Lecture 1 – introduction to pharmacology
Pharmacology = explanation of action of pharmaca in the human (or animal) body (what drugs do
and how they do it)
- Pharmaca = biologically active substances
o It is a chemical that is usually used to treat disease. But it can also mean other stuff
such as toxic compounds.
o Toxicology = is a subdiscipline of pharmacology
- Medicine = pharmacon (‘drug’) specifically applied for therapy
o They intended to have a selective action but this ideal is seldom achieved.
▪ There is always a risk of adverse (side) effects as well as a benefit connected
with using any drug --> toxic effects. This is why selective action is usually not
always achieved.
▪ Therefore knowledge of pharmacology is needed for using drugs effectively
in therapy.
- Two main areas of investigation into the action of pharmaca
o Pharmacodynamics = “What does the drug do with the body”
o Pharmacokinetics = “What does the body do with the drug”
Pharmacotherapy = applied pharmacology Use of knowledge and insights gained from
pharmacology for the treatment of diseased humans in a responsible, effective and safe manner.
- Each pharmaca has:
o Minimum toxic concentration
o Therapeutic window
o Minimum effective concentration
- There is a direct relationship between
concentration of drug in blood plasm and
its therapeutic effects.
o The concentration in blood plasm
(Cp) has to be in between the
minimum toxic concentration and
Minimum effective concentration
- Primary effect = effect(s) for which the compound is administered
- Side effect = adverse/unwanted effect(s)
o The distinction between primary and side effect is determined by the aim for which
the medicine is administered
▪ I.e. acetylsalicylic acid (aspirin) can be used as a pain killer or against blood
clotting.
- Placebo = a preparation without any pharmacologically active substance
o It may have a therapeutic effect
o The expectation(s) of the patient determine the strength of the placebo effect
o Randomized, placebo-controlled clinical trials = The contribution of the placebo
effect to the overall effects of a drug are investigated in this
- Nocebo = a placebo with unwanted effects (side effects)
, o Nausea = the most common nocebo effect when taking in oral medication even
though the medication does not have this side effect
Phases of making drug:
1. Discovery: takes 2-5 years
2. Development: takes 5-9 years
▪ Phase 1: safety exposure
▪ Phase 2: Efficacy and dose selection
▪ Phase 3: Registration trials
▪ Phase 4: Post approval regulation = after the approval of use they still have
to check how it is going and what the side effects are
Lecture 2 – PD
Pharmacodynamics = what does the drug do to the body
The 4 levels of drug action
1. System level effects = an effect on system function (a system in a body: organs,
cardiovascular system)
o I.e. Blood pressure medication on the system
o But it does not say anything about how to make a better medication
2. Tissue level = effect on tissue function
o i.e. looking at the heart tissue or metabolic activity
3. Cellular level = looking at transduction metabolisms --> the biochemicals linked to drug
target
o I.e. looking at amount of cyclic AMP after giving the drug
4. Molecular level = establish interaction of drug with the molecular targets
o Molecular targets = proteins most of the times --> the drug target
o You can now see what the compound does and interferes with in the body and
develop a better drug --> pharmacodynamics
Molecular level = fourth level and consists of:
Drug targets can be (so drugs can interact with: ) =
- Receptors:
o 2 main groups of drug:
1. Agonist: drug binds to receptor and changes the conformation and
activates thereby the receptors --> has effect on the cell in which this
happens and activates or deactivates transduction mechanisms:
o Enzyme is being activated or inhibited
o Ion channels modulation --> open up or close
o DNA transcription changes
2. Antagonist: drug bind to receptor but conformation does not change of
the receptor
o Does not has effect
o Does have a biological effect
▪ It prevents the binding of endogenous mediators to
the receptor
, - Ion channels as drug targets
o Ion channel = a hole in the membrane through which ions can pass (pores). The hole
is formed by insertions of proteins
▪ They can be either opened or closed
1. Ion channel blockers = permeation is blocked of the ions from inside to
outside of other way around
2. Modulators = they modulate by binding to the protein --> change the
probability of the channel being open of closed
- Enzymes
o They catalyze reactions = turn a substrate into a product
1. Enzyme inhibitors = normal reaction is inhibited
2. Drug that act as false substrate = they look like the substrate and can
bind to the enzyme --> the enzyme thinks it is a normal substrate and
turns it into a product
o So the normal reaction is inhibited AND also a new product is
being formed --> this new product might have a biological
effect that the body did not want.
