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Semester 4 > case 5 - liver pharmacology > Flashcards

case 5 - liver pharmacology Flashcards

1
Q

what kind of drug has an effect

A

only free or unbound drugs

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2
Q

what does decreased plasma albumin and increased bilirubin lead to

A

drug displacement

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3
Q

what does increased volume of distribution represent

A

Represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a uniform concentration equivalence to that in the plasma at steady state
Relates the amount of drug in the body to the total concentration
A theoretical volume

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4
Q

what are most drugs

A

lipophilic therefore re circulate

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5
Q

what happens to lipid soluble drugs

A

Lipid soluble drug is metabolised into a water soluble metabolite and then the water-soluble metabolite excreted

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6
Q

where in the liver do phase 1 and 2 DME reactions take place

A

Smooth endoplasmic reticulum mainly and cytosol and mitochondria

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7
Q

what is one of the most important enzymes in drug metabolism

A

P450

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8
Q

give examples of phase1 metabolism reactions

A

oxidation
Hydrolysis
Hydroxylation
Dealkylation
Deamination

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9
Q

what does it produce

A

chemically reactive functional groups

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10
Q

what are the oxidation genes

A

oxidation e.g alcohol dehydrogenase, MAO, CYP450
57 CYP genes divided into 18 families: CYP1-3 (most important families)

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11
Q

what do pro drugs lead to

A

pharmacological activation

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12
Q

what are examples of phase 2 conjugation reactions

A

glucuronidtion - most widespread
Sulphating
Acetylation
Amino acid
Glutathione
Fatty acid

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13
Q

what are features of the products of phase 2 reactions

A

Water-soluble and easily secreted
Increased Molecular weight
Inactive: pharmacological inactivation
Decreased receptor affinity
Enhance excretion

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14
Q

where do drug-glucoronide reactions take place

A

in the liver

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15
Q

what is the enzyme used

A

glucoronyl transferase

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16
Q

what happens next

A

can then be excreted into the bile , then into the GI tract and then into the faeces

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17
Q

what can the bacteria in the GI tract do

A

The bacteria in the GI tract can then produce Beta-glucuronidase which will hydrolyse of cleave off the glucaronide from the drug to release the active drug to then start the whole cycle again

This is an important step for oestrogen, rifampicin, chloramphenicol, morphine

18
Q

what factors affect metabolism

A

internal
Age
Reduced as liver mass and blood flow decrease
Drug inactivation is slower - mostly phase 1 oxidation
Decreased first-pass metabolism
sex (to a lesser extent)
Pregnancy
Increased hepatic metabolism
Disease

19
Q

what tests are done for cholestasis

A

Alkaline phosphatase, gamma-glutamyl transpeptidase

20
Q

what is a result of reduced hepatocyte function

A

CYP450 reduced in severe disease

21
Q

what does decreased first pass metabolism lead to

A

increased plasma of metoprolol, labetalol and clomethiazole

22
Q

what genetic factors affect metabolism

A

DNA insertions and depletions
Disparity In the number of repeated sequences and SNPs e.g TACG - TACC all lead to polymorphisms

23
Q

what polyphorphisms metabolise around 40% of the drug

A

CYP2C9, CYP2C19 and CYP2D6 metabolise around 40% of the drug

24
Q

what metabolises a third of the drugs in phase one

A

CYP3A4/5/7

25
Q

describe the different CYP polymorphisms

A

a poor metaboliser is homozygous for defective gene

An intermediate metaboliser is heterozygous for the defective gene

The extensive metaboliser is homozygous for the functional gene - most of us are extensive metabolisers

The ultra rapid metaboliser has extra copies of the functional gene

26
Q

what is the CYP2D6 phenotype

A

ultra-rapid metabolisers
Increased metabolism and decreased plasma
Occurs by gene amplification: up to 13 copies of the gene

27
Q

what can immunosupressors such as tacrolimus do

A

disrupt signalling in t lymphocytes
high doses lead to nephrotoxicity

28
Q

what are the major enzymes responsible for metabolising tacrolimus

A

CYP2A4 and CYP3A5

29
Q

what happens if there is a SNP in CYP3A5

A

increased risk of nephrotoxicity

30
Q

what factors affect metabolism

A

External:
drug induced
Lifestyle: cigarette smoking induces metabolism of
Theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, estradiol
environment e.g arsenic, toluene, fluorine
Diet (BBQed meat, brussel sprouts increased and grapefruit juice decreased)
Inducers or inhibitors

31
Q

what does most of paracetamol turn into

A

Most of the drug turns into glucuronide and sulphate conjugates of -OH group and then to inactive metabolite and then is excreted in the urine

32
Q

what is the other part turned into

A

A small amount of the drug is turned into N-hydroxylation - CYP450 and then goes to a re-arrangement: N-acetyl-p-benzoquinone imine. This then allows the phase one metabolite to undergo a glutathione conjugation which leads to an inactive metabolite and then is also excreted in the urine

33
Q

what happens when the glutathione concentration gets depleted

A

When the glutathione concentration gets depleted there is another pathway that leads to hepatotoxicity and cell death

34
Q

what drugs can induce liver toxicity

A

licensed e.g co-amoxiclav, isoniazid, methyldopa, halothane, rifampicin, paracetamol
Unlicensed herbal remedies e.g black cohosh, comfrey, kava

35
Q

what is a type A adverse drug reaction

A

Type A: ‘augmented’ reactions, exaggerated response to drugs normal actions when given at usual dose; normally dose dependent

36
Q

what is a type B adverse drug reaction

A

Type B: bizarre reactions, novel response to drug that was not expected based upon known pharmacological actions of the drug

37
Q

what is the hepatocellular pattern of drug induced liver injury

A

Hepatocellular e.g paracetamol, isoniazid, green tea
hepatocytes necrosis and inflammation
Further subdivided by histological pattern and clinical presentations
Increase ALT and AMT
Increase gamma glutamyl transpeptidase

38
Q

what is the cholestatic pattern of drug induced liver injury

A

Cholestatic e.g co-amoxiclav, sulphonylureas
resembles bile duct obstruction
Increased alkaline phosphatase and gamma glutamyl transpeptidase
Increased alkaline and aspartate transferase

39
Q

what is the mixed pattern of drug induced liver injury

A

Mixed hepatocellular-cholestatic e.g phenytoin, enalapril
most characteristic pattern seen
Increased alkaline phosphatase and alanine transferase

40
Q

what are inducers

A

carbamazepine
Alcohol
St John’s wort - herab remedy

41
Q

what are inhibitors

A

fluoxetine, erythromycin, ketoconazole
Grapefruit juice inhibits CYP2A4
Metabolises around 30% of all drugs
Increased in plasma > prolonged effect

Semester 4 (80 decks)

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