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MP224- Normal Function of Renal and Hepatic Systems > 8- Drug Elimination > Flashcards

8- Drug Elimination Flashcards

1
Q

What is the purpose of biotransformations in terms of Metabolism

A

Alters the pharmacological activity by increasing hydrophilic character to render metabolites water soluble which aids

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2
Q

What are polar, hydrophilic groups

A

OH NH2 COOH

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3
Q

What are examples of Non-Polar, Hydrophobic groups

A

CH2, CH3 C6H5

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4
Q

What are the two ways the hydrophilicity of a molecule

A

By introducing or unmasking polar functional groups into the molecule.
By removing non-polar functional groups into the molecule.

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5
Q

What will happen to terbutaline if it goes through oxidative deamination.

A

Removal of an amine group via a CYP450 enzyme.

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6
Q

What will happen to codeine if it goes through oxidative O-dealkylation.

A

An alkyl group will be removed from an oxygen molecule via a CYP450 enzyme.

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7
Q

What would happen to propranolol if it goes through N-dealkylation

A

The removal of an alkyl group from a nitrogen group via a CYP450 enzyme.

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8
Q

What are Phase 1 reactions of drug metabolism

A

Covert parent compound into a more hydrophillic metabolite by adding or unmasking functional groups.

Oxidation
Reduction
Hydrolytic Cleavage
Isomerization

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9
Q

What are phase 2 reactions of metabolism

A

Conjugation with endogenous substrate to further increase aqueous solubility.
Via glucuronidation, salvation, amidation

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10
Q

What is the major organ for drug metabolism

A

The liver

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11
Q

What processes do extrahepatic microsomal enzymes put drugs through and where are they found

A

Found in the digestive system, put through oxidation, conjugation and hydrolysis.

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12
Q

What are examples of processes that hepatic microsomal enzymes would put drug through.

A

Oxidation, Conjugation

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13
Q

What are examples of processes that hepatic non-microsomal enzymes would put drug through

A

Sulfation, GSH, Alcohol/aldehyde dehydrogenase, hydrolysis, ox/reduct

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14
Q

What are the two types of oxidation reactions

A

N-dealkylation O-dealkylation

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15
Q

What is cytochrome p450

A

A hemoprotein containing an iron atom which can alternate between ferrous and ferric states.

Electron acceptor

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16
Q

Where is Cytochrome p450 found.

A

Found mainly in the liver but sometimes the lungs.

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17
Q

What cytochrome isoform is used in ibuprofen metabolism.

A

CYP450 2D6

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18
Q

How does CYP450 metabolise drugs

A

The drug substrate enters the binding site of CYP450.

The haem co-factor transfers oxygen onto drug molecule.

Therefore making it more polar.

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19
Q

What are the steps of aromatic hydroxylation by CYP450

A

Substrate needs a C-H for the P450 to cleave

H transferred onto P450- Fe-O to form a hydroxide

OH transferred from p450 back to substrate where original CH was cleaved

20
Q

What is the process of aromatic hydroxylation via CYP450 enzymes.

A

Substrate needs a C-H for P450 to cleave.

H transferred onto P450- Fe-O to form hydroxide

OH transferred from P450 back to substrate where original CH was cleaved

21
Q

What is the process of O-dealkylation of ethers via a CYP450 enzyme

A

Substrate needs a CH for P450 to cleave

H transferred onto P450 Fe-O to form a hydroxide

OH transferred from P450 back to substrate where original CH was cleaved

22
Q

What is the name for the functional group that forms after O-dealkylation of ethers and N-dealkylation of amines

A

Hemi-acetal

23
Q

What happens to the Semi-Acetal group during O-dealkylation of ethers

A

C between two heteroatoms is unstable and breaks down

The alkyl group is removed as an aldehyde

24
Q

What is the process of N-dealkylation of amines via a CYP450 enzyme

A

Substrate needs a C-H for P450 to cleave

H transferred onto P450-Fe-O to form hydroxide

OH transferred from P450 back to substrate where original C-H was cleaved

The C bond becomes unstable and breaks releasing the acetyl group as an aldehyde.

25
Q

What does “nor” infront of a metabolite indicate and what are examples

A

That an alkyl group has been removed from a Nitrogen.

Morphine to Nor-morphine
Propranolol to Nor-propranolol

26
Q

What does “Des” in front of a metabolite indicate and examples

A

An alkyl group has been removed from an oxygen or a nitrogen, is always followed by the alkyl group that has been removed.

Metoprolol to Desmethyl metoprolol (removal of a methyl group) or Didesmethyl metoprolol ( removal of both alkyl groups)

27
Q

Are oxidation rwactions catalysed by CYP450 enzymes.

A

NO

28
Q

What is flavin.

A

The monoxygenase system is present in the liver mainly but also in gut and lung.

Oxidizes nitrogen, sulfur and phosphorus heteroatoms directly.

29
Q

What is methanol broken down into and what can the metabolite cause

A

Methanol to formaldehyde to Formic acid which can lead to the destructiuon of the optic nerve.

30
Q

What enzyme is cocaine hydrolysed by

A

Esterases

31
Q

What enzyme is lidocaine hydrolysed by

A

Amindases

32
Q

What enzyme is required for glucuronidation

A

UDP-glucuronosyltransferase (UGT)

33
Q

What is glucuronidation

A

The conjugation of a glucuronic acid group to the metabolite.

34
Q

What is sulfation

A

The attatchment of a sulfate group onto the metabolite

35
Q

What co-factor is required for sulfation

A

PAPS
3’-Phosphoadenosine-5’-phosphosulfate

36
Q

What enzymes catalyse transfer of sulfate to substrate

A

Sulfotransferases (SULTs)

37
Q

What is the by-product of a sulfation reaction

A

Adenosine

38
Q

What is the enzyme that assists in glutathione conjugation

A

Glutathione-S-transferase (GST)

39
Q

What is Glutathione important for

A

A protective factor for removal of potentially toxic electrophiles.

40
Q

What is the toxic metabolite of Paracetamol

A

NAPQI

41
Q

What is the function of glutathione in paracetamol metabolism

A

As soon as NAPQI is made glutathione reacts with the toxic electrophiles to deactivate them.

42
Q

What does NAPQI toxicity lead to.

A

Hepatic cell death leading to liver failure

43
Q

How does drug molecules larger than 400 MW leave the body

A

Via Bile after phase 2 reactions

44
Q

What isoform does grapefruit interact with and what drugs

A

Contains a CYP4503A4 inhibitor so interacts with for example felodipine/Amlodipine

45
Q

What is the results of CYP2D6 poor metabolisers

A

Too slow drug metabolism
Too high drug levels at normal dosage
High risk of adverse drug reactions
No response from certain drugs eg codeine

46
Q

What is the results of CYP2D6 ultrarapid metabolisers

A

Too rapid drug metabolism
No response at normal dosage

MP224- Normal Function of Renal and Hepatic Systems (20 decks)

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