Drug receptor interactions

DRUG RECEPTOR INTERACTIONS

INDIAN DENTAL ACADEMY
Leader in continuing dental education
www.indiandentalacademy.com

Law of Mass Action
When a drug (D) combines with a receptor (R), it
does so at a rate which is dependent on the
concentration of the drug and the concentration of the
receptor.
[D] + [R]

D = drug
R = receptor,
DR = drug-receptor complex
k1 = rate for association and
k2 = rate for dissociation.
KD = Dissociation Constant
KA = Association Constant

k2

=

k1
 [DR]
k2

KD =

k1
1

[D][R]
[DR]

=

KA =

KD


k1
k2

Read the Appendix at the back

=

[DR]
[D] [R]

Drug-Receptor Complex

DR

SATURATION CURVE

[Drug] nM

Log [Drug]

SATURATION CURVE
[DR] max

[DR]

RT = Bmax

k2

=

KD = [D][R]

k1

[Drug] nM

RT = Total number of receptors

Bmax = Maximal number of receptors Bound

[DR]

TIME COURSE
[D] + [R] = [DR]

[DR]

Equilibrium

k2

=

KD

k1

0

10

= [D][R]
[DR]

20

30

40

Time (min)

KD = Equilibrium Dissociation Constant

50

60

[DR]

SATURATION CURVE

KD

[Drug] nM

At equilibrium, the dissociation constant is KD and the affinity is K A = 1/KD
Thus when [D] = KD , half the total number of receptors will be occupied.

Agonists and Antagonists
AGONIST
• A drug is said to be an agonist when it binds to a receptor
and causes a response or effect.
It has intrinsic activity = 1

+++

++-

---

---

+--

+++


Depolarization

ANTAGONIST
• A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the receptor. An
antagonist has NO activity.
Its intrinsic activity is = 0


PHARMACOLOGICAL ANTAGONISTS
1.

Competitive
They compete for the binding site
•
•

2.

Reversible
Irreversible

Non-competitve
Bind elsewhere in the receptor (Channel Blockers).


FUNCTIONAL ANTAGONISTS
1. Physiologic Antagonists
2. Chemical Antagonist


Physiologic ANTAGONIST
• A drug that binds to a non-related receptor, producing an
effect opposite to that produced by the drug of interest.
• Its intrinsic activity is = 1, but on another receptor.
Glucocorticoid Hormones

 Blood Sugar

Insulin

 Blood Sugar


Chemical ANTAGONIST
• A chelator (sequester) of similar agent that interacts
directly with the drug being antagonized to remove it or
prevent it from binding its receptor.
• A chemical antagonist does not depend on interaction with
the agonist’s receptor (although such interaction may
occur).
Heparin, an anticoagulant, acidic
If there is too much  bleeding and haemorrhaging
Protamine sulfate is a base. It forms a stable
inactive complex www.indiandentalacademy.com
with heparin and inactivates it.

Competition Binding

IC50
Log [I] nM

Binding of Drug D www.indiandentalacademy.com
I = Competitor

Competition Binding
Four drugs

A

B

C

D

IC50
Log [I] nM

RANK ORDER OF POTENCY: A > B > C > D

Effect or
Response

SEMILOG DOSE-RESPONSE CURVE

Drug Concentration


Effect or
Response

Maximal Effect

50% Effect

ED50

Drug Concentration


EFFECT

Maximal Effect

EFFICACY
POTENCY

ED50

Log [Dose]

B

C

EFFECT

A

Log [Dose]


D

A

RESPONSE

B

C
D
ED50

RANK ORDER OF EFFICACY: A = C > B > D

PARTIAL AGONIST
• A drug is said to be a partial agonist when it binds
to a receptor and causes a partial response.
• It has intrinsic activity < 1.


1. COMPETITIVE ANTAGONIST
Reversible & Surmountable
The effect of a reversible antagonist can be
overcome by more drug (agonist). A small dose of
the antagonist (inhibitor) will compete with a
fraction of the
receptors thus,
the higher the
concentration of
antagonist used,
the more drug
you need to get
the same effect. www.indiandentalacademy.com

RECEPTOR RESERVE OR SPARE RECEPTORS.
• Maximal effect does not require occupation of all
receptors by agonist.
• Low concentrations of competitive irreversible
antagonists may bind to receptors and a maximal
response can still be achieved.
• The actual number of receptors may exceed the
number of effector molecules available.


1. COMPETITIVE ANTAGONIST
Irreversible & Non-surmountable
The effect of irreversible antagonists cannot be
overcome by more drug (agonist). The antagonist
inactivates the receptors.


LINEWEAVER-BURKE PLOT

1
KD

Effect
1
KD

Bmax
1
Bmax

11
Drug Concentration
[D]


Synergism
The combined effect of two drugs is higher
than the sum of their individual effects.

Additivity
The combined effect of two drugs is equal
to the sum of their individual effects.

Quantal Dose-response Curves

% population responding

Frequency of distribution
% population responding to drug A

1 10 20 30 40 50 60 70 80 90 100

Dose (mg/kg)

Quantal Dose-response Curves

% population responding

Cumulative distribution of population responding to
drug A

ED50
ED90

ED10
1

10

100

Dose (mg/kg) log scale

Therapeutic Index

Toxic effect


Therapeutic index
Therapeutic Index = TxD50
ED50
As long as the slopes of the curves are similar, however,
if not similar, we use the Standard Margin of safety:
Standard Margin of safety = TxD1–1 x 100
ED99
Which determines the percent to which the dose
effective in 99% of the population must be raised to
cause toxicity in 1% of the population.

Therapeutic Index
ED99

Toxic effect

ED1
ED13

WEB Sites
•
•
•
•
•
•

Howard University
Howard University Site.htm
HU College of Medicine.htm
HUCM Departments.htm
pharmacology.htm
Pharmacology Course Materials.htm


APPENDIX


Law of Mass Action
When a drug (D) combines with a receptor (R), it
does so at a rate which is dependent on the
concentration of the drug and the concentration of the
receptor.

[D] + [R]

k1

k2

[DR]

(1)

D = drug
R = receptor,
DR = drug-receptor complex
k1 = rate for association and
k2 = rate for dissociation.


Law of Mass Action
At equilibrium, the rate at which the radioligand binds to the receptor is equal to
the rate at which it dissociates:

association rate
k1 [D][R]
k2

=
=
=

k1
k2
k1

dissociation rate
k2 [DR]
[D][R]
[DR]

=

KD =

(2)

(3)

[D][R]
[DR]

(4)

Where KD is the equilibrium dissociation constant. The units for the K D are
concentration units (e.g. nM).

Law of Mass Action
Another constant related to the KD is the affinity (KA) which is essentially
equivalent to the reciprocal of the K D. The units for the KA are inverse
concentration units (e.g. nM-1).
1

=

KA

=

KD

k1
k2

=

[DR]
[D] [R]

(5)

The relationship between the binding of a drug to a receptor at equilibrium and the
free concentration of the drug provides the basis for characterizing the affinity of
the drug for the receptor. The mathematical derivation of this relationship is
given below:
KD

=

KD [DR] =

[D][R]
[DR]
[D][R]

(6)
(7)

Law of Mass Action
Substitutions:
…

[RT] = [R] = [DR]
[R] = [RT] - [DR]

(8)

KD[DR]

=

[D]([RT] - [DR])

(9)

KD[DR]

=

[D][RT] - [D][DR]

(10)

KD[DR] + [D][DR]

=

[D][RT]

(11)

[DR](KD + [D])

=

[D][RT]

(12)

=

[D][RT]
[D] + KD

(13)

[DR]

RT: Total number of receptors


Law of Mass Action
[DR]

=

[D][RT]
[D] + KD

(13)

This relationship between specific binding [DR] and the free drug concentration
[D] in (13) is essentially the same as the relationship between the substrate
concentration ([S]) and the velocity of an enzymatic reaction (v) as described by
the Michaelis-Menten relationship:
v =

[S] Vmax
[S] + KM

Michaelis-Menten Relationship
where Vmax denotes the maximum rate of the reaction and K M denotes the
Michaelis constant, which is equivalent to the concentration of substrate required
for half-maximal velocity

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Drug receptor interactions

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