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Case 3 > How the Liver Processes (Metabolises) Drugs and Toxins > Flashcards

How the Liver Processes (Metabolises) Drugs and Toxins Flashcards

1
Q

What are the two reasons why drug metabolism occurs

A

To de-activate any pharmacological activity and to create a water soluble metabolite primed for extraction

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2
Q

How many drug molecules can the enzyme metabolise before saturating

A

Maximum of 4 drug molecules

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3
Q

Explain what is happening at 25% rate of enzyme reaction

A

The amount of drug present is a rate-limiting factor for substrate conversion (drug metabolism)

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4
Q

Explain what is happening at 50% rate of enzyme reaction

A

Although the drug concentration as increased, the amount of enzyme present is still not the rate-limiting factor for substrate conversion

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5
Q

Explain what is happening at 75% rate of enzyme reaction

A

The concentration of drug is approaching the maximum the enzyme can handle, but it’s not quite there

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6
Q

Explain what is happening at 100% rate of enzyme reaction

A

The enzyme is now working at full capacity converting as much drug as possible

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7
Q

What happens if you add more drug to the system at 100% rate of enzyme reaction

A

The system is over-saturated. The enzyme cannot work any faster to metabolise the excess drug present. The drug may build up to toxic levels because of this

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8
Q

What is the Michaelis-Menten equation

A

v = Vmax x [drug] / Km + [drug]

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9
Q

What does Vmax represent

A

A drug concentration causing the fastest turnover an enzyme can achieve. Any higher a drug concentration may cause toxic saturation effects

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10
Q

What does the Km of an enzyme represent

A

The concentration of drug (substrate) that makes the enzyme turnover at half the maximum rate (Vmax/2)

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11
Q

What is another name for phase I metabolism

A

Functional metabolism

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12
Q

What is the role of phase I metabolism

A

To expose/ create a mechanically reactive group on the drug to facilitate further metabolism processing in phase II

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13
Q

What do phase I mediated enzyme reactions include

A

Oxidation, reduction, de-esterification, isomerisation plus many more

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14
Q

What can phase I do

A

Activate the therapeutic activity of ‘pro-drugs’ but it can have very unwanted toxic effects too

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15
Q

Describe phase II metabolism

A

The drug (or intermediate metabolite generated from phase I) can now be a) deactivated and b) made water soluble by phase I enzymes in advance of either renal or hepatobiliary excretion

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16
Q

How are drugs made water soluble during phase II metabolism

A

Typically by replacing the drug’s pharmacophoric regions with a sugar or sulphate group

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17
Q

What is the most significant family of Phase I enzymes

A

Cytosome P450 (CYP

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18
Q

What are CYP responsible for

A

Oxidative modification usually in advance of Phase II

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19
Q

What enter CYP

A

Oxygen ans a drug molecule

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20
Q

What leaves CYP

A

An oxidised intermediate metabolite and water

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21
Q

What does CYP contain

A

A haem group

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22
Q

What does the fact that CYP are ‘on demand’ enzymes mean

A

They are induced only when the drug/ toxin they metabolise is detected

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23
Q

What are UTGs

A

UDP-glucuronsyl tranferase are phase II enzymes

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24
Q

What do UTGs do

A

Conjugate a water soluble glucuronide to the drug/ metabolite (that also de-activates pharmacological activity)

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25
Q

Describe how unconjugated bilirubin interacts with UGT

A

Uncojugated bilirubin and UDP glucuronic acid enter UGT, water soluble conjugated bilirubin leaves

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26
Q

What happens in Gilbert’s and Crigler-najjar syndromes

A

There is mutated or deleted UDT1A1 which results in build-up of unconjugated bilirubin and hence jaundice in the patient

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27
Q

What is the evolutionary advantage of multiple isoforms

A

There is ‘overlap’ in what drugs can be metabolised in the event of enzyme dysfucntion/ deletion

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28
Q

Why do multiple isoforms of CYPs and UGTs exist

A

As a function of substrate/ drug specificity

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29
Q

What does CYP3A4 do

A

Responsible for approximately half of all Phase I drug metabolism

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30
Q

What does CYP1A1 do

A

Prefers to metabolise theophylline

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31
Q

What does CYP1A2 do

A

Metabolises caffeine and theophylline

32
Q

What does CYP2E1

A

Metabolises ethanol (alcohol) and the list goes on

33
Q

Describe pharmacogenetics in relation to CYP and UGT

A

Subtle mutations in genes coding for CYP and UGT lead to significant differences in how individuals process drugs

34
Q

What is the function of genetic screening in relation to CYP and UGT

A

Genetic screening allows certain drugs to be avoided to reduce ADRs

35
Q

What can a point mutation result in

A

Changes in a haem group causing ADRs

36
Q

What does each drug have the potential to influence

A

The pharmacodynamics of another drug by altering its pharmacokinetics, particularly its metabolism

37
Q

What is pharmacokinetics

A

What the body does to the drug

38
Q

What is pharmacodynamics

A

What the drug does to the body

39
Q

What are drug interactions

A

A drug influencing the pharmacodynamics of another drug by altering its pharmacokinetics

40
Q

What drug-drug interactions may manifest in the liver

A

Drug interactions (drugs affecting drugs), enzyme induction effects, enzyme inhibition effects, pre-systemic elimination

41
Q

Describe how enzyme induction effects occur

A

Drug A may lower the circulating concentration of Drug B by inducing an enzyme that metabolises drug B

