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Y2S2 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What are the two types of metabolism?

A

Phase I
Phase II

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2
Q

What is phase I metabolism?

A

Functionalisation reaction
Produces or uncovers a chemically reactive functional group
It prepares the drug for phase II

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3
Q

What is phase II metabolism?

A

Conjugation reactions
Conjugation of functional group with less reactive species
Phase II reactions represent a detoxification step and generate compounds that are inactive and readily excreted

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4
Q

What are the features of cytochrome p450 enzymes?

A

Oxidise anything
Membrane bound monooxygenase in the sER
An enzyme which is not specific and can metabolise more than 120 different drugs

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5
Q

Describe the cytochrome p450 enzyme:

A

Has a large lipophilic space that molecules can enter into in a range of different orientations
At the bottom there is a redox reactive haem group, the reduce active ion

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6
Q

How is CYP450 produced?

A

Needs a co-factor of cytochrome reductase
NADPH binds to the NADPH-binding domain of P450 reductase and electrons are shuttled from NADPH through FAD and FMN to the P450 heme.

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7
Q

What are the two most common CYP450 phase conversions?

A

Hydroxylation and Dealkylation

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8
Q

Describe hydroxylation in a CYP450 phase conversions:

A

Addition of an oxygen into the subsrate
The highly reactive Fe(V) species abstracts a proton from the substrate to give the carbon centred radical R. attached to the Fe(IV)-OH species
This radical then pulls the OH from the Fe4+ followed by release of the product and regeneration of Fe3+.

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9
Q

Describe dealkylation in a CYP450 phase conversions:

A

Whenever hydroxylation occurs α to a heteroatom you will get a dealkylation reaction because a “hemiacetal type” intermediate will be formed.

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10
Q

What are the conditions in which a dealkylation in a CYP450 phase conversion happens?

A

Occurs to the carbon next to the X
X= O,N, S or P
Has to be atleast one hydrogen on the carbon as needs to be extraction on the hydrogen

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11
Q

Name 5 other important phase I conversions using CYP450:

A
  • Dehydrogenation to give alkenes
  • Epoxidation of alkenes
  • Epoxidation of aromatic rings
  • Dihydroxylation of aromatic rings
  • Hydroxylation of aromatic rings
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12
Q

Name 4 important phase I conversions not using CYP450:

A

Hydrolytic enzymes
Epoxide hydrolase
Ethanol metabolism
Other oxidases

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13
Q

Describe how hydrolytic enzymes are involved in non- CYP450 phase I conversions:

A

Carboxylesterases hydrolyse esters and some amides
Amides are more stable than esters
The more lipophilic the amide, the better the substrate

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14
Q

Describe what are epoxies?

A

Often generated by CYP450 activity
Electrophillic and alkalate
Very reactive with DNA and proteins
-polycylic aromatic hydrocarbons
-Aflatoxin B1
Usually carcinogenic

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15
Q

How do epoxies cause cancer?

A

Covalently bound epoxide to nitrogen on DNA so breaks purine base
Leads to apurinic DNA so strands break and mutate

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16
Q

How is ethanol metabolised?

A

Ethanol is metabolised to ethanal using alcohol dehydrogenase and NAD+
Ethanal is then converted into ethanoic acid using aldehyde dehydrogenase and NAD+
These dehydrogenase are oxidation reactions

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17
Q

Why is the rate of ethanol metabolism limited?

A

Large amounts of NAD+ cofactor are needed for metabolism
2 moles of ethanol requires 1.5 Kg
Rate of ethanol metabolism limited to 8g/h in most adults

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18
Q

What symptoms can ethanol cause and why?

A

Ethanol is converted into ethanal
Large amounts of circulating ethanal is the factor contributing to:
-Flushing
- Tachycardia
- Hyperventilation
- Panic/distress
Ethanal can leak into the system in high concentration and have toxic side effects

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19
Q

What drugs are used in ethanol aversion therapy and how do they work?

A

Disulfiram
Used to inhibit aldehyde dehydrogenase so elevated levels of ethanal in the blood, which causes extremely unpleasant side effects but isn’t harmful

20
Q

What other drugs react in a similar way as ethanol aversion therapy?

A

Chlorpropamide
Nitrofurantoin
Metronidazole

21
Q

What is the consequence of chronic alcohol consumption?

A

Results in induction of CYP2E1 activity
CYP2E1 metabolises alcohol and other drugs:
-Warfarin
-Paracetamol
-Phenobarbital
So may need higher doses as lower doses not as effective

22
Q

What are non-CYP450 phase II reactions for?

A

Prepare functionally activated compounds for excretion in the bile or urine
Conjugation of xenobiotic with one of a variety of different compounds
Results in a pharmacologically inactive soluble compound

23
Q

What are the main reaction types of non-CYP450 phase II reactions and the enzyme used?

A

*Glucuronidation- UDP- Glucuronyltransferase
*Methylation- Methyltransferase
*Glutathione conjugation- Glutathione-S- transferase
*Sulphation

24
Q

What is Glucuronidation?

