drug receptor interactions
TRANSCRIPT
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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 = drugR = receptor, DR = drug-receptor complex
k1 = rate for association and
k2 = rate for dissociation.
KD = Dissociation Constant
KA = 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
Com
plex
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 60
Time (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 Antagonists
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.www.freelivedoctor.com
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Competition Binding
Log [I] nM
IC50
Binding of Drug D I = Competitorwww.freelivedoctor.com
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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
Eff
ect
or
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Drug Concentration
Res
pons
e
SEMILOG DOSE-RESPONSE CURVE
ED50
50% Effect
Maximal EffectEff
ect
or
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SEMILOG DOSE-RESPONSE CURVEEFFEC
T
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
EFFEC
T
Log [Dose]
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SEMILOG DOSE-RESPONSE CURVE
RANK ORDER OF POTENCY: A > B > C > D
RANK ORDER OF EFFICACY: A = C > B > D
A
B
C
D
RES
PO
NS
E
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
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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
1
Bmax
KD
Bmax
1
[D]
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Agonists and Antagonists
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.
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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
opu
lati
on r
esp
ondin
g
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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
opu
lati
on r
esp
ondin
g
ED50ED90ED10
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Therapeutic IndexToxic
eff
ect
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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.
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Therapeutic IndexToxic
eff
ect
ED99
ED13ED1
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APPENDIX
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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 = drugR = receptor, DR = drug-receptor complex
k1 = rate for association and
k2 = rate for dissociation. www.freelivedoctor.com
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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
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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)www.freelivedoctor.com
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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 receptors www.freelivedoctor.com
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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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