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module 104 - theme 2 > liver & metabolism - pharmokinetics > Flashcards

liver & metabolism - pharmokinetics Flashcards

1
Q

what is pharmacokinetics?

A

what the body does to the drug

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2
Q

what does the A, D, M, E stand for in pharmacokinetics?

A
  • absorption
  • distribution
  • metabolism
  • excretion
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3
Q

what does absorption mean in terms of pharmacokinetics?

A

drug transfer from its site of administration to the systemic circulation (blood)

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4
Q

what are the enteral routes of drug administration?

A
  • oral

- rectal

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5
Q

what are the oral routes of drug administration?

A
  • sublingual

- buccal

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6
Q

what are the factors that influence enteral absorption?

A
  • GI motility
  • absorptive area
  • GI blood flow
  • drug particle size and formulation
  • drug physicochemical properties
  • drug binding
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7
Q

what type of molecules are lipid soluble?

A

non-ionised molecules

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8
Q

what types of molecules are hydrophilic?

A

polar molecules - ionised molecules

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9
Q

what types of molecules in a drug are better absorbed?

A

lipid soluble molecules

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10
Q

how does pH affect the drug physiochemical properties?

A
  • acidic drugs are better absorbed in acidic media
  • basic drugs are better absorbed in basic media
  • acidic drugs are better excreted in basic media
  • basic drugs can be excreted better in acidic media
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11
Q

what are the parenteral routes of drug administration?

A
  • intramuscular
  • subcutaneous
  • intravenous
  • intradermal
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12
Q

what are the other routes of drug administration?

A
  • topical
  • transdermal
  • inhalation
  • intrathecal
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13
Q

what is bioavailability?

A

fraction of the administered (oral) dose of a drug that reaches the systemic circulation

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14
Q

what is the equation for bioavailability?

A

IV area under the curve (AUC)

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15
Q

what is first pass (pre-systemic) metabolism?

A
  • the metabolism of the drug prior to reaching systemic circulation
  • first pass effect —> bioavailability
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16
Q

what is bioequivalence?

A

2 drugs are considered bioequivalent when there is no signifiant difference in the rate or extent of bioavailability at the same molar dose and under the same conditions

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17
Q

what relevance does bioequivalence have?

A
  • different formulations from different companies

- different batches of drugs from the same company

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18
Q

where do most drugs end up after absorption?

A

systemic circulation

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19
Q

what is drug distribution?

A

process by which the drug is transferred reversibly from the systemic circulation into the tissues as concentrations in the blood increase, and from the tissues into blood when the blood concentrations decrease during elimination

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20
Q

where are the drugs distributed?

A

into vascular, interstitial and intracellular compartments

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21
Q

how does drug distribution occur?

A
  • most drugs transfer by passive diffusion
  • across capillary walls down a concentration gradient
  • into interstitial fluid until concentration of free drug molecules in interstitium is equal to that in plasma
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22
Q

what are the key features of plasma protein binding?

A
  • drugs bind non-specifically to albumin in plasma
  • reversible and saturable
  • unbound or free fraction distributes
  • unbound portion is responsible for the clinical effect
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23
Q

what is the equation for plasma protein binding?

A

Drug + Protein Drug-Protein complex

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24
Q

what drugs are highly protein bound?

A
  • warfarin
  • phenytoin
  • aspirin
  • thyroxine
  • ibuprofen
  • heparin
  • furosemide
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25
Q

what factors influence drug distribution?

A
  • drug physiochemical properties
  • lipid solubility
  • water solubility
  • drug particle size
  • drug protein binding
  • the environment; blood flow, pH
26
Q

what is apparent volume of distribution?

A
  • a concept that seeks to predict how extensively a drug is distributed throughout the body
  • volume into which a drug appears to be distributed with a concentration equal to that of plasma
27
Q

what is the equation for apparent volume of distribution (Vd)?

A

Vd = Dose (mg) / Concentration (mg/L)

28
Q

why doe drugs with a large Vd need to be administered in larger doses?

A

to achieve a target concentration in the plasma

29
Q

what do we mean if a drug has a low Vd?

A

Vd < 10L (warfarin)

- highly protein bound drug so retained in plasma

30
Q

what do we mean if a drug has a medium Vd?

A

Vd = 10-30L

  • water soluble drugs, low lipid solubility
  • distributes into interstitial fluid but not cells
  • dose on distal body weight to avoid toxicity
31
Q

what do we mean if a drug has a high Vd?

