Lecture_2-Basic_Pharmacological_Principles

Direct consequence of the drug-receptor interaction

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Unformatted text preview: direct consequence of the drug-receptor interaction – Amount of drug that interactions with receptors is negligible compared to the amount of drug to which the receptors are exposed; effective drug concentration does not change during drug-receptor interaction Quantitative aspects of drug-receptor interactions • C = concentration of drug (=concentration of the drug which is essentially equal to that of unbound drug) • Y = % of total number of receptors occupied by a drug • (100-Y) = % unoccupied, free receptors • k1: constant specific for the given reaction of the drug/receptor combination • k2: constant specific for the reverse reaction of the given drug/receptor combination • The rate at which a drug-receptor complex is formed is proportional to the product of the concentration of the drug (C) and the amount of free receptors (100-Y) – Rate of drug-receptor combination = k1C(100-Y) • The rate of dissociation of a drug-receptor complex is proportion to the drug-receptor complex – Rate of dissociation of the drug-receptor combination = k2Y • In equilibrium, rate of combination = rate of dissociation k1C(100-Y) = k2Y or C= k2Y k1(100-Y) • Ratios of 2 constants is a constant, substitute Kd (dissociation constant) for k2/k1 C= Y Kd(100-Y) k1 Drug + free receptor Drug-receptor complex C (100-Y) k2 Y Radioligand binding assays: Used to estimate how much receptor might be in a given tissue and the affinity of the receptor for the drug 1) Homogenize (grind up) tissue of interest that contains your receptor (this liberates the cellular compartment that contains your receptor) 2) Incubate your tissue with increasing concentrations of a radioactive drug that is known to bind to your receptor or (if you are testing a new drug) that you suspect binds to your receptor 3) In control tissue, add your radioactive drug + a high concentration of a non- radioactive drug that is known to also bind to the receptor (non-specific binding control) 4) Wash off excess drug(s) 5) Measure radioactivity in samples from both conditions 2 curves 6) Subtract the area under the curve for your non-specific binding from that of your total binding Specific binding curve Quantitative aspects of drug-receptor interactions C= Y Kd(100-Y) Dose-response Log Dose-response Bmax =maximal binding=100% receptors are occupied ~ total number of receptors at target site Quantitative aspects of drug-receptor interactions C= Y Kd(100-Y) 1 binding site 2 binding sites Interpreting dose-effect curves • Assumes that the magnitude of response elicited by a drug is directly proportional to the number of receptors occupied by the drug – ?why are different doses of different drugs needed to achieve same effect? – Max effect = 100% of receptors are occupied – Kd must have different values for different drugs! • K d = measure of affinity of a drug for a particular receptor; effectiveness of drug-receptor interaction – Higher the affinity better the propensity to bind to a receptor, LOWER the Kd – The LOWER the value of Kd, the lower the concentration of drug needed to produce the same intensity of response as a drug with a higher Kd – Position of the curves along the X-axis is indicative of their relative affinities (higher affinities lie closer...
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direct consequence of the drug-receptor interaction –...

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