Pharmacology Flashcards
1
Q
Which four processes are part of pharmacokinetics?
A
ADME
1. Absorption
2. Distribution
3. Metabolism
4. Excretion
2
Q
What is absorption?
A
The process of uptake of medication into the body
3
Q
What is the absorption of IV medication?
A
100%
4
Q
Why should oral administration of drugs not be used after surgery/in ICU?
A
Stomach and intestine often delayed or functionally immobile
5
Q
What is bioavailability?
A
Fraction of the administered dose of unchanged drug that reaches the systemic circulation (as a % of IV administration)
6
Q
What is the symbol for bioavailability?
A
F or BB
7
Q
The way of administration of a drug determines peak levels in blood. Which administration method reaches peak levels quickest?
A
IV administration
8
Q
What is the order of administration methods, based on which peaks fastest?
A
- IV
- IM
- SC
- Oral
- Rectal
9
Q
What is the main factor determining the distribution of a drug throughout the body?
A
Whether it is hydrophilic or lipophilic
10
Q
What are the main hydrophilic tissues of the body? (2)
A
- Blood
- Muscles
11
Q
What are the main hydrophobic tissues of the body? (3)
A
- Dermis
- Nerves
- Fat tissue
12
Q
Which measure is used to quantitatively describe drug distribution?
A
Volume of distribution = Vd -> hypothetical volume in which drug is dispersed
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
14
Q
What is the formula to calculate volume of distribution after oral adminstration?
A
Vd = F*dose/plasma concentration
F = bioavailability
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
16
Q
Hydrophilic drugs have a [small/large] Vd
A
Small -> they distribute exclusively into the fluid component
17
Q
What are the 3 fluid compartments of the body?
A
- Intracellualr fluid (ICF)
Extracellular fluid (ECF), consisting of: - Interstitial fluid -> fluid outside of cells
- Plasma -> fluid component of blood
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
19
Q
Which drugs are overrepresented in the plasma?
A
High molecular weight drugs and drugs that bind to plasma proteins
20
Q
Where do low molecular weight hydrophilic drugs mainly distribute to?
A
Intracellular volume
21
Q
What is metabolism in terms of pharmacokinetics?
A
Chemical conversion of drugs in the body
22
Q
Which system is predominantly responsible for the metabolism of drugs?
A
Cytochrome P450 system
23
Q
What are generally considered the most important enzymes of the cytochrome P450 system for the metabolism of pharmalogicals? (3)
A
- CYP3A4
- CYP3A5
- CYP2D6
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
25
What are 'prodrugs'?
Drugs that require metabolism by the liver to become active
26
Why are there differences in the cytochrome P450 system between individuals?
This system has a lot of genetic polymorphisms and copy number variations
27
Which three general classes of drug metabolizers are there, based on cytochrome P450 activity?
1. Ultra-rapid metabolizers
2. Extensive metabolizers = normal
3. Poor metabolizers
28
What effect to poor metabolizers experience from:
1. Prodrugs
2. Normal drugs
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
29
Which three ways are there for the elimination of drugs? Which is most important?
1. Urine = most important
2. Bile
3. Faeces
30
Why is it important to have knowledge of pharmacokinetic properties of drugs and patients?
It allows to predict reactions to medicines
31
What is Tmax?
Timepoint at which the maximum blood concentration is reached
32
What is Cmax?
Maximum concentration of drug in the blood (=at Tmax)
33
What is clearance rate?
Elimination out of the body -> volume of plasma cleared of the drug per unit of time
34
What is T1/2?
Time necessary to decrease blood concentration of medication by 50%
35
Why is knowledge of the T1/2 of a drug important?
To prevent overdosing in case of repeated doses (prevent accumulation after repeated doses)
36
What are the main causes of a prolonged T1/2? (2)
1. Renal impairment
2. Intoxication (=decreased liver function)
37
How many T1/2 need to pass before medication is cleared from the blood (as a general rule)?
4-5x T1/2
38
How many T1/2 need to pass before a steady state concentration is reached (as a general rule)?
3-5x T1/2
39
What is accumulation (in pharmacokinetics)?
Stacking of medication after repeated doses
40
What does the area under the curve (AUC) represent within pharmacokinetics?
