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Samenvatting Lijn Farmacologie
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Samenvatting van de lijn Farmacologie, met de leerdoelen, afbeeldingen en hoorcolleges
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Samenvatting door Lieke Touwen. Alleen voor individueel gebruik (2020).Leerdoelen Lijn Pharmacology
Theme I: How do drugs work? Basic pharmacodynamic concepts
Know the following types of molecular drug targets and can explain their characteristics: G-coupled
protein receptor, receptor with enzyme activity (kinase receptor), intracellular receptor, transporter,
and ion channel.
In pharmacology many different words are used. Pharmaceutic means the production and
formulation of a drug. Pharmacokinetics focusses on what determinates the concentration. It covers
the processes of how much drug is in the body. It can also be thought of as what the body does to the
drug. The main subparts are absorption, excretion, distribution and metabolism. Under
pharmacodynamics we describe what the drug does to the body. It is a detailed study of how drugs
act and tries to answer the question whether a drug provides a meaningful pharmacological action.
Drugs do not have an effect unless they bind to a receptor. However, this is not true for all drug
actions. There always has to be a drug-receptor interaction. Pharmacology is about the molecular
interaction between the drug and the drug target.
There are a lot of different targets. Exogenous compounds are natural products or synthetics drugs.
Natural products have two categories: phytotherapy (plants, for ever) and purified (e.g. opium, for
200 years). Synthetic drugs are for example aspirin, arsenical antisyphilis and penicillin.
Another target are physiological/endogenous compounds. This could be hormones or
neurotransmitters.
There are 3 players in drug action: drug, receptor and endogenous ligand. The
endogenous ligand and drug can both bind to the same receptor. This will lead to a
competition between the endogenous ligand and the drug. Whether the drug can bound
depends on the activity of the endogenous ligand and the amount in the body.
Substances that bind to a receptor are named ligands. Each receptor in the body is
recognized by an endogenous ligand. If they bind, it leads to a signal. Receptors are big
proteins that serve to convey a signal to the body. The ligand is called an agonist if a
response will take place by the receptor. Agonism is the production of a response by a
receptor after ligand-receptor interaction. Some of the endogenous agonists are used as
drugs (growth hormone, adrenaline). Antagonists are ligands that bind to a receptor, but
they do not elicit a response. In fact, antagonists block the receptor from the agonists and
thus inhibit the action of the agonists. Partial agonist will also bind to the receptor, but
their signal is not as strong as a full agonist. Therefore, only a small effect will take place and the
maximum effect will never be reached.
The ligand and the receptor can interact based on a combination of different bond types. This is
necessary to form a stable ligand-receptor complex. The different bond types are:
- Van der waals forces; weak, result from transient positive or negative charges on a
molecule-caused by the shifting of its electron density
- Hydrogen bonding; hydrogen atoms bound to nitrogen or oxygen that leads to more
positively polarized atoms This allows these hydrogen atoms to bind to more negatively
polarized atoms.
- Ionic interactions; between atoms with opposite charges.
- Covalent bonding; strongest, sharing electrons between atoms. The
energy required to break such a bond is irreversible.
Most drugs work by non-covalent interaction with biomolecules (proteins or RNA).
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Not only the charges are important for binding, but size and shape determine binding as well. The
receptor has only a small part of atoms where the ligand can bind. It depends on the interaction
within the binding spot (e.g. positive/negative), remaining on the receptor and the 3D shape
(isomers).
There are a lot of different types of drug targets. Human cellular targets are for example
proteins of nucleic acids. Non-human targets are chemical targets (ions, surfactants, bowel
in Gi tract) or microorganisms. Receptors are a human cellular target localized in the cell
membrane, cytoplasm or nucleus. Classification occurs according to the effector mechanism
and the time between ligand binding and cellular response. They are targets for endogenous
signalling molecules, while other targets (pumps, enzymes, channels) are not meant for
intercellular signalling.