A

Vd > 100L (amiodarone)

- fat soluble drug distributes into tissues

32
Q

what are the 3 forms of the drug in phase 1 drug metabolism?

A
  • active (pro-drug)
  • inactive
  • toxic
33
Q

what happens in phase 1 drug metabolism?

A
  • oxidation (P450 cytochrome)
  • reduction
  • hydrolysis (esterase’s)
34
Q

what happens in phase 2 of drug metabolism?

A

drug solubilisation by conjugation:

  • glucuronidation
  • acetylation
  • sulfation
  • methylation
  • eliminated in urine or bile
35
Q

what do you start and end with in drug metabolism?

A

start: lipophilic drug
end: water-soluble metabolites

36
Q

what is a prodrug?

A

a drug or compound that is metabolised into a pharmacologically active drug

37
Q

what are some examples of prodrugs?

A
  • enalapril to enalaprilat
  • codeine into morphine
  • levodopa to dopamine
38
Q

what are the cytochrome P450 inhibitors?

A
  • Amiodarone
  • Ciprofloxacin
  • Erythromycin/Clarithromycin
  • Metronidazole
  • Fluconazole
  • Isoniazid
  • Alcohol (acute)
  • Grapefruit juice
39
Q

what are the cytochrome P450 inducers?

A
  • Carbamazepine
  • Phenytoin
  • Rifampicin
  • Alcohol (Chronic)
40
Q

what type of process is cytochrome P450 inhibitor?

A

a rapid process

41
Q

what type of process is cytochrome P450 induction?

A

a slow process

42
Q

what is the therapeutic index?

A

ration of concentration associated with toxicity (MTC) vs concentration associated with efficacy (MEC)

43
Q

what general combination has a potential for adverse drug interaction?

A
  • drug metabolised by CYP450 with narrow therapeutic index/window
    AND
  • cytochrome P450 inhibitor
44
Q

what are genetic polymorphisms?

A

multiple genetic variants which result in different phenotypes

45
Q

what do polymorphisms of drug metabolising enzymes affect?

A

drug handling

46
Q

what is an extensive metaboliser?

A

two active ‘normal’ alleles

47
Q

what is an intermediate metaboliser?

A

one normal and one abnormal allele

48
Q

what is a poor metaboliser?

A

two abnormal alleles

49
Q

what is an ultra rapid metaboliser?

A

duplication of normal alleles

50
Q

what happens with CYP2D6 polymorphisms with ultra rapid metaboliser?

A
  • causes opiate toxicity in some individuals even at a low dose
  • this causes an exaggerated response to codeine
51
Q

what happens with CYP2D6 polymorphism with poor metaboliser?

A
  • causes inadequate pain relief by codeine in some individuals
52
Q

what is the phase 2 reaction equation?

A

drug + glucuronidation, acetylation, sulfation and methylation ——> water soluble conjugate

53
Q

what genetically determines the activity of N-acetyltransferase?

A
  • fast acetylators at increased risk of isoniazid hepatoxicity
  • slow acetylators at increased risk of isoniazid neuropathy
  • slow acetylators at increased risk of drug induced lupus with hydralazine
54
Q

what is drug clearance?

A
  • the sum of all the drug-eliminating processes, principally determined by hepatic metabolism and renal excretion
  • theoretical volume of fluid from which a drug is completely removed in a given period of time
55
Q

what are the components of renal excretion?

A
  • glomerular filtration: glomerulus
  • secretion: proximal convoluted tubule
  • reabsorption: distal convoluted tubule
56
Q

what are the other excretory methods (other than urine)?

A
  • bile (faeces)
  • sweat
  • exhaled air
  • saliva
  • breast milk
57
Q

what are the causes of low drug clearance?

A
  • normal variation
  • renal impairment
  • liver impairment
  • enzyme inhibition
  • genetic poor metaboliser
  • neonate
  • old age
58
Q

what are the causes of high drug clearance?

A
  • normal variation
  • increased renal blood flow
  • genetic hyper-metabolism
  • enzyme induction
59
Q

what does half-life provide information on?

A
  • time course of drug elimination
  • time course of drug accumulation
  • choice of dose interval
60
Q

what determines loading dose?

A

volume of distribution

61
Q

what determines maintenance dose?

A

clearance

62
Q

what determines dose interval?

A

half life

module 104 - theme 2 (18 decks)

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