3. Pro-drug = are inactive by themselves --> recognized by enzyme -->
activates the drug
o They only activate in specific places (organs) that express the
specific enzyme
o i.e. treating Parkinson’s disease with levodopa = tyrosine
hydroxylase (enzyme) activates this drug --> dopamine
- Carrier molecules = transporters
o They transport a substrate form one side of the membrane to the other side of the
membrane
1. Inhibitor = bind to the binding site of the transporter --> the compound
cannot be transported anymore
2. False substrate = accumulation of an abnormal compound happens
because the substrate is carried by the transporter
Types of receptors on which and (ant)agonist can bind = all receptors have different time scales in
which the reaction happens
1. Type 1: Ligand-gated ion channels = ionotropic receptors
o These are present in cell membranes
o They are proteins, so a receptor, and have also ion channels inside the protein
structure
▪ So they are: receptors and ion channels
o When something binds on the binding domain --> the ion channels open up or close
o I.e. nicotinic Ach receptor
receptors
▪ Very fast = depolarization
or hyperpolarization (ms)
, 2. Type 2: G-protein-coupled receptors = metabotropic receptors
o Expressed inside membranes
o When drug binds to binding domain --> G-proteins are directed towards the
receptors --> activity is altered of second messenger proteins (cyclic AMP for
example)
o Takes a bit more time for the effect to be seen --> protein phosphorylation takes
time
▪ i.e. muscarinic ACH receptors
3. Type 3: Kinase-linked receptors
o Are proteins in membranes + have a catalytic domain
o When drug bind to binding domain --> kinase activity is altered (blocked or
stimulated)
o Receptors is also an enzyme --> leads immediately to alteration of protein
phosphorylation --> gene transcription which takes a lot of time
▪ i.e. cytokine receptors --> takes hours
▪ I.e. insulin
4. Type 4: nuclear receptors
o Located = in cell nucleus membrane
▪ Inactive = in cytosol
▪ Binding of ligand --> they move in cell nucleus --> bind to DNA parts -->
modify DNA transcription
o So they are: transcription factors
▪ All type 4 receptors are transcription factors but not all transcription factors
are type 4 receptors
o I.e. oestrogen receptors
▪ The activation takes time and gene transcription takes time --> takes hours
Pharmacology = explanation of action of pharmaca in the human (or animal) body (what drugs do
and how they do it)
- Pharmaca = biologically active substances
o It is a chemical that is usually used to treat disease. But it can also mean other stuff
such as toxic compounds.
o Toxicology = is a subdiscipline of pharmacology
- Medicine = pharmacon (‘drug’) specifically applied for therapy
o They intended to have a selective action but this ideal is seldom achieved.
▪ There is always a risk of adverse (side) effects as well as a benefit connected
with using any drug --> toxic effects. This is why selective action is usually not
always achieved.
▪ Therefore knowledge of pharmacology is needed for using drugs effectively
in therapy.
- Two main areas of investigation into the action of pharmaca
o Pharmacodynamics = “What does the drug do with the body”
o Pharmacokinetics = “What does the body do with the drug”
Pharmacotherapy = applied pharmacology Use of knowledge and insights gained from
pharmacology for the treatment of diseased humans in a responsible, effective and safe manner.
- Each pharmaca has:
o Minimum toxic concentration
o Therapeutic window
o Minimum effective concentration
- There is a direct relationship between
concentration of drug in blood plasm and
its therapeutic effects.
o The concentration in blood plasm
(Cp) has to be in between the
minimum toxic concentration and
Minimum effective concentration
- Primary effect = effect(s) for which the compound is administered
- Side effect = adverse/unwanted effect(s)
o The distinction between primary and side effect is determined by the aim for which
the medicine is administered
▪ I.e. acetylsalicylic acid (aspirin) can be used as a pain killer or against blood
clotting.
