BGZ2026
Basic principles of pharmacology
Maastricht University
Bachelor health sciences, specialization biology and health | Year 2019 - 2020
,Inhoudsopgave
Problem 1 – pharmacokinetics ......................................................................................................................... 2
Problem 2 – pharmacodynamics .................................................................................................................... 15
Problem 3 – Therapeutic and toxic effects of drugs – a matter of individuality?! ........................................... 28
Problem 4 – in the hepatologist’s practice ..................................................................................................... 35
Problem 5 - How can we win the race for new coronavirus drugs? ................................................................ 43
Problem 6 – Big pharma business - from “blockbusters” to “niche busters” ................................................... 52
Lecture – introduction .................................................................................................................................... 58
Lecture – pharmacokinetics............................................................................................................................ 62
Lecture – pharmacodynamics ......................................................................................................................... 76
Lecture – polymorphisms ............................................................................................................................... 90
Lecture – nonalcoholic fatty liver disease ....................................................................................................... 97
Lecture – clinical studies............................................................................................................................... 108
Practical - Assignment computer simulation “Pharmacokinetics” ................................................................ 118
Practical – pharmacodynamics ..................................................................................................................... 124
Practical – beaker glass ................................................................................................................................ 132
,Problem 1 – pharmacokinetics
Problem statement
Therapeutic and toxic effect of compounds – pharmacokinetics?
Brainstorm
Part 1A Part 1B Part 1C
➢ Alcohol ➢ Multiple tablets → Overdoses of paracetamol
➢ The body and alcohol, does the time of empty stomach
body weight and effect stretch? NAC
composition ➢ Amount of enzymes AST and ATL
➢ Into the liver: ➢ It may last longer, Paracetamol level is 68
detoxication but not the double mg/ml a high value
➢ Concentration per amount of time Metabolism toxic
amount
➢ Liver and kidney work
them out of the body
– metabolism
➢ Coffee and waiting →
how quickly is it
broken down? Coffee
influencing anything.
➢ Enzyme function
Learning goals
1. What is the definition of pharmacokinetics?
2. What does ADME mean? (Absorption) (Distribution) (Metabolism) (Elimination)
3. What parameters describes the pharmacokinetics (volume of distribution, the
clearance, half-life of the drug, elimination constant and the absorption constant)
(Tmax and Cmax)
4. How does the concentration plasma concentration curve look for an intravenous
injection and for a a tablet?
5. What are the zero order and first order kinetics? (Alcohol and paracetamol)
6. What is the ADME for alcohol?
7. Can you put numbers/values on some pharmacokinetic parameters for alcohol?
8. How is ethanol effecting the body? (dizzy, drunk)
9. When does ethanol become toxic in your body?
10. What is the underlying course that people react differently on alcohol?
11. What is the ADME for paracetamol?
12. How does paracetamol act? As a pain killer
13. Look at pharmacokinetic parameters (values) for paracetamol?
14. What is the toxic dose for paracetamol?
15. Why is it dangerous when you have an overdose of paracetamol and how can you
treat it?
16. Underlying mechanism of paracetamol toxicity
,1. What is the definition of pharmacokinetics?
Pharmacokinetics – refers to the movement of drug into, trough, and out of the body—the
time course of its absorption, bioavailability, distribution, metabolism, and excretion.
➢ Sometimes described as what the body does to a drug,
Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion.
Pharmacokinetics may be defined as the measurement and formal interpretation of changes
with time of drug concentrations in one or more different regions of the body in relation to
dosing (‘what the body does to the drug’).
2. What does ADME mean? (Absorption) (Distribution) (Metabolism) (Elimination)
ADME, the absorption, distribution, metabolism, and elimination of drugs, are the processes
of pharmacokinetics.
Drug disposition is divided into four stages designated by the acronym ‘ADME’:
➢ Absorption from the site of administration
➢ Distribution within the body
➢ Metabolism
➢ Excretion/Elimination
,Absorption
➢ The passage of a drug from its site of administration into the plasma.
➢ Absorption is the process by which drugs cross body membranes and enter the
bloodstream.
➢ The main sites of absorption are the GI tract, lungs and skin. However, it may also
occur from other sites (e.g. subcutaneous, peritoneum or muscle)
➢ The rate of absorption is determined by the site of administration and the drug
formulation.
Different ways of membrane passage: mentioned in the lecture on pharmacokinetics (also
mentioned in the tutorial)
Bioavailability describes the fractional extent to which an administered dose of drug reaches
its site of action or a biological fluid from which the drug has access to its site of action.
E.g. For a drug given orally net absorption may be limited by the characteristics of the
dosage form, the drug’s physicochemical properties, metabolic attack in the intestine,
and transport across the intestinal epithelium and into the portal circulation.
