HC1 - Introduction
Pharmacology = knowledge of drugs.
PDynamics = what does the drug do with the body
PKinetics = what does the body do with the drugs
PTherapeutics = what does a doctor do with a drug to a patient’s body
TRC-pharmacology is een chille website met filmpjes etc. https://trc-p.nl Heeft ook zelf-test
vragen.
Theme 1 – Basic pharmacodynamic concepts
HC2 – Receptors and binding / Drug action
Pharmacodynamics = what does the drug do with the body.
Phases of a drug:
(1) Pharmaceutic (production and formulation of a drug).
(2) Pharmacokinetics (absorption, distribution, metabolism, excretion).
(3) Pharmacodynamics (drug-receptor interaction).
a. Dose-effect relationship
Early drug targets
- Exogenous compounds
o Natural products
▪ Phytotherapy (altijd al) (= the use of plants/herbs to manage health)
▪ Purified (opium 1805)
o Synthetic drugs
▪ Aspirin
▪ Penicillin
- Physiological compounds
o Hormones
▪ Testis extract (1848)
o Neurotransmitters
▪ ‘vagusstoff’ (1921)
This gave us insight into receptor concept & receptor theory.
Activation and inactivation of biological processes – often acting on receptors.
• Agonist = compound that binds to a receptor protein and activates it.
• Antagonist = compound that binds and thereby prevents the own ligand from binding.
By cloning, we obtained a lot of knowledge. Sequence alignment led to the info that we have
~400 different genes that look like adrenalin receptors. These are 400 potential drug targets!
Ehrlich’s principle: “a drug will not act, unless bound”.
3 players in drug action
(1) Drug.
(2) Receptor.
(3) Endogenous ligand.
Molecular interactions underlying drug effects
,Size and shape are important in how well the drug will bind to the receptor. It needs to fit, but
it also needs to stay. The following interactions are important for this:
• Van der Waals interaction (positief trekt negatief aan; heeft te maken met
oppervlakte en gewicht).
• Ionic bonds (tussen bv Na+ en Cl-).
• Covalent bonds (sharing electrons to form electron pairs between atoms; bv CH4).
• Hydrogen bonds (H-bruggen tussen verschillende moleculen).
So, what determines binding → size, shape, and charges.
The better the drug binds, the higher the affinity of the drug is.
Stereospecificity is important because the chemical structure of the molecule is the same, but
the 3D form can be different because of mirror images of the molecule (isomerie). The shape
is then different, and one version may fit the binding pocket, and the other may not. This has
consequences for the effect of the drug of course.
Types of drug targets
• Human cellular targets.
o Proteins.
▪ Receptors
▪ Enzymes
▪ Ion channels
▪ Transporters
▪ Pumps
o Nucleic acids.
• Non-human targets (for example, antibiotics shouldn’t affect human cells)
o Chemical targets
▪ Ions
▪ Surfactants
▪ Bowel in GI tract
o Microorganisms
Biologicals (= antibody treatment) = antibodies that will recognize mutating cells. Anno
2023: basically, any protein that can be reached with antibodies.
The pharmacokinetics is important here.
Drugs interfering with physiological binding sites
Receptors ‘proper’ = targets for endogenous signaling molecules. Receptors proper are
proteins that are expressed on/in cells which goal it is to bind endogenous molecules (NT,
hormones, metabolites, vitamins, inflammatory mediators).
Other targets (pumps, enzymes, channels) are also important but not ‘meant’ for intercellular
signaling.
Four major types of membrane bound receptors
(1) Ion channel coupled receptor.
a. FAST (milli seconds)– pentamers.
b. Many NTs (GABA, glutamate, serotonin, acetylcholine)
c. Effector mechanism = ion-flux; electricity.
, d. (Je moet weten hoe het eruit ziet namelijk)
e. Build-up of several different receptor units (encoded for by different genes).
f. Example → muscle movement by ACh on ligand-gated ion channel.
(2) G-protein coupled receptor.
a. = one protein.
b. Effects within seconds.
c. Has a transmembrane domain (chain of amino acids) that is lipophilic (sticks to
the membrane). This is good because you want it to be in the membrane.
d. >350 different types.
e. Effector mechanism = G-protein (that becomes activated and passes on the
signal in the cell). The G-protein is a second messenger.
i. Some G-proteins are inhibitory, some are stimulatory. They all do
something different. You have Gs, Go, Gq, Gi.
f.
