Pharmacology -1 (Y22/23) S2

Lecture 2
Pharmacodynamics …
Drug-Response Relationships

Dr. Rasha Tawfiq

The British University in Egypt - BUE

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Lecture outline
1) Characteristics of signal transduction.

2) Defining some pharmacological terms like drug potency, refractory receptors, spare

receptors, tachyphylaxis, receptor up- or down-regulation, receptor tolerance, constitutive

activity, LD50, ED50, EC50, TI & therapeutic window.

3) Differentiation of drugs regarding efficacy & potency.

4) Types of dose-response curves.

5) Determination of drug safety according to therapeutic index & therapeutic window.

Take notes from lecture 1:

1- Cells communicate together chemically through signaling molecules or electrically
through ions that cause an alteration in action potential as in neurons.
2- Most, but not all, drugs act by drug-receptor binding.
3- The effect of the signal (ligand) is determined also by the receiver, not only by the signal.
4- Receptors are either located on cell surface (transmembraneous) or intracellular.
5- Each receptor has its own active & inactive state.
6- All cell surface receptors have an extracellular domain for ligand binding &
transmembrane domain.
7- Lipophilic drugs can diffuse in the cell membrane & act on intracellular receptors, while
hydrophilic drugs act on cell surface receptors only.
8- Ligand-gated ion channel receptor conducts electric potential on activation by a
ligand, i.e. it converts a chemical signal into an electrical one.
9- The voltage-gated ion channel is a special type of ion channels.
10- GPCRs activate 2ry messengers.
11- GPCRs is a family of many subtypes Gs, Gi, Gq where each activates an effector.
12- Effector is a target component of an activated receptor, located inside a cell. It can be
an enzyme or an ion-channel.
13- Signal fades after ligand leaves the receptor & receptor return to its inactive state.
14- Drug-receptor binding needs to be reversible as to receive further signals.
15- Magnitude of drug response depends on the no. of drug-receptor complexes & its
intrinsic activity.

1 DR. RASHA TAWFIQ, 22/23, S2

Lecture 2

How can drugs produce their effects?

Through altering the normal functions of a cell or tissue via 1 of the following mechanisms:

1- Drugs can activate or inhibit enzymes activities

2- Drugs can interfere with the normal metabolism of naturally occurring metabolites
3- Chemical or physical interactions, e.g. antacids neutralize stomach hyperacidity;
osmotic agents act as laxatives to treat constipation; and chelators can chelate with
free radicals to protect the body from their harmful effects.
4- Drug interacts with a receptor, e.g. drugs activate or inhibit any of the 4 types of
receptors, where some of them involve series of signal transduction events.

State some characteristics of signal transduction

1- Signal amplification.
2- Signal counteraction.

1- Signal amplification
A characteristic of GPCRs and enzyme-linked receptors.

Is the ability to amplify signal intensity and duration via the signal cascade (like dominos)
effect. Additionally, activated G proteins persist for a longer duration than the original
agonist–receptor complex. For example, the binding of albuterol to its receptor may only
exist for a few milliseconds, but the subsequent activation of G proteins may last for
hundreds of milliseconds. Further prolongation and amplification of the initial signal are
mediated by the interaction between G proteins and their respective intracellular targets
(effectors).

In short, ligands acting via 2ry messengers are very effective in extremely small amounts.

What are spare receptors?

Due to signal amplification, not all the receptors of a certain ligand need to be occupied to
give 100% efficacy. The unoccupied receptors are considered SPARE receptors. They will be used
only in case of receptor damage or blockage, or if a very high demand for the receptors is
required.

e.g. Only 1 % of INSULIN RECEPTORS are enough to give max. efficacy, i.e. 99% of insulin
receptors are spare.

e.g. Only about 5 % - 10 % of total β-adrenergic receptors in the heart are spare.
Therefore, little receptor reserve exists in the failing heart because most receptors must be
occupied to obtain maximum contractility.

2 DR. RASHA TAWFIQ, 22/23, S2

2- Signal counteraction
Repeated or continuous administration of an agonist or antagonist may lead to changes in the
responsiveness of the receptor. The receptor may become desensitized due to too much agonist
(by receptor activating ligand) stimulation, resulting in a diminished response. On the other hand,
upon repeated exposure of a receptor to its antagonist (receptor blocker), the receptor may
become more sensitive to agonists and/or more resistant to the effect of antagonists, this is to
counteract the excessive stimulation exerted by a ligand or a blocker on a receptor. These
changes in response can occur through different mechanisms:

a. Tachyphylaxis

Is the desensitization (a decrease in sensitivity) of a receptor following excessive agonist