Total exposure to the drug (time*concentration)
41
Decreased clearance of medication leads to a [decreased/increased] AUC. What is the effect of this?
Increased -> higher chances of side effects and toxicity
42
What is a therapeutic range?
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)
43
What is pharmacogenetics?
Analysis of DNA to explain/predict responses of patients to drug therapy
44
Which factors can influence drug effect (among others)? (3)
1. Receptors
2. Effectors
3. Enzymes/metabolism
45
How many % of drugs are metabolized by the CYP450 system?
80%
46
Which groups of drugs are metabolized by CYP3A4? (3)
1. Oncology drugs
2. Psychiatric drugs
3. Cyclosporin & tacrolimus
47
Which groups of drugs are metabolized by CYP2D6? (4)
1. Antidepressives
2. Antipsychotics
3. Beta-blockers
4. Tamoxifen
48
Which important group of drugs is metabolized by CYP2C9?
Vitamin K antagonists
49
What causes differences in activity of CYP enzymes?
SNPs
50
What is a SNP?
A DNA variant that occurs in >1% of the population
51
Which areas of CYP-genes are most often affected by SNPs? What is the effect of this?
Promotors/enhancers -> influences the amount of transcription
52
What should be investigated if SNPs cannot explain CYP-enzyme activity?
Copy numver bariations
53
Which SNPs are included in SNP analysis of CYP-enzymes?
SNPs of known effect and clinical relevance (so: not all SNPs)
54
How many % of people is CYP2D6 ultra-rapid metabolizer? What is the cause of this?
2-5% is ultra-rapid metabolizer, due to the presence of extra copies of genes
55
How many % of people is CYP2D6 normal metabolizer? How many functional genes do they have?
60-70% of population, with 2 functional genes
56
How many % of people is CYP2D6 intermediate metabolizer? What is the cause of this?
10-15% has only 1 functional gene copy and is intermediate metabolizer
57
How many % of people is CYP2D6 poor metabolizer? What is the cause of this?
5-10%, who have 2 less functional genes
58
Which CYP-enzyme metabolizes imipramine?
CYP2D6
59
How many % of patients taking imipramine require dose adjustments based on drug concentration in blood?
50%
60
How many % of the standard dose do poor imipramine metabolizers need? How many % do ultra-rapid metabolizers need?
Poor metabolizers: 30%
Ultra-rapid metabolizers: 175%
61
Which CYP-enzyme metabolizes metoprolol?
CYP2D6
62
Which % of the standard dosage of metoprolol do PM, IM, NM and UM need?
PM = 25%
IM = 50%
NM = 100%
UM = 250%
63
What is an important property of tramadol & codeine?
They are prodrugs of morphine, converted by CYP2D6
64
Which enzyme converts the prodrugs tramadol & codeine into morphine? What is the effect of ultra-rapid metabolism?
CYP2D6, ultra-rapid metabolism leads to increased levels of morphine -> side effects
65
Which enzyme metabolizes azathioprine? Which drug is also metabolized by this drug?
TPMT, also metabolizes (6)-mercaptpurine
66
What is the effect of low TPMT activity?
Accumulation of azathioprine & 6-mercaptopurine, leading to haematologic toxicity
67
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?
Haematologic toxicity
Slow TPMT metabolism requires 50% dose reduction
68
What is an important property of tamoxifen?
It is a prodrug, needs to be activated by CYP2D6
69
Which CYP-enzyme is needed to activate the prodrug tamoxifen?
CYP2D6
70
How many % of the population is fully CYP2D6 deficient? How many % of drugs is metabolized by CYP2D6?
5-10% of population is fully CYP2D6 deficient
20% of drugs is metabolized by CYP2D6
71
Which patient samples can be used for genetic typic for pharmacogenetics? (2)
1. EDTA blood
2. Cheek swab
72
What is the average turnaround time for pharmacogenetic analysis? Which one can be performed faster, and why?
~7 days
CYP2D6 and TPMT can be performed faster, so that starting dosages of drugs metabolized by these enzymes can be altered
73
What is an important characteristic of clopidogrel?
It is a prodrug, needs to activated by CYP2C19
74
Which enzyme converts prodrug clopidogrel into an active form?
