BBS3012: FROM PHARMACOLOGICAL
MECHANISMS TO PRECISION MEDICINE
All cases and lectures
Biomedical Sciences: Minor Drug Intervention Track
1
,INHOUDSOPGAVE
Case 1: pharmacodynamics ............................................................................................................................ 5
Katzung, B. (2018). Basic & clinical pharmacology Chapter 2: Drug Receptors & Pharmacodynamics ............ 12
MACROMOLECULAR NATURE OF DRUG RECEPTORS ................................................................................... 12
(Case 2) ........................................................................................................................................................ 25
Case 3 .......................................................................................................................................................... 26
How is alcohol metabolized? ............................................................................................................................ 26
Interference (pharmacokinetics, pharmacodynamics) ................................................................................. 27
Estimate Peters’ blood alcohol level? ........................................................................................................... 27
ADME of paracetamol....................................................................................................................................... 28
WHat is the mechanism behind paracetamol toxicity? .................................................................................... 28
How can you treat this toxicity (NAC, gastric lavage)? ................................................................................. 30
Case 4: phenytoin interactions ..................................................................................................................... 32
What is phenytoin? Mode of action? Pharmacokinetic profile? ....................................................................... 32
Mechanism of action .................................................................................................................................... 32
Pharmacokinetic profile ................................................................................................................................ 32
What is plasma protein binding? What proteins are involved? ........................................................................ 33
What is the effect on the pharmaco-dynamics and -kinetics of the compounds? ............................................ 34
Explain the case (displacement of plasma proteins à how?, consequences?)................................................. 34
Would reduction of the dose solve this problem? If so, how?........................................................................... 35
Case 5: drug-drug interactions ...................................................................................................................... 36
Drug-drug interactions...................................................................................................................................... 36
Chapter 4, Drug-drug interactions ................................................................................................................ 36
Pharmacodynamic interactions .................................................................................................................... 37
Pharmacokinetic interactions ....................................................................................................................... 38
Mode of action of the mentioned drugs, pd, Toxic effects, concentrations and dose, PK, possible interactions?
.......................................................................................................................................................................... 40
Colchicine ...................................................................................................................................................... 40
Cyclosporine.................................................................................................................................................. 41
Mycophenolate mofetil ................................................................................................................................ 43
Prednisone .................................................................................................................................................... 44
Simvastatin ................................................................................................................................................... 46
Propofol ........................................................................................................................................................ 47
What is rhabdomyolysis? Drug-related causes? ............................................................................................... 49
Case 6 .......................................................................................................................................................... 52
PK and PD of codeine ........................................................................................................................................ 52
Impact of polymorphisms of CYP enzymes, prevalence of polymorphisms ....................................................... 53
What are CYP450 enzymes? Nomenclature? role in metabolism? ................................................................... 53
Genetic Polymorphism and Toxicology—With Emphasis on Cytochrome P450 Inger Johansson, Magnus
Ingelman-Sundberg....................................................................................................................................... 56
Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects
and functional diversity M Ingelman-Sundberg............................................................................................ 58
How do diet and other drugs interact with codeine? ........................................................................................ 58
2
, Information on opioids in general ..................................................................................................................... 58
Case 7 .......................................................................................................................................................... 60
What are the effects of age on drug response? ................................................................................................ 60
PK (body composition, metabolism) ............................................................................................................. 60
PD (sensitivity) .............................................................................................................................................. 61
What is the mode of action of sulphidimidine and chloramphenicol? .............................................................. 62
Sulphadimidine (Sulfamethazine) ................................................................................................................. 62
Chloramphenicol ........................................................................................................................................... 62
Ampicillin ...................................................................................................................................................... 63
What is the mode of action of methotrexate? .................................................................................................. 63
Side-effects (incl. nausea) ............................................................................................................................. 63
Interaction with folic acid ............................................................................................................................. 64
Case 8 .......................................................................................................................................................... 66
Lungcancer ........................................................................................................................................................ 66
