pharmacology of the liver Flashcards
where does the majority of absorption occur
SI because of the larger SA
what does a free drug do in the plasma?
binds to proteins eg. 99% of warfarin is bound to albumin
—> only free or unbound drug can have an effect
what leads to drug displacement in liver disease?
decreased plasma albumin and increased bilirubin (bilirubin normally conjugated in liver for excretion in bile - liver unable to do this)
lead to more free drug
how does having more free drug influence the volume of distribution ?
increases the Vd
what is the volume distribution?
represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a uniform conc equivalent to that in the plasma at steady state
— relates the amount of drug in the body to the blood conc
— a theoretical volume
bigger volume of distribution = more widely distributed the drug is
what does drug removal include?
metabolism and excretion
what happens to lipophilic drugs?
they re-circulate
blood filtered by glomerulus in kidneys, and any lipid soluble drugs/small enough drugs enter nephron and then get reabsorbed across nephron into peritubular capillaries and get re-circulated in blood
what happens to water soluble drugs in elimination?
remain in the contents of the nephron and then pass through to the collecting duct and the bladder for excretion
what is a lipid-soluble drug metabolised to?
water soluble metabolite which can be excreted
what is drug metabolism?
the enzyme-mediated conversion of a lipid-soluble compound into a more water-soluble one
where is drug metabolism carried out?
- mainly in liver — hepatocytes - smooth endoplasmic reticulum (and cytosol and mitochondria)
- kidney
- lung
- GIT
- brain eg. BBB
- plasma eg. esterases
- skin
what are some of the most important drug metabolising enzymes?
cytochrome P450 (CYP450) enzymes (in liver, kidney, lung, GIT)
phase 1 vs phase 2 metabolising reactions
usually occur sequentially
- phase 1 : drug —> metabolite : oxidation , hydrolysis, hydroxylation, dealkylation, deamination
- phase 2 : metabolite —> conjugate : glucuronidation, sulphation, amino acids, glutathione, fatty acids
describe aspirin phase 1 and phase 2 reactions
aspirin —> salicylic acid —> glucuronide
what is a functionalisation reaction?
- part of phase 1
- produce/uncover chemically reactive functional groups
- slight tweaking of structure
- add in chemical groups eg. OH, NH3, SH, COOH
give examples of oxidation reactions in phase 1
- alcohol dehydrogenase
- MAO
- CYP450
how many CYP genes are there?
57 — diided into 18 families. most important are CYP1-3
descirbe phase 2 reactions - what type of reaction and describe the products
- conjugation reactions
- products generally : water-soluble and easily excreted, increased molecular weight, have less of an affinity to their receptor (as they are too big)
describe amino acid reactions in phase 2 and how they are affected when the hepatocytes are damaged
glycine and glutamine are important amino acids in this process
damage to hepatocytes —> declining availability of these amino acids - harder to conjugate the drug metabolites to the amino acids - slows down metabolism
what is glucuronyl transferase used for?
glucuronide reactions in the liver to form a drug-glucuronide combination
describe enterophatic drug circulation
- drug-glucuronide combination formed in liver via glucuronide reactions
- this combination can then be excreted in bile and into the GI tract
- bacteria in the GIT produce B-glucuronidase which will cleave off the glucuronide from the drug to release the active drug again
- drug absorbed across GIT again and back into the blood to be taken back to the liver again
enterohepatic drug circulation is an esp important step for what drugs?
glucuronides eg. oestrogens, rifampicin, chloramphenicol, morhpine
recirculation of drug can act as a drug reservoir, increasing the amount in the blood to an extra what %?
20%
how does liver dysfunction affect enterohepatic circulation of drugs?
- dont have glucuronyl transferase enzymes working as wel as they should
- therefore have less of this drug-glucuronide metabolite produces and being excreted into bile
what internal factors affect metabolism?
- age
- sex (to a lesser extent)
- pregnancy (increases hepatic metabolism)
- disease
how does age influence metabolism?
- reduced as liver mass and blood flow decrease
- drug inactivaiton is slower (mostly phase 1 oxidation)
- decreased first pass metabolism
how do we assess metabolism?
- liver function tests : serum albumin (better of 2 in terms of severity of liver disease), prothrombin time
- liver biochemistry : AST and ALT (leak into bloodstream when hepatocytes are damaged), alkaline phosphatase and y-glutamyl transpeptidase
- reduced hepatocyte function — CYP450 reduced in severe disease
- decreased blood flow through the liver (decreases speed at which drug molecules are delivered)
- decreased first pass metabolism —> increased plasma concentration of metoprolol, labetalol and clomethiazole (a no. of drugs)
- increased t1/2 (half life) and decreased clearance
where is AST mainly found?
mitochondria (20% in cytoplasm)
you can see incrased levels of what enzyme in a myocardial infarction?