The first group of receptors are the ion channels and transport proteins. Binding of
a ligand opens the ion channel very quickly (milliseconds) and specific ions can go
in or out down their concentration gradient. Mostly neurotransmitters use ion
channels. The effector mechanism is ion-flux and/or electricity. Transport proteins
can let enter or release certain molecules upon binding of a ligand. An example of
an ion channel is a ligand-gated ion channel. It composed of 5 subunits. It has one
main binding site and several additional binding sites. The interaction with the
main ligand and receptor is the most important one. If additional sides are also
bound, can lead this to different effect on the outcome. For example, a more
enhanced or weaker effect of the ligand. Drugs can also bind on these additional sides and are called
allosteric modulators. They modulate the effect, not activate the receptor. There must always be an
active main ligand for activation otherwise the allosteric modulators could not change the outcome
of the effect. GABA is an inhibiting agonistic neurotransmitter that binds to the receptor. The
receptor is activated, but the effect of the receptor is negative for the cell. There are also endogenous
compounds that modulate binding sites on receptors, but they are not known yet.
In rest, an ion channel is closed. When an agonist binds the channel, it opens fast that results in a
direct ion exchange. The conformational changes due to binding of the ligand open the channel. An
antagonist usually keeps the channel closed, but some agonists can also act as a channel blocker.
The second group are G-protein coupled receptors (GPCRs). They are
membrane receptors with seven transmembrane helices which are in
connection with a G-protein. Their effect can be established within
seconds. Peptide hormones and neurotransmitters usually bind to G-
protein coupled receptors. Ligands bind at the extracellular part and activate signal transduction
pathways inside the cell which evoke cellular responses and set a cascade reaction in progress. The
human genome contains about 400 different GPCRs. The G-protein exists of 3 subunits: alfa, beta and
gamma. There is a subdivision of the gamma side. Some will stimulate when activated and some will
inhibit when activated. Activation of the whole receptor will not tell you if it will stimulate or
inhibit. While at rest, the receptor is bound to the alfa-subunit of the G-protein. Ligand
binding leads to a conformational change of the receptor. GDP is replaced by GTP that leads
to activation of the receptor. The alfa-subunit then dissociates from the receptor and
activates a membrane bound enzyme. Further signal transduction depends on the type of
G-protein. The enzyme converts a second messenger that evokes a cellular response. The last
step is the hydrolysis of GTP into GDP + phosphate (inactivation) and return of the alfa-
subunit to the G-protein coupled receptor.
The third group of receptors are kinase receptors. They are localized in the cell
membrane and consist of an extracellular domain with ligand binding site, a
transmembrane helix, an intracellular tyrosine kinases domain and specific sites for
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autophosphorylation. Phosphorylation of other enzymes evokes the response. The effector time till
tissue response takes several minutes. Growth factors and insulin bind to the tyrosine kinase
receptors. The effect is dimerization (=binding to another kinase receptor) that leads to a cascade
reaction of enzyme activation, leading to a cellular response.
The fourth group of receptors are nuclear/intracellular receptors. They are localized in
the cytoplasm or nucleus. It contains about 50 soluble receptors. They sense lipophilic
ligands. The general structure consists of 5 distinguishable domains. After binding to the
receptor, the receptor-complex interacts with the DNA and initiates gene transcription.
The effector mechanism is thus mRNA synthesis. The process between ligand
binding and protein synthesis can take hours or days. Steroid hormones act
throughout these receptors (corticosteroids, oestrogens, androgens and
progestogens).
As said before, there are also a few non-receptor targets. Enzymes for example, converts the
ligand into something else. The receptor only changes shape, but the ligand remains the same.
Understand the concept of binding and can apply the terms occupancy, affinity, Ka, agonism,
antagonism, and competitive vs. non-competitive in the context of binding.
Binding of a ligand to its receptor can be shown in a graph. Ligands can also attach to other binding
sites than the receptor (e.g. other proteins). This is called non-specific or aspecific binding. An
increasing concentration of ligand L] is plotted against the bound ligand. The total binding is not
equal to the ligand-receptor complex [LR], but is the sum of the specific and non-specific binding. The
specific binding is usually calculated by subtracting the non-specific binding from the total binding.
The curve of the specific binding approaches a maximum, when all receptors are occupied. The non-
specific binding is binding of the ligand to molecules other than the receptor. Specific binding of
ligand to receptor increases with increasing ligand concentration. The same is true for unspecific
binding of the ligand. At a very low ligand concentration the degree of specific and unspecific binding
is almost the same. At high ligand concentration, the receptors are saturated and specific binding is
maximal, whereas unspecific binding still increases.
Agonism at receptor does not define activation/inactivation of the tissue. The agonist does not
always have and activation response for the body. It depends on the effect of the receptor and
what the receptor does as a result. An agonist does always stimulate the receptor into action,
while an antagonist the effect of the receptor blocks.