42
Q

How can St John’s Wort cause enzyme induction

A

St John’s Wort (containing hyperforin) can induce CYP3A4 which then also metabolises the combined oral contraceptive pill containing eithinylestradiol, reducing it to sub-therapeutic levels

43
Q

Describe enzyme inhibition

A

Drug A may increase the circulating concentration of drug B by inhibiting the enzyme that normally metabolises drug B

44
Q

Describe how the antibiotic erthromycin exerts enzyme inhibition effects

A

Erythromycin occupies CYP3A4 preventing metabolism of the combined oral contraceptive pill containing ethinylestradiol which increases the potential for ethinylestradiol ADRs

45
Q

Describe pre-systemic elimination

A

Some orally administered drugs are extensively metabolised by gut and liver enzymes before reaching the systemic circulation.

46
Q

Outline how pre-systemic elimination may occur

A

Drug is metabolised by GI tract enzymes, drug is also transported via hepatic portal vein to the liver where CYP and UGT continue to metabolise the drug, sub-therapeutic levels of the active drug reach the systemic circulation

47
Q

How can you compensate for pre-systemic circulation

A

Altering the drug dose an/or route of administration

48
Q

What can drugs cause

A

Hepatitis and cholestatis

49
Q

What does any pathology that affects the liver have the potential to do

A

Uncouple normal drug metabolism

50
Q

What are the implications of cholestatis

A

Implications for drug metabolite excretion in the faeces

51
Q

What is cholestatis

A

Impaired bile flow from liver to duodenum

52
Q

What do liver function tests do

A

Blood tests for levels of key biochemicals, give an indication of the general state of the liver

53
Q

What does the standard LFT battery include

A

Prothrombin time (INR), gamma glutamyl transpeptidase, albumin, total conjugated bilirubin, alanine- asparate transaminases, alkaline phosphatase

54
Q

What does a long prothrombin time suggest

A

A deficiency of clotting factors made by the liver or a deficiency of vitamin K which is needed for the factors to work

55
Q

What does gamma glutamyl transpeptidase detect

A

Liver damage from the drugs and alcohol and for early detection of rejection after liver transplantation

56
Q

What does raised GGT and ALP mean

A

Biliary tract disease

57
Q

What causes decreased albumin

A

Extensive loss of liver tissue in long-standing liver disease, malnutrition, kidney disease due to loss of protein in urine and inflammatory conditions in body

58
Q

What does raised total conjugates bilirubin mean

A

Liver disease or a blockage of passage of bile to gut e.g. by gall stones

59
Q

What does raised alanine asparate transaminases indicate

A

Leakage from cells due to inflammation or cell death

60
Q

When does AAT rise more than ALP

A

In acute liver damage such as hepatitis

61
Q

What causes an increase in ALP

A

Liver blockage and blockage of ducts due to increased bile duct pressure causing the liver to make more ALP

62
Q

What does any hepatic dysfunction have the potential to do

A

Impede normal drug metabolism

63
Q

What may you have to consider in hepatic dysfunction

A

Alternative non-pharmacological options or reduce the frequency and/or dose of the drug given

64
Q

What is a toxic dose of paracetamol

A

4-6g

65
Q

In the UK what do paracetamol tablets come as

A

0.5g doses

66
Q

What is a lethal dose of paracetamol

A

> 12g in one go

67
Q

What is the normal metabolism of paracetamol

A

1g paracetamol- majority of this dose is directly glucuronidated by UGT (bit of sulphation), water soluble inactivated paracetamol-glucuronide is easily excreted. 1g paracetamol generates small amount of Phase I toxic species (via CYP1A2 and CYP2E1) n-acetyl-p-benxoquinone imine (NAPBQI). NAPBQI very rapidly de-activated to conjugated glutathione (anit-oxidant). No net damage to hepatocytes

68
Q

Describe overdose metabolic pathway

A

Toxic dose of paracetamol means no UGT as the glucuronidation pathway is overwhelmed with the paracetamol concentration. Excess paracetamol forced down CYP pathway. CYP1A2 & CYP2E1 generate large amounts of phase I toxic species NAPBQI. Glutathione reserves are rapidly depleted from the liver. Significant damage to hepatocytes

69
Q

Describe paracetamol overdose pathway

A

Rapidly replenishing hepatic glutathione is achieved with IV infusions of n-acetyl cysteine (NAC) which limits hepatotoxicity of NAPBQI

70
Q

What do you do on admission of a person with paracetamol overdose

A

Measure plasma levels on admission. If levels on or above treatment line begin infusions of NAC, consult BNF for NAC dosing

71
Q

What is the liver the principle organ for metabolising

A

Xenobiotic and endobiotic compounds

72
Q

What two phases is drug metabolism split into

A

Phase I (functionalism) and Phase I (conjugative)

73
Q

What can Phase I metabolism generate

A

Chemically reactive intermediates which can be good or bad

74
Q

What does liver dysfunction have the potential to seriously alter

A

Rates of drug metabolism in the patient

75
Q

What is the hepatotoxix species generated in significant quantities following paracetamol overdose

A

n-acetly-p-benzoquinone imine) NAPBI

76
Q

Which enzyme is likely to dysfunctional in Gilbert’s syndrome leading to jaundice

A

UDP-glucuronosyl tranferase 1A1 (UGT1A1)

Case 3 (9 decks)

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