Lecture 2 Dose Response Relationship 1

Dose Response Relationship & Therapeutic Index Dr Rizwan

quantal (cumulative) D/R curve tachyphylaxis graded (quantitative) D/R curve therapeutic index potency median toxic dose (TD50) efficacy (effectiveness) median effective dose (ED50) dose/response (D/R) Objectives

Systemic description of the magnitude of the effect of a drug as a function of the dose (very low to very high)

Dose response curves ,[object Object]

[object Object],[object Object],[object Object],[object Object]

Shape of the curve ,[object Object],[object Object],[object Object],[object Object],[object Object]

Threshold ,[object Object],[object Object]

BIOLOGICAL STIMULUS PERCENT RECEPTOR OCCUPANCY 0% 100% BIOLOGICAL RESPONSE RECEPTOR RESERVE TRETHOLD 0% 100% Max Effect Threshold Effect Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological response

When a threshold is difficult to determine ,[object Object],Why?

[object Object],[object Object],A relatively flat slope suggest that effect of an increasing dose is minimal

Dose Response Curve ,[object Object]

Is there any relationship between shape of curve and potency ,[object Object]

Reason for steep curve ,[object Object],[object Object],[object Object]

Used to measure ,[object Object],[object Object],[object Object]

POTENCY CONCENTRATION (EC50) OR DOSE (ED50) OF A DRUG REQUIRED TO PRODUCE 50% OF THAT DRUG’S MAXIMUM EFFECT

X 0 Average Response Magnitude DRUG DOSE Potency HI ,[object Object],A B

DRUG DOSE X 0 Average Response Magnitude HI LO Maximum Efficacy ,[object Object],A B

[D] (concentration units) % Maximal Effect 0.01 0.10 1.00 10.00 100.00 1000.00 0.0 0.2 0.4 0.6 0.8 1.0 Partial agonist Full Agonist Partial agonist PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ.

[object Object],[object Object]

Difference between the 3 drugs is their ,[object Object],ISOPROTERENOL > EPINEPHRINE > NOR EPINEPHRINE

[object Object],[object Object],[object Object]

What is the difference between Quantal and graded dose-response curves?

Graded (Quantitative) dose-effect relationships ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Graded dose response curves show effects on a continuous scale And the intensity of the effect is proportional to the dose

Exposure to ethanol Graded responses between no effect and death

Requirements ,[object Object],[object Object]

Plot of the contraction of the intestinal smooth muscle in response to varied doses of acetylcholine

Observation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Quantal (All-or-none; binary) dose-effect relationships ,[object Object],[object Object]

All or None ,[object Object],[object Object],[object Object],[object Object]

Defined specific effect and degree of response -- ,[object Object],[object Object],[object Object],[object Object]

Problem ,[object Object],[object Object]

Titration ,[object Object],[object Object],[object Object],[object Object]

Titration of each individual Administer increasing doses of drug to each individual until a response is elicited, then note the dose. Do this for all members of the test population. very impractical ------serious conceptual disadvantages, e.g., multiple doses of drug may produce a false effect compared to a single exposure to a larger dose. ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Shape of curve ,[object Object],[object Object]

Description of data ,[object Object]

Construction of quantal (binary) dose-effect curves ,[object Object],[object Object]

Method A: Titrate each animal Sample experiment ,[object Object],[object Object],[object Object],[object Object],[object Object]

BELL SHAPED CURVE majority of responders in the middle mean response is approx. 110 mg/kg fewer responders at the end of bell curve (expected) known as biological variability responders at the far left of the mean are typically hypersusceptible whereas those at the far right are resistant

Comments ,[object Object],[object Object],[object Object]

Method B -- Titration of groups ,[object Object],[object Object]

Sample experiment ,[object Object],[object Object],[object Object],[object Object],[object Object]

Cumulative quantal dose response plot

Both curves provide ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Quantal D/R curves used to define ,[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],Decision Making ,[object Object],[object Object],[object Object],LD 50 ED 50

[object Object],100 50 0 DRUG DOSE 0 X ED LD % subjects TI = LD 50 / ED 50

Lecture 2 Dose Response Relationship 1

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Lecture 2 Dose Response Relationship 1