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yr 2 lcrs - pharm > 5 - Drug Metabolism > Flashcards

5 - Drug Metabolism Flashcards

1
Q

Define ‘Xenobiotic’

A

Relating to a substance, typically a synthetic chemical, that is foreign to the body or to an ecological system.

A drug.

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2
Q

What is Toxicology?

A

‘High-dose Pharmacology’

The branch of science concerned with the nature, effects, and detection of poisons.

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3
Q

What are the requirements for drug metabolism?

A

Xenobiotics are usually lipophilic

Metabolism tends to reduce or eliminate pharmacological/toxicological activity.

Metabolism converts lipophilic chemicals to polar derivatives (readily excreted).

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4
Q

What is the main site for drug metabolism?

A

The liver

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5
Q

Other than the main site, where else can drug metabolism take place in the body?

A

Gut, kidneys, skin, brain etc

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6
Q

How does drug metabolism occur in the liver?

A
  • the liver picks up all the blood supply from the stomach etc
  • major drug metabolism site
  • key organ
  • majority of metabolic enzymes are here
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7
Q

What is Hepatic ‘First Pass’ Metabolism?

A

The first time the drug has passed through the liver.
It is then released back into the circulation.
Then it comes back to the liver.
The drug can circulate multiple times through the liver before being excreted.

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8
Q

What determines how many times the drug circulates through and is metabolised by the liver?

A

How extensive the hepatic first pass metabolism was.

If it was very extensive, then the drug may not need to pass through the liver many more times before being excreted.

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9
Q

What happens to the concentration of a drug in the systemic circulation depending on the extent of hepatic first pass metabolism?

A

If the first pass metabolism was very extensive, the concentration of the drug in the systemic circulation decreases significantly.

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10
Q

How is the process of drug metabolism subdivided?

A

PHASE I
- Oxidation, Reduction, Hydrolysis

PHASE II
- Glucuronidation, Acetylation, Amino acid conjugation, Sulphating, Methylation, Glutathione conjugation

EXCRETION

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11
Q

What is the purpose of drug metabolism Phase I?

A

To unmask/create new functional groups (point of attachment for Phase II).

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12
Q

What is the purpose of drug metabolism Phase II?

A

To change the polarity of a drug to make it easier to excrete.

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13
Q

Explain the process of Phase I Metabolism.

A

Oxidation/reduction creates new functional groups, hydrolysis unmasks them (hydrolysis creates 2 new functional groups).

Important – functional group serves as a point of attachment for phase II reactions

Phase I reactions often inactivate chemicals, but can also activate (e.g. a prodrug).

After phase I metabolism, there is little change in polarity of the drug.

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14
Q

What is a ‘prodrug’?

A

A compound that is not a pharmacologically active drug until it has been metabolised.

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15
Q

What system of enzymes is involved in Phase I metabolism?

A

Cytochrome P450 enzyme system

  • Important enzymes in Phase I oxidising reactions
  • Involved in metabolism of majority of drugs
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16
Q

Explain the structure of enzymes in the Cytochrome P450 enzyme system

A

They are all individual enzymes, not isoenzymes (57 in humans),

They all have a similar structure, with a porphyrin ring with iron in the middle.

They are membrane-bound enzymes.

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17
Q

Where are enzymes of the Cytochrome P450 enzyme system found?

A

Predominantly in the endoplasmic reticulum of the liver.

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18
Q

What effect can certain drugs have on the Cytochrome P450 enzyme system?

A

Sine drugs can inhibit/induce the system, so there can be problems with drug interactions.

e. g.
- on the contraceptive pill
- take another drug that induces the cytochrome system
- metabolises the pill faster than expected

19
Q

What is the shorthand name for the Cytochrome P450 enzyme system?

A

CYP

20
Q

What is the overall equation for mediated oxidation via the Cytochrome P450 enzyme system?

A

RH (Drug) + NADPH + O2 + H+
—–>
ROH (Oxidised Drug) + NADP+ + H20

21
Q

Outline all the steps in mediated oxidation via the Cytochrome P450 enzyme system

A

Oxidation reactions generally start with a hydroxylation step catalysed by the P450 system.

  • drug interacts with iron in enzyme’s active site (Fe3+)
  • electron comes in from NADPH (or NADH)
  • electron picked up by iron (Fe2+)
  • oxygen binds
  • electronic rearrangement, electron from iron given to oxygen (Fe3+)
  • stable Fe3+ has now been formed
  • second electron from NADPH (NADH) picked up by iron (Fe2+)
  • electronic rearrangement, electron from iron given to oxygen (Fe3+)
  • oxgen has been reduced twice and is now highly reactive
  • oxygen is cleaved and reacts with 2 protons
  • drug is metabolised to its oxidised form
  • water is released

USED:

  • one oxygen molecule
  • 2 NADPHs
  • one drug molecule
22
Q

Which is the most rate-limiting step in mediated oxidation via Cytochrome P450 enzyme system?

A

The second reduction of oxygen (to O2-)

23
Q

Can other enzymes be used in metabolism other than the Cytochrome P450 enzymes?

A

Yes, but 9 times out of 10 it is the CYP enzymes.

24
Q

Give some examples of oxidative reactions carried out by P450 enzymes?

A

Pentobarbitone

  • aliphatic side chain
  • oxidation of a carbon
  • however, the oxidation can occur at many of the carbons in the side chain
25
Q

How is Acetanilide a prodrug?

A

When it is oxidised on its aromatic benzene ring by the P450 enzymes, it produces paracetamol.