In many cases, less than all of the administered dose reaches the systemic circulation and is
distributed to the drug’s sites of action.
The decrease in drug availability is a function of the anatomical site from which absorption
takes place.
E.g. intravenous administration generally permits all of the drug to enter the systemic
circulation.
Bioavailability (F) =
Distribution
After entering the blood by absorption or intravenous administration, a toxicant is distributed
to tissues throughout the body. Distribution usually occurs rapidly.
The body is divided into five main compartments:
➢ Plasma (5% of body weight)
➢ Interstitial fluid (16%)
➢ Intracellular fluid (35%)
➢ Transcellular fluid (2%)
➢ Fat (20%).
The equilibrium pattern of distribution between these various compartments depends on:
➢ Permeability across tissue barriers
➢ Binding within compartments
➢ pH partition
➢ Fat / water partition.
, Metabolism
Animals have evolved complex systems that detoxify foreign chemicals (‘xenobiotics’),
including carcinogens and toxins present in poisonous plants. Drugs are a special case of such
xenobiotics and they often exhibit chirality (i.e. there is more than one stereoisomer), which
affects their overall metabolism.
Changing a compound into another compound
Drug metabolism involves two kinds of reaction, known as phase 1 and phase 2, which often
occur sequentially. Both phases decrease lipid solubility, thus increasing renal elimination.
Phase 1 reactions
Phase 1 reactions (e.g. oxidation, reduction or hydrolysis) are catabolic, and the products are
often more chemically reactive and hence, paradoxically, sometimes more toxic or
carcinogenic than the parent drug.
Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a
process known as ‘functionalisation’. This group then serves as the point of attack for the
conjugating system to attach a substituent.
The liver is especially important in phase 1 reactions. Many hepatic drug-metabolizing
enzymes, including CYP enzymes, are embedded in the smooth endoplasmic reticulum. To
reach these metabolizing enzymes in life, a drug must cross the plasma membrane. Polar
molecules do this less readily than non-polar molecules except where there are specific
transport mechanisms (Ch. 8), so intra- cellular metabolism is important for lipid-soluble
drugs, while polar drugs are, at least partly, excreted unchanged in the urine.
Phase 2 reactions
Phase 2 reactions are synthetic (‘anabolic’) and involve conjugation (i.e. attachment of a
substituent group), which usually results in inactive products.
Basic principles of pharmacology
Maastricht University
Bachelor health sciences, specialization biology and health | Year 2019 - 2020
,Inhoudsopgave
Problem 1 – pharmacokinetics ......................................................................................................................... 2
Problem 2 – pharmacodynamics .................................................................................................................... 15
Problem 3 – Therapeutic and toxic effects of drugs – a matter of individuality?! ........................................... 28
Problem 4 – in the hepatologist’s practice ..................................................................................................... 35
Problem 5 - How can we win the race for new coronavirus drugs? ................................................................ 43
Problem 6 – Big pharma business - from “blockbusters” to “niche busters” ................................................... 52
Lecture – introduction .................................................................................................................................... 58
Lecture – pharmacokinetics............................................................................................................................ 62
Lecture – pharmacodynamics ......................................................................................................................... 76
Lecture – polymorphisms ............................................................................................................................... 90
Lecture – nonalcoholic fatty liver disease ....................................................................................................... 97
Lecture – clinical studies............................................................................................................................... 108
Practical - Assignment computer simulation “Pharmacokinetics” ................................................................ 118
Practical – pharmacodynamics ..................................................................................................................... 124
Practical – beaker glass ................................................................................................................................ 132
,Problem 1 – pharmacokinetics
Problem statement
Therapeutic and toxic effect of compounds – pharmacokinetics?
Brainstorm
Part 1A Part 1B Part 1C
➢ Alcohol ➢ Multiple tablets → Overdoses of paracetamol
➢ The body and alcohol, does the time of empty stomach
body weight and effect stretch? NAC
composition ➢ Amount of enzymes AST and ATL
➢ Into the liver: ➢ It may last longer, Paracetamol level is 68
detoxication but not the double mg/ml a high value
➢ Concentration per amount of time Metabolism toxic
amount
➢ Liver and kidney work
them out of the body
– metabolism
➢ Coffee and waiting →
how quickly is it
broken down? Coffee
influencing anything.
➢ Enzyme function
Learning goals
1. What is the definition of pharmacokinetics?
2. What does ADME mean? (Absorption) (Distribution) (Metabolism) (Elimination)
3. What parameters describes the pharmacokinetics (volume of distribution, the
clearance, half-life of the drug, elimination constant and the absorption constant)
(Tmax and Cmax)
4. How does the concentration plasma concentration curve look for an intravenous
injection and for a a tablet?
