Drug-Receptor Interactions PHARM Lec1B

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

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. D = drug R = receptor, DR = drug-receptor complex k 1 = rate for association and k 2 = rate for dissociation. K D = Dissociation Constant K A = Association Constant   Read the Appendix at the back k 1 [D] + [R]  [DR] k 2 k 2 = K D = [D][R] k 1 [DR] 1 = K A = k 1 = [DR] K D k 2 [D] [R] www.indiandentalacademy.com

SATURATION CURVE:

Log [Drug] Drug-Receptor Complex SATURATION CURVE [Drug] nM DR www.indiandentalacademy.com

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SATURATION CURVE [DR] [Drug] nM R T = Bmax R T = Total number of receptors Bmax = Maximal number of receptors Bound k 2 = K D = [D][R] k 1 [DR] [DR] max www.indiandentalacademy.com

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TIME COURSE [DR] Equilibrium K D = Equilibrium Dissociation Constant k 2 = K D = [D][R] k 1 [DR] [D] + [R] = [DR] 0 10 20 30 40 50 60 Time (min) www.indiandentalacademy.com

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SATURATION CURVE [Drug] nM [DR] K D At equilibrium, the dissociation constant is K D and the affinity is K A = 1/K D Thus when [D] = K D , half the total number of receptors will be occupied. www.indiandentalacademy.com

Agonists and Antagonists:

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 www.indiandentalacademy.com

Agonists and Antagonists:

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 www.indiandentalacademy.com

Agonists and Antagonists:

Agonists and Antagonists PHARMACOLOGICAL ANTAGONISTS Competitive They compete for the binding site Reversible Irreversible Non-competitve Bind elsewhere in the receptor (Channel Blockers). www.indiandentalacademy.com

Agonists and Antagonists:

Agonists and Antagonists FUNCTIONAL ANTAGONISTS Physiologic Antagonists Chemical Antagonist www.indiandentalacademy.com

Agonists and Antagonists:

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 www.indiandentalacademy.com

Agonists and Antagonists:

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.indiandentalacademy.com

Competition Binding:

Competition Binding Log [I] nM IC50 Binding of Drug D I = Competitor www.indiandentalacademy.com

Competition Binding:

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

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Drug Concentration Response SEMILOG DOSE-RESPONSE CURVE Effect or www.indiandentalacademy.com

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Drug Concentration Response SEMILOG DOSE-RESPONSE CURVE ED50 50% Effect Maximal Effect Effect or www.indiandentalacademy.com

SEMILOG DOSE-RESPONSE CURVE:

SEMILOG DOSE-RESPONSE CURVE EFFECT POTENCY EFFICACY ED50 Maximal Effect Log [Dose] www.indiandentalacademy.com

SEMILOG DOSE-RESPONSE CURVE:

SEMILOG DOSE-RESPONSE CURVE RANK ORDER OF POTENCY: A > B > C > D A B C D EFFECT Log [Dose] www.indiandentalacademy.com

SEMILOG DOSE-RESPONSE CURVE:

SEMILOG DOSE-RESPONSE CURVE RANK ORDER OF POTENCY: A > B > C > D RANK ORDER OF EFFICACY: A = C > B > D A B C D RESPONSE ED50 www.indiandentalacademy.com

Agonists and Antagonists:

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. www.indiandentalacademy.com

Agonists and Antagonists:

Agonists and Antagonists 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

Agonists and Antagonists:

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. www.indiandentalacademy.com

Agonists and Antagonists:

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

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Drug Concentration LINEWEAVER-BURKE PLOT 1 1 K D 1 Effect 1 Bmax K D Bmax 1 [D] www.indiandentalacademy.com

Agonists and Antagonists:

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. www.indiandentalacademy.com

Quantal Dose-response Curves:

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) % population responding www.indiandentalacademy.com

Quantal Dose-response Curves:

Quantal Dose-response Curves Cumulative distribution of population responding to drug A 1 10 100 Dose (mg/kg) log scale % population responding ED50 ED90 ED10 www.indiandentalacademy.com

Therapeutic Index:

Therapeutic Index Toxic effect www.indiandentalacademy.com

Therapeutic index:

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. www.indiandentalacademy.com

Therapeutic Index:

Therapeutic Index Toxic effect ED99 ED13 ED1 www.indiandentalacademy.com

WEB Sites:

WEB Sites Howard University Howard University Site.htm HU College of Medicine.htm HUCM Departments.htm pharmacology.htm Pharmacology Course Materials.htm www.indiandentalacademy.com

APPENDIX:

APPENDIX www.indiandentalacademy.com

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. k 1 [D] + [R]  [DR] (1) k 2 D = drug R = receptor, DR = drug-receptor complex k 1 = rate for association and k 2 = rate for dissociation.   www.indiandentalacademy.com

Law of Mass Action:

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   k 1 [D][R] = k 2 [DR] (2)   k 2 = [D][R] k 1 [DR] (3)   k 2 = K D = [D][R] k 1 [DR] (4)   Where K D is the equilibrium dissociation constant. The units for the K D are concentration units (e.g. nM). www.indiandentalacademy.com

Law of Mass Action:

Law of Mass Action Another constant related to the K D is the affinity (K A ) which is essentially equivalent to the reciprocal of the K D . The units for the K A are inverse concentration units (e.g. nM -1 ).   1 = K A = k 1 = [DR] K D k 2 [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:   K D = [D][R] [DR] (6)   K D [DR] = [D][R] (7) www.indiandentalacademy.com

Law of Mass Action:

Law of Mass Action Substitutions: [R T ] = [R] = [DR] … [R] = [R T ] - [DR] (8)   K D [DR] = [D]([R T ] - [DR]) (9)   K D [DR] = [D][R T ] - [D][DR] (10)   K D [DR] + [D][DR] = [D][R T ] (11) [DR](K D + [D]) = [D][R T ] (12) [DR] = [D][R T ] (13) [D] + K D R T : Total number of receptors www.indiandentalacademy.com

Law of Mass Action:

Law of Mass Action [DR] = [D][R T ] (13) [D] + K D   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] V max [S] + K M   Michaelis-Menten Relationship    where V max 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 www.indiandentalacademy.com

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Thank You www.indiandentalacademy.com Leader in continuing dental education www.indiandentalacademy.com

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