Transcript
Law of Mass ActionWhen 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 = drugR = receptor, DR = drug-receptor complexk1 = rate for association and k2 = rate for dissociation.KD = Dissociation ConstantKA = Association Constant
k1
[D] + [R] [DR] k2
k2 = KD = [D][R] k1 [DR]
1 = KA = k1 = [DR] KD k2 [D] [R]
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Log [Drug]
Dru
g-R
ecep
tor C
ompl
ex
SATURATION CURVE
[Drug] nM
DR
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SATURATION CURVE
[DR]
[Drug] nM
RT = Bmax
RT = Total number of receptors
Bmax = Maximal number of receptors Bound
k2 = KD = [D][R] k1 [DR]
[DR] max
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TIME COURSE
[DR]
Equilibrium
KD = Equilibrium Dissociation Constant
k2 = KD = [D][R] k1 [DR]
[D] + [R] = [DR]
0 10 20 30 40 50 60Time (min)
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SATURATION CURVE
[Drug] nM
[DR]
KD
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.
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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
+ + + + + -
- - - + - -
- - -
+ + +
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Agonists and Antagonists
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
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Agonists and AntagonistsPHARMACOLOGICAL ANTAGONISTS
1. CompetitiveThey compete for the binding site
• Reversible• Irreversible
2. Non-competitveBind elsewhere in the receptor (Channel Blockers).
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Agonists and Antagonists
FUNCTIONAL ANTAGONISTS
1. Physiologic Antagonists
2. Chemical Antagonist
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Agonists and Antagonists
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
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Agonists and AntagonistsChemical 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.www.freelivedoctor.com
Competition Binding
Log [I] nM
IC50
Binding of Drug D I = Competitorwww.freelivedoctor.com
Competition Binding
RANK ORDER OF POTENCY: A > B > C > D
Log [I] nM
IC50
A B C D
Four drugs
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Drug Concentration
Res
pons
e
SEMILOG DOSE-RESPONSE CURVE
Effec
t or
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Drug Concentration
Res
pons
e
SEMILOG DOSE-RESPONSE CURVE
ED50
50% Effect
Maximal EffectEff
ect o
r
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SEMILOG DOSE-RESPONSE CURVEEF
FECT
POTENCYEFFICACY
ED50
Maximal Effect
Log [Dose]
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SEMILOG DOSE-RESPONSE CURVE
RANK ORDER OF POTENCY: A > B > C > D
A B C D
EFFE
CT
Log [Dose]
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SEMILOG DOSE-RESPONSE CURVE
RANK ORDER OF POTENCY: A > B > C > DRANK ORDER OF EFFICACY: A = C > B > D
A
B
C
D
RESP
ON
SE
ED50
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Agonists and Antagonists
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.
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Agonists and Antagonists1. COMPETITIVE ANTAGONIST
Reversible & SurmountableThe effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with afraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect. www.freelivedoctor.com
Agonists and Antagonists
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.
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Agonists and Antagonists1. COMPETITIVE ANTAGONIST
Irreversible & Non-surmountableThe effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors.
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Drug Concentration
LINEWEAVER-BURKE PLOT
1
1
KD
1
Effect
1Bmax
KD
Bmax
1
[D]
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Agonists and AntagonistsSynergismThe combined effect of two drugs is
higher than the sum of their individual effects.
AdditivityThe combined effect of two drugs is equal
to the sum of their individual effects.www.freelivedoctor.com
Quantal Dose-response Curves
Frequency of distribution % population responding to drug A
1 10 20 30 40 50 60 70 80 90 100
Dose (mg/kg)
% p
opul
atio
n re
spon
ding
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Quantal Dose-response Curves
Cumulative distribution of population responding to drug A
1 10 100
Dose (mg/kg) log scale
% p
opul
atio
n re
spon
ding
ED50ED90ED10
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Therapeutic IndexToxi c eff
ect
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Therapeutic indexTherapeutic Index = TxD50 ED50As 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.
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Therapeutic IndexToxi c eff
ect
ED99
ED13ED1
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APPENDIX
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Law of Mass ActionWhen 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 = drugR = receptor, DR = drug-receptor complexk1 = rate for association and
k2 = rate for dissociation. www.freelivedoctor.com
Law of Mass ActionAt 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 ActionAnother 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)
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Law of Mass ActionSubstitutions:
[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 receptorswww.freelivedoctor.com
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
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