FARMACOLOGY
Claire Snel
GEZONDHEID EN LEVEN
VRIJE UNIVERSITEIT VAN AMSTERDAM
JAAR 2
,Inhoudsopgave
Introduction to pharmacology .......................................................................................................................... 3
Part 1: Pharmacology defined ............................................................................................................................ 3
Part 2: Effects of drugs and drug discovery ........................................................................................................ 3
Pharmacodynamics .......................................................................................................................................... 6
Part 1: Introduction pharmacodynamics ............................................................................................................ 6
Part 2: Molecular theory of drug action ............................................................................................................. 7
Part 3: Molecular drug action: agonists ............................................................................................................. 9
Part 4: Molecular drug action: antagonists and inverse agonists .................................................................... 10
Autonomic nervous system pharmacology ..................................................................................................... 12
Part 1: Introduction to the ANS (design and function)...................................................................................... 12
Part 2: Neurotransmission in the ANS .............................................................................................................. 14
Part 3: Cholinergic neurotransmission in the ANS ............................................................................................ 16
Part 4: Pharmacological control of cholinergic neurotransmission .................................................................. 18
Part 5: Indirect acting (anti)cholinergic drugs and neuromuscular blockers .................................................... 20
Part 6: Adrenergic neurotransmission in the ANS ............................................................................................ 22
Part 7: Pharmacological control of NA neurotransmission .............................................................................. 24
Part 8: Major neurotransmitter systems of the central nervous system .......................................................... 26
Pharmacokinetics ........................................................................................................................................... 29
Part 1: Introduction pharmacokinetics ............................................................................................................. 29
Part 2: Absorption: the role of diffusion ........................................................................................................... 30
Part 3: Absorption: the role of lipid solubility and first-pass effect ................................................................... 31
Part 4: Distribution and excretion ..................................................................................................................... 33
Part 5: Metabolism of drugs ............................................................................................................................. 36
Part 6: Drug distribution and elimination kinetics ............................................................................................ 39
Part 7: Principles of dosing ............................................................................................................................... 42
Part 8: Drug toxicity .......................................................................................................................................... 45
Part 9: Variability in reactions to drugs and population pharmacology ........................................................... 46
Variation in Pharmacokinetics/ Pharmacodynamics ....................................................................................... 49
Part 1: Variation in PK/ PD and variation in PK in children ............................................................................... 49
Part 2: Variation in PK/ PD in elderly, pregnancy and polypharmacy ............................................................... 51
Clinical pharmacological research................................................................................................................... 54
Part 1: Introduction to clinical pharmacological research ................................................................................ 54
Part 2: The phases of CPR and RCT ................................................................................................................... 55
Ethics and drug research in humans ............................................................................................................... 57
Part 1: Defining the field and historical background ........................................................................................ 57
1
, Part 2: Modern practice and moral dilemma’s ................................................................................................. 59
Pharmacotherapy ........................................................................................................................................... 60
2
,Introduction to pharmacology
Part 1: Pharmacology defined
- Pharmacology = explanation of action of pharmaceuticals (= biologically active substances,
including toxins) in the human (or animal) body
- Medicine = pharmaceutical applied for therapy
- Pharmacodynamics (PD) = what does the drug do with the body
- Pharmacokinetics (PK) = what does the body do with the drug
- Pharmacotherapy = applied pharmacology
o Use of knowledge and insight gained from pharmacology for the treatment of diseased
