PHARM 5: Drug Metabolism Flashcards

1
Q

Why do we need metabolism?

A
  • drugs tend to be lipophilic
  • so lipid soluble drugs must be metabolized –> to become more water soluble –> so they can be excreted easily.
  • metabolism eliminates/ reduces pharmacological + toxicological activity.
  • and converts drug into something more polar + soluble
  • -> more easily excreted by the kidneys
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2
Q

Where is the major organ for drug metabolism?

A
  • LIVER
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3
Q

What is Hepatic First Pass Metabolism?

A

Hepatic First Pass Metabolism = metabolic conversion of drug into something different, before drug enters general circulation

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4
Q

What happens if a drug undergoes extensive first pass metabolism?

A
  • low bioavailability

—> option: give drug intravenously

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5
Q

list briefly the stages of metabolic change

A

Phase I
Phase II
Excretion

  • but some drug undergo only phase 1 / 2
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6
Q

Describe Phase 1 reactions?

A

PHASE 1 = releasing/ making functional groups

  • oxidation/reduction CREATES new functional groups
  • hydrolysis UNMASKS functions groups
  • functional groups serves as pt of attachment for Phase II reactions
  • little change in polarity

–> prepared drugs for Phase 2 metabolism by introducing functional group

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7
Q

Where does Phase I reactions primarily occur?

why?

A
  • in the liver
  • contains enzyme system cytochrome P450
  • which has capability to metabolize lots of xenobiotics
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8
Q

What is the cytochrome P450 enzyme system?

A
  • main system involved in Phase I oxidizing reactions
  • predominantly found in liver
  • also involved in metabolism of endogenous compounds such as steroid/ estrogens

note: some drugs can inhibit/induce CYP450

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9
Q

Give the reaction equation for cytochrome P450 mediated oxidation.

A

RH + NADPH + O2 + H+ –(cytochrome P450) —> ROH + NADP+ + H2O

in: drug, NADPH (reducing agent), molecular oxygen, source of protons.
out: oxidized drug, NADP+, Water

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10
Q

Describe the process of CYP450 oxidation.

A
  • all P450 enzymes have porphyrin ring + iron at its active site
  1. drug binds to iron in catalytic site + reacts
  2. electron = donated by NADPH
  3. e- = picked up iron
  4. Fe3+ –> reduced to Fe2+
  5. Then oxygen binds to the catalytic side
  6. Then Fe2+ loses an e-
  7. becomes Fe3+
  8. oxygen picks up extra electron –> becomes unstable
  9. 2nd e- donated by NADPH
  10. e- picked up by Fe3+ –> Fe2+
  11. Fe2+ donates e- to O2 so oxygen is very unstable –> ready to reach
  12. Then drug is converted into hydroxylated derivative
    and reactive oxygen is lost as water by picking up 2H+
  13. drug is released
  14. P450 returns to cycle with Fe3+ to undergo next cycle

note: oxidation reaction involves hydroxylation step catalyzed by P450 system.

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11
Q

What are characteristics of Phase II metabolism conjugated products?

A

conjugate formed:

  • almost always inactive
  • less lipid soluble
  • more polar
  • easier to excrete
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12
Q

What is the most common phase 2 metabolism reaction ?

A

GLUCURONIDATION

  • addition of sugar to a foreign compound.
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13
Q

Describe Glutathione conjugation

A
  • Glutathione reacts with electrophiles

- electrophiles damage DNA + proteins so they must be removed.

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14
Q

Explain Glucuronidation of ibuprofen.

a) What is the conjugating agent?
b) What is it catalyzed by?
c) what does it form?

A

Ibuprofen

a) conjugating agent = UDPGA
b) catalyzed by = Glucuronyl Transferase
c) –> to form sugar derivative of xenobiotic

derivative = polar (so can be removed)

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15
Q

Explain acetylation.

A
  • if drug has amino group
  • high energy intermediate = acetyl coA
  • it is catalyzed by acetyl transferase
  • acetylated derivation of drug + coA goes into intermediary metabolism.
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16
Q

Explain Methylation.

what is the high energy intermediate?

What is enzyme used?

A
  • RZH + S-adenosylmethionine –> RZ-CH3 + S-adenosythomocysteine
  • high energy intermediate = S-adenosyl methionine
  • enzyme = methyl transferase
  • methyl group on sulphur of S-adenosylmethionine = transferred to NH2 of NA –> to generate Adrenaline (the methylated derivative)

-

17
Q

What is the effect of methylation?

A
  • it decreases polarity
18
Q

What is sulphation?

what are characteristics of the derivatives?

what is it catalyzed by?

A
  • PAPS = sulfate donor
  • xenobiotic is taken with PAPS
  • xenobiotic gets sulfated to produce sulfuric acid derivative of the molecule
  • derivative characteristics = very polar + water soluble
  • catalyzed by: sulfotranferases
19
Q

Describe conjugation with glutathione.

what is it catalyzed by?

A

RX + GSH —> R-SG + XH

  • ## catalyzed by glutathione transferase
20
Q

Why does the body have lots of glutathione?

A
  • important to protect body from toxic metabolites
21
Q

Glutathione is a tripeptide.
what does it consist of ?

what is the most important part of the molecule + why?

A
  • glycine
  • glutamine
  • cysteine

most important = cysteine

  • because it has the thiol
  • which is the part that reacts
22
Q

What are the 5 Phase II reactions?

A
  • Glucuronidation
  • Sulphation
  • Acetylation
  • Methylation
  • Conjugation with a.acids / glutathione
23
Q

What is a key characteristic of Phase II reactions?

A
  • involves a high energy intermediate

e. g UDPGA/ PAPS

24
Q

Give 5 reasons of the importance of drug metabolism

A
  • biological half life of the chemical is decreased
  • duration of exposure is reduced
  • accumulation of compound is avoided
  • duration of biological activity of chemical can be altered
  • pharmacology/toxicology of the drug can be governed by its metabolism.
25
Q

note: after phase 1 –> not v soluble

after phase 2 –> more soluble

A

-

26
Q

note: enzymes involved in metabolism –> 9/10 times usually CYP450 enzyme

A

-

27
Q

why do u not see acetanilide in pharmacy although it is a pro rug of paracetamol

A

it is toxic to blood cells

28
Q

What happens in the oxidation of imipramine?

A
  • N demethylation
  • N methyl groups are oxidized

to form desimipramine

29
Q

What happens in the oxidation of Codeine

A
  • O demethylation
  • O methyl groups are oxidized

to form Morphine

30
Q
  • N oxidation can also occur
A

-

31
Q

note: diff individuals have diff levels of CYP450

A

-

32
Q

tri methylinine (fish odor ) –> metabolized to something that is odorless occurs through what type of oxidation?

A

occurs via N - oxidation

33
Q

describe alcohol oxidation.

what enzymes are used?

A
  • ethanol –> acetaldehyde –> acetic acid

enzyme: cytoplasmic alcohol dehydrogenase

34
Q

Glucuronidation is catalyzed by what enzyme?

A

Glucuronyl transferase

35
Q

Methylation is catalyzed by what enzyme?

A

Methyl Transferase

36
Q

What is the conjugating agent used in the process of glucuronidation?

A

UDPGA