MBBS-BDS LECTURE NOTES 2014-2015 DOSE-RESPONSE RELATIONSHIPS

Course Objectives After completing the lecture, students would be expected to: 1. Understand the relationship between dose and response. 2. Distinguish between Graded and Quantal Dose Response. 3. Describe the characteristics of the LDR curves. 4. Explain the unique traits of curves describing competitive and non-competitive antagonism.

D-R Relationship The relationship between the dose (amount) of a drug and the response observed can often be extremely complex, depending on a variety of factors including the absorption, metabolism, and elimination of the drug; the site of action of the drug in the body; and the presence of other drugs or disease. In general, however, at relatively low doses, the response to a drug generally increases in direct proportion to increases in the dose.

Cont’d At higher doses of the drug, the amount of change in response to an increase in the dose gradually decreases until a dose is reached that produces no further increase in the observed response (i.e., a plateau). The relationship between the concentration of the drug and the observed effect can therefore be graphically represented as a hyperbolic curve.

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Cont’d Regardless of how a drug effect occurs—through binding or chemical interaction—the concentration of the drug at the site of action controls the effect. D-R effect is therefore defined as Measurement of the relationship between the quantity/concentration of a substance and its overall effect on an organism.

Cont’d The following graph shows a simple example of a dose-response curve for an individual with a single exposure to the chemical ethanol (alcohol), with graded responses between no effect and death

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Cont’d Often, however, the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa) to transform the dose-response relationship into a sigmoidal curve. This transformation makes it easier to compare different dose-response curves—since the scale of the drug concentration axis is expanded at low concentrations where the effect is rapidly changing, while compressing the scale at higher doses where the effect is changing more slowly

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Cont’d The salient features are: Threshold Slope Emax

Cont’d Below the threshold concentration, there are no adverse effects from exposure to the chemical. The human body has defenses against many toxic agents. Cells in human organs, especially in the liver and kidneys, break down chemicals into nontoxic substances that can be eliminated from the body in urine and feces. In this way, the human body can take some toxic insult (at a dose that is below the threshold) and still remain healthy.

Cont’d Thresholds based on acute responses, such as death, are more easily determined, while thresholds for chemicals that cause cancer or other chronic responses are more difficult to determine.

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Cont’d When a threshold is difficult to determine, toxicologists look at the slope of the dose-response curve to give them information about the toxicity of a chemical. A sharp increase in the slope of the curve can suggest increasingly higher risks of toxic responses as the dose increases, as illustrated by line A on the next graph. A relatively flat slope suggests that the effect of an increase in dose is minimal (line B).

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Cont’d A comparison of dose-response curves among chemicals can offer information about the chemicals as well. A steep curve that begins to climb even at a small dose suggests a chemical of high potency. The potency of a chemical is a measure of its strength as a poison compared with other chemicals. The more potent the chemical, the less it takes to kill.

Comparison of dose-response curves.

Characteristics of LDR curves i. curves are sigmoid, having between 20 and 80 % as straight lines for statistical analysis. ii. Drugs with a similar mechanism of action have parallel curves. iii. Beyond Emax, further increase in drug concentration cannot produce any increase in response.

Types of D-R Relationships There are two basic types of dose-response relationships. A graded dose- response curve plots the degree of a given response against the concentration of the drug. The second type of dose-response curve is the quantal dose-effect curve.

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Dose-Response Parameters POTENCY: Amount of a drug needed to produce a given effect. It has to do with administration of a small dose to produce a large biological effect. Often measured at 50 % concentration or dose level. Relatively unimportant in clinical use of drugs. EFFICACY: The maximal effect that can be produced by a drug. - Determined mainly by the properties of the drug and its receptor-effector system. Important clinical measure. - Partial agonist have lower maximal efficacy than full agonists.

Cont’d Relative Safety of A Drug: Dose-response curves help estimating the safety of a drug. - Therapeutic Index: TI= LD50/ED50 * LD50= the median lethal dose of a drug in animals.

Therapeutic and Toxic Effects

Antagonism Pharmacological Physiological Chemical

Cont’d Chemical: caused by combination of agonists with antagonists, with resulting inactivation of the agonists e.g. dimercaprol and mercuric ion. Physiological: caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects. E.g. histamine and adrenaline.

Cont’d Pharmacological: caused by action of the agonist and antagonist at the same site. In the case of pharmacological antagonisms, the terms competitive and non- competitive antagonism are used.

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