However, it is not given as a prodrug because acetanilide is toxic to blood cells.

26
Q

Explain a few forms of oxidation reactions carried out by P450 enzymes.

A

Aliphatic
- oxidation of carbon on a chain

Aromatic
- oxidation of carbon in a ring

N-demethylation

  • oxidation of carbons attached to a nitrogen
  • loss of formaldehyde (HCHO)
  • this is because hydroxyl on a carbon when attached to a nitrogen is unstable
  • a proton is picked up

O-demethylation

  • oxidation of carbons attached to an oxygen
  • loss of formaldehyde (HCHO)

N-oxidation

  • oxidation on a nitrogen group
  • generate an amine oxide (oxide of tertiary amines)
  • not a P450 reaction example given
  • trimethylamine smells of fish because their flavine-containing monoxygenase is defective

Alcohol oxidation
- cytoplasmic alcohol dehydrogenase not P450

27
Q

How is codeine a prodrug?

A

When it is oxidised in O-demethylation, it becomes morphine.

The majority of people do this reaction very poorly and so they do not feel the strength of codeine that some people feel. In extreme pain, they would need morphine directly.

28
Q

What is the most common of the Phase I reactions?

A

Oxidation

It is far more common than hydrolysis or reduction.

29
Q

What enzymes carry out the Phase I reactions?

A

Oxidation
- mainly Cytochrome P450 enzymes

Reduction

  • reductases
  • mainly in the GI tract, bacterial not mammalian

Hydrolysis

  • occurs at esters or amides
  • esterases or amidases
30
Q

What enzymes carry out the Phase II reactions?

A

Methylation
- methyl transferase

Glucuronidation
- glucuronyl transferase

Acetylation
- acetyl transferase

Aminoacid Conjugation
- acyl transferase

Gluthanione
- gluthatione-S-transferase

Sulphation
- sulphotransferase

31
Q

What is the purpose of the Phase II reactions?

A
  • Put large, endogenous, very polar molecules onto metabolites
  • Conjugate is almost always pharmacologically inactive
  • Usually produces an inactive molecule (excl. prodrug reactions)
  • Makes the molecule less lipid soluble
  • Easier to excrete
32
Q

What is the most common of the Phase II reactions?

A

Glucoronidation is the most common and most important Phase II reaction.

33
Q

What is the name that can describe all the Phase II reactions?

A

They are all CONJUGATION reactions.

34
Q

For the Phase II reactions to occur, what is required?

A
  • conjugating agent

- enzyme

35
Q

Where do conjugating agents come from?

A
  • Large, endogenous molecules
  • Require a lot of energy to be formed
  • Body invests the energy because the drugs need to be excreted
36
Q

Explain the mechanism behind Glucuronidation reactions

A
  • introduce hydroxyl group during Phase I
  • need UDPGA (UDP-Glucoronic Acid) cofactor
  • makes molecule very polar
  • generate high energy phosphate camped
  • glucuronic acid part transferred to an electron rich atom (N, O or S)
  • normally excreted in bile because large Mr
  • quantitively most important reaction
37
Q

Explain the mechanism behind Acetylation reactions

A
  • N, O, S usually attached
  • Acetyl CoA acts as donor compound
  • Acetyl group transferred to an electron rich atom (N, O or S)
  • produce a acetlytified druh
38
Q

What happens to any products left after metabolism that aren’t excreted?

A

They go into intermediate biochemistry.

39
Q

Explain the mechanism behind Methylation reactions

A
  • N, O, S usually attached
  • Methyl group donated to product
  • S-adenosyl methionine acts as donor compound
  • Methyl group transferred to an electron rich atom (N, O or S)
  • Makes drug less polar and less H20 soluble
  • Less easier to excrete
  • Occurs with body endogenous molecules, not drugs typically (e.g. NA)
  • Therefore, if it occurs to drug. Usually, because body mistakes a drug for NA (body makes a mistake)
    e. g. amphetamines
40
Q

Explain the mechanism behind Sulphation reactions.

A
  • Energy rich donor required
  • Body uses lots of energy to make PAP
  • Sulfotransferases catalyse transfer of sulphate to substrates
  • Sulphating makes very lipophilic drugs into very polar, water soluble drugs
41
Q

What is the difference between “First Pass Metabolism” and “First Pass Hepatic Metabolism”

A
  • First Pass Metabolism = All metabolism before it re-enters circulation.
  • First Pass Hepatic Metabolism = First metabolism in liver.
42
Q

Explain the mechanism of Conjugation with Glutathione reactions.

A
  • Glutathione is a protective factor, used for the removal of potentially toxic compounds
    (Glycine + glutamine + cysteine tripeptide)
  • Protects body from very electrophilic molecules (e.g. halogens)
  • Electrophilic molecules are very damaging
  • Very common reactions
  • Liver/Kidneys have high glutathione
43
Q

Summarise Phase II reactions.

A
  • Are conjugation reactions which utilise -OH, -NH2, -SH and -COOH.
  • Include glucuronidation, sulphation, acetylation, methylation, conjugation with amino acids and with glutathione.
  • Involve a high energy intermediate such as UDPGA for glucuronidation or PAPS for sulphation.
44
Q

What is the importance of drug metabolism?

A
  • The biological half-life of the chemical is decreased.
  • The duration of exposure is reduced.
  • Accumulation of the compound in the body is avoided.
  • Potency/duration of the biological activity of the chemical can be altered.
  • The pharmacology/ toxicology of the drug can be governed by its metabolism.

yr 2 lcrs - pharm (44 decks)

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