Law of Mass Action

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.
k1
[D] + [R]  [DR]
k2
D = drug
R = receptor,
DR = drug-receptor complex k2 = KD = [D][R]
k1 = rate for association and k1 [DR]
k2 = rate for dissociation.
KD = Dissociation Constant 1 = KA = k1 = [DR]
KA = Association Constant
KD k2 [D] [R]
www.freelivedoctor.com
SATURATION CURVE
Drug-Receptor Complex
DR
[Drug] nM
Log [Drug]
SATURATION CURVE
[DR] max
RT = Bmax
[DR]
k2 = KD = [D][R]
k1 [DR]
[Drug] nM
RT = Total number of receptors

Bmax = Maximal number of receptors Bound www.freelivedoctor.com
TIME COURSE
[D] + [R] = [DR]
Equilibrium
[DR]
k2 = KD = [D][R]
k1 [DR]
0 10 20 30 40 50 60
Time (min)
KD = Equilibrium Dissociation Constant

SATURATION CURVE
[DR]
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
+++ ++- ---
--- +-- +++
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
• Reversible
• Irreversible
1. 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 with heparin and inactivates it.
Competition Binding
IC50
Log [I] nM
Binding of Drug D I = Competitor

Competition Binding
Four drugs
A B C D
IC50
Log [I] nM
RANK ORDER OF POTENCY: A > B > C > D

SEMILOG DOSE-RESPONSE CURVE
Response
Effect or
Drug Concentration
Maximal Effect
50% Effect
Response
Effect or
ED50
Drug Concentration
Maximal Effect
EFFECT
EFFICACY
POTENCY
ED50
Log [Dose]
A B C D
EFFECT
Log [Dose]

A C
B
D
RESPONSE
ED50

RANK ORDERwww.freelivedoctor.com
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.freelivedoctor.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
Effect KD
Bmax
1
1
KD
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
Frequency of distribution
% population responding to drug A
% population responding
1 10 20 30 40 50 60 70 80 90 100
Dose (mg/kg)
Quantal Dose-response Curves
Cumulative distribution of population responding to

drug A % population responding
ED50
ED10 ED90
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%www.freelivedoctor.com
of the population.
Therapeutic Index
ED99
Toxic effect
ED1
ED13
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.
k1
[D] + [R]  [DR] (1)
k2
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 = dissociation rate
k1 [D][R] = k2 [DR] (2)
k2 = [D][R]
k1 [DR] (3)
k2 = KD = [D][R]
k1 [DR] (4)
Where KD is the equilibrium dissociation constant. The units for the KD are
concentration units (e.g. nM). www.freelivedoctor.com
Law of Mass Action
Another constant related to the KD is the affinity (KA) which is essentially
equivalent to the reciprocal of the KD. The units for the KA are inverse
concentration units (e.g. nM-1).
1 = KA = k1 = [DR]
KD k2 [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 = [D][R]
[DR] (6)
KD [DR] = [D][R] (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)
[DR] = [D][RT] (13)

[D] + KD
RT: Total number of receptors
Law of Mass Action
[DR] = [D][RT] (13)
[D] + KD
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 KM denotes the Michaelis
constant, which is equivalent to the concentration of substrate required for half-
maximal velocity

Law of Mass Action

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Law of Mass Action

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Law of Mass Action

When a drug (D) combines with a receptor (R), it does so

RT = Total number of receptors

[D] + [R] = [DR]

KD = Equilibrium Dissociation Constant

At equilibrium, the dissociation constant is KD and the affinity is K A = 1/KD

+++ ++- ---

--- +-- +++

• Its intrinsic activity is = 1, but on another receptor.

Glucocorticoid Hormones  Blood Sugar

• A chemical antagonist does not depend on interaction with

Heparin, an anticoagulant, acidic

Binding of Drug D I = Competitor

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

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

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

RECEPTOR RESERVE OR SPARE RECEPTORS.

Cumulative distribution of population responding to

Standard Margin of safety = TxD1–1 x 100

Which determines the percent to which the dose

k2 = rate for dissociation.

association rate = dissociation rate

k1 [D][R] = k2 [DR] (2)

KD [DR] = [D][R] (7)

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)

[DR] = [D][RT] (13)

RT: Total number of receptors

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