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- 1. Dose Response Relationship & Therapeutic Index Dr Rizwan
- 2. 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
- 3. <ul><li>What is a dose response relationship? </li></ul>
- 4. Systemic description of the magnitude of the effect of a drug as a function of the dose (very low to very high)
- 5. Dose response curves <ul><li>The relationship of dose to response can be illustrated as a graph called as dose response curve. </li></ul>
- 6. <ul><li>Dose-response curves can be used to plot the results of many kinds of experiments. </li></ul><ul><li>The X-axis plots concentration of a drug or hormone. </li></ul><ul><li>The Y-axis plots response, which could be almost anything. </li></ul><ul><li>For example, the response might be enzyme activity, accumulation of an intracellular second messenger, membrane potential, secretion of a hormone, heart rate or contraction of a muscle. </li></ul>
- 7. Shape of the curve <ul><li>A standard dose-response curve is defined by four parameters: </li></ul><ul><li>the baseline response (Bottom), </li></ul><ul><li>the maximum response (Top), </li></ul><ul><li>the slope, and the </li></ul><ul><li>drug concentration that provokes a response halfway between baseline and maximum (EC50). </li></ul>
- 9. Threshold <ul><li>Important aspect of dose response relationship. </li></ul><ul><li>A dose below which there are no adverse effects from exposure to chemical. </li></ul>
- 10. 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
- 12. When a threshold is difficult to determine <ul><li>Look for slope of the dose response curve. </li></ul>Why?
- 13. <ul><li>A sharp increase in slope suggest </li></ul><ul><li>increasingly higher risk of toxic response as the dose increases </li></ul>A relatively flat slope suggest that effect of an increasing dose is minimal
- 14. Dose Response Curve <ul><li>Many dose-response curves follow exactly the shape of a receptor binding curve. As shown below, 81 times more agonist is needed to achieve 90% response than a 10% response. </li></ul>
- 16. <ul><li>Some dose-response curves however, are steeper or shallower than the standard curve. </li></ul><ul><li>The steepness is quantified by the Hill slope, also called a slope factor. </li></ul><ul><li>A dose-response curve with a standard slope has a Hill slope of 1.0. </li></ul><ul><li>A steeper curve has a higher slope factor, and a shallower curve has a lower slope factor. </li></ul>
- 18. Is there any relationship between shape of curve and potency <ul><li>A Steep curve even at a small dose suggest a chemical of high potency </li></ul>
- 19. Reason for steep curve <ul><li>Cooperative interaction of several different actions of drug </li></ul><ul><li>E.g. effect on brain, heart, and peripheral vessels, all contributing to lowering of blood pressure. </li></ul><ul><li>Coma caused by sedative hypnotics. </li></ul>
- 21. Used to measure <ul><li>Drug potency </li></ul><ul><li>Drug efficacy </li></ul><ul><li>Drug safety </li></ul>
- 22. POTENCY CONCENTRATION (EC50) OR DOSE (ED50) OF A DRUG REQUIRED TO PRODUCE 50% OF THAT DRUG’S MAXIMUM EFFECT
- 23. X 0 Average Response Magnitude DRUG DOSE Potency HI <ul><li>A is more potent than B </li></ul>A B
- 24. DRUG DOSE X 0 Average Response Magnitude HI LO Maximum Efficacy <ul><li>B has greater max efficacy than A </li></ul>A B
- 25. [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.
- 28. Example <ul><li>Isoproterenol, Epinephrine and Nor epinephrine all interact with the same receptor and produce the same maximal effect (efficacy). Thus isoproternol, epinephrine & nor epinephrine are equally effective (because all activate the same number of receptors and are described as full agonist) </li></ul>BUT
- 29. <ul><li>Dose response curve don’t look the same </li></ul><ul><li>What's different? </li></ul>
- 30. Difference between the 3 drugs is their <ul><li>POTENCY </li></ul>ISOPROTERENOL > EPINEPHRINE > NOR EPINEPHRINE
- 31. <ul><li>Types of dose response curves </li></ul><ul><li>Graded dose response curves </li></ul><ul><li>Quantal dose response curves </li></ul>
- 32. What is the difference between Quantal and graded dose-response curves?