humans in a responsible, effective and safe manner
What is pharmacology
➢ Pharmacology is the study of what drugs do and how they do it
➢ A drug is a chemical that is usually used to treat disease
➢ Drugs are intended to have a selective action, but this ideals is seldom achieved
➢ There is always a risk of adverse effects as well as benefit connected with the use of any drug
> they have to be rated against each other
Pharmacological basis of pharmacotherapy
• In blue: the therapeutic window
o = the concentration of the drug in between the minimum
effective concentration and minimum toxic concentration
o Concentration with acceptable level of benefits versus risk
o The smaller the therapeutic window, the more difficult to
treat patients with a medicine
Part 2: Effects of drugs and drug discovery
- Primary effect = effects for which the compound is administered
- Side effect = adverse/ unwanted effect
o The distinction between the primary effect and side effect is determined by the aim for
which the medicine is administered (e.g. acetylsalicylic acid (aspirine) as a pain killer
(=analgetic) or against blood clotting (= anti-coagulant)
▪ In this case the main side effect is the anti-coagulant effect of aspirine
▪ Nowadays anti-coagulant is the primary effect
>> to conclude, whether it is a primary or side effect depends on what the aim is
for which the drug is used in a moment of time
- Placebo = a preparation without any pharmacologically active substance
- Nocebo = a placebo with unwanted effects (= side effects)
- Placebo effect = a placebo with a (therapeutic) effect
o The strength of this effect is determined to a large extent to the expectations of the
patient
o The contribution of the placebo effect to the overall effects of a drug is investigated in
randomized placebo-controlled clinical trials (RCT)
3
,Sequence of phases in drug discovery and development
➢ The development of drugs is distinguished in two main phases (preclinical phases)
1. Drug discovery
a. Discovery chemistry – synthesizing of the new compounds
b. Discovery biology – to find out whether a large group of synthesized compounds
of a category indeed interact with the target to which they are intended to bind
c. ADME – A (absorption), D (distribution), M (metabolism), E (excretion) >> looking
in vitro whether metabolites are formed
d. Toxicology screening
▪ Information of these activities is fed into lead optimalization and preclinical
development
• Because when started with a library of compounds, eventually that
can only lead to introduction of one optimized compound which can
be introduced
• So, we have to find out as early as possible what is the most likely
small number/ 1 compound to be accepted after performing clinical
trials
▪ Introduce animal models of disease you are interested in
o Pharmacokinetics is extended, looking into more detail of the ADME characteristics of
the drug
o Toxicology screening is extended during lead optimalization and further preclinical
development phases
o Before drugs can be evaluated in humans (phase 1) a proper evaluation must be made
of all the data gathered during the preclinical drug discovery and drug development
2. Drug development
a. Phase 1, 2, 3
Includes:
o Further investigation of the ADME in
humans (both healthy and diseased
humans)
o Medical effects are on a large scale
evaluated during phase 3 (= the phase
prior to a possible registration of the
drug)
Life cycle of drug approval and regulation of use
- Drug discovery: 2-5 years
- Drug development 5-9 years
- FDA (Food and Drug Administration)
approval > has to approve that the drug
can enter the market
o In Europe: EMA (European
Medicines Agency)
- Post-approval regulation = drug is used
in large numbers of patients under the
actual circumstances
4
, College aantekeningen Q&A1
- The four levels of drug action and drug classification > het is lastiger dan het lijkt, we denken
vaak vanuit moleculair niveau (receptoren) iets op te lossen op systemisch niveau, maar zitten
veel stappen tussen
- Levodopa is voorbeeld van een prodrug
- Efficacy = effectiviteit (hoe goed is je stof in staat om een biologisch effect te veroorzaken), dat
is bij een antogonist 0 want er gebeurt niets, daarom geef je die ook
- Efficacy bij agonist is er wel
- S-curve is logaritmische schaal
- Partiele agonist haalt niet de 100%
- Mate van bezetting geeft mate van respons weer = receptortheorie
- Potency = hoogste potency, diegene waarvan je het minste nodig hebt om hetzelfde biologische
effect te bereiken
- Partiele agonisten hebben altijd een lagere efficacy dan volle agonisten
- Niet competitief = Allosterische activators en inhibitors > moduleren de receptor, binden op
een andere plek en beienvloeden zo of de receptor gebonden kan worden
Vragen:
➢ Hoe noemt men een farmacon dat bij binding aan een receptor de activiteit hiervan niet
verandert?
o Inverse agonist (de activiteit van de receptor (die de receptor zelf heeft) gaat omlaag)
o Antagonist
o Placebo (stof bindt wel maar er gebeurt klinisch niets)
o Vals substraat (bindt wel aan enzym, je geeft hem zodat het enzym zijn eigen substraat
minder aanpakt)
➢ Welke van onderstaande parameters bepaalt de mate van receptorbezetting bij een gegeven
concentratie van een geneesmiddel
o De effectiviteit van de binding van het middel aan de receptor (effectiviteit zegt iets over
het biologische effect)
o De aard van het middel (agonist of antagonist)
o De concentratie van het middel in de omgeving van de receptor (conc bepaalt niet wat de
affiniteit is)
o De affiniteit van het middel voor binding aan de receptor
➢ Uit deze curven (zie iphone) blijkt:
o Farmaca B en C zijn volle agonisten
o Farmaca B en C hebben een verschillende effectiviteit (want beiden kunnen 80% van het
effect halen)
o A en C hebben dezelfde affiniteit (bij welke conc krijg ik de helft van de reactie, A heeft
hogere affiniteit want je hebt veel minder nodig van de stof voor 50% van de reactie)
o A en B hebben dezelfde affiniteit (concentratie bij EC50 is hetzelfde, dus zelfde affiniteit.
