Summary BGZ2026
Inhoud
Cases ........................................................................................................................................................ 2
Case 1 Pharmacodynamics, (antagonist/agonist, receptor and effects of compounds) .................... 2
Case 2 Kinetics ................................................................................................................................... 16
Case 3 Polymorphism and genetic toxicity........................................................................................ 27
Case 4 NAFLD / NASH ........................................................................................................................ 32
Case 5 Drug development, clinical trials and flavanol....................................................................... 37
Case 6 patents, orphan and blockbuster drugs ................................................................................. 43
Lectures ................................................................................................................................................. 47
Opening lecture ................................................................................................................................. 47
Lecture 1. Dynamics .......................................................................................................................... 50
Lecture 2. Kinetics ............................................................................................................................. 57
Lecture 3. Genetic toxicity ................................................................................................................. 62
Lecture 4. Patient presentation NAFLD ............................................................................................. 70
Lecture 5. Clinical trials and drug development ................................................................................ 81
Lecture paracetamol interactive ....................................................................................................... 86
Lecture question hour + example test questions .............................................................................. 90
Practicum............................................................................................................................................... 95
Pharmacodynamics ........................................................................................................................... 95
Pharmacokinetics .............................................................................................................................. 97
Beaker glass ....................................................................................................................................... 98
Formula sheet/overview ................................................................................................................. 101
,Cases
Case 1 Pharmacodynamics, (antagonist/agonist, receptor and effects of
compounds)
Pharmacodynamics the relationship between drug concentration at the site of action and the
resulting effect, including the time course and intensity of therapeutic and adverse effects.
The effect of a drug present at the site of action is determined by that drug’s binding with a receptor.
For most drugs, the concentration at the site of the receptor determines the intensity of a drug’s
effect.
Other factors affecting the drug reponse are:
- Density of receptors on cell surface
- The mechanism by which a signal is transmitted into the cell by second messengers
(substances within the cell).
- Regulatory factors that control gene translation and protein production.
A drug = a chemical substance of known structure, other than a nutrient or an essential dietary
ingredient, which, when administered to a living organism, produces a biological effect.
Drugs may be synthetic chemicals, chemicals obtained from plants or animals, or products of genetic
engineering.
A medicine = a chemical preparation, which usually but not necessarily contains one or more drugs,
administered with the intention of producing a therapeutic effect. Medicines usually contain other
substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more
convenient to use.
To count as a drug, the substance must be administered as such, rather than released by
physiological mechanisms. Many substances, such as insulin or thyroxine, are endogenous hormones
but are also drugs when they are administered intentionally.
,A drug will not work unless it is bound. These critical binding sites are often referred to as ‘’drug
targets’’.
Four main kinds of regulatory protein are commonly involved as primary drug targets:
Receptors
Enzymes
Carrier molecules (transporters)
Ion channels
Receptors
Receptors = the term is often used to describe the target molecules through which soluble
physiological mediators, hormones, neurotransmitters, inflammatory mediators etc produce their
effects.
The term receptor specifically refers to proteins that participate in intracellular communication via
chemical signals.
E.g. acetylcholine receptors, cytokine receptors, steroid receptors, and growth hormone receptors.
Receptor functions
- Reorganization of specific ligand molecule (ligand binding domain)
- Transduction of signal into response (effector domain)
Substances that bind to a receptor are named ligand (drugs, endogenous signaling molecules)
,Receptor classification occurs according to the effector mechanism and the time between ligand
binding and cellular response.
Type 1. Ligand-gated Ion channels (ionotropic receptors) fast neurotransmitters act on these.
Type 2. G-protein coupled receptors (GPCRs, metabotropic receptors or 7-transmembrane
receptors). these are membrane receptors that are coupled to intracellular effector systems
via a G-protein.
Type 3. Kinase-linked and related receptors Heterogenous group of membrane receptors
responding mainly to protein mediators. They comprise an extracellular ligand-binding.
Type 4 nuclear receptors these receptors regulate gene transcription. Some are actually
located in the cytosol and migrate to the nuclear compartment when a ligand is present.
, Overview
ligand-gated ion channel G-protein coupled receptors Receptor kinases Nuclear receptor
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Channel or enzyme Protein kinases Gene transcription
Coupling Direct G-protein Direct Via DNA
Example GABA, nicotinic Adrenoceptors, muscarinic Insulin, growth factors, Steroid receptors
acetylcholine receptor acetylcholine receptor cytokine receptors
Structure Oligometric assembly of Monometric or oligometric Single transmembrane Monometric structure
subunits surrounding assembly of subunits helix linking extracellular with separate
central pore comprising seven receptor domein to receptor- and DNA-
transmembrane helices with intracellular kinase binding domains
intracellular G-protein domain
coupling domain
Ligand-gated Ion channels (ionotropic receptors):
Ligand gated channels have different subunits, of which there are four types: α, β, γ and δ. The
subunits show marked sequence homology and each contains four membrane-spanning alfa-helices,
inserted into the membrane. The pentameric structure (α2, β, γ and δ) possess two acetylcholine
binding sites, each lying at the interface between one of the two alfa subunits and its neighbor. Both
must bind acetylcholine molecules in order for the receptor to be activated.
