RECEPTOR PHARMACOLOGY
LECTURE 1
Pharmacology: interactions of chemical substances (drugs) with the living organism
Drug: chemical applied to a physiological system that affects its function in a specific
way
2 important concepts in pharmacology:
- Pharmacodynamics – how drugs affect the body
- Pharmacokinetics – how the body affects the drugs
Pharmacodynamics refers to the study of how drugs interact with the body and
produce their therapeutic or toxic effects. It explores the relationship between drug
concentration at the site of action and the resulting pharmacological response.
On the other hand, pharmacokinetics focuses on the study of the movement of drugs
within the body, including their absorption, distribution, metabolism, and excretion
(ADME). Pharmacokinetics helps to determine how the body processes a drug, which
in turn affects its concentration at the site of action and its overall therapeutic effect.
Non-specific drug actions:
- Biological effect at relatively high drug concentrations
Non-specific drug actions are generally not related to specific targets or receptors but
instead result from the general chemical or physical properties of the drug itself.
Specific drug actions:
- Biological effect at relatively low drug concentrations
However, the primary mode of action for most drugs involves specific interactions
with receptors, ion channels, enzymes, or transporters/carriers in the body. These
specific interactions allow drugs to produce their desired effects by modulating
specific biochemical processes. Most drugs act on target proteins with high affinity to
the drug.
Receptors: target molecules whose function is to recognize and respond to specific
endogenous chemical signals, such as hormones, neurotransmitters and
inflammatory mediators. Receptors play a crucial role in cell communication. They
allow cells to respond to signals from their external environment or from other cells in
a highly specific and controlled manner.
Receptor interactions: By binding to receptors, drugs can either activate or inhibit
their function, altering cellular signaling and producing a desired response. For
example, beta-blockers bind to beta-adrenergic receptors and block the effects of
adrenaline, resulting in decreased heart rate and blood pressure.
1
,Enzyme interactions: Some drugs can inhibit or enhance the activity of specific
enzymes in the body. This can affect biochemical pathways and processes within
cells. For instance, statins inhibit the enzyme HMG-CoA reductase, which is involved
in cholesterol synthesis, leading to reduced cholesterol levels.
Transporter interactions: Drugs can interact with membrane transporters, affecting
the movement of molecules into or out of cells. This interaction can alter the
concentration of certain substances in specific tissues or organs. For example,
selective serotonin reuptake inhibitors (SSRIs) block the reuptake transporter for
serotonin, increasing its concentration in the synaptic cleft and enhancing its effects.
Reciprocal – bidirectional, thus a two-way relationship.
Reciprocal specificity of receptor-drug interaction: individual classes of drugs bind to
discrete receptors, while individual receptors recognize only discrete classes of
drugs. There is high specificity by high affinity.
However, no drugs are completely specific in their action, which leads to side effects.
Side effects may occur at relatively high drug concentrations, due to binding to other
targets (receptors) with lower affinity.
- Off-target side effects
- On-target side effects
Off-target side effects, also known as non-specific side effects, refer to the effects
that occur when a drug interacts with other targets or receptors in the body besides
its intended target. At relatively high drug concentrations, drugs may also bind to
other receptors or targets in the body with lower affinity. This can lead to side effects
or unintended actions. These off-target interactions can occur when the drug
concentration is significantly higher than what is required for its intended therapeutic
effect.
On-target side effects, also known as specific side effects, are effects that occur as a
direct result of the drug's intended interaction with its target receptor or pathway. On-
target side effects can occur when the drug's intended target is also present in
tissues or organs where the drug's effect is not desired. Example:
B-receptor in the lung - relaxing bronchial smooth muscle
B-receptor in the heart - increasing heart rate
When you apply a drug that binds to B-receptors, it causes a therapeutic effect in the
lung, but it also causes side effects in the heart. Since there are b-receptors present
in both the lungs and the heart.
Agonist: receptor occupation leads to biological response
Antagonist: receptor occupation does not lead to response and prevents the effect of
an agonist, mostly by preventing it from binding
Agonist: receptor occupation + biological response
Antagonist: receptor occupation + NO biological response
2
,The antagonist can bind to the active side (where agonist binds), but it doesn’t have
to. It can also bind at another place where it still blocks the binding of the agonist at
the receptor. So no effect will be reached.
In this image, the following applies:
- Agonist: acetylcholine - causes drop in blood
pressure
- Antagonist: atropine - blocks acetylcholine, thereby
preventing the drop in blood pressure
After an agonist binds to its receptor, the receptor undergoes a conformational
change that stabilizes the receptor-agonist complex. This conformational change
allows the receptor to interact with and activate a specific type of intracellular protein
called a G-protein.