The interaction between ligand and receptor is dynamic. There is a constant equilibrium
between free ligand and receptor and ligand-receptor complex. Binding to a ligand-receptor
complex is called association (K+1). Unbounding to free ligand and receptor is called
dissociation (K-1). The proportion of the balance between association and dissociation determinates
the amount ligand-receptor complex. If the interaction is not very strong, there can be spoken of a
high dissociation rate that leads to freer ligand and receptor. Each receptor has its own dynamic
binding.
A few words are related to the binding between a ligand and the receptor. They will be explained
further on.
The first word is affinity. Affinity means the number of bindings between the ligand and
the receptor. Some drugs bind better to a given receptor than others. The tendency of a
ligand to bind a receptor is referred to as affinity. Usually, the natural ligand is the agonist
with a high affinity, but synthetic drugs may bind even better. A high affinity means a high
association rate and low dissociation rate. Beware though that high affinity binding of a
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ligand to its receptor does not automatically mean that the receptor becomes activated. In practice
high affinity means that a ligand will bind the receptor already at low concentrations. With affinity
comes the affinity constant (Ka). The formula for affinity constant is Ka = K-1 : K+1. It means the
concentration at half maximal occupation of population. It can be used to define the affinity. Plotting
different ligands of a receptor in a binding curve enables you to compare the different affinities. The
more the curve is placed to the left, the lower the Ka and the higher the affinity. The unit for affinity
is nM.
The Ka can be found in a concentration binding curve. The higher the concentration, the higher the
occupancy. On the horizontal line is a logarithmic scale with a bending point. The bending point is the
affinity constant. Half of the receptors are occupied. The curve gives us information about the
number of receptors through the height of the line and about the affinity of receptor for ligand (Ka). If
there is a high affinity, the curve moves to the left (lower Ka). If you know Ka, you can calculate
where you are on the curve.
With a high affinity comes a high likelihood of occupancy. All kinds of ligands can
occupy a binding site on a receptor. Occupation of a receptor by a ligand does not
automatically mean that a receptor becomes activated. Pa stands for the degree of
occupancy of a receptor population. It could be calculated with the following formula:
Pa = [L] / Ka + [L].
It always gives a number between 0 and 1. It depends on 2 factors: the concentration of
the agonist and the binding constant. If the concentration of the ligand is >>> Ka, it will
be close to 1. If the concentration of the ligand is <<< Ka, it will be close to 0.
The occupancy at different concentrations of ligand provides information on the number of receptors
and the affinity of the receptor for its ligand. If the ligand concentration is equal to the Ka then half of
the total receptors is occupied.
If an agonist and antagonist are given at the same time, or if one of them is already in the body,
antagonism occurs. There are a few ways in which they could compete with each other.
The first one is competitive antagonism. The agonist is bound and an antagonist is added that
binds to the same part of the receptor. This gives a competition between the bound –
unbound agonist and the bound – unbound antagonist. The more antagonist is added, the
higher the concentration of agonist needs to be for the same maximum specific binding. This
is called a right-shift in dose response. There is a righter curve for the agonist with a higher
concentration of antagonist. The agonist can still have effect, but there is more needed for the
same effect. The effect depends on the occupancy by the agonist, the capacity of the agonist
to induce a signal and the number of receptors. Thus, a lower effect when a competitive antagonist
is added due to changes in the occupancy and number of receptors from the agonist. A competitive
antagonist reduces agonist potency. This mechanism is found in the most antagonists.
The second antagonism is non-competitive binding, for example non-reversible binding. In
this mechanism the antagonist is going to bind covalently (non-reversible) and the receptor
cannot bind to an agonist. This causes that there are fewer receptors available for the
agonist to bind to. The maximum binding is lower because the receptors have been taken
out. Once the antagonist has bound the receptor, the agonist cannot achieve full binding
anymore, no matter how high its concentration. The higher the antagonist concentration, the
lower the maximum binding of the agonist. Non-competitive antagonists reduce agonist
maximal response (efficacy), but not its affinity. The lifetime of the receptor is the half-life time of the
drug targets. The receptors reside in the membrane after 24 hours. New ones will be made that do
not have this irreversible binding with the antagonist. So, the half time of the drug equals the half
time of the receptors. Another way of non-competitive antagonism are several binding sites the
antagonist binds to. This are allosteric binding site, so not the main binding site for the agonist. This
prevents that the active formation takes place.
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