Week 2 Lecture Handout

PHMD 210
Pharmacodynamics
Week 2
Learning Outcomes
By the end of this week and after completing the required reading and
homework, you will be able to:
1. Define receptor, dissociation constant, affinity, intrinsic activity

2. Draw a dose response curve and a log dose response curve.
3. Determine potency and intrinsic activity of drugs using dose response
curve.
4. Define spare receptors.
5. Apply knowledge to compare affinity, potency, and efficacy of different
drugs
Drug Actions
General Concept of Drug Receptors/targets
 Receptor: Macromolecule on, or in, cells with which
hormones/drugs/transmitters interact to modulate cell function
 Binding of drugs to receptors initiates biochemical reactions
 Pharmacological effect is due to the alteration of an intrinsic

physiologic process and not the creation of a new process
1. Proteins
a. Receptors (specific definition)
b. Carriers
c. Enzymes
d. Ion Channels
2. Nucleic acids DNA/RNA
Types of Receptors (specific definition)
Membrane Bound Receptors
 Ligand-gated ion channel receptors
• Nicotinic, GABA, glutamate
 G-Protein-linked receptors
• Serotonin, Muscarinic, Dopaminergic, Noradrenergic
 Enzyme receptors
• Tyrosine kinase (Growth factors receptors, Insulin receptors)
Intracellular And Nuclear Receptors

 Hormone receptors
 Lipophilic vitamins receptors
Receptor Signaling Pathways
Drug-Receptor Interactions
Physicochemical and steric interactions
Chemical Bonds
1) Covalent
2) Lipophilic
3) Ionic
4) Hydrogen bonds
5) Vander waals
Drug-Receptor Interactions
• Drug-receptor interactions serve as signals to trigger a cascade of events.
• Signaling pathway is a collection of many cellular responses which serve to

amplify the signal and produce a final effect.
• Effectors are thus the molecules that translate the drug-receptor interaction
into changes in cellular activity.
Theory of drug-receptor
interactions
Theory of drug-receptor interactions
• Drug Receptor interaction follows simple mass-action relationships, i.e.

only one drug molecule occupies each receptor and binding is reversible
(there are some exceptions).
• For a given drug, the magnitude of the response is proportional to the

fraction of total receptor sites occupied by drug molecules.
• Combination or binding to receptor causes some event which leads to a

response.
• Response to a drug is dose-dependent.

Drug-receptor Interaction
• Specificity (Selectivity)
– Specific affinity for certain receptors (vs. others)
• Affinity
– Propensity of a drug to bind with a receptor
Specificity of Drug
NT: Neurotransmitter
NT
Receptor A
• Same NT can bind to different -R
– different part of NT
NT
Receptor A Receptor B
Specificity of drugs
NT
Drug A
Drug B
Receptor A Receptor B
Drug-receptor interaction
• In most cases the binding is transient, i.e. the drug molecule
binds and dissociates, binds again and so on.
• Each binding triggers a signal
Drug molecule
A
Equilibrium
between drug
molecule and its A
receptor –
association and Receptor
dissociation
If we put two drugs (A

Drug molecule & B) acting at the same
A A
receptor, they will
Equilibrium compete for the
between drug A receptor due to the
A transient binding.
molecule and its B
receptor – The drug with a higher
association and Receptor concentration will have
dissociation a greater chance of
binding
Quantifying Drug Effects
1. Affinity – describes “tightness” of interaction between a

receptor and drug
2. Efficacy – describes the “strength” or “extent” of the
pharmacological effect
3. Potency – in clinical settings, reflects both 1 and 2.
1. Amount of drug required to produce 50% of the maximal
response the drug
2. Used to compare compounds within classes of drugs
Equation for drug-receptor interaction
Affinity is the measure of propensity of a drug to bind receptor; the force of
attraction between drug and receptor
Where:
D = free drug concentration

R = free receptor concentration
DR = concentration of drug-receptor complex
Rt = total receptor concentration
R= Rt - DR
Where:

Rt = total receptor concentration
R= Rt - DR
Where:

Rt = total receptor concentration (OR called Rmax)
R= Rt - DR
Affinity of Drugs
Equation for Drug Affinity
At equilibrium:
[D] x [R] x k1 = [DR] x k2
At equilibrium:
[D] x [R] x k1 = [DR] x k2
At equilibrium:
[D] x [R] x k1 = [DR] x k2
- or -
At equilibrium:
[D] x [R] x k1 = [DR] x k2
- or -
k1/k2 = affinity constant (ka)

k2/k1 = dissociation constant (kd)
At equilibrium:
[D] x [R] x k1 = [DR] x k2
- or -
k1/k2 = affinity constant (ka)

k2/k1 = dissociation constant (kd)
kd = k2/k1 the lower the kd the more affintiy the drug has for the
receptor
Kd – concentration of a drug that occupies 50% of the total number of
receptors at equilibrium
Kd – concentration of a drug that occupies 50% of the total number of
receptors at equilibrium
• The concentration of DR is affected by both [D] and [R]!

