case 5 - liver pharmacology

Question 1

what kind of drug has an effect

Answer 1

only free or unbound drugs

Question 2

what does decreased plasma albumin and increased bilirubin lead to

Answer 2

drug displacement

Question 3

what does increased volume of distribution represent

Answer 3

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

Question 4

what are most drugs

Answer 4

lipophilic therefore re circulate

Question 5

what happens to lipid soluble drugs

Answer 5

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

Question 6

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

Answer 6

Smooth endoplasmic reticulum mainly and cytosol and mitochondria

Question 7

what is one of the most important enzymes in drug metabolism

Answer 7

P450

Question 8

give examples of phase1 metabolism reactions

Answer 8

oxidation
Hydrolysis
Hydroxylation
Dealkylation
Deamination

Question 9

what does it produce

Answer 9

chemically reactive functional groups

Question 10

what are the oxidation genes

Answer 10

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

Question 11

what do pro drugs lead to

Answer 11

pharmacological activation

Question 12

what are examples of phase 2 conjugation reactions

Answer 12

glucuronidtion - most widespread
Sulphating
Acetylation
Amino acid
Glutathione
Fatty acid

Question 13

what are features of the products of phase 2 reactions

Answer 13

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

Question 14

where do drug-glucoronide reactions take place

Answer 14

in the liver

Question 15

what is the enzyme used

Answer 15

glucoronyl transferase

Question 16

what happens next

Answer 16

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

Question 17

what can the bacteria in the GI tract do

Answer 17

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

Question 18

what factors affect metabolism

Answer 18

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

Question 19

what tests are done for cholestasis

Answer 19

Alkaline phosphatase, gamma-glutamyl transpeptidase

Question 20

what is a result of reduced hepatocyte function

Answer 20

CYP450 reduced in severe disease

Question 21

what does decreased first pass metabolism lead to

Answer 21

increased plasma of metoprolol, labetalol and clomethiazole

Question 22

what genetic factors affect metabolism

Answer 22

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

Question 23

what polyphorphisms metabolise around 40% of the drug

Answer 23

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

Question 24

what metabolises a third of the drugs in phase one

Answer 24

CYP3A4/5/7

Question 25

describe the different CYP polymorphisms

Answer 25

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

Question 26

what is the CYP2D6 phenotype

Answer 26

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

Question 27

what can immunosupressors such as tacrolimus do

Answer 27

disrupt signalling in t lymphocytes high doses lead to nephrotoxicity

Question 28

what are the major enzymes responsible for metabolising tacrolimus

Answer 28

CYP2A4 and CYP3A5

Question 29

what happens if there is a SNP in CYP3A5

Answer 29

increased risk of nephrotoxicity

Question 30

what factors affect metabolism

Answer 30

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

Question 31

what does most of paracetamol turn into

Answer 31

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

Question 32

what is the other part turned into

Answer 32

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

Question 33

what happens when the glutathione concentration gets depleted

Answer 33

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

Question 34

what drugs can induce liver toxicity

Answer 34

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

Question 35

what is a type A adverse drug reaction

Answer 35

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

Question 36

what is a type B adverse drug reaction

Answer 36

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

Question 37

what is the hepatocellular pattern of drug induced liver injury

Answer 37

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

Question 38

what is the cholestatic pattern of drug induced liver injury

Answer 38

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

Question 39

what is the mixed pattern of drug induced liver injury

Answer 39

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

Question 40

what are inducers

Answer 40

carbamazepine Alcohol St John’s wort - herab remedy

Question 41

what are inhibitors

Answer 41

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