Ze hebben wel een verschillende efffectiviteit)
➢ Welk van de onderstaande eigenschappen geldt voor een volle receptor antagonist
o Affiniteit die hoger is dan een partiele antagonist (affiniteit heeft er niets mee te maken,
het gaat om effectiviteit)
o Zwakker therapeutisch effect dan een volle agonist
o Intrinsieke effectiviteit/ activiteit is 0
o Hoger molecuulgewicht dan een partiele antagonist
5
Claire Snel
GEZONDHEID EN LEVEN
VRIJE UNIVERSITEIT VAN AMSTERDAM
JAAR 2
,Inhoudsopgave
Introduction to pharmacology .......................................................................................................................... 3
Part 1: Pharmacology defined ............................................................................................................................ 3
Part 2: Effects of drugs and drug discovery ........................................................................................................ 3
Pharmacodynamics .......................................................................................................................................... 6
Part 1: Introduction pharmacodynamics ............................................................................................................ 6
Part 2: Molecular theory of drug action ............................................................................................................. 7
Part 3: Molecular drug action: agonists ............................................................................................................. 9
Part 4: Molecular drug action: antagonists and inverse agonists .................................................................... 10
Autonomic nervous system pharmacology ..................................................................................................... 12
Part 1: Introduction to the ANS (design and function)...................................................................................... 12
Part 2: Neurotransmission in the ANS .............................................................................................................. 14
Part 3: Cholinergic neurotransmission in the ANS ............................................................................................ 16
Part 4: Pharmacological control of cholinergic neurotransmission .................................................................. 18
Part 5: Indirect acting (anti)cholinergic drugs and neuromuscular blockers .................................................... 20
Part 6: Adrenergic neurotransmission in the ANS ............................................................................................ 22
Part 7: Pharmacological control of NA neurotransmission .............................................................................. 24
Part 8: Major neurotransmitter systems of the central nervous system .......................................................... 26
Pharmacokinetics ........................................................................................................................................... 29
Part 1: Introduction pharmacokinetics ............................................................................................................. 29
Part 2: Absorption: the role of diffusion ........................................................................................................... 30
Part 3: Absorption: the role of lipid solubility and first-pass effect ................................................................... 31
Part 4: Distribution and excretion ..................................................................................................................... 33
Part 5: Metabolism of drugs ............................................................................................................................. 36
Part 6: Drug distribution and elimination kinetics ............................................................................................ 39
Part 7: Principles of dosing ............................................................................................................................... 42
Part 8: Drug toxicity .......................................................................................................................................... 45
Part 9: Variability in reactions to drugs and population pharmacology ........................................................... 46
Variation in Pharmacokinetics/ Pharmacodynamics ....................................................................................... 49
Part 1: Variation in PK/ PD and variation in PK in children ............................................................................... 49
Part 2: Variation in PK/ PD in elderly, pregnancy and polypharmacy ............................................................... 51
Clinical pharmacological research................................................................................................................... 54
Part 1: Introduction to clinical pharmacological research ................................................................................ 54
Part 2: The phases of CPR and RCT ................................................................................................................... 55
Ethics and drug research in humans ............................................................................................................... 57
Part 1: Defining the field and historical background ........................................................................................ 57
1
, Part 2: Modern practice and moral dilemma’s ................................................................................................. 59
Pharmacotherapy ........................................................................................................................................... 60
2
,Introduction to pharmacology
Part 1: Pharmacology defined
- Pharmacology = explanation of action of pharmaceuticals (= biologically active substances,
including toxins) in the human (or animal) body
- Medicine = pharmaceutical applied for therapy
- Pharmacodynamics (PD) = what does the drug do with the body
- Pharmacokinetics (PK) = what does the body do with the drug
- Pharmacotherapy = applied pharmacology
o Use of knowledge and insight gained from pharmacology for the treatment of diseased
humans in a responsible, effective and safe manner
What is pharmacology
➢ Pharmacology is the study of what drugs do and how they do it
➢ A drug is a chemical that is usually used to treat disease
➢ Drugs are intended to have a selective action, but this ideals is seldom achieved
➢ There is always a risk of adverse effects as well as benefit connected with the use of any drug
> they have to be rated against each other
Pharmacological basis of pharmacotherapy
• In blue: the therapeutic window
o = the concentration of the drug in between the minimum
effective concentration and minimum toxic concentration
o Concentration with acceptable level of benefits versus risk
o The smaller the therapeutic window, the more difficult to
treat patients with a medicine
Part 2: Effects of drugs and drug discovery
- Primary effect = effects for which the compound is administered
- Side effect = adverse/ unwanted effect
o The distinction between the primary effect and side effect is determined by the aim for
which the medicine is administered (e.g. acetylsalicylic acid (aspirine) as a pain killer
(=analgetic) or against blood clotting (= anti-coagulant)
▪ In this case the main side effect is the anti-coagulant effect of aspirine
▪ Nowadays anti-coagulant is the primary effect
>> to conclude, whether it is a primary or side effect depends on what the aim is
for which the drug is used in a moment of time
- Placebo = a preparation without any pharmacologically active substance
- Nocebo = a placebo with unwanted effects (= side effects)
- Placebo effect = a placebo with a (therapeutic) effect
o The strength of this effect is determined to a large extent to the expectations of the
patient
o The contribution of the placebo effect to the overall effects of a drug is investigated in
randomized placebo-controlled clinical trials (RCT)
3
,Sequence of phases in drug discovery and development
➢ The development of drugs is distinguished in two main phases (preclinical phases)
1. Drug discovery
a. Discovery chemistry – synthesizing of the new compounds
b. Discovery biology – to find out whether a large group of synthesized compounds
of a category indeed interact with the target to which they are intended to bind
c. ADME – A (absorption), D (distribution), M (metabolism), E (excretion) >> looking
in vitro whether metabolites are formed
d. Toxicology screening
▪ Information of these activities is fed into lead optimalization and preclinical
development
• Because when started with a library of compounds, eventually that
can only lead to introduction of one optimized compound which can
be introduced
• So, we have to find out as early as possible what is the most likely
small number/ 1 compound to be accepted after performing clinical
trials
▪ Introduce animal models of disease you are interested in
o Pharmacokinetics is extended, looking into more detail of the ADME characteristics of
the drug
o Toxicology screening is extended during lead optimalization and further preclinical
development phases
o Before drugs can be evaluated in humans (phase 1) a proper evaluation must be made
of all the data gathered during the preclinical drug discovery and drug development
2. Drug development
a. Phase 1, 2, 3
Includes:
o Further investigation of the ADME in
humans (both healthy and diseased
humans)
o Medical effects are on a large scale
evaluated during phase 3 (= the phase
prior to a possible registration of the
drug)
Life cycle of drug approval and regulation of use
- Drug discovery: 2-5 years
- Drug development 5-9 years
- FDA (Food and Drug Administration)
approval > has to approve that the drug
can enter the market
o In Europe: EMA (European
Medicines Agency)
- Post-approval regulation = drug is used
in large numbers of patients under the
actual circumstances
4
, College aantekeningen Q&A1
- The four levels of drug action and drug classification > het is lastiger dan het lijkt, we denken
vaak vanuit moleculair niveau (receptoren) iets op te lossen op systemisch niveau, maar zitten
veel stappen tussen
- Levodopa is voorbeeld van een prodrug
- Efficacy = effectiviteit (hoe goed is je stof in staat om een biologisch effect te veroorzaken), dat
is bij een antogonist 0 want er gebeurt niets, daarom geef je die ook
- Efficacy bij agonist is er wel
- S-curve is logaritmische schaal
- Partiele agonist haalt niet de 100%
- Mate van bezetting geeft mate van respons weer = receptortheorie
- Potency = hoogste potency, diegene waarvan je het minste nodig hebt om hetzelfde biologische
effect te bereiken
- Partiele agonisten hebben altijd een lagere efficacy dan volle agonisten
- Niet competitief = Allosterische activators en inhibitors > moduleren de receptor, binden op
een andere plek en beienvloeden zo of de receptor gebonden kan worden
Vragen:
➢ Hoe noemt men een farmacon dat bij binding aan een receptor de activiteit hiervan niet
verandert?
o Inverse agonist (de activiteit van de receptor (die de receptor zelf heeft) gaat omlaag)
o Antagonist
o Placebo (stof bindt wel maar er gebeurt klinisch niets)
o Vals substraat (bindt wel aan enzym, je geeft hem zodat het enzym zijn eigen substraat
minder aanpakt)
➢ Welke van onderstaande parameters bepaalt de mate van receptorbezetting bij een gegeven
concentratie van een geneesmiddel
o De effectiviteit van de binding van het middel aan de receptor (effectiviteit zegt iets over
het biologische effect)
o De aard van het middel (agonist of antagonist)
o De concentratie van het middel in de omgeving van de receptor (conc bepaalt niet wat de
affiniteit is)
o De affiniteit van het middel voor binding aan de receptor
➢ Uit deze curven (zie iphone) blijkt:
o Farmaca B en C zijn volle agonisten
o Farmaca B en C hebben een verschillende effectiviteit (want beiden kunnen 80% van het
effect halen)
o A en C hebben dezelfde affiniteit (bij welke conc krijg ik de helft van de reactie, A heeft
hogere affiniteit want je hebt veel minder nodig van de stof voor 50% van de reactie)
o A en B hebben dezelfde affiniteit (concentratie bij EC50 is hetzelfde, dus zelfde affiniteit.
Ze hebben wel een verschillende efffectiviteit)
➢ Welk van de onderstaande eigenschappen geldt voor een volle receptor antagonist
o Affiniteit die hoger is dan een partiele antagonist (affiniteit heeft er niets mee te maken,
het gaat om effectiviteit)
o Zwakker therapeutisch effect dan een volle agonist
o Intrinsieke effectiviteit/ activiteit is 0
o Hoger molecuulgewicht dan een partiele antagonist
5