Hill-Langmuir equation:
PA: fractional occupancy, which refers to the proportion of receptor binding sites that
are occupied by a ligand (such as a drug).
PA = 0 – none of the receptor binding sites are occupied
PA = 1 – all receptor binding sites are occupied by the ligand
XA: drug/ligand concentration
KA: binding constant = 50% of the compound is bound
2 EXAMPLES:
KA = 1 nM
XA = 1 nM
1 1
PA = 1+ 1 = 2 = 0.5
KA = 1 nM
XA = 10 nM
10 10
PA = 1+ 10 = 11 = 0.91
The lower the binding constant, KA, the less drug you need to occupy the receptors,
leading to less side effects. So KA is inversely corelated to affinity. When KA is low,
the affinity is high and vice versa.
Total bindings = non-specific bindings + specific bindings
- Non-specific binding: linear curve
- Specific binding: sigmoid curve
3
, The radioactive ligand binds to b-receptors (specific) but it also binds to proteins and
membranes (non-specific). The experiment can be performed with b-blockers
(propranolol), which prevents the binding of radioactive ligands to the b-receptors. So
the radioactive ligand can now only bind
to proteins and membranes. The non-
specific binding is now determined and
can be subtracted from the total bindings
to determine the specific binding.
SCATSCHARD PLOT!
The following 2 terms have to do with EFFECT, not binding. Since an agonist can
only cause an effect, it is about agonists.
Effect – E.
Efficacy – Emax: maximum biological effect of drug.
Potency – EC50: drug concentration where the biological effect is 50% of its own
maximal effect.
Drug A has a greater potency than drug B since it elicits
a half-maximal effect at a lower concentration. Drug A
and B exhibit the same efficacy (maximal effect – 1.0).
Most potent drug: the drug that achieves 50% biological
effect at the lowest drug concentration.
Occupation theory: effect (EA) is proportional to occupancy (NA).
EA = NA x ε
ε = intrinsic efficacy = 0 - 1
ε = 1: full agonist = full effect)
ε = 0 – 1: partial agonist/partial antagonist = partial effect)
ε = 0: full antagonist = no effect)
The graphs are ALWAYS in log scale since it is easier to get information about EC 50.
4
LECTURE 1
Pharmacology: interactions of chemical substances (drugs) with the living organism
Drug: chemical applied to a physiological system that affects its function in a specific
way
2 important concepts in pharmacology:
- Pharmacodynamics – how drugs affect the body
- Pharmacokinetics – how the body affects the drugs
Pharmacodynamics refers to the study of how drugs interact with the body and
produce their therapeutic or toxic effects. It explores the relationship between drug
concentration at the site of action and the resulting pharmacological response.
On the other hand, pharmacokinetics focuses on the study of the movement of drugs
within the body, including their absorption, distribution, metabolism, and excretion
(ADME). Pharmacokinetics helps to determine how the body processes a drug, which
in turn affects its concentration at the site of action and its overall therapeutic effect.
Non-specific drug actions:
- Biological effect at relatively high drug concentrations
Non-specific drug actions are generally not related to specific targets or receptors but
instead result from the general chemical or physical properties of the drug itself.
Specific drug actions:
- Biological effect at relatively low drug concentrations
However, the primary mode of action for most drugs involves specific interactions
with receptors, ion channels, enzymes, or transporters/carriers in the body. These
specific interactions allow drugs to produce their desired effects by modulating
specific biochemical processes. Most drugs act on target proteins with high affinity to
the drug.
Receptors: target molecules whose function is to recognize and respond to specific
endogenous chemical signals, such as hormones, neurotransmitters and
inflammatory mediators. Receptors play a crucial role in cell communication. They
allow cells to respond to signals from their external environment or from other cells in
a highly specific and controlled manner.
Receptor interactions: By binding to receptors, drugs can either activate or inhibit
their function, altering cellular signaling and producing a desired response. For
example, beta-blockers bind to beta-adrenergic receptors and block the effects of
adrenaline, resulting in decreased heart rate and blood pressure.
1
,Enzyme interactions: Some drugs can inhibit or enhance the activity of specific
enzymes in the body. This can affect biochemical pathways and processes within
cells. For instance, statins inhibit the enzyme HMG-CoA reductase, which is involved
in cholesterol synthesis, leading to reduced cholesterol levels.