5. What are the zero order and first order kinetics? (Alcohol and paracetamol)
6. What is the ADME for alcohol?
7. Can you put numbers/values on some pharmacokinetic parameters for alcohol?
8. How is ethanol effecting the body? (dizzy, drunk)
9. When does ethanol become toxic in your body?
10. What is the underlying course that people react differently on alcohol?
11. What is the ADME for paracetamol?
12. How does paracetamol act? As a pain killer
13. Look at pharmacokinetic parameters (values) for paracetamol?
14. What is the toxic dose for paracetamol?
15. Why is it dangerous when you have an overdose of paracetamol and how can you
treat it?
16. Underlying mechanism of paracetamol toxicity
,1. What is the definition of pharmacokinetics?
Pharmacokinetics – refers to the movement of drug into, trough, and out of the body—the
time course of its absorption, bioavailability, distribution, metabolism, and excretion.
➢ Sometimes described as what the body does to a drug,
Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion.
Pharmacokinetics may be defined as the measurement and formal interpretation of changes
with time of drug concentrations in one or more different regions of the body in relation to
dosing (‘what the body does to the drug’).
2. What does ADME mean? (Absorption) (Distribution) (Metabolism) (Elimination)
ADME, the absorption, distribution, metabolism, and elimination of drugs, are the processes
of pharmacokinetics.
Drug disposition is divided into four stages designated by the acronym ‘ADME’:
➢ Absorption from the site of administration
➢ Distribution within the body
➢ Metabolism
➢ Excretion/Elimination
,Absorption
➢ The passage of a drug from its site of administration into the plasma.
➢ Absorption is the process by which drugs cross body membranes and enter the
bloodstream.
➢ The main sites of absorption are the GI tract, lungs and skin. However, it may also
occur from other sites (e.g. subcutaneous, peritoneum or muscle)
➢ The rate of absorption is determined by the site of administration and the drug
formulation.
Different ways of membrane passage: mentioned in the lecture on pharmacokinetics (also
mentioned in the tutorial)
Bioavailability describes the fractional extent to which an administered dose of drug reaches
its site of action or a biological fluid from which the drug has access to its site of action.
E.g. For a drug given orally net absorption may be limited by the characteristics of the
dosage form, the drug’s physicochemical properties, metabolic attack in the intestine,
and transport across the intestinal epithelium and into the portal circulation.
In many cases, less than all of the administered dose reaches the systemic circulation and is
distributed to the drug’s sites of action.
The decrease in drug availability is a function of the anatomical site from which absorption
takes place.
E.g. intravenous administration generally permits all of the drug to enter the systemic
circulation.
Bioavailability (F) =
Distribution
After entering the blood by absorption or intravenous administration, a toxicant is distributed
to tissues throughout the body. Distribution usually occurs rapidly.
The body is divided into five main compartments:
➢ Plasma (5% of body weight)
➢ Interstitial fluid (16%)
➢ Intracellular fluid (35%)
➢ Transcellular fluid (2%)
➢ Fat (20%).
The equilibrium pattern of distribution between these various compartments depends on:
➢ Permeability across tissue barriers
➢ Binding within compartments
➢ pH partition
➢ Fat / water partition.
, Metabolism
Animals have evolved complex systems that detoxify foreign chemicals (‘xenobiotics’),
including carcinogens and toxins present in poisonous plants. Drugs are a special case of such
xenobiotics and they often exhibit chirality (i.e. there is more than one stereoisomer), which
affects their overall metabolism.
Changing a compound into another compound
Drug metabolism involves two kinds of reaction, known as phase 1 and phase 2, which often
occur sequentially. Both phases decrease lipid solubility, thus increasing renal elimination.
Phase 1 reactions
Phase 1 reactions (e.g. oxidation, reduction or hydrolysis) are catabolic, and the products are
often more chemically reactive and hence, paradoxically, sometimes more toxic or
carcinogenic than the parent drug.
Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a
process known as ‘functionalisation’. This group then serves as the point of attack for the
conjugating system to attach a substituent.
The liver is especially important in phase 1 reactions. Many hepatic drug-metabolizing
enzymes, including CYP enzymes, are embedded in the smooth endoplasmic reticulum. To
reach these metabolizing enzymes in life, a drug must cross the plasma membrane. Polar
molecules do this less readily than non-polar molecules except where there are specific
transport mechanisms (Ch. 8), so intra- cellular metabolism is important for lipid-soluble
drugs, while polar drugs are, at least partly, excreted unchanged in the urine.
Phase 2 reactions
Phase 2 reactions are synthetic (‘anabolic’) and involve conjugation (i.e. attachment of a
substituent group), which usually results in inactive products.