CYP2C19
75
How can knowledge of CYP2C19 mutations affect clinical practice?
Patients with poor CYP2C19 function can receive prasugrel/ticagrelor instead of clopidogrel -> does not have to be activated
76
Why are the active drugs prasugrel/ticagrelor not always immediately prescribed over prodrug clopidogrel?
They are (far) more expensive -> only worth it when patients are poor CYP2C19 metabolizers
77
Which enzyme metabolizes voriconazole?
CYP2C19
78
Which enzyme metabolizes omeprazole?
CYP2C19
79
Why is pharmacogenetics extra important when it comes to tacrolimus? (2)
1. High interindividual variation in pharmacogenetics
2. Small therapeutic window
80
Which enzymes metabolize tacrolimus? (2) Which of these is remarkable, and why?
1. CYP3A4
2. CYP3A5 -> high inter-individual variation of expression, patients with higher expression require higher concentrations to be therapeutically active
81
Which drugs are metabolized by CYP2D6? (4)
1. Imipramine
2. Metoprolol
3. Codeine/tramadol
4. Tamoxifen
82
Which drugs are metabolized by CYP2C19? (3)
1. Clopidogrel
2. Voriconazole
3. Omeprazole
83
What is a biopharmaceutical (definition)?
Any pharmaceutical product manufactured in, extracted from or semi-synthesized from biological sources
84
What does the term 'biological' commonly refer to?
Monoclonal antibodies and fusion proteins
85
In the treatment of which groups of diseases to biologicals currently have an important role? (4)
1. Haematological malignancies & malignancies
2. Transplant rejection
3. Auto-immune disease
4. Auto-inflammatory disease
86
Which two general modes of action can biologicals have?
1. Targeting of cell surface molecules
2. Targeting of soluble mediators
87
What are biologicals ending in -omab derived of?
Mouse
88
What are biologicals ending in -ximab derived of?
Chimeric mouse-human antibodies
89
Which part of chimeric mouse-human antibodies is mouse, and which is human?
Variable domain = mouse
Constant domain = human
90
What are biologicals ending in -zumab derived of?
Humanized mouse antibodies
91
Which part of humanized mouse antibodies is mouse, and which is human?
Antigen-recognition domain = mouse
Rest = human
92
What are biologicals ending in -umab derived of?
Fully human antibodies
93
What is the benefit of fully human antibodies as biologicals?
Less immunogenic -> lower infusion-site reactions
94
What is an important issue when using biologicals for treatment?
Anti-drug antibodies (ADA)
95
What is the effect of the presence of ADAs? (2)
1. Rapid clearance of biologicals -> loss of response
2. Hypersensitivity reactions
96
What is an example of an ADA-induced hypersensitivity reaction to biologicals?
Cytokine storm
97
Which two parameters are monitored in therapeutic drug monitoring of biologicals?
1. Biological through levels/total levels
2. Presence of ADAs (on indication)
98
What does the bioavailability of biologicals depend on? (4)
1. Distribution
2. Recycling by FcRn
3. Degradation
4. Neutralization by ADA
99
What is a common modality for detecting levels of biologicals in blood?
ELISA
100
Which two methods of ELISA are available to detect levels of biologicals in blood?
1. SQ-system
2. LT-system
101
What are the steps in the LT-ELISA system for the detection of biologicals in blood? Use infliximab (anti-TNF) as example.
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
What are the steps in the SQ-ELISA system for the detection of biologicals in blood? Use infliximab (anti-TNF) as example.
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
What are biosimilars? What is the advantage of using them?
Structurally related to biologicals, but often times at a lower pricepoint
103
What are the main isotypes of ADAs?
IgG1, IgG4
104
Why do ADAs need to be measured at through levels of drug?
Otherwise all ADAs are in complex with biological and cannot be detected -> at through level, free ADAs are highest
105
What has to be the conclusion if there are low drug levels/effects but there are no ADAs present?
Patients are not taking drugs
106
Which step has to be taken in case of the presence of ADAs against drugs?
Switch to a differerent drug
107
True or false: patients that develop ADAs against one drug don't have an increased chance of developing them for another drug
False; increased risk of development of ADAs to new drugs in case they have already been developed against other drugs