A

Most widespread form of conjugation
Conjugation with sugar, glucuronic acid (liver is a rich source of this)
Glucuronic acid transferred from high energy phosphate compound UDP-GA to electron rich atom (N, O or S)

25
Q

What it UGT?

A

Involved in Glucuronidation
UDP-glucuronosyl transferase enzymes
Located in the endoplasmic reticulum of the liver

26
Q

What is sulphate conjugation ?

A

Involves the addition of SO3- to drug
Major conjugation pathway for phenols and can occur for alcohols, amines and occasionally thiols
Requires energy rich donor compound
Sulphate conjugation involves the interaction of drug with PAPS
Metabolism involves the enzyme sulfotransferase- non specific

27
Q

What is glutathione conjugation?

A

Tripeptide glutathione (GSH) contains Glu-Cys-Gly
Many drugs are metabolised to toxic electrophiles and GSH is conjugated with these toxic electrophiles
Includes epoxides, haloalkanes, nitroalkanes, alkenes, aromatic halo- & nitro-compounds

28
Q

What is GST and what is it used for?

A

Glutathione S-transferase- where glutathione exists as a thiolate anion
GST catalyses the nucleophilic addition of thiolate anion to electrophilic centres in xenobiotics
Generates a less toxic compound that is modified to a mercapturic acid derivative that is excreted

29
Q

How can glutathione be linked to cancer?

A

Overexpression of glutathione can be linked to resistance in cancer
As N-mustards work by alkylating guanine residues in DNA and Glutathione deactivates the N-mustards as they cant reach the active site

30
Q

How is the over expression of glutathione in cancer stopped?

A

Drugs sometimes given with buthione sulfoximine- an inhibitor of GST

31
Q

What is the major route of paracetamol metabolism?

A

Phase II metabolism
O-sulfate in children
O-glucoronate in adults
Then elimination

32
Q

What is the minor route of paracetamol metabolism?

A

Phase I metabolism using CYP 2E1
Which produces a highly reactive Micheal acceptor
N-acetyl iminoquinone

33
Q

What can happen if you overdose on paracetamol?

A

N-acetylimidoquinone is either eliminated by glutathione
It can also form hepatic proteins, when there is high levels of paracetamol, a depleted level of glutathione so has to form hepatic proteins (toxic metabolite) which leads to:
-hepatic necrosis
-renal failure
-death

34
Q

How would you treat a paracetamol overdose?

A

Treat with N-acetylcysteine (GSH precursor) within 12 hours

35
Q

What is polymorphism?

A

Mutations that can change the gene sequence
Polymorphism can result in amino acid changes that alter activity of the protein

36
Q

What are the consequences of polymorphism?

A

Can cause an increase in protein activity (extensive metabolisers)
Can cause decreased/absent protein activity (poor metabolisers)
Altered substrate specificity of enzyme

37
Q

What are SNIPS?

A

SNP- Single nucleotide polymorphism
Represent the most extensive genetic difference between individuals

38
Q

What is the polymorphism mutation that causes codeine to not be able to form morphine?

A

Variant of CYP2D6

39
Q

What is CYP3A4?

A

Metabolises 50% of drugs
Polymorphisms rare, unknown functional consequence

40
Q

What is CYP2C9 and the polymorphism consequence?

A

Metabolises 20% of drugs; NSAIDs, warfarin, phenytoin
2 allelic variants are poor metabolisers

41
Q

How can St Johns Wort interact with other drugs?

A

Increased levels of CYP3A4
CYP3A4 metabolises 50% of all prescription drugs

42
Q

Name and describe how some drugs can inhibit CYP450 metabolism:

A

Competitive/non-competitive inhibition- chloramphenicol
Metabolite of drug binds CYP450 and forms an inactive complex- Desipramine & Isoniazid
Olefinic & Acetylinic drugs can cause CYP450 haem destruction- Secobarbital & Ethynylestradiol

43
Q

How can a young age exhibit poor drug metabolism and give examples:

A

Virtually no phase 2 metabolism- Chloramphenicol toxicity due to poor glucuronidation
Limited Phase 1 enzyme activity- CYP3 activity only

44
Q

How can an old age exhibit poor drug metabolism and give examples:

A

Men and women >65-70 years significantly decreased drug metabolism
Diminished enzyme induction

45
Q

How can alcohol liver disease cause an impact on drug metabolism?

A

Prolonged exposure leads to inflammation and hepatocytes accumulating fat droplets
Continued exposure results in fibrosis & cirrhosis

46
Q

How can cirrhosis have an impact on drug metabolism?

A

Liver tissue replaced with fibrous tissue so a decrease number of functional hepatocytes
Greatest impact on CYP450 dependent metabolism
Little effect on glucuronidation dependent metabolism
It can affect blood flow through liver

47
Q

Name the amino acids which can be protonated at physiological pH:

A

Lysine (+ve)
Arginine (+ve)
Glutamic acid (-ve)
Aspartic acid (-ve)

Y2S2 (14 decks)

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