(3) Enzyme-coupled receptor (=Receptor-tyrosine-kinases).
a. Kinase receptor with dimerization --> autophosphorylation.
b. E.g., for insulin, growth factors (cancer mutations leads to activity independent
of ligand).
c. Effects within minutes.
d. Often growth related.
e.
(4) Nuclear receptors (in the nucleus) (e.g., Steroid receptors).
a. Slowest receptor (effect < hours).
b. Effector mechanism = mRNA synthesis.
c. How can a receptor be inside of the cell? Tells you something about the type of
ligand: should be lipophilic (to pass the cell membrane by itself).
, d. Receptor is in the cytoplasm, and it binds to the ligand, then travels to the
nucleus and will enter and will sit on the DNA to induce mRNA synthesis.
e. Very powerful receptor.
f.
Funny → some ion channel receptors have multiple sites of drug action! They have a main
binding pocket with a main ligand, and they have ‘allosteric modulators’ that can bind to
different binding pockets and modulate the effects of the main ligand.
E.g., valium/oxazepam don’t bind to the main pocket but to the allosteric binding site and
there they modulate the effect of the main ligand (in this case GABA).
Drugs acting at ‘other targets’ (other than receptors)
• Enzymes
• Pumps
• Channels
Enzymes, pumps, and channels can only be blocked. Drugs can either influence the substrate
or bind to the enzyme itself.
HC3 – Agonists/antagonists
‘Vagusstoff’ = acetylcholine.
1900: add pilocarpine (agonist) → heart slows down. Add atropine (antagonist) →
heart speeds up.
1925: stimulate nervus vagus → ACh comes out → bradycardia (=slower heart rate).
Agonist = activates receptor. Is like the effect of endogenous substance.
Antagonist = blocks the effect of the agonist by binding to the same receptor. Doesn’t do
anything to the shape of the receptor but only prevents the endogenous ligand from binding.
Agonist at receptor does not define ‘activation/inactivation’ of the tissue
AGONIST = acetylcholine (heart rate lower)
Pharmacology = knowledge of drugs.
PDynamics = what does the drug do with the body
PKinetics = what does the body do with the drugs
PTherapeutics = what does a doctor do with a drug to a patient’s body
TRC-pharmacology is een chille website met filmpjes etc. https://trc-p.nl Heeft ook zelf-test
vragen.
Theme 1 – Basic pharmacodynamic concepts
HC2 – Receptors and binding / Drug action
Pharmacodynamics = what does the drug do with the body.
Phases of a drug:
(1) Pharmaceutic (production and formulation of a drug).
(2) Pharmacokinetics (absorption, distribution, metabolism, excretion).
(3) Pharmacodynamics (drug-receptor interaction).
a. Dose-effect relationship
Early drug targets
- Exogenous compounds
o Natural products
▪ Phytotherapy (altijd al) (= the use of plants/herbs to manage health)
▪ Purified (opium 1805)
o Synthetic drugs
▪ Aspirin
▪ Penicillin
- Physiological compounds
o Hormones
▪ Testis extract (1848)
o Neurotransmitters
▪ ‘vagusstoff’ (1921)
This gave us insight into receptor concept & receptor theory.
Activation and inactivation of biological processes – often acting on receptors.
• Agonist = compound that binds to a receptor protein and activates it.
• Antagonist = compound that binds and thereby prevents the own ligand from binding.
By cloning, we obtained a lot of knowledge. Sequence alignment led to the info that we have
~400 different genes that look like adrenalin receptors. These are 400 potential drug targets!
Ehrlich’s principle: “a drug will not act, unless bound”.
3 players in drug action
(1) Drug.
(2) Receptor.
(3) Endogenous ligand.
Molecular interactions underlying drug effects
,Size and shape are important in how well the drug will bind to the receptor. It needs to fit, but
it also needs to stay. The following interactions are important for this:
• Van der Waals interaction (positief trekt negatief aan; heeft te maken met
oppervlakte en gewicht).
• Ionic bonds (tussen bv Na+ en Cl-).
• Covalent bonds (sharing electrons to form electron pairs between atoms; bv CH4).