(ligand) stimulation to minimize agonist response. It often happens due to phosphorylation
that renders receptors unresponsive to the agonist.

b. Down-regulation

Decrease in receptors number due to repeated exposure to the agonist. These decrease
in no. of receptors may occur through a decrease in receptor synthesis or receptors may be
internalized inside the cell (which is called sequestration), making them unavailable for
further agonist interaction.

c. Up-regulation

An increase in the number of receptors available due to repeated exposure to an

antagonist. Receptor reserves are inserted across the membrane to expose more receptors to
the cell surface.

d. Super sensitization

Continuous or repeated exposure to antagonists may lead to an increase in the response

of the receptor to agonists and/or makes the receptor more resistant to the antagonist.

e. Tolerance

Diminished response to the same dose of a drug over days or weeks. It happens after
repeated doses. It occurs by 2 mechanisms, (i) tachyphylaxis and (ii) down-regulation. Thus,
tachyphylaxis is considered as rapid development of tolerance or “acute tolerance”.

What is a refractory receptor?

Some receptors, particularly ion channels, require a finite time following stimulation
before they can be activated again. During this recovery phase, unresponsive receptors
are said to be “refractory.”

3 DR. RASHA TAWFIQ, 22/23, S2

Drug-Receptor Interaction

Constitutive Activity
Remember

The intrinsic activity of a drug, which is known as “efficacy”, is the ability of an agonist to
activate its specific receptor.

The maximum activity “Emax” obtained by a drug depends on both, the number of drug-
receptor complexes & the intrinsic activity of the drug.

Receptors are present in an equilibrium between active & inactive states, trying to reach
the stable state (the “inactive” condition). Unbounded receptors are inactive (Rinactive)and require
an agonist to be active (Ractive).

Some receptors show a spontaneous conversion from Rinactive to Ractive in the absence of
an agonist. This is called “Constitutive Activity”.

Types of ligands according to their activity

There are 2 main types of ligands

1- Agonist

2- Antagonists

Agonists
They mimic the action of an endogenous ligand on a receptor.

They can bind to a specific receptor ----- high affinity

They can activate receptors ----- high efficacy

They have “Zero < intrinsic activity ≤ 1”

There are 3 types of agonists:

1- Full agonist

2- Partial agonist

3- Inverse agonist

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1- Full agonist
Has affinity

When binds to a receptor  maximal response (equal to the response of endogenous ligand)

Produces 100% efficacy at high dose, so its intrinsic activity = 1

E.g. phenylephrine is a full agonist at α1-adrenergic receptors, because it produces the same
Emax as the endogenous ligand, norepinephrine.

2- Partial agonist

Has affinity as it binds to the receptor but can only elicit a submaximal response (less than the
response of endogenous ligand).

Produces efficacy < 100% even at high dose, so it has Zero < intrinsic activity < 1.

N.B.

The partial agonist in the presence of a full

agonist  partially antagonizes the effect of
the full agonist.

The partial agonist in absence of a full

agonist  acts as a partial agonist.

3- Inverse agonists
They have affinity.

They stabilize the receptor that has

constitutive activity (spontaneous activity)
and cause Ractive to be converted into the
Rinactive. This decreases the number of the
activated receptors.

Inverse agonists have an intrinsic

activity < zero, reverse the activation state
of receptors, and exert the opposite
pharmacological effect of agonists, so their
http://europepmc.org/article/PMC/2855430
Emax can reach to -1.

5 DR. RASHA TAWFIQ, 22/23, S2

 Antagonists
They have no effect on biological functions in the absence of an agonist but can decrease the
effect of an agonist, if present, as they block the binding site of the receptor, hindering the
agonist from binding to the receptor. Some antagonists also prevent receptor activation
following agonist binding.

They can bind to a specific receptor ----- high affinity

They can’t activate the receptor ----- high no efficacy

Intrinsic activity = Zero

There are 2 types of antagonists

1- Physiological or functional --- when 2 agonists acting on 2 different receptors that
produce an opposing effect to the agonist
e.g. adrenaline (bronchodilator) antagonizes histamine (bronchoconstrictor)
2- Pharmacological ---- it can be divided into
a. Competitive
b. Non-competitive

a. Competitive antagonist b. Non-competitive antagonist

They can bind to the receptor in the same They can bind to the receptor at a site other
binding site of the agonist. than the agonist-binding site.

The binding between the receptor and the If the binding between the receptor and the
antagonist is weak (non-covalent bond) ---- antagonist is by covalent bond (strong) ----
reversible binding irreversible binding

Antagonist can be displaced by high dose Its effect can’t be overcome by high dose
of the agonist. of agonist.
It gives no effect, or it inhibits agonist effect It can hinder the binding of an agonist to its
receptor, or can prevent its activation after
agonist binding.

