DOSE RESPONSE CURVE

Dr.RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Bioassay of drugs

Quantitative estimation of drugs Biological methods Physico-chemical methods-

chromatographic, spectrophotometric, flourimetric and mass spectrometric techniques

Radio-immunological methods Microbiological methods

Bioassay

Means the measurement of the concentration or potency of a drug from the magnitude of its biological effect.

Bioassay involves comparison of the main pharmacological response of unknown preparation with that of the standard

Types –Quantal and Graded

Dose response curves

Dose response relationships describe the effect on an organism caused by differing levels of exposure (or dose)

Dose levels are usually expressed in mg/kg body weight of the test animal for solids and mg/m3 or parts per million for aerosols/vapours These levels can be plotted on a graph against

the response The dose response curve is a valuable tool to

understand the levels at which substances begin to exert adverse effects and the degree of harm expected at various levels

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What is a dose?

Dose is the amount of a substance administered at one time.

Dosage is the amount per unit weight of the exposed individual.

Exposure is characterized by Number of doses Frequency of dosing The total period of time for the exposure

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Dose Response Curve

Graded – response measured on a continuous scale (efficacy)

Quantal – response is an either/or event(potency) relates dose and frequency of response in

a population of individuals often derived from frequency distribution

of doses required to produce a specified effect

2004-2005

Potency and Clinical Efficacy

Potency refers to the amount of drug necessary to produce a certain effect. A drug which produces a certain effect at 5 mg dosage is ten times more potent than a drug which produces the same effect at 50 mg dosage.

Clinical efficacy refers to the maximal clinical response that can be obtained by a particular drug (morphine is more clinically efficacious than aspirin as an analgesic)

ED100/EDmax (ceiling effect): Conc. which produces maximal response

Potency

Relative position of the dose-effect curve along the dose axisHas little clinical significance for a given therapeutic effectA more potent of two drugs is not clinically superiorLow potency is a disadvantage only if the dose is so large that it is awkward to administer

Analgesia

Dose

hydromorphone

morphine

codeine

aspirin

Relative Potency

Effect of various conc. of ACh on isolated small intestine of rabbit

showing graded response

Graded dose-response

When dose of drug results as response e.g., contraction or relaxation of muscles, ∆ BP, ∆ blood sugar etc. Studied in vitro on a piece of small intestineRelationship b/w dose & response can be plotted on curve (x-axis=dose; y-axis=response)Conc./dose on arithmetic scale, curve is hyperbolic (not linear relationship)Conc./dose on log scale, curve is sigmoid-shaped (semi log dose-response curve)

Graded dose-response curve

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Dose-response curve

The cumulative curve is used to show dataY-axis: Response % (lethality, toxic response, effective drug dose)X-axis: Dose (mg) Dose may be on a linear or a log scaleNo response below thres-holdCeiling effect: no difference once all individuals are affected

Resistant individuals

Threshold

Sensitive individuals

Ceiling effect100%

Therapeutic Index

Effective dose (ED50) = dose at

which 50% population shows response

Lethal dose (LD50) =dose at

which 50% population dies

TI = LD50/ED50, an indication

of safety of a drug (higher is better)

Ex-digoxin & warfarin have TI; Penicillin = TI

ED50 LD50

Advantages of semi log Dose-Response Curve

Wide range of drug doses is depictedEasy comparison between agonistsEasy study of antagonists The middle portion (25-75%) of curve is linear; direct relationship between dose and response can be obtained

Quantal dose-response

Response follow all or none phenomenon (e.g., analgesics, convulsants, anticonvulsant activity, death etc)

Dose of drug evokes a fixed pharmacological response Studied in whole animal (in vivo); data derived from

group of animals or population Results can be plotted as Log dose-percentage curve Gaussian Distribution Curve (sigmoid > graded

response) is obtained by keeping log doses on horizontal-axis and % response on vertical-axis

Quantal dose-response curve

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Quantal dose-response

Following valuable data can be drawn -Median Effective Dose (ED50)-Dose of a drug required to

produce 50% of maximum responseTD50 - Median Toxic Dose 50 - dose at which 50

percent of the population manifests a given toxic effect

Median lethal dose (LD50)-Dose of a drug required to kill 50% of experimental animals; measurement of toxicity

Comparison of drug toxicity

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NOAEL and LOAEL

Two terms often encountered are No Observed Adverse Effect Level (NOAEL) and Low Observed Adverse Effect Level (LOAEL).

They are the actual data points from human clinical or experimental animal studies.

 http://aquaticpath.umd.edu/appliedtox/module1-dose.html

Dose response curve-uses

1. Identify the therapeutic dose/concentration

2. Define site of drug action (receptor)

3. Classify effect produced by drug-receptor interaction (agonist, antagonist)

4. Compare the relative potency and efficacy of drugs that produce the same effect

5. Assess mechanism of drug interactions

Dose response curve-uses

LD50 – Median Lethal Dose, quantity of the chemical that is estimated to be fatal to 50% of the organismsLD50 values are the standard for comparison of acute toxicity between chemical compounds and between species

TD50 – Median Toxic Dose ED50 – Median Effective Dose LC50 – Median Lethal Concentration

“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”

Paracelsus (1493-1541)

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