AST
is AST or ALT more specific to the liver?
ALT - has better correlation with liver disease
increased levels of alkaline phosphatase and y-gutamyl transpeptidase reflex what?
cholestasis
what is first pass-metabolism?
when drug molecules are absorbed from the GI tract into the blood and can then be extracted by the liver before they enter systemic circulation
what genetic changes can affect metabolism?
- DNA insertions, deletions, disparity in the number of repeated sequences, and SNPs (eg. TAGC - TACC) all lead to polymorphisms
describe polymorphisms
- present in virtually every pathway of drug metabolism
- CYP2C9, CYP2C19 and CYP2D6 metabolise about 40% of drugs
how can we classified individuals according to CYP polymorphisms and how good they are at metabolising?
- homozygous for defective gene = poor metaboliser
- heterozygous for defective gene = intermediate metaboliser
- homozygous for functional gene (most people) = extensive metaboliser
- extra copies of functional gene = ultra rapid metaboliser
homozygous for defective gene — how are drug conc and metabolites conc affected?
slow down elimination of drug — increased conc of drug and decreases conc of metabolites
extra copies of functional gene — how is conc of drug and metabolites affected
lowered conc of drug and increased conc of metabolisers
describe tacrolimus
- drug used in liver transplants
- disrupts signalling in T lymphocytes
- metabolised mainly by CYP3A4 and CYP3A5 (SNPs in both enzymes —> lack of functional enzyme —> patients screened before to make sure they dont have SNPs in either of these so they can metabolise the drug effectively
- narrow therapeutic window, variable pharmacokinetics, nephrotoxicity
what external factors affect metabolism?
- drug induced
- lifestyle : cigarette smoking induces metabolism of — theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, estradiol
- environment eg. arsenic, fluorine, toluene
- diet (BBQed meat, brussels sprouts increases, grapefruit decreases)
- inducers or inhibitors
what is paracetamol mostly metabolised by and into?
- by glucuronide and sulphate conjugates of -OH group
- into inactive metabolites that can be excreted in urine
what happens to a small amount of paracetamol?
undergoes an oxidation reaction by a CYP450 enzyme
- phase one metabolite undergoes a glutathione conjugation to form an inactive metabolite —> urinary excretion
what happens in higher does of paracetamol?
- more of the metabolic reaction is pushed to the CYP450 side
- more metabolite produced
- when glutathione stores become depleted, another pathway is generated
- this pathway leads to hepatotoxicity and cell death
what drugs can cause liver toxicity? — licensed drugs and unlicensed herbal remedies
- licensed eg. co-amoxiclav, isoniazid, methyldopa, halothane, rifampicin, paracetamol
- unlicensed herbal remedies eg. black cohosh, comfrey, kava
what are the 2 types of adverse drug reactions (ADRs)?
- type A = ‘augmented’ reactions, exaggerated response to drug’s normal actions when given at usual dose; normally dose-dependent
- type B = ‘bizarre’ reactions, novel respond to drug that was not expected based upon known pharmacological actions of the drug
ADRs account for 1:___ hospital admissions?
1 in 16
what are the different patterns of drug-induced liver injury
- hepatocellular
- cholestatic
- mixed hepatocellular-cholestatic
describe the hepatocellular pattern of drug induced liver injury
eg. paracetamol, isoniazid, green tea
- hepatocyte necrosis and inflammation
- further subdivided by histological pattern and clinical presentations
- increased levels of alanine (ALT) and aspartate (AMT) aminotransferase
- increase in y-glutamyl transpeptide
describe the cholestatic pattern of drug induced liver injury
eg. co-amoxiclav, sulphonylureas
- resembles bile duct obstruction
- increase in alkaline phsophatase and y-glutamyl transpeptidase
- increase in alanine and aspartate transferase
describe the mixed hepatocellular-cholestatic pattern of drug induced liver injury
eg. phenytoin, enalapril
- most characteristic pattern seen
- increase in alkaline phosphatase and alanine transferase
give examples of inducers of drug metabolising enzymes
carbamazepine, alcohol, St. John’s wort
give examples of inhibitors of drug metabolising enzymes
fluoxetine, erythromycin, ketoconazole
what does grapefruit juice do?
inhibits CYP3A4
- metabolises 30% of all drugs (statins, verapamil, nifedipine,,,)
- increase in plasma conc —> prolonged effect
how to prescribe for patients with liver disease
- risk/benefit analysis
- select alternative drugs eliminated by routes other than liver
- monitoring of drugs with narrow therapeutic windows
- drugs with known hepatotoxcitiy (eg. cytotoxic drugs) should only be used for strongest of indications
