case 5 - liver pharmacology Flashcards
what kind of drug has an effect
only free or unbound drugs
what does decreased plasma albumin and increased bilirubin lead to
drug displacement
what does increased volume of distribution represent
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
what are most drugs
lipophilic therefore re circulate
what happens to lipid soluble drugs
Lipid soluble drug is metabolised into a water soluble metabolite and then the water-soluble metabolite excreted
where in the liver do phase 1 and 2 DME reactions take place
Smooth endoplasmic reticulum mainly and cytosol and mitochondria
what is one of the most important enzymes in drug metabolism
P450
give examples of phase1 metabolism reactions
oxidation
Hydrolysis
Hydroxylation
Dealkylation
Deamination
what does it produce
chemically reactive functional groups
what are the oxidation genes
oxidation e.g alcohol dehydrogenase, MAO, CYP450
57 CYP genes divided into 18 families: CYP1-3 (most important families)
what do pro drugs lead to
pharmacological activation
what are examples of phase 2 conjugation reactions
glucuronidtion - most widespread
Sulphating
Acetylation
Amino acid
Glutathione
Fatty acid
what are features of the products of phase 2 reactions
Water-soluble and easily secreted
Increased Molecular weight
Inactive: pharmacological inactivation
Decreased receptor affinity
Enhance excretion
where do drug-glucoronide reactions take place
in the liver
what is the enzyme used
glucoronyl transferase
what happens next
can then be excreted into the bile , then into the GI tract and then into the faeces
what can the bacteria in the GI tract do
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
what factors affect metabolism
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
what tests are done for cholestasis
Alkaline phosphatase, gamma-glutamyl transpeptidase
what is a result of reduced hepatocyte function
CYP450 reduced in severe disease
what does decreased first pass metabolism lead to
increased plasma of metoprolol, labetalol and clomethiazole
what genetic factors affect metabolism
DNA insertions and depletions
Disparity In the number of repeated sequences and SNPs e.g TACG - TACC all lead to polymorphisms
what polyphorphisms metabolise around 40% of the drug
CYP2C9, CYP2C19 and CYP2D6 metabolise around 40% of the drug
what metabolises a third of the drugs in phase one
CYP3A4/5/7
describe the different CYP polymorphisms
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
what is the CYP2D6 phenotype
ultra-rapid metabolisers
Increased metabolism and decreased plasma
Occurs by gene amplification: up to 13 copies of the gene
what can immunosupressors such as tacrolimus do
disrupt signalling in t lymphocytes
high doses lead to nephrotoxicity
what are the major enzymes responsible for metabolising tacrolimus
CYP2A4 and CYP3A5
what happens if there is a SNP in CYP3A5
increased risk of nephrotoxicity
what factors affect metabolism
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
what does most of paracetamol turn into
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
what is the other part turned into
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
what happens when the glutathione concentration gets depleted
When the glutathione concentration gets depleted there is another pathway that leads to hepatotoxicity and cell death
what drugs can induce liver toxicity
licensed e.g co-amoxiclav, isoniazid, methyldopa, halothane, rifampicin, paracetamol
Unlicensed herbal remedies e.g black cohosh, comfrey, kava
what is a type A adverse drug reaction
Type A: ‘augmented’ reactions, exaggerated response to drugs normal actions when given at usual dose; normally dose dependent
what is a type B adverse drug reaction
Type B: bizarre reactions, novel response to drug that was not expected based upon known pharmacological actions of the drug
what is the hepatocellular pattern of drug induced liver injury
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
what is the cholestatic pattern of drug induced liver injury
Cholestatic e.g co-amoxiclav, sulphonylureas
resembles bile duct obstruction
Increased alkaline phosphatase and gamma glutamyl transpeptidase
Increased alkaline and aspartate transferase
what is the mixed pattern of drug induced liver injury
Mixed hepatocellular-cholestatic e.g phenytoin, enalapril
most characteristic pattern seen
Increased alkaline phosphatase and alanine transferase
what are inducers
carbamazepine
Alcohol
St John’s wort - herab remedy
what are inhibitors
fluoxetine, erythromycin, ketoconazole
Grapefruit juice inhibits CYP2A4
Metabolises around 30% of all drugs
Increased in plasma > prolonged effect
