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YEAR 2 PHARM WITH ADDITIONS > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What does metabolism tend to do to a drug?

A

Metabolism tends to eliminate or reduce the pharmacological and toxicological activity of a drug.
It makes the drug more polar and soluble so that it can more easily be excreted.
- lipid soluble drugs are made more water soluble so can be more easily excreted

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2
Q

What is hepatic first pass metabolism?

A

Metabolic conversion of the drug into something that is different before the drug enters the circulation.
In other words – the effect that occurs the very first time the drug passes through the liver.

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3
Q

What effect does extensive first pass metabolism have on bioavailability?

A

Extensive first pass metabolism -> low bioavailability

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4
Q

How can you avoid hepatic first pass metabolism?

A

Gibing a drug intravenously

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5
Q

What are the three types of reaction that fall under phase I reactions?

A

Oxidation
Reduction
Hydrolysis

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6
Q

What is the purpose of Phase I metabolism? and what is metabolism order?

A

It is meant to release or unmask functional groups that can be used in phase II reactions
- most drugs undergo phase one then phase 2, but some can have only 1 or 2, and some drugs can be excreted without any metabolic changes

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7
Q

How do phase I reactions affect polarity of the drug?

A

They have little effect on the polarity of a drug

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8
Q

What enzyme system is extremely important to drug metabolism?Where are these enzymes found?

A

Cytochrome P450
It is a family of 57 enzymes that are mainly found in the liver and they are capable of metabolising loads of xenobiotics
- main system involved in phase 1 reactions
- also involved in metabolism of endogenous compounds such as steroids and oestrogens
- several isozymes involved in drug metabolism
- some drugs inhib or induce CYP450, this is bad as interferes with body’s ability to handle certain drugs

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9
Q

What are the substrates and products of the Cytochrome P450mediated oxidation reaction?

A 
Substrates = drug (RH), NADPH (reducing agent), oxygen (O2), protons (H+) - can get H+ from any aqueous environment
Products = hydroxylated (oxidised) drug (ROH), NADP+, water
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10
Q

What do P450 enzymes have in their catalytic site?

A

They all have a porphyrin ring and an iron group (Fe3+)

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11
Q

Describe the oxidation cycle of Cytochrome P450.

A

The drug binds to the iron in the catalytic site of CYP450 An electron is fed in from NADPH, which is picked up by the Fe3+ making it Fe2+
Then molecular oxygen binds to the catalytic site and Fe2+ loses its electron to become Fe3+ again, and oxygen picks up the extra electronand becomes unstable
Then a second electron is donated by NADPH, which, again, reduces Fe3+ to Fe2+ Fe2+ then donates this electron to the already unstable oxygen to make it even less stable
Then we get conversion of the drug to the hydroxylated derivative and we lose reactive oxygen as water with the uptake of two protons
The drug is released and P450, along with its Fe3+, is ready to undergo another cycle

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12
Q

What is N-demethylation? What does this reaction produce?

A

This is the oxidation of a methyl group in a nitrogen environment (carbon on a nitrogen)
It produces formaldehyde (HCHO)
- V common reaction, 80-90% of drugs have amine functions in them

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13
Q

What does N-demethylation do to a drug’s activity?

A

It is an effective way of removing the pharmacological activity of a drug

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14
Q

What is O-demethylation?

A

Oxidative attack of P450 on a methyl group attached to oxygen
This converts oxygen to the hydroxyl group and release formaldehyde (HCHO)

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15
Q

What is N-oxidation? Describe the type of bond formed.

A

It is the oxidation of the nitrogen group itself
Nitrogen has two free electrons that can form a dative bond with oxygen
This generates an amine oxide
- this reaction is catalysed by flavin containing monooxygenase

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16
Q

Which enzyme catalyses the N-oxidation reaction?

A

Flavin containing monooxygenase

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17
Q

Describe a condition involving flavin containing monooxygenase?

A

Flavin containing monooxygenase deficiency (fish odour syndrome)
Trimethylamine is produced in the GI tract as a product of protein metabolism Trimethylamine is foul smelling but is converted by flavin containing monooxygenase in the liver to trimethylamine N-oxide, which is odourless and can be excreted in the urine
People without flavin containing monooxygenase are unable to do this conversion so they produce trimethylamine that they can’t excrete so they breathe and sweat it out and end up smelling terrible

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18
Q

Describe alcohol oxidation.

A

Alcohol is first converted to acetaldehyde by alcohol dehydrogenase It is then converted from acetaldehyde to acetic acid, which is excreted

19
Q

Where, within the ultrastructure of a cell, are flavin containing monooxygenase and cytochrome P450 enzymes found?

A

Endoplasmic reticulum

20
Q

Where, within the ultrastructure of a cell, is alcohol dehydrogenase found?

A

Cytoplasm

21
Q

Where do reduction reactions tend to take place within the body and why?