• Hydrogen bonds (H-bruggen tussen verschillende moleculen).
So, what determines binding → size, shape, and charges.
The better the drug binds, the higher the affinity of the drug is.
Stereospecificity is important because the chemical structure of the molecule is the same, but
the 3D form can be different because of mirror images of the molecule (isomerie). The shape
is then different, and one version may fit the binding pocket, and the other may not. This has
consequences for the effect of the drug of course.
Types of drug targets
• Human cellular targets.
o Proteins.
▪ Receptors
▪ Enzymes
▪ Ion channels
▪ Transporters
▪ Pumps
o Nucleic acids.
• Non-human targets (for example, antibiotics shouldn’t affect human cells)
o Chemical targets
▪ Ions
▪ Surfactants
▪ Bowel in GI tract
o Microorganisms
Biologicals (= antibody treatment) = antibodies that will recognize mutating cells. Anno
2023: basically, any protein that can be reached with antibodies.
The pharmacokinetics is important here.
Drugs interfering with physiological binding sites
Receptors ‘proper’ = targets for endogenous signaling molecules. Receptors proper are
proteins that are expressed on/in cells which goal it is to bind endogenous molecules (NT,
hormones, metabolites, vitamins, inflammatory mediators).
Other targets (pumps, enzymes, channels) are also important but not ‘meant’ for intercellular
signaling.
Four major types of membrane bound receptors
(1) Ion channel coupled receptor.
a. FAST (milli seconds)– pentamers.
b. Many NTs (GABA, glutamate, serotonin, acetylcholine)
c. Effector mechanism = ion-flux; electricity.
, d. (Je moet weten hoe het eruit ziet namelijk)
e. Build-up of several different receptor units (encoded for by different genes).
f. Example → muscle movement by ACh on ligand-gated ion channel.
(2) G-protein coupled receptor.
a. = one protein.
b. Effects within seconds.
c. Has a transmembrane domain (chain of amino acids) that is lipophilic (sticks to
the membrane). This is good because you want it to be in the membrane.
d. >350 different types.
e. Effector mechanism = G-protein (that becomes activated and passes on the
signal in the cell). The G-protein is a second messenger.
i. Some G-proteins are inhibitory, some are stimulatory. They all do
something different. You have Gs, Go, Gq, Gi.
f.
(3) Enzyme-coupled receptor (=Receptor-tyrosine-kinases).
a. Kinase receptor with dimerization --> autophosphorylation.
b. E.g., for insulin, growth factors (cancer mutations leads to activity independent
of ligand).
c. Effects within minutes.
d. Often growth related.
e.
(4) Nuclear receptors (in the nucleus) (e.g., Steroid receptors).
a. Slowest receptor (effect < hours).
b. Effector mechanism = mRNA synthesis.
c. How can a receptor be inside of the cell? Tells you something about the type of
ligand: should be lipophilic (to pass the cell membrane by itself).
, d. Receptor is in the cytoplasm, and it binds to the ligand, then travels to the
nucleus and will enter and will sit on the DNA to induce mRNA synthesis.
e. Very powerful receptor.
f.
Funny → some ion channel receptors have multiple sites of drug action! They have a main
binding pocket with a main ligand, and they have ‘allosteric modulators’ that can bind to
different binding pockets and modulate the effects of the main ligand.
E.g., valium/oxazepam don’t bind to the main pocket but to the allosteric binding site and
there they modulate the effect of the main ligand (in this case GABA).
Drugs acting at ‘other targets’ (other than receptors)
• Enzymes
• Pumps
• Channels
Enzymes, pumps, and channels can only be blocked. Drugs can either influence the substrate
or bind to the enzyme itself.
HC3 – Agonists/antagonists
‘Vagusstoff’ = acetylcholine.
1900: add pilocarpine (agonist) → heart slows down. Add atropine (antagonist) →
heart speeds up.
1925: stimulate nervus vagus → ACh comes out → bradycardia (=slower heart rate).
Agonist = activates receptor. Is like the effect of endogenous substance.
Antagonist = blocks the effect of the agonist by binding to the same receptor. Doesn’t do
anything to the shape of the receptor but only prevents the endogenous ligand from binding.
Agonist at receptor does not define ‘activation/inactivation’ of the tissue
AGONIST = acetylcholine (heart rate lower)
