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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

25
what is the second most important conjugation reaction
Sulfate conjugation
26
what is a difference between sulfate and glucoronide conjugation
Sulfate conjugation reactions are saturable when substrate concentration increases.
27
what is the sulfate donor for this reaction
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
what is sulfate conjugation catalyzed by
sulfotransferases (SULTS) in cytosol of the liver
29
what is N acetyl conjugation catalyzed by? What is the acetyl donor?
N-acetyltransferases; acetyl donor is acetyl-CoA
30
What serves as the methyl donor in methylation conguation
S adenosylmethionine
31
Humans can be classified as either rapid or slow acetylators of _____
isoniazid
32
what is example of methylation conjugation
norephineprine to epinephrine
33
what methylates norepi to epinephrine
Phenylethanolamine N methyl transferase (PNMT)
34
what catalyzes transfer of a methyl group to a phenolic OH of catecholamines
Catechol O methyltransferases (COMT)
35
What is classical ex of metabolism of acetominaphen
Glutathione conjugation
36
What happens when acetaminophen is not in active form?
convert to amine intermediate which combines with gluthathione which is hard to deplete and then forms choline linkages which can cause necrosis?
37
What catalyzes the transfer of glutathione to reactive electrophiles
Glutathione-s transferases; makes it more polar
38
what are two subfamilies of GST in humans? which is more common
1. cytosolic: most common | 2. microsomal
39
in amino acid conjugation, aa only combine with _____ reactive centers
carboxylic
40
how do drug-drug interactions involving enzyme induction work?
transcriptional activation with CYP450 enzymes.
41
The second drug starts to metabolize or remove first drug rapidly thereby rendering it ineffective. What needs to be done clinically
adjust dose of first drug to compensate the second drug's action
42
Rifampicin enhances expression of enzyme (P450). What is this drug responsible for?
Treats terminal patients to treat MRSA
43
____induces metabolism of itself or other drugs like warfarin and phenytoin which is a drug used for seizure
Phenobarbitone
44
Carbamazepine
starts induction of its own
45
Cigarette smoke induces ____ which interacts with clozapine, and warfarin which causes one to increase dosage of drugs to maintain efficacy of these meds
CYP1A2
46
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?
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
How can P450 enzyme be inhibited?
1. a second drug acting as a competitive inhibitor | 2. an irreversible inhibitor
48
if drug is being inhibited and not being metabolized then drug concentrations will be ___ causing toxicity
higher
49
what are potent CYP inhibitors
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
In enzyme inhibition: the enzyme concentration goes ____and the drug concentration goes ____
down; up
51
which factors affect drug metabolism
1. Enzyme induction and inhibition 2. age: unconjugated billirubin which causes kernicterus in neonates 3. diet 4. genetic differences
52
charcoal beef can induce ___and can reduce plasma concentration of drugs that are substrates to this isoenzyme.
CYP1A2
53
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.
CYP2C9; VKORC1
54
Individuals lacking ____ metabolize these substrates at a lower rate than normal. What is an ex of this
CYP2D6; codeine that undergoes O-demethylation to form morphine
55
what is first pass effect
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
when would you suspect FPE
concentrations going into oral systemic circulation would be lower compared to systemic exposure from iv.

IDIT (44 decks)

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