Lippincott’s 7th edition https://doctorlib.info/pharmacology/pharmacology-examination-board-review/2.html

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Dose-Responses Relationship
The relationship between the concentration of a drug and the magnitude of the response. It
can be presented in a graph form called dose-response curve (concentration-effect curve)
which is of 2 types

I. Graded dose-response curve

II. Quantal dose-response curve

I. Graded dose-response curve

A plot showing the relationship between the response of a patient against increasing doses of
a drug.

As the concentration of a drug increases  no. of drug-receptor complexes increases  the

pharmacological effect gradually increases (until all the receptors are occupied)  here it
reaches to the maximum effect.

When the response (effect) is plotted on Y-

axis against the concentration of the drug
on X-axis on a linear SCALE GRAPH PAPER, a
curve is produced that is often HYPERBOLIC.

When the response is plotted against the

logarithm of drug concentration on a
SEMILOG SCALE GRAPH PAPER, a curve is
produced that is SIGMOID (S shaped)

What data can be obtained from the graded dose response curve?
I. Potency (or EC50)
Is the concentration of a drug necessary to produce certain effect (for e.g. 50% effect), so it
is determined by EC50.

EC50: The concentration of a drug that produces

50% of the maximum response

 EC50 =  potency

II. Efficacy or Emax

The maximal response (Emax) or
efficacy is more important than drug
potency.

N.B.

A drug with greater efficacy is more beneficial therapeutically than one that is more potent.

7 DR. RASHA TAWFIQ, 21/22, S2

 II. Quantal dose-response curve

A plot showing the relationship between the dose of a drug and the percent of a population
of patients that respond to it.

It can be drawn with the drugs that their effect on a patient is ALL or NONE, e.g. antiepileptic
drugs inhibit seizures or not.

It is presented as a logarithmic graph.

What data can be obtained from the quantal dose response curve?

Used to determine doses to which most of the population responds, ED50, LD50, therapeutic
index (TI) & therapeutic window.

ED50 (Median Effective Dose): drug dose that causes

certain therapeutic response in 50% of the population

LD50 or TD50 (Median Lethal or Toxic Dose): drug

dose that produces toxic/lethal effect in 50% of the
human population or experimental animals.

Drug with  LD50 = Safe drug

Therapeutic Index (TI): the ratio between the dose

that produces toxicity in half the population (TD50) to
the dose that produces desired therapeutic response
in half the population (ED50).

i.e. TI= TD50 or LD50/ ED50

Therapeutic window: The dose range between the

minimum effective dose and the minimum toxic
dose.

N.B. The larger the therapeutic index and window,

the greater the safety margin. https://www.youtube.com/watch?v=rHh5V5BJMLA

E.g. If the average minimum therapeutic plasma concentration of theophylline is 8 mg/L and
the toxic effects are observed at 18 mg/L, then the therapeutic window of theophylline is 8-18
mg/L.

Question:

What happens on the dose-response curve of an agonist if it is given with an antagonist?

7 DR. RASHA TAWFIQ, 21/22, S2

Answer:

If the antagonist is competitive ----- it’ll shift the log dose-response

curve of the agonist to the right parallel to the original one ( EC50
while Emax is not changed i.e.  potency but with same efficacy).

If the antagonist is non-competitive ----- it’ll shift the log dose-

response curve downward from the right side parallel to the original
one (same EC50 while Emax is reduced i.e.  efficacy but with same
potency).

End of lecture
Dear Students …. Thank You

Some helpful video links

Signal amplification

https://www.youtube.com/watch?v=PQxQ1joKd1o
https://www.youtube.com/watch?v=wo_fXINA9U0
https://www.youtube.com/watch?v=PT5ptJZJ-58

Agonist and antagonist

https://www.youtube.com/watch?v=t8v4a0hbkjc
https://www.youtube.com/watch?v=w3d37cAL7VU

Types of antagonists

https://www.youtube.com/watch?v=nFfPAklivHU

Agonist DR Curves with Competitive and Noncompetitive Antagonist

https://www.youtube.com/watch?v=lyPNea1zduk
https://www.youtube.com/watch?v=p2xf1hYvvpg

Dose response curve

https://www.youtube.com/watch?v=cnnaKiXCHzE

Efficacy and potency

https://www.youtube.com/watch?v=t0OEm-cJs40

Therapeutic window

https://www.youtube.com/watch?v=rHh5V5BJMLA

9 DR. RASHA TAWFIQ – S2-21/22