, Acetylcholine (neuromuscular junctions) and glutamate (neuromuscular junction) cause an increase
in Na+ and K+ permeability. This causes an action potential, the receptor and ligand-gated channel
coupe.
Binding of a ligand opens the ion channel very quickly and specific ions can go in or out down their
concentration gradient. Transport proteins can let enter or release certain molecules upon binding of
a ligand. Ion channels control the fastest synaptic events in the nervous system. Without ligand, the
gate is closed. When ligand binds to the receptor, the gate opens (Na+ and K+ channels) and ions can
travel along the concentration gradient.
Overview:
Sometimes called iontropic receptors
Mainly involved in fast synaptic transmission
Several structural families, the most common is the
heteromeric assemblies of four – five subunits with
transmembrane helices arranged around a central aquous
timescale
Ligand binding and channel opening occur on a millisecond
timescale
G protein coupled receptors (GPCRs) (metabotropic
receptors):
Mostly for hormones and slow transmitters.
G-protein coupled receptors consist of a single polypeptide chain of up to 1100 residues. Their
characteristic structure comprises seven transmembrane α-helices, similar to those of the ion
channels discussed above, with an extracellular N-terminal domain of varying length and an
intracellular C-terminal domain. There are three GPCR families A, B and C (table)
The G-proteins comprise a family of membrane resident proteins whose function is to recognize
activated GPCRs and pass on the message to the effector systems that generate a cellular response.
G-proteins consist of three subunits, α, β and γ.
* The α subunit has enzymatic activity (catalyzes GTP GDP).
* The β and γ subunits remain together as a βγ complex.
All 3 the subunits are anchored to the membrane through a fatty acid chain, coupled to the G-protein
through a reaction known as prenylation.
In the resting state the G-protein is an unattached αβγ trimer. GDP occupies the α subunit. When
GPCR is activated by an agonist, there is an association of αβγ with the receptor. The GDP dissociates
and is replaced by GTP. Which in turn causes dissociation of the G-protein trimmer, releasing α-GTP
and βγ subunits; these are the ‘’active’’ forms of the G-protein, which diffuse in the membrane and
can associate with various enzymes and ion channels, causing activation of the target. Signalling is
terminated when the hydrolysis of GTP to GDP occurs through the GTPase activity of the α subunit.
The resulting α-GDP then dissociates from the effector and reunites with βγ, completing the cycle.
Inhoud
Cases ........................................................................................................................................................ 2
Case 1 Pharmacodynamics, (antagonist/agonist, receptor and effects of compounds) .................... 2
Case 2 Kinetics ................................................................................................................................... 16
Case 3 Polymorphism and genetic toxicity........................................................................................ 27
Case 4 NAFLD / NASH ........................................................................................................................ 32
Case 5 Drug development, clinical trials and flavanol....................................................................... 37
Case 6 patents, orphan and blockbuster drugs ................................................................................. 43
Lectures ................................................................................................................................................. 47
Opening lecture ................................................................................................................................. 47
Lecture 1. Dynamics .......................................................................................................................... 50
Lecture 2. Kinetics ............................................................................................................................. 57
Lecture 3. Genetic toxicity ................................................................................................................. 62
Lecture 4. Patient presentation NAFLD ............................................................................................. 70
Lecture 5. Clinical trials and drug development ................................................................................ 81
Lecture paracetamol interactive ....................................................................................................... 86
Lecture question hour + example test questions .............................................................................. 90
Practicum............................................................................................................................................... 95
Pharmacodynamics ........................................................................................................................... 95
Pharmacokinetics .............................................................................................................................. 97
Beaker glass ....................................................................................................................................... 98
Formula sheet/overview ................................................................................................................. 101
,Cases
Case 1 Pharmacodynamics, (antagonist/agonist, receptor and effects of
compounds)
Pharmacodynamics the relationship between drug concentration at the site of action and the
resulting effect, including the time course and intensity of therapeutic and adverse effects.
The effect of a drug present at the site of action is determined by that drug’s binding with a receptor.
For most drugs, the concentration at the site of the receptor determines the intensity of a drug’s
effect.
Other factors affecting the drug reponse are:
- Density of receptors on cell surface
- The mechanism by which a signal is transmitted into the cell by second messengers
(substances within the cell).
- Regulatory factors that control gene translation and protein production.
A drug = a chemical substance of known structure, other than a nutrient or an essential dietary
ingredient, which, when administered to a living organism, produces a biological effect.
Drugs may be synthetic chemicals, chemicals obtained from plants or animals, or products of genetic
engineering.
A medicine = a chemical preparation, which usually but not necessarily contains one or more drugs,
administered with the intention of producing a therapeutic effect. Medicines usually contain other
substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more
convenient to use.
To count as a drug, the substance must be administered as such, rather than released by
physiological mechanisms. Many substances, such as insulin or thyroxine, are endogenous hormones
but are also drugs when they are administered intentionally.