Pathophysiology............................................................................................................................................ 66
types and stages ........................................................................................................................................... 67
What are EGFR and ALK? .................................................................................................................................. 69
How does screening help in choosing cancer treatment? ............................................................................ 69
What is a panel test? What panels are there? .................................................................................................. 69
What is RET? ................................................................................................................................................. 70
What is Alectinib? Why is it used in this case?.................................................................................................. 70
What is germline genetic screening? What is it used for? ................................................................................ 71
What kind of genes do you have to screen in order to predict efficacy and toxicity of drugs? ......................... 72
Look at results of genetic toxicity practical ....................................................................................................... 73
Lecture: pharmacodynamics 2 M. Blankesteijn ............................................................................................. 74
Lecture: pharmacokinetics 1 G. den Hartog .................................................................................................. 80
Quantifying events following an intravenous bolus .......................................................................................... 86
Volume of distribution and clearance........................................................................................................... 87
Quantifying Events Following an Oral Dose ...................................................................................................... 89
Lecture pharmacokinetics 2 G. den Hartog ................................................................................................... 91
Renal excretion ................................................................................................................................................. 91
Enzyme induction .............................................................................................................................................. 93
Multiple dosing ................................................................................................................................................. 95
Lecture: question hour ................................................................................................................................. 98
Lecture: pharmacoepigenetics A. Weseler .................................................................................................. 100
DNA modification: (de)methylation ................................................................................................................ 100
Histone modifications ..................................................................................................................................... 101
Non-coding (nc)-RNA’s .................................................................................................................................... 101
ADME genes .................................................................................................................................................... 101
Epigenetic effects of drugs .............................................................................................................................. 102
3
, Pharmaco-epigenetics à precision medicine ................................................................................................. 103
Take home messages ...................................................................................................................................... 104
Lecture: pharmacotherapy from cradle to grave A. Weseler ....................................................................... 105
What to take into account for the pharmacotherapy of patients of different age? ....................................... 108
Lecture: Gut microbiome and drug response D. Jonkers ............................................................................. 113
4
MECHANISMS TO PRECISION MEDICINE
All cases and lectures
Biomedical Sciences: Minor Drug Intervention Track
1
,INHOUDSOPGAVE
Case 1: pharmacodynamics ............................................................................................................................ 5
Katzung, B. (2018). Basic & clinical pharmacology Chapter 2: Drug Receptors & Pharmacodynamics ............ 12
MACROMOLECULAR NATURE OF DRUG RECEPTORS ................................................................................... 12
(Case 2) ........................................................................................................................................................ 25
Case 3 .......................................................................................................................................................... 26
How is alcohol metabolized? ............................................................................................................................ 26
Interference (pharmacokinetics, pharmacodynamics) ................................................................................. 27
Estimate Peters’ blood alcohol level? ........................................................................................................... 27
ADME of paracetamol....................................................................................................................................... 28
WHat is the mechanism behind paracetamol toxicity? .................................................................................... 28
How can you treat this toxicity (NAC, gastric lavage)? ................................................................................. 30
Case 4: phenytoin interactions ..................................................................................................................... 32
What is phenytoin? Mode of action? Pharmacokinetic profile? ....................................................................... 32
Mechanism of action .................................................................................................................................... 32
Pharmacokinetic profile ................................................................................................................................ 32
What is plasma protein binding? What proteins are involved? ........................................................................ 33
What is the effect on the pharmaco-dynamics and -kinetics of the compounds? ............................................ 34
Explain the case (displacement of plasma proteins à how?, consequences?)................................................. 34
Would reduction of the dose solve this problem? If so, how?........................................................................... 35
Case 5: drug-drug interactions ...................................................................................................................... 36
Drug-drug interactions...................................................................................................................................... 36
Chapter 4, Drug-drug interactions ................................................................................................................ 36
Pharmacodynamic interactions .................................................................................................................... 37
Pharmacokinetic interactions ....................................................................................................................... 38
Mode of action of the mentioned drugs, pd, Toxic effects, concentrations and dose, PK, possible interactions?