- 33. Graded (Quantitative) dose-effect relationships <ul><li>A graph of the relationship between dose </li></ul><ul><li>and response. </li></ul><ul><li>minimum detectable response and a maximum </li></ul><ul><li>response by </li></ul><ul><li>varying the dose or drug concentration, </li></ul><ul><li>i.e., the curve is continuous. </li></ul>
- 34. Graded dose response curves show effects on a continuous scale And the intensity of the effect is proportional to the dose
- 35. Exposure to ethanol Graded responses between no effect and death
- 36. Requirements <ul><li>Single biological unit or average of many such units for each data point </li></ul><ul><li>A preparation of a single animal or organ can produce the curve </li></ul>
- 37. Problem <ul><li>Poor predictors of how other specimens might respond. </li></ul>
- 38. Plot of the contraction of the intestinal smooth muscle in response to varied doses of acetylcholine
- 39. Observation <ul><li>The response varies continuously with dose. </li></ul><ul><li>Shape -- sigmoidal </li></ul><ul><li>Threshold dose -- The lowest dose that produces a detectable response </li></ul><ul><li>Dose units -- the independent variable is plotted on the X-axis as the </li></ul><ul><li>logarithm of the dose. This -- </li></ul><ul><li>produces a symmetrical curve </li></ul><ul><li>allows a broader range of doses on the graph </li></ul><ul><li>Response units -- the dependent variable is plotted on the Y-axis in </li></ul><ul><li>arithmetic units. The scale can be -- </li></ul><ul><li>actual units, e.g., grams of tension, mm change in length, etc. </li></ul><ul><li>derived units, e.g., % of maximum response </li></ul><ul><li>Abstract summary of data , to allow for easy comparisons and mathematical treatment, e.g., ED 50 </li></ul>
- 40. Quantal (All-or-none; binary) dose-effect relationships <ul><li>Graph of relationship between dose and effect </li></ul><ul><li>describes the distribution of MINIMUM doses of drug required to produce a defined degree of a specific response in a population of subjects. </li></ul>
- 41. All or None <ul><li>Percentage of population affected </li></ul><ul><ul><li>> threshold response </li></ul></ul><ul><ul><li>As function of drug dose </li></ul></ul><ul><li>NOT magnitude of drug effects </li></ul>
- 43. Purpose <ul><li>To allow predictions about what proportion of a population of subjects will respond to given doses of the drug or toxin. </li></ul>
- 44. Defined specific effect and degree of response -- <ul><li>The specific effect being measured </li></ul><ul><li>Only two responses are allowed -- Yes or No; 0 or 1 </li></ul><ul><li>Response is quantal , i.e., not continuously variable </li></ul><ul><li>increments or decrements by 1 unit (e.g., individual) at a time. </li></ul>
- 45. Problem <ul><li>Many units (animals, humans, organs) required to create a quantal dose-effect curve. </li></ul><ul><li>From these many units, one can make predictions about what proportion of a similar population will respond to the drug in the same way . </li></ul>
- 46. Titration <ul><li>Because the plot represents the distribution of minimum doses that produce the effect, </li></ul><ul><li>one must titrate the population with increasing doses until virtually all members respond. </li></ul><ul><li>In essence, one is finding the individual effective dose. </li></ul><ul><li>This can be done in two ways </li></ul>
- 47. 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. <ul><li>Titration of groups </li></ul><ul><li>Divide the test population into groups, </li></ul><ul><li>give each group only one of a series of increasing </li></ul><ul><li>doses. </li></ul><ul><li>Responses will vary, e.g., from no responses in a </li></ul><ul><li>group to 100% of responses. Record the % of the </li></ul><ul><li>group responding to each dose. </li></ul>
- 48. Shape of curve <ul><li>"cumulative" dose-effect curve is sigmoidal </li></ul><ul><li>when % responding is plotted against the log-dose. </li></ul>
- 49. Description of data <ul><li>One can define the mid-point as for the graded curve, i.e., the ED 50 , the dose that produces the effect in 50% of the test population. </li></ul>
- 50. Construction of quantal (binary) dose-effect curves <ul><li>Method A: Titrate each animal </li></ul><ul><li>Method B -- Titration of groups </li></ul>
- 51. Method A: Titrate each animal Sample experiment <ul><li>70 rats are given the same initial dose </li></ul><ul><li>Did the dose elicit the predefined degree of response in any of the animals? If so, note the % that responded (Yes or "1") and remove them from the test population </li></ul><ul><li>Administer the next higher dose to the remaining animals </li></ul><ul><li>Note the number responding and remove them from the test </li></ul><ul><li>Repeat steps 3 and 4 until ALL of the animals have responded. </li></ul>
- 52. 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
- 53. Comments <ul><li>expensive in labor, materials, and drug because many animals receive multiple doses </li></ul><ul><li>Requires long periods of time to conduct the experiment because one must wait until the animals have recovered completely from the previous dose </li></ul><ul><li>Results confounded by previous and multiple exposures to the drug </li></ul>
- 54. Method B -- Titration of groups <ul><li>Give one and the same dose to each animal of a group. </li></ul><ul><li>From a series of doses, give each group one dose. </li></ul>
- 55. Sample experiment <ul><li>Obtain, e.g., 70 rats </li></ul><ul><li>Randomly allot them to 7 groups of 10 each </li></ul><ul><li>Select 7 doses and give one dose to each member of a group (70 injections) </li></ul><ul><li>Note the PERCENTAGE of each group that responds </li></ul><ul><li>Plot the % responding versus dose </li></ul>
- 56. Cumulative quantal dose response plot
- 58. Both curves provide <ul><li>Information regarding </li></ul><ul><li>potency. </li></ul><ul><li>Selectivity </li></ul><ul><li>But </li></ul><ul><li>Graded dose response curve indicates </li></ul><ul><li>maximum efficacy </li></ul><ul><li>Quantal dose response indicates </li></ul><ul><li>potential variability of responsiveness among individuals </li></ul>
- 59. Quantal D/R curves used to define <ul><li>median effective (and toxic) doses, </li></ul><ul><li>concept of “therapeutic index” </li></ul><ul><li>the potential range of inter-subject variability in drug response. </li></ul>
- 62. <ul><li>To use or not to use? </li></ul><ul><li>Need information </li></ul><ul><li>Therapeutic Index (safety margin) </li></ul>Decision Making <ul><li>TI: 10mg/10mg = 1 </li></ul><ul><li> 100mg/10mg = 10 </li></ul><ul><li> 1000mg/10mg = 100 ~ </li></ul>LD 50 ED 50
- 63. 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
- 64. <ul><li>Relatively safe ~ </li></ul>100 50 0 DRUG DOSE 0 X ED LD % subjects TI = LD 50 / ED 50
- 65. <ul><li>Less safe drug ~ </li></ul>100 50 0 DRUG DOSE 0 X ED LD % subjects TI = LD 50 / ED 50

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