,A drug will not work unless it is bound. These critical binding sites are often referred to as ‘’drug
targets’’.
Four main kinds of regulatory protein are commonly involved as primary drug targets:
Receptors
Enzymes
Carrier molecules (transporters)
Ion channels
Receptors
Receptors = the term is often used to describe the target molecules through which soluble
physiological mediators, hormones, neurotransmitters, inflammatory mediators etc produce their
effects.
The term receptor specifically refers to proteins that participate in intracellular communication via
chemical signals.
E.g. acetylcholine receptors, cytokine receptors, steroid receptors, and growth hormone receptors.
Receptor functions
- Reorganization of specific ligand molecule (ligand binding domain)
- Transduction of signal into response (effector domain)
Substances that bind to a receptor are named ligand (drugs, endogenous signaling molecules)
,Receptor classification occurs according to the effector mechanism and the time between ligand
binding and cellular response.
Type 1. Ligand-gated Ion channels (ionotropic receptors) fast neurotransmitters act on these.
Type 2. G-protein coupled receptors (GPCRs, metabotropic receptors or 7-transmembrane
receptors). these are membrane receptors that are coupled to intracellular effector systems
via a G-protein.
Type 3. Kinase-linked and related receptors Heterogenous group of membrane receptors
responding mainly to protein mediators. They comprise an extracellular ligand-binding.
Type 4 nuclear receptors these receptors regulate gene transcription. Some are actually
located in the cytosol and migrate to the nuclear compartment when a ligand is present.
, Overview
ligand-gated ion channel G-protein coupled receptors Receptor kinases Nuclear receptor
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Channel or enzyme Protein kinases Gene transcription
Coupling Direct G-protein Direct Via DNA
Example GABA, nicotinic Adrenoceptors, muscarinic Insulin, growth factors, Steroid receptors
acetylcholine receptor acetylcholine receptor cytokine receptors
Structure Oligometric assembly of Monometric or oligometric Single transmembrane Monometric structure
subunits surrounding assembly of subunits helix linking extracellular with separate
central pore comprising seven receptor domein to receptor- and DNA-
transmembrane helices with intracellular kinase binding domains
intracellular G-protein domain
coupling domain
Ligand-gated Ion channels (ionotropic receptors):
Ligand gated channels have different subunits, of which there are four types: α, β, γ and δ. The
subunits show marked sequence homology and each contains four membrane-spanning alfa-helices,
inserted into the membrane. The pentameric structure (α2, β, γ and δ) possess two acetylcholine
binding sites, each lying at the interface between one of the two alfa subunits and its neighbor. Both
must bind acetylcholine molecules in order for the receptor to be activated.
, Acetylcholine (neuromuscular junctions) and glutamate (neuromuscular junction) cause an increase
in Na+ and K+ permeability. This causes an action potential, the receptor and ligand-gated channel
coupe.
Binding of a ligand opens the ion channel very quickly and specific ions can go in or out down their
concentration gradient. Transport proteins can let enter or release certain molecules upon binding of
a ligand. Ion channels control the fastest synaptic events in the nervous system. Without ligand, the
gate is closed. When ligand binds to the receptor, the gate opens (Na+ and K+ channels) and ions can
travel along the concentration gradient.
Overview:
Sometimes called iontropic receptors
Mainly involved in fast synaptic transmission
Several structural families, the most common is the
heteromeric assemblies of four – five subunits with
transmembrane helices arranged around a central aquous
timescale
Ligand binding and channel opening occur on a millisecond
timescale
G protein coupled receptors (GPCRs) (metabotropic
receptors):
Mostly for hormones and slow transmitters.
G-protein coupled receptors consist of a single polypeptide chain of up to 1100 residues. Their
characteristic structure comprises seven transmembrane α-helices, similar to those of the ion
channels discussed above, with an extracellular N-terminal domain of varying length and an
intracellular C-terminal domain. There are three GPCR families A, B and C (table)
The G-proteins comprise a family of membrane resident proteins whose function is to recognize
activated GPCRs and pass on the message to the effector systems that generate a cellular response.
G-proteins consist of three subunits, α, β and γ.
* The α subunit has enzymatic activity (catalyzes GTP GDP).
* The β and γ subunits remain together as a βγ complex.
All 3 the subunits are anchored to the membrane through a fatty acid chain, coupled to the G-protein
through a reaction known as prenylation.
In the resting state the G-protein is an unattached αβγ trimer. GDP occupies the α subunit. When
GPCR is activated by an agonist, there is an association of αβγ with the receptor. The GDP dissociates
and is replaced by GTP. Which in turn causes dissociation of the G-protein trimmer, releasing α-GTP
and βγ subunits; these are the ‘’active’’ forms of the G-protein, which diffuse in the membrane and
can associate with various enzymes and ion channels, causing activation of the target. Signalling is
terminated when the hydrolysis of GTP to GDP occurs through the GTPase activity of the α subunit.
The resulting α-GDP then dissociates from the effector and reunites with βγ, completing the cycle.
