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Gastrointestinal pathophysiology > Drugs and the liver > Flashcards

Drugs and the liver Flashcards

1
Q

What is the definition of metabolism?

A

All chemical reactions involved in maintaining the living state of the cells and the organism

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2
Q

What is intrinsic clearance?

A

Theoretical unrestricted maximum clearance of unbound drug by an eliminating organ, in absence of blood flow or plasma protein binding limitations

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3
Q

What is conjugation?

A

Addition of chemical groups to drugs during metabolism

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4
Q

What is hydrolysis?

A

The chemical breakdown of a compound due to reaction with water

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5
Q

What is reduction?

A

The loss of oxygen (gain of electrons) within a chemical reaction

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6
Q

What is oxidation?

A

The gain of oxygen (loss of electrons) within a chemical reaction

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7
Q

Which nutrients are metabolised by the liver?

A

Carbohydrates
Protein
Lipids

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8
Q

Which proteins are synthesised by the liver?

A
  1. Albumin
  2. Coagulation factors (vit K)
  3. Complement factors
  4. Haptoglobin
  5. Ceruloplasmin
  6. Transferrin
  7. Protease inhibitors
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9
Q

Which molecules are stored in the liver?

A
  1. Iron
  2. Copper
  3. Vitamins A, D and B12
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10
Q

What does the liver secrete?

A

Bile salts

Bilirubin

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11
Q

The sinusoids contain 2 regions, what are they?

A

Perivenal region (low O2 conc) - glucoronidation occurs here

Periportal region (high O2 conc) - Ox phos and gluconeogenesis occur here

  • This creates an oxygen gradient within the sinusoid
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12
Q

What are the 2 ways that drugs enter into the hepatocyte?

A
  1. Via the hepatic artery as circulating drugs

2. Via the hepatic portal vein as absorbed drugs

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13
Q

How are the metabolites excreted from the hepatocyte?

A
  1. Hepatic vein (to undergo excretion via the kidney)

2. Bile salts

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14
Q

What does hepatic clearance of drugs depend on?

A
  1. Liver blood flow
  2. Intrinsic clearance
  3. Protein binding
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15
Q

What is the extraction ratio?

A

A way to characterise your drugs

- The ratio of hepatic clearance of a drug:flow of hepatic blood

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16
Q

There are 3 classes of extraction ratio, what are they?

A
  1. High extraction ratio
  2. Low extraction ratio
  3. Intermediate extraction ratio
17
Q

High extraction ratio drugs are rapidly cleared from the blood by the liver, true or false?

18
Q

For high extraction ratio drugs, what is clearance dependent on?

A

Primarily dependent on hepatic blood flow

19
Q

Examples of high extraction ratio drugs

A
  1. Verapamil
  2. Morphine
  3. Propanolol
20
Q

What is clearance of low extraction ratio drugs dependent on?

A
  • It is dependent on the intrinsic metabolising capacity of the liver and by the free drug fraction
21
Q

Examples of low extraction ratio drugs

A

Warfarin

Phenytoin

22
Q

What is clearance of intermediate extraction ratio drugs dependent on?

A

Both hepatic blood flor, intrinsic metabolising capacity of the liver an the free drug fraction

23
Q

Examples of intermediate extraction ratio drugs

A

Aspirin

Codeine

24
Q

Which types of enzyme mediate the phase 1 (hydrolysis/oxidation) reactions in the liver?

A

Esterases

Oxidoreductases such as CYP450

25
Q

What do the phase 2 conjugation (sulphonation/glucoronidation) reactions do to the drug?

A

Make the metabolites less reactive, less toxic and more polar
- CONJUGATING ENZYMES carry these out

26
Q

The main purpose of drug metabolism is to do what?

A

Make the drug non-reactive, non-toxic and easy as possible to excrete preferentially via the kidney

27
Q

The phase 2 reaction in the liver involves the addition of which substances to a toxic chemical or drug?

A

Cysteine, glycine, sulphur molecule

28
Q

What is the most common phase 2 reaction in the liver?

A

Glucoronidation

29
Q

What are the other conjugation reactions in the liver?

A

Amino acid conjugation and sulfoconjugation

30
Q

Aspirin is hydrolysed into which substance?

A

Salicylic acid

31
Q

How does paracetamol cause toxicity in a normal situation?

A

Paracetamol is metabolised to two metabolites

1) Formation of sulfur/glucaronide metabolites - which are secreted by urine (95% of paracetamol is metabolised via this mechanism)
2) The other 5% is metabolised into an intermediate called NAPQI. This is a toxic metabolite which is removed by addition of glutathione and excreted via the urine. IF THIS IS NOT REMOVED EFFECTIVELY, HEPATOTOXICITY WILL OCCUR

32
Q

What happens during a paracetamol overdose?

A

The majority of paracetamol is now metabolised into NAPQI due to the levels of glutathione being exhausted by the excess paracetamol
- The >NAPQI levels cause liver damage, potentially ending with transplant requirement

33
Q

Paracetamol toxicity cannot be seen for the first how many hours?

34
Q

Treatment for paracetamol overdose

A

IV infusion of acetylcholine

Gastrointestinal pathophysiology (22 decks)

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