A

GI tract because this is a low oxygen environment

Most reductases are bacterial enzymes that are colonising our gut, which is why these tend to happen in the GI tract

22
Q

State two types of hydrolysis enzymes.

A

Esterases (ester hydrolysis) and Amidases (amine hydrolysis)

23
Q

What at the six types of phase II reactions?

A 
Glucuronidation 
Acetylation 
Sulphation 
Methylation 
Amino Acid Conjugation 
Glutathione Conjugation
24
Q

State each of the enzymes that are responsible for carrying outthese six types of phase II reactions.

A 
Glucuronyl Transferase 
Acetyl Transferase 
Sulphotransferase 
Methyl Transferase 
Acyl Transferase  
Glutathione S-Transferase
25
Q

What effect do phase II reactions have on the drugs?

A

They make drugs more polar and water-soluble (less lipid-soluble) so that they can be excreted more easily, conjugate formed is almost always inactive.

26
Q

What are some features of conjugating agents?

A

Large
Polar
Endogenous
- they target specific types of functional groups

27
Q

What is the most common type of phase II reaction?

A

Glucuronidation (addition of a sugar to a molecule)

28
Q

What is the importance of glutathione conjugation?

A

Glutathione is conjugated with electrophiles so that they can be excreted
Electrophiles are damaging species that are often generated during metabolism – they must be removed because they can cause DNA and protein damage

29
Q

State a conjugating agent that is used for glucuronidation.

A

UDPGA

30
Q

State an important property of the conjugates formed fromglucuronidation and its impact on its excretion.

A

They are large molecular weight products so it has a problem with glomerular filtration
High molecular weight molecules are often excreted in the bile

31
Q

What is the conjugating agent in acetylation and what is the product?

A

Acetyl coA - conjugating agent
catalysed by - acetyl transferase
- process: acetyl group transferred to electron rich N,O or S in drug
The product is the acetylated derivative of the drug and CoA (CoA then goes into intermediary metabolism)

32
Q

What is the conjugating agent/high energy intermediate for methylation? and how does methylation work?

A

S-adenosyl methionine
Process: methyl group of the sulpur of s-adenosyl methionine is transfered to the NH2 of drug to generate methylated derivative
- enzyme is methyl transferase

33
Q

What effect does methylation have on polarity?

A

It DECREASES polarity

34
Q

What is the conjugating agent, process and enzyme used in sulphation?

A

agent: PAPS – 3’-phosphoadenosine-5’-phosphosulphate (sulphate donor)
enzyme: sulfotransferase
process: drug gets sulphated to produce sulfuric acid derivative of the molecule

35
Q

What are the properties of the derivative formed in sulphation?

A

The product is the sulphuric acid derivative of the drug

This is very polar and water-soluble

36
Q

What type of molecule is glutathione?

A

Tripeptide consisting of: Glycine
Glutamine
Cysteine

37
Q

What effect does drug metabolism have on biological half-life, duration of exposure and accumulation of drugs in the body?

A 
Decreases biological half-life  
Decreases duration of exposure  
Avoids accumulation of drugs in the body
potency/duration of drug can be altered
pharmacology/toxicology of drug is goverened by its metabolism
38
Q

pre hepatic first pass metabolism?

A

small amounts can occour in buccal cav, stomach and intestines and oesphagus

39
Q

Details on phase 1 reactions

A
  • Oxidation/reduction create new funct groups
  • hydrolysis unmasks functional groups
  • these functional groups often serve as points of attachment for phase 2 reactions
  • phase 1 reactions usually inactivate drugs, but if its a prodrug will activate it
  • phase 1 reactions cause little change in polarity
  • phase 1 reactions usually occour in the liver
40
Q

Examples of oxidation reactions

A
  • hydroxlaytion, removes pharmacological activity in some cases (happens if you hydroxylate phenobarbitone), but hydroxilation of acetanilide produces paracetamol (EG OF PHASE 1 prodrug conversion)
  • N-demethylation
    o-demethylation
    N-oxidation
41
Q

what type of reactions are CYP450 and flavin containing monooxygenase? and where are they found

A

first order, and found in the endoplasmic reticulum

42
Q

give an example of a zero order reaction

A

alcohol metabolised by alcohol dehydrogenase (a soluble cytoplasmic enzyme) (first metabolised to acetaldehyde and then acetic acid

43
Q

phase 1 summary

A
  • little effect on polarity
  • prep drugs for phase 2 reactions
  • often unmask or introduce functional groups
  • often generate pharacological inactive products
  • sometimes produce toxic metabolites
44
Q

details on conjugation with glutathione

A
  • catalysed by glutathione transferase
  • glutathione is made up of glycine, glytamine and cystine
  • cystine has a thiol which is the part that reacts
  • glutathione is the conjugating agent
  • important in removing/protecting body from toxic metabolites (reacts with electrophiles)

YEAR 2 PHARM WITH ADDITIONS (33 decks)

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