reactions require the presence of

A
  1. molecular oxygen
  2. NADPH (cofactor)
  3. complete MFO system.
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13
Q

What are characteristics of reduction

A
  1. addition of hydrogen or removal of oxygen atom.
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14
Q

what is ex of reduction

A

azo (-N to =N) or

nitro groups leading to formation of amines

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15
Q

what is hydrolysis

A

addition of water with breakdown of molecule in blood and in liver.

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16
Q

what is ex of hydrolysis

A

aspirin to salicylic acid and cocaine to methyl ecgonine

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17
Q

What do conjugation reactions involve

A

the addition of molecules naturally present in the body to the drug molecule. The drug may have undergone a phase 1 reaction.

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18
Q

what is a conjugating agent

A

a carbohydrate, an amino acid, or a substance derived from these nutrients that attaches to the drug and or metabolite.

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19
Q

The tendency for a particular drug to combine with a given conjugating agent depends only on possession of an appropriate group such as

A
  1. carboxyl (COOH)
  2. hydroxyl (OH)
  3. amino (NH)
  4. sulfhydryl (SH)
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20
Q

Phase II reactions generally follow Phase I reactions and produce a product which has _____pharmacological activity and decreased _____ which leads to a more water soluble product which can be excreted via the kidneys or through bile into feces

A

decreased; toxicity

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21
Q

what is the most common conjugation reaction and what are they catalyzed by

A

Glucoronide; microsomal enzymes

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22
Q

What is happening in Phase II (synthetic reactions)

A

conjugating agent combinds with drug to form drug conjugate which is extremely polar. Some drugs can get conjugated directly.

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23
Q

what is a common way of eliminating bilirubin

A

congugating with glucoronic acid (make it hydrophilic so they can get out)

24
Q

what can get directly conjugated

A

morphine

25
Q

what is the second most important conjugation reaction

A

Sulfate conjugation

26
Q

what is a difference between sulfate and glucoronide conjugation

A

Sulfate conjugation reactions are saturable when substrate concentration increases.

27
Q

what is the sulfate donor for this reaction

A

an activated form of sulfate known as 3-phosphoadenosine -5-phosphosulfate (PAPS); depletion of this cofactor can result in the saturability of the activity of the sulfotransferases

28
Q

what is sulfate conjugation catalyzed by

A

sulfotransferases (SULTS) in cytosol of the liver

29
Q

what is N acetyl conjugation catalyzed by? What is the acetyl donor?

A

N-acetyltransferases; acetyl donor is acetyl-CoA

30
Q

What serves as the methyl donor in methylation conguation

A

S adenosylmethionine

31
Q

Humans can be classified as either rapid or slow acetylators of _____

A

isoniazid

32
Q

what is example of methylation conjugation

A

norephineprine to epinephrine

33
Q

what methylates norepi to epinephrine

A

Phenylethanolamine N methyl transferase (PNMT)

34
Q

what catalyzes transfer of a methyl group to a phenolic OH of catecholamines

A

Catechol O methyltransferases (COMT)

35
Q

What is classical ex of metabolism of acetominaphen

A

Glutathione conjugation

36
Q

What happens when acetaminophen is not in active form?

A

convert to amine intermediate which combines with gluthathione which is hard to deplete and then forms choline linkages which can cause necrosis?

37
Q

What catalyzes the transfer of glutathione to reactive electrophiles

A

Glutathione-s transferases; makes it more polar

38
Q

what are two subfamilies of GST in humans? which is more common

A
  1. cytosolic: most common

2. microsomal

39
Q

in amino acid conjugation, aa only combine with _____ reactive centers

A

carboxylic

40
Q

how do drug-drug interactions involving enzyme induction work?

A

transcriptional activation with CYP450 enzymes.

41
Q

The second drug starts to metabolize or remove first drug rapidly thereby rendering it ineffective. What needs to be done clinically

A

adjust dose of first drug to compensate the second drug’s action

42
Q

Rifampicin enhances expression of enzyme (P450). What is this drug responsible for?

A

Treats terminal patients to treat MRSA

43
Q

____induces metabolism of itself or other drugs like warfarin and phenytoin which is a drug used for seizure

A

Phenobarbitone

44
Q

Carbamazepine

A

starts induction of its own

45
Q

Cigarette smoke induces ____ which interacts with clozapine, and warfarin which causes one to increase dosage of drugs to maintain efficacy of these meds

A

CYP1A2

46
Q

St. John’s Wort is a powerful inducer of ____ and ____. This causes change of metabolism of drugs they are on. Which drugs get affected by induction of these izoenzymes and what happens?

A

CYP 3A4; P-GP

  1. cyclosporine: levels can go down and cause organ rejection.
  2. cyclophosphamide: gets metabolized at a faster rate which inc toxic side effects
  3. Imatinib: reduced efficacy for chronic myeloid leukemia
47
Q

How can P450 enzyme be inhibited?

A
  1. a second drug acting as a competitive inhibitor

2. an irreversible inhibitor

48
Q

if drug is being inhibited and not being metabolized then drug concentrations will be ___ causing toxicity

A

higher

49
Q

what are potent CYP inhibitors

A
  1. erythromycin
  2. grapefruit juice: inhibits CYP3A4; simvastatin conc goes up
  3. omeprazole: inhibits CYP2C19 which decreases clopidogrel effectiveness (antiplatelet drug)
  4. Quinidine: inhibits P-gp and MDR1: inc digoxin
  5. Ketoconazole: inhibits P-gp and MDR1: inc. digoxin

-Quinidone and Ketoconazole alter systemic levels of drugs like digoxin which is a substrate of P-gp and MDR1 transporters

50
Q

In enzyme inhibition: the enzyme concentration goes ____and the drug concentration goes ____

A

down; up

51
Q

which factors affect drug metabolism

A
  1. Enzyme induction and inhibition
  2. age: unconjugated billirubin which causes kernicterus in neonates
  3. diet
  4. genetic differences
52
Q

charcoal beef can induce ___and can reduce plasma concentration of drugs that are substrates to this isoenzyme.

A

CYP1A2

53
Q

Warfarin is metabolized by _____ to inactivate hydroxylated metabolites in liver. ____ is the site for genetic resistance towards warfarin, thereby patients can be more/ less sensitive to warfarin.

A

CYP2C9; VKORC1

54
Q

Individuals lacking ____ metabolize these substrates at a lower rate than normal. What is an ex of this

A

CYP2D6; codeine that undergoes O-demethylation to form morphine

55
Q

what is first pass effect

A

drug gets absorbed in liver and gets metabolized. What gets out of liver is actually lowered. Which is how you determine bioavailability of drug. (how much drug is being metabolized by liver compared to iv injection)

56
Q

when would you suspect FPE

A

concentrations going into oral systemic circulation would be lower compared to systemic exposure from iv.

IDIT (44 decks)

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