• Therefore receptor density will affect the dose response.
• The more receptors are present, the more leftward shifted will be the dose
response curve.
Affinity of Drug (Summary)
[ DR] [ D]

Rt K D  [ D]
[ DR] [ D] [ D].Rt
 [ DR] 
Rt K D  [ D] K D  [ D]
• Kd – concentration of a drug that occupies 50% of the total
number of receptors at equilibrium
The equation states that the amount of drug bound to the receptor is
dependent on the drug concentration and Kd.
Efficacy
The Concept Intrinsic Activity
Efficacy
Efficacy: (Power, or Intrinsic Activity)

A measure of the efficiency in which a bound ligand activates its target receptor’s
signal transduction/biological response.
Ability of a bound drug to change the receptor in a way that produces an effect;
ability of drug to produce a response
Some drugs possess affinity but NOT efficacy

Efficacy
Efficacy: (Power, or Intrinsic Activity)

A measure of the efficiency in which a bound ligand activates its target receptor’s
signal transduction/biological response.
Ability of a bound drug to change the receptor in a way that produces an effect;
ability of drug to produce a response
Some drugs possess affinity but NOT efficacy

Dose-response curves
Emax – maximal effect produced by a drug. It is

a measure of efficacy of a drug
EC50 is the concentration of drug

that produces a response one-half
of the maximum response. It is measure of
potency of a drug
Since the magnitude of the response of a “receptor” to a drug must be
proportional to the concentration of bound drug, therefore,
1) Response and drug binding curves are similar
2) EC50 is related to KD.
Since the magnitude of the response of a “receptor” to a drug must be
proportional to the concentration of bound drug, therefore,
1) Response and drug binding curves are similar
2) EC50 is related to KD.
Potency
• Potency: An overall measure of the ability of a ligand to
activate its target receptor.
• Related to the EC50; the concentration at which a half
maximal effect is achieved.
• Has little clinical significance for a given therapeutic effect
• A more potent of two drugs is not clinically superior
• Low potency is a disadvantage only if the dose is so large that

it is awkward to administer
Relative Efficacy, Potency and Affinity
We use:
Kd to compare affinity
Emax to compare efficacy
EC50 eo compare potency
Relative Affinity, Efficacy and Potency
Examples
Examples
Examples
100 Hyd rom orphine
Morp hine
Cod eine
Aspirin
10 50 100
log Dose (m g)
Concept of Spare Receptors
• Spare receptors allow maximal response without total receptor
occupancy – increase sensitivity of the system
• Not all of the receptors in the tissue are required to achieve a

maximal response
• Spare receptors can bind (and internalize) extra ligand preventing

an exaggerated response if too much ligand is present
EC50, Kd and spare receptors
Here there are a total of 10 receptors
10 receptors produce
maximal response
5 receptors produce
half-maximal
response
EC50 = concentration that produces half-maximal response (5 receptors)
Kd = concentration that occupies 50% of receptors (5 receptors)
In this case EC50 = Kd ; there are no spare receptors

Here there are a total of 20 receptors
But only 10 are required to produce a maximal response
10 receptors produce
maximal response
5 receptors produce
half-maximal
response
EC50 = concentration that produces half-maximal response (5 receptors)
Kd = concentration that occupies 50% of receptors (10 receptors)
When EC50 < Kd ; it suggests existence of spare receptors

When all receptors need to be occupied for a full response: then EC50 = Kd i.e.
the concentration of a drug which produces half-maximal response (EC50) will
equal the concentration that occupies half the number of total receptors (Kd)
In the presence of spare receptors: the effect ‘precedes’ receptor saturation in
cascade systems
Example:
Rat heart contractility and b-
adrenergic receptors 50% response
at 1-3% receptor occupancy

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PHMD 210

1. Define receptor, dissociation constant, affinity, intrinsic activity

 Binding of drugs to receptors initiates biochemical reactions

 Pharmacological effect is due to the alteration of an intrinsic

Intracellular And Nuclear Receptors

• Signaling pathway is a collection of many cellular responses which serve to

• Drug Receptor interaction follows simple mass-action relationships, i.e.

• For a given drug, the magnitude of the response is proportional to the

• Combination or binding to receptor causes some event which leads to a

• Response to a drug is dose-dependent.

If we put two drugs (A

1. Affinity – describes “tightness” of interaction between a

D = free drug concentration

D = free drug concentration

D = free drug concentration

k1/k2 = affinity constant (ka)

k1/k2 = affinity constant (ka)

• The concentration of DR is affected by both [D] and [R]!

Efficacy: (Power, or Intrinsic Activity)

Some drugs possess affinity but NOT efficacy

Efficacy: (Power, or Intrinsic Activity)

Some drugs possess affinity but NOT efficacy

Emax – maximal effect produced by a drug. It is

EC50 is the concentration of drug

• A more potent of two drugs is not clinically superior

• Low potency is a disadvantage only if the dose is so large that

100 Hyd rom orphine

• Not all of the receptors in the tissue are required to achieve a

• Spare receptors can bind (and internalize) extra ligand preventing

EC50 = concentration that produces half-maximal response (5 receptors)

Kd = concentration that occupies 50% of receptors (5 receptors)

In this case EC50 = Kd ; there are no spare receptors

EC50 = concentration that produces half-maximal response (5 receptors)

Kd = concentration that occupies 50% of receptors (10 receptors)

When EC50 < Kd ; it suggests existence of spare receptors

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