Transporter interactions: Drugs can interact with membrane transporters, affecting
the movement of molecules into or out of cells. This interaction can alter the
concentration of certain substances in specific tissues or organs. For example,
selective serotonin reuptake inhibitors (SSRIs) block the reuptake transporter for
serotonin, increasing its concentration in the synaptic cleft and enhancing its effects.
Reciprocal – bidirectional, thus a two-way relationship.
Reciprocal specificity of receptor-drug interaction: individual classes of drugs bind to
discrete receptors, while individual receptors recognize only discrete classes of
drugs. There is high specificity by high affinity.
However, no drugs are completely specific in their action, which leads to side effects.
Side effects may occur at relatively high drug concentrations, due to binding to other
targets (receptors) with lower affinity.
- Off-target side effects
- On-target side effects
Off-target side effects, also known as non-specific side effects, refer to the effects
that occur when a drug interacts with other targets or receptors in the body besides
its intended target. At relatively high drug concentrations, drugs may also bind to
other receptors or targets in the body with lower affinity. This can lead to side effects
or unintended actions. These off-target interactions can occur when the drug
concentration is significantly higher than what is required for its intended therapeutic
effect.
On-target side effects, also known as specific side effects, are effects that occur as a
direct result of the drug's intended interaction with its target receptor or pathway. On-
target side effects can occur when the drug's intended target is also present in
tissues or organs where the drug's effect is not desired. Example:
B-receptor in the lung - relaxing bronchial smooth muscle
B-receptor in the heart - increasing heart rate
When you apply a drug that binds to B-receptors, it causes a therapeutic effect in the
lung, but it also causes side effects in the heart. Since there are b-receptors present
in both the lungs and the heart.
Agonist: receptor occupation leads to biological response
Antagonist: receptor occupation does not lead to response and prevents the effect of
an agonist, mostly by preventing it from binding
Agonist: receptor occupation + biological response
Antagonist: receptor occupation + NO biological response
2
,The antagonist can bind to the active side (where agonist binds), but it doesn’t have
to. It can also bind at another place where it still blocks the binding of the agonist at
the receptor. So no effect will be reached.
In this image, the following applies:
- Agonist: acetylcholine - causes drop in blood
pressure
- Antagonist: atropine - blocks acetylcholine, thereby
preventing the drop in blood pressure
After an agonist binds to its receptor, the receptor undergoes a conformational
change that stabilizes the receptor-agonist complex. This conformational change
allows the receptor to interact with and activate a specific type of intracellular protein
called a G-protein.
Hill-Langmuir equation:
PA: fractional occupancy, which refers to the proportion of receptor binding sites that
are occupied by a ligand (such as a drug).
PA = 0 – none of the receptor binding sites are occupied
PA = 1 – all receptor binding sites are occupied by the ligand
XA: drug/ligand concentration
KA: binding constant = 50% of the compound is bound
2 EXAMPLES:
KA = 1 nM
XA = 1 nM
1 1
PA = 1+ 1 = 2 = 0.5
KA = 1 nM
XA = 10 nM
10 10
PA = 1+ 10 = 11 = 0.91
The lower the binding constant, KA, the less drug you need to occupy the receptors,
leading to less side effects. So KA is inversely corelated to affinity. When KA is low,
the affinity is high and vice versa.
Total bindings = non-specific bindings + specific bindings
- Non-specific binding: linear curve
- Specific binding: sigmoid curve
3
, The radioactive ligand binds to b-receptors (specific) but it also binds to proteins and
membranes (non-specific). The experiment can be performed with b-blockers
(propranolol), which prevents the binding of radioactive ligands to the b-receptors. So
the radioactive ligand can now only bind
to proteins and membranes. The non-
specific binding is now determined and
can be subtracted from the total bindings
to determine the specific binding.
SCATSCHARD PLOT!
The following 2 terms have to do with EFFECT, not binding. Since an agonist can
only cause an effect, it is about agonists.
Effect – E.
Efficacy – Emax: maximum biological effect of drug.
Potency – EC50: drug concentration where the biological effect is 50% of its own
maximal effect.
Drug A has a greater potency than drug B since it elicits
a half-maximal effect at a lower concentration. Drug A
and B exhibit the same efficacy (maximal effect – 1.0).
Most potent drug: the drug that achieves 50% biological
effect at the lowest drug concentration.
Occupation theory: effect (EA) is proportional to occupancy (NA).
EA = NA x ε
ε = intrinsic efficacy = 0 - 1
ε = 1: full agonist = full effect)
ε = 0 – 1: partial agonist/partial antagonist = partial effect)
ε = 0: full antagonist = no effect)
The graphs are ALWAYS in log scale since it is easier to get information about EC 50.
4