- Placebo = a preparation without any pharmacologically active substance
o It may have a therapeutic effect
o The expectation(s) of the patient determine the strength of the placebo effect
o Randomized, placebo-controlled clinical trials = The contribution of the placebo
effect to the overall effects of a drug are investigated in this
- Nocebo = a placebo with unwanted effects (side effects)
, o Nausea = the most common nocebo effect when taking in oral medication even
though the medication does not have this side effect
Phases of making drug:
1. Discovery: takes 2-5 years
2. Development: takes 5-9 years
▪ Phase 1: safety exposure
▪ Phase 2: Efficacy and dose selection
▪ Phase 3: Registration trials
▪ Phase 4: Post approval regulation = after the approval of use they still have
to check how it is going and what the side effects are
Lecture 2 – PD
Pharmacodynamics = what does the drug do to the body
The 4 levels of drug action
1. System level effects = an effect on system function (a system in a body: organs,
cardiovascular system)
o I.e. Blood pressure medication on the system
o But it does not say anything about how to make a better medication
2. Tissue level = effect on tissue function
o i.e. looking at the heart tissue or metabolic activity
3. Cellular level = looking at transduction metabolisms --> the biochemicals linked to drug
target
o I.e. looking at amount of cyclic AMP after giving the drug
4. Molecular level = establish interaction of drug with the molecular targets
o Molecular targets = proteins most of the times --> the drug target
o You can now see what the compound does and interferes with in the body and
develop a better drug --> pharmacodynamics
Molecular level = fourth level and consists of:
Drug targets can be (so drugs can interact with: ) =
- Receptors:
o 2 main groups of drug:
1. Agonist: drug binds to receptor and changes the conformation and
activates thereby the receptors --> has effect on the cell in which this
happens and activates or deactivates transduction mechanisms:
o Enzyme is being activated or inhibited
o Ion channels modulation --> open up or close
o DNA transcription changes
2. Antagonist: drug bind to receptor but conformation does not change of
the receptor
o Does not has effect
o Does have a biological effect
▪ It prevents the binding of endogenous mediators to
the receptor
, - Ion channels as drug targets
o Ion channel = a hole in the membrane through which ions can pass (pores). The hole
is formed by insertions of proteins
▪ They can be either opened or closed
1. Ion channel blockers = permeation is blocked of the ions from inside to
outside of other way around
2. Modulators = they modulate by binding to the protein --> change the
probability of the channel being open of closed
- Enzymes
o They catalyze reactions = turn a substrate into a product
1. Enzyme inhibitors = normal reaction is inhibited
2. Drug that act as false substrate = they look like the substrate and can
bind to the enzyme --> the enzyme thinks it is a normal substrate and
turns it into a product
o So the normal reaction is inhibited AND also a new product is
being formed --> this new product might have a biological
effect that the body did not want.
3. Pro-drug = are inactive by themselves --> recognized by enzyme -->
activates the drug
o They only activate in specific places (organs) that express the
specific enzyme
o i.e. treating Parkinson’s disease with levodopa = tyrosine
hydroxylase (enzyme) activates this drug --> dopamine
- Carrier molecules = transporters
o They transport a substrate form one side of the membrane to the other side of the
membrane
1. Inhibitor = bind to the binding site of the transporter --> the compound
cannot be transported anymore
2. False substrate = accumulation of an abnormal compound happens
because the substrate is carried by the transporter
Types of receptors on which and (ant)agonist can bind = all receptors have different time scales in
which the reaction happens
1. Type 1: Ligand-gated ion channels = ionotropic receptors
o These are present in cell membranes
o They are proteins, so a receptor, and have also ion channels inside the protein
structure
▪ So they are: receptors and ion channels
o When something binds on the binding domain --> the ion channels open up or close
o I.e. nicotinic Ach receptor
receptors
▪ Very fast = depolarization
or hyperpolarization (ms)
, 2. Type 2: G-protein-coupled receptors = metabotropic receptors
o Expressed inside membranes
o When drug binds to binding domain --> G-proteins are directed towards the
receptors --> activity is altered of second messenger proteins (cyclic AMP for
example)
o Takes a bit more time for the effect to be seen --> protein phosphorylation takes
time
▪ i.e. muscarinic ACH receptors
3. Type 3: Kinase-linked receptors
o Are proteins in membranes + have a catalytic domain
o When drug bind to binding domain --> kinase activity is altered (blocked or
stimulated)
o Receptors is also an enzyme --> leads immediately to alteration of protein
phosphorylation --> gene transcription which takes a lot of time
▪ i.e. cytokine receptors --> takes hours
▪ I.e. insulin
4. Type 4: nuclear receptors
o Located = in cell nucleus membrane
▪ Inactive = in cytosol
▪ Binding of ligand --> they move in cell nucleus --> bind to DNA parts -->
modify DNA transcription
o So they are: transcription factors
▪ All type 4 receptors are transcription factors but not all transcription factors
are type 4 receptors
o I.e. oestrogen receptors
▪ The activation takes time and gene transcription takes time --> takes hours