.......................................................................................................................................................................... 40
Colchicine ...................................................................................................................................................... 40
Cyclosporine.................................................................................................................................................. 41
Mycophenolate mofetil ................................................................................................................................ 43
Prednisone .................................................................................................................................................... 44
Simvastatin ................................................................................................................................................... 46
Propofol ........................................................................................................................................................ 47
What is rhabdomyolysis? Drug-related causes? ............................................................................................... 49
Case 6 .......................................................................................................................................................... 52
PK and PD of codeine ........................................................................................................................................ 52
Impact of polymorphisms of CYP enzymes, prevalence of polymorphisms ....................................................... 53
What are CYP450 enzymes? Nomenclature? role in metabolism? ................................................................... 53
Genetic Polymorphism and Toxicology—With Emphasis on Cytochrome P450 Inger Johansson, Magnus
Ingelman-Sundberg....................................................................................................................................... 56
Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects
and functional diversity M Ingelman-Sundberg............................................................................................ 58
How do diet and other drugs interact with codeine? ........................................................................................ 58
2
, Information on opioids in general ..................................................................................................................... 58
Case 7 .......................................................................................................................................................... 60
What are the effects of age on drug response? ................................................................................................ 60
PK (body composition, metabolism) ............................................................................................................. 60
PD (sensitivity) .............................................................................................................................................. 61
What is the mode of action of sulphidimidine and chloramphenicol? .............................................................. 62
Sulphadimidine (Sulfamethazine) ................................................................................................................. 62
Chloramphenicol ........................................................................................................................................... 62
Ampicillin ...................................................................................................................................................... 63
What is the mode of action of methotrexate? .................................................................................................. 63
Side-effects (incl. nausea) ............................................................................................................................. 63
Interaction with folic acid ............................................................................................................................. 64
Case 8 .......................................................................................................................................................... 66
Lungcancer ........................................................................................................................................................ 66
Pathophysiology............................................................................................................................................ 66
types and stages ........................................................................................................................................... 67
What are EGFR and ALK? .................................................................................................................................. 69
How does screening help in choosing cancer treatment? ............................................................................ 69
What is a panel test? What panels are there? .................................................................................................. 69
What is RET? ................................................................................................................................................. 70
What is Alectinib? Why is it used in this case?.................................................................................................. 70
What is germline genetic screening? What is it used for? ................................................................................ 71
What kind of genes do you have to screen in order to predict efficacy and toxicity of drugs? ......................... 72
Look at results of genetic toxicity practical ....................................................................................................... 73
Lecture: pharmacodynamics 2 M. Blankesteijn ............................................................................................. 74
Lecture: pharmacokinetics 1 G. den Hartog .................................................................................................. 80
Quantifying events following an intravenous bolus .......................................................................................... 86
Volume of distribution and clearance........................................................................................................... 87
Quantifying Events Following an Oral Dose ...................................................................................................... 89
Lecture pharmacokinetics 2 G. den Hartog ................................................................................................... 91
Renal excretion ................................................................................................................................................. 91
Enzyme induction .............................................................................................................................................. 93
Multiple dosing ................................................................................................................................................. 95
Lecture: question hour ................................................................................................................................. 98
Lecture: pharmacoepigenetics A. Weseler .................................................................................................. 100
DNA modification: (de)methylation ................................................................................................................ 100
Histone modifications ..................................................................................................................................... 101
Non-coding (nc)-RNA’s .................................................................................................................................... 101
ADME genes .................................................................................................................................................... 101
Epigenetic effects of drugs .............................................................................................................................. 102
3
, Pharmaco-epigenetics à precision medicine ................................................................................................. 103
Take home messages ...................................................................................................................................... 104
Lecture: pharmacotherapy from cradle to grave A. Weseler ....................................................................... 105
What to take into account for the pharmacotherapy of patients of different age? ....................................... 108
Lecture: Gut microbiome and drug response D. Jonkers ............................................................................. 113
4
