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I&I WC1 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Which four processes are part of pharmacokinetics?

A

ADME
1. Absorption
2. Distribution
3. Metabolism
4. Excretion

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2
Q

What is absorption?

A

The process of uptake of medication into the body

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3
Q

What is the absorption of IV medication?

A

100%

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4
Q

Why should oral administration of drugs not be used after surgery/in ICU?

A

Stomach and intestine often delayed or functionally immobile

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5
Q

What is bioavailability?

A

Fraction of the administered dose of unchanged drug that reaches the systemic circulation (as a % of IV administration)

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6
Q

What is the symbol for bioavailability?

A

F or BB

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7
Q

The way of administration of a drug determines peak levels in blood. Which administration method reaches peak levels quickest?

A

IV administration

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8
Q

What is the order of administration methods, based on which peaks fastest?

A
  1. IV
  2. IM
  3. SC
  4. Oral
  5. Rectal
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9
Q

What is the main factor determining the distribution of a drug throughout the body?

A

Whether it is hydrophilic or lipophilic

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10
Q

What are the main hydrophilic tissues of the body? (2)

A
  1. Blood
  2. Muscles
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11
Q

What are the main hydrophobic tissues of the body? (3)

A
  1. Dermis
  2. Nerves
  3. Fat tissue
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12
Q

Which measure is used to quantitatively describe drug distribution?

A

Volume of distribution = Vd -> hypothetical volume in which drug is dispersed

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13
Q

What is the formula to calculate volume of distribution after IV administration?

A

Vd = Ab/C

Ab = quantity of drug in the body system
C = concentration in blood

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14
Q

What is the formula to calculate volume of distribution after oral adminstration?

A

Vd = F*dose/plasma concentration

F = bioavailability

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15
Q

Lipophilic drugs have a [small/large] Vd

A

Large -> they distribute to fat, so the apparent volume of water they are dispersed in is large

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16
Q

Hydrophilic drugs have a [small/large] Vd

A

Small -> they distribute exclusively into the fluid component

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17
Q

What are the 3 fluid compartments of the body?

A
  1. Intracellualr fluid (ICF)
    Extracellular fluid (ECF), consisting of:
  2. Interstitial fluid -> fluid outside of cells
  3. Plasma -> fluid component of blood
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18
Q

What are the volumes of plasma, interstitial fluid and intracellular fluid for a 70 kg person?

A

Plasma volume = 4L
Interstitial volume = 10L
Intracellular volume = 28L

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19
Q

Which drugs are overrepresented in the plasma?

A

High molecular weight drugs and drugs that bind to plasma proteins

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20
Q

Where do low molecular weight hydrophilic drugs mainly distribute to?

A

Intracellular volume

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21
Q

What is metabolism in terms of pharmacokinetics?

A

Chemical conversion of drugs in the body

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22
Q

Which system is predominantly responsible for the metabolism of drugs?

A

Cytochrome P450 system

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23
Q

What are generally considered the most important enzymes of the cytochrome P450 system for the metabolism of pharmalogicals? (3)

A
  1. CYP3A4
  2. CYP3A5
  3. CYP2D6
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24
Q

What is the main change that the liver introduces to drugs? Why?

A

It turns them from lipophilic into hydrophilic, allowing them to be excreted by the kidney

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25
Q

What are ‘prodrugs’?

A

Drugs that require metabolism by the liver to become active

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26
Q

Why are there differences in the cytochrome P450 system between individuals?

A

This system has a lot of genetic polymorphisms and copy number variations

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27
Q

Which three general classes of drug metabolizers are there, based on cytochrome P450 activity?

A
  1. Ultra-rapid metabolizers
  2. Extensive metabolizers = normal
  3. Poor metabolizers
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28
Q

What effect to poor metabolizers experience from:
1. Prodrugs
2. Normal drugs

A
  1. Prodrugs are activated in a less efficient way -> less effect of drug
  2. Drugs are metabolized in a less efficient way, leading to accumulation and side effects
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29
Q

Which three ways are there for the elimination of drugs? Which is most important?

A
  1. Urine = most important
  2. Bile
  3. Faeces
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30
Q

Why is it important to have knowledge of pharmacokinetic properties of drugs and patients?

A

It allows to predict reactions to medicines

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31
Q

What is Tmax?

A

Timepoint at which the maximum blood concentration is reached

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32
Q

What is Cmax?

A

Maximum concentration of drug in the blood (=at Tmax)

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33
Q

What is clearance rate?

A

Elimination out of the body -> volume of plasma cleared of the drug per unit of time

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34
Q

What is T1/2?

A

Time necessary to decrease blood concentration of medication by 50%

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35
Q

Why is knowledge of the T1/2 of a drug important?

A

To prevent overdosing in case of repeated doses (prevent accumulation after repeated doses)

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36
Q

What are the main causes of a prolonged T1/2? (2)

A
  1. Renal impairment
  2. Intoxication (=decreased liver function)
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37
Q

How many T1/2 need to pass before medication is cleared from the blood (as a general rule)?

A

4-5x T1/2

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38
Q

How many T1/2 need to pass before a steady state concentration is reached (as a general rule)?

A

3-5x T1/2

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39
Q

What is accumulation (in pharmacokinetics)?

A

Stacking of medication after repeated doses

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40
Q

What does the area under the curve (AUC) represent within pharmacokinetics?

A

Total exposure to the drug (time*concentration)

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41
Q

Decreased clearance of medication leads to a [decreased/increased] AUC. What is the effect of this?

A

Increased -> higher chances of side effects and toxicity

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42
Q

What is a therapeutic range?

A

The range that the drug concentrations needs to reach to be above subtherapeutic levels (=no effects), but not high enough to cause (severe) side effects (toxic levels)

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43
Q

What is pharmacogenetics?

A

Analysis of DNA to explain/predict responses of patients to drug therapy

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44
Q

Which factors can influence drug effect (among others)? (3)

A
  1. Receptors
  2. Effectors
  3. Enzymes/metabolism
45
Q

How many % of drugs are metabolized by the CYP450 system?

A

80%

46
Q

Which groups of drugs are metabolized by CYP3A4? (3)

A
  1. Oncology drugs
  2. Psychiatric drugs
  3. Cyclosporin & tacrolimus
47
Q

Which groups of drugs are metabolized by CYP2D6? (4)

A
  1. Antidepressives
  2. Antipsychotics
  3. Beta-blockers
  4. Tamoxifen
48
Q

Which important group of drugs is metabolized by CYP2C9?

A

Vitamin K antagonists

49
Q

What causes differences in activity of CYP enzymes?

A

SNPs

50
Q

What is a SNP?

A

A DNA variant that occurs in >1% of the population

51
Q

Which areas of CYP-genes are most often affected by SNPs? What is the effect of this?

A

Promotors/enhancers -> influences the amount of transcription

52
Q

What should be investigated if SNPs cannot explain CYP-enzyme activity?

A

Copy numver bariations

53
Q

Which SNPs are included in SNP analysis of CYP-enzymes?

A

SNPs of known effect and clinical relevance (so: not all SNPs)

54
Q

How many % of people is CYP2D6 ultra-rapid metabolizer? What is the cause of this?

A

2-5% is ultra-rapid metabolizer, due to the presence of extra copies of genes

55
Q

How many % of people is CYP2D6 normal metabolizer? How many functional genes do they have?

A

60-70% of population, with 2 functional genes

56
Q

How many % of people is CYP2D6 intermediate metabolizer? What is the cause of this?

A

10-15% has only 1 functional gene copy and is intermediate metabolizer

57
Q

How many % of people is CYP2D6 poor metabolizer? What is the cause of this?

A

5-10%, who have 2 less functional genes

58
Q

Which CYP-enzyme metabolizes imipramine?

A

CYP2D6

59
Q

How many % of patients taking imipramine require dose adjustments based on drug concentration in blood?

A

50%

60
Q

How many % of the standard dose do poor imipramine metabolizers need? How many % do ultra-rapid metabolizers need?

A

Poor metabolizers: 30%
Ultra-rapid metabolizers: 175%

61
Q

Which CYP-enzyme metabolizes metoprolol?

A

CYP2D6

62
Q

Which % of the standard dosage of metoprolol do PM, IM, NM and UM need?

A

PM = 25%
IM = 50%
NM = 100%
UM = 250%

63
Q

What is an important property of tramadol & codeine?

A

They are prodrugs of morphine, converted by CYP2D6

64
Q

Which enzyme converts the prodrugs tramadol & codeine into morphine? What is the effect of ultra-rapid metabolism?

A

CYP2D6, ultra-rapid metabolism leads to increased levels of morphine -> side effects

65
Q

Which enzyme metabolizes azathioprine? Which drug is also metabolized by this drug?

A

TPMT, also metabolizes (6)-mercaptpurine

66
Q

What is the effect of low TPMT activity?

A

Accumulation of azathioprine & 6-mercaptopurine, leading to haematologic toxicity

67
Q

What is the effect of accumulation of azathioprine/6-mercaptopurine? How much do their dosages need to be reduced in case of a slow TPMT metabolism?

A

Haematologic toxicity

Slow TPMT metabolism requires 50% dose reduction

68
Q

What is an important property of tamoxifen?

A

It is a prodrug, needs to be activated by CYP2D6

69
Q

Which CYP-enzyme is needed to activate the prodrug tamoxifen?

A

CYP2D6

70
Q

How many % of the population is fully CYP2D6 deficient? How many % of drugs is metabolized by CYP2D6?

A

5-10% of population is fully CYP2D6 deficient
20% of drugs is metabolized by CYP2D6

71
Q

Which patient samples can be used for genetic typic for pharmacogenetics? (2)

A
  1. EDTA blood
  2. Cheek swab
72
Q

What is the average turnaround time for pharmacogenetic analysis? Which one can be performed faster, and why?

A

~7 days

CYP2D6 and TPMT can be performed faster, so that starting dosages of drugs metabolized by these enzymes can be altered

73
Q

What is an important characteristic of clopidogrel?

A

It is a prodrug, needs to activated by CYP2C19

74
Q

Which enzyme converts prodrug clopidogrel into an active form?

A

CYP2C19

75
Q

How can knowledge of CYP2C19 mutations affect clinical practice?

A

Patients with poor CYP2C19 function can receive prasugrel/ticagrelor instead of clopidogrel -> does not have to be activated

76
Q

Why are the active drugs prasugrel/ticagrelor not always immediately prescribed over prodrug clopidogrel?

A

They are (far) more expensive -> only worth it when patients are poor CYP2C19 metabolizers

77
Q

Which enzyme metabolizes voriconazole?

A

CYP2C19

78
Q

Which enzyme metabolizes omeprazole?

A

CYP2C19

79
Q

Why is pharmacogenetics extra important when it comes to tacrolimus? (2)

A
  1. High interindividual variation in pharmacogenetics
  2. Small therapeutic window
80
Q

Which enzymes metabolize tacrolimus? (2) Which of these is remarkable, and why?

A
  1. CYP3A4
  2. CYP3A5 -> high inter-individual variation of expression, patients with higher expression require higher concentrations to be therapeutically active
81
Q

Which drugs are metabolized by CYP2D6? (4)

A
  1. Imipramine
  2. Metoprolol
  3. Codeine/tramadol
  4. Tamoxifen
82
Q

Which drugs are metabolized by CYP2C19? (3)

A
  1. Clopidogrel
  2. Voriconazole
  3. Omeprazole
83
Q

What is a biopharmaceutical (definition)?

A

Any pharmaceutical product manufactured in, extracted from or semi-synthesized from biological sources

84
Q

What does the term ‘biological’ commonly refer to?

A

Monoclonal antibodies and fusion proteins

85
Q

In the treatment of which groups of diseases to biologicals currently have an important role? (4)

A
  1. Haematological malignancies & malignancies
  2. Transplant rejection
  3. Auto-immune disease
  4. Auto-inflammatory disease
86
Q

Which two general modes of action can biologicals have?

A
  1. Targeting of cell surface molecules
  2. Targeting of soluble mediators
87
Q

What are biologicals ending in -omab derived of?

A

Mouse

88
Q

What are biologicals ending in -ximab derived of?

A

Chimeric mouse-human antibodies

89
Q

Which part of chimeric mouse-human antibodies is mouse, and which is human?

A

Variable domain = mouse
Constant domain = human

90
Q

What are biologicals ending in -zumab derived of?

A

Humanized mouse antibodies

91
Q

Which part of humanized mouse antibodies is mouse, and which is human?

A

Antigen-recognition domain = mouse
Rest = human

92
Q

What are biologicals ending in -umab derived of?

A

Fully human antibodies

93
Q

What is the benefit of fully human antibodies as biologicals?

A

Less immunogenic -> lower infusion-site reactions

94
Q

What is an important issue when using biologicals for treatment?

A

Anti-drug antibodies (ADA)

95
Q

What is the effect of the presence of ADAs? (2)

A
  1. Rapid clearance of biologicals -> loss of response
  2. Hypersensitivity reactions
96
Q

What is an example of an ADA-induced hypersensitivity reaction to biologicals?

A

Cytokine storm

97
Q

Which two parameters are monitored in therapeutic drug monitoring of biologicals?

A
  1. Biological through levels/total levels
  2. Presence of ADAs (on indication)
98
Q

What does the bioavailability of biologicals depend on? (4)

A
  1. Distribution
  2. Recycling by FcRn
  3. Degradation
  4. Neutralization by ADA
99
Q

What is a common modality for detecting levels of biologicals in blood?

A

ELISA

100
Q

Which two methods of ELISA are available to detect levels of biologicals in blood?

A
  1. SQ-system
  2. LT-system
101
Q

What are the steps in the LT-ELISA system for the detection of biologicals in blood? Use infliximab (anti-TNF) as example.

A
  1. TNF directly bound to plate
  2. Plate incubated with serum, antibodies bind to TNF on plate
  3. Secondary antibody added -> binds Fc-domain of IgG serum biological
101
Q

What are the steps in the SQ-ELISA system for the detection of biologicals in blood? Use infliximab (anti-TNF) as example.

A
  1. Anti-TNF mAb bound to plate
  2. TNF added -> binds to antibodies
  3. Serum added -> serum biologicals bind to TNF
  4. Read out using secondary antibodies that bind the variable domain of IgG
102
Q

What are biosimilars? What is the advantage of using them?

A

Structurally related to biologicals, but often times at a lower pricepoint

103
Q

What are the main isotypes of ADAs?

A

IgG1, IgG4

104
Q

Why do ADAs need to be measured at through levels of drug?

A

Otherwise all ADAs are in complex with biological and cannot be detected -> at through level, free ADAs are highest

105
Q

What has to be the conclusion if there are low drug levels/effects but there are no ADAs present?

A

Patients are not taking drugs

106
Q

Which step has to be taken in case of the presence of ADAs against drugs?

A

Switch to a differerent drug

107
Q

True or false: patients that develop ADAs against one drug don’t have an increased chance of developing them for another drug

A

False; increased risk of development of ADAs to new drugs in case they have already been developed against other drugs

I&I WC1 (20 decks)

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