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PBL SEM 4 > pharmacology of the liver > Flashcards

pharmacology of the liver Flashcards

1
Q

where does the majority of absorption occur

A

SI because of the larger SA

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2
Q

what does a free drug do in the plasma?

A

binds to proteins eg. 99% of warfarin is bound to albumin

—> only free or unbound drug can have an effect

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3
Q

what leads to drug displacement in liver disease?

A

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

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4
Q

how does having more free drug influence the volume of distribution ?

A

increases the Vd

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5
Q

what is the volume distribution?

A

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

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6
Q

what does drug removal include?

A

metabolism and excretion

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7
Q

what happens to lipophilic drugs?

A

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

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8
Q

what happens to water soluble drugs in elimination?

A

remain in the contents of the nephron and then pass through to the collecting duct and the bladder for excretion

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9
Q

what is a lipid-soluble drug metabolised to?

A

water soluble metabolite which can be excreted

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10
Q

what is drug metabolism?

A

the enzyme-mediated conversion of a lipid-soluble compound into a more water-soluble one

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11
Q

where is drug metabolism carried out?

A
  • mainly in liver — hepatocytes - smooth endoplasmic reticulum (and cytosol and mitochondria)
  • kidney
  • lung
  • GIT
  • brain eg. BBB
  • plasma eg. esterases
  • skin
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12
Q

what are some of the most important drug metabolising enzymes?

A

cytochrome P450 (CYP450) enzymes (in liver, kidney, lung, GIT)

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13
Q

phase 1 vs phase 2 metabolising reactions

A

usually occur sequentially

  • phase 1 : drug —> metabolite : oxidation , hydrolysis, hydroxylation, dealkylation, deamination
  • phase 2 : metabolite —> conjugate : glucuronidation, sulphation, amino acids, glutathione, fatty acids
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14
Q

describe aspirin phase 1 and phase 2 reactions

A

aspirin —> salicylic acid —> glucuronide

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15
Q

what is a functionalisation reaction?

A
  • part of phase 1
  • produce/uncover chemically reactive functional groups
  • slight tweaking of structure
  • add in chemical groups eg. OH, NH3, SH, COOH
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16
Q

give examples of oxidation reactions in phase 1

A
  • alcohol dehydrogenase
  • MAO
  • CYP450
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17
Q

how many CYP genes are there?

A

57 — diided into 18 families. most important are CYP1-3

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18
Q

descirbe phase 2 reactions - what type of reaction and describe the products

A
  • 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)
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19
Q

describe amino acid reactions in phase 2 and how they are affected when the hepatocytes are damaged

A

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

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20
Q

what is glucuronyl transferase used for?

A

glucuronide reactions in the liver to form a drug-glucuronide combination

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21
Q

describe enterophatic drug circulation

A
  • 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
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22
Q

enterohepatic drug circulation is an esp important step for what drugs?

A

glucuronides eg. oestrogens, rifampicin, chloramphenicol, morhpine

23
Q

recirculation of drug can act as a drug reservoir, increasing the amount in the blood to an extra what %?

A

20%

24
Q

how does liver dysfunction affect enterohepatic circulation of drugs?

A
  • 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
25
Q

what internal factors affect metabolism?

A
  • age
  • sex (to a lesser extent)
  • pregnancy (increases hepatic metabolism)
  • disease
26
Q

how does age influence metabolism?

A
  • reduced as liver mass and blood flow decrease
  • drug inactivaiton is slower (mostly phase 1 oxidation)
  • decreased first pass metabolism
27
Q

how do we assess metabolism?

A
  • 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
28
Q

where is AST mainly found?

A

mitochondria (20% in cytoplasm)

29
Q

you can see incrased levels of what enzyme in a myocardial infarction?

A

AST

30
Q

is AST or ALT more specific to the liver?

A

ALT - has better correlation with liver disease

31
Q

increased levels of alkaline phosphatase and y-gutamyl transpeptidase reflex what?

A

cholestasis

32
Q

what is first pass-metabolism?

A

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

33
Q

what genetic changes can affect metabolism?

A
  • DNA insertions, deletions, disparity in the number of repeated sequences, and SNPs (eg. TAGC - TACC) all lead to polymorphisms
34
Q

describe polymorphisms

A
  • present in virtually every pathway of drug metabolism
  • CYP2C9, CYP2C19 and CYP2D6 metabolise about 40% of drugs
35
Q

how can we classified individuals according to CYP polymorphisms and how good they are at metabolising?

A
  • 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
36
Q

homozygous for defective gene — how are drug conc and metabolites conc affected?

A

slow down elimination of drug — increased conc of drug and decreases conc of metabolites

37
Q

extra copies of functional gene — how is conc of drug and metabolites affected

A

lowered conc of drug and increased conc of metabolisers

38
Q

describe tacrolimus

A
  • 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
39
Q

what external factors affect metabolism?

A
  • 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
40
Q

what is paracetamol mostly metabolised by and into?

A
  • by glucuronide and sulphate conjugates of -OH group
  • into inactive metabolites that can be excreted in urine
41
Q

what happens to a small amount of paracetamol?

A

undergoes an oxidation reaction by a CYP450 enzyme

  • phase one metabolite undergoes a glutathione conjugation to form an inactive metabolite —> urinary excretion
42
Q

what happens in higher does of paracetamol?

A
  • 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
43
Q

what drugs can cause liver toxicity? — licensed drugs and unlicensed herbal remedies

A
  • licensed eg. co-amoxiclav, isoniazid, methyldopa, halothane, rifampicin, paracetamol
  • unlicensed herbal remedies eg. black cohosh, comfrey, kava
44
Q

what are the 2 types of adverse drug reactions (ADRs)?

A
  • 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
45
Q

ADRs account for 1:___ hospital admissions?

A

1 in 16

46
Q

what are the different patterns of drug-induced liver injury

A
  1. hepatocellular
  2. cholestatic
  3. mixed hepatocellular-cholestatic
47
Q

describe the hepatocellular pattern of drug induced liver injury

A

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
48
Q

describe the cholestatic pattern of drug induced liver injury

A

eg. co-amoxiclav, sulphonylureas

  • resembles bile duct obstruction
  • increase in alkaline phsophatase and y-glutamyl transpeptidase
  • increase in alanine and aspartate transferase
49
Q

describe the mixed hepatocellular-cholestatic pattern of drug induced liver injury

A

eg. phenytoin, enalapril

  • most characteristic pattern seen
  • increase in alkaline phosphatase and alanine transferase
50
Q

give examples of inducers of drug metabolising enzymes

A

carbamazepine, alcohol, St. John’s wort

51
Q

give examples of inhibitors of drug metabolising enzymes

A

fluoxetine, erythromycin, ketoconazole

52
Q

what does grapefruit juice do?

A

inhibits CYP3A4

  • metabolises 30% of all drugs (statins, verapamil, nifedipine,,,)
  • increase in plasma conc —> prolonged effect
53
Q

how to prescribe for patients with liver disease

A
  • 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

PBL SEM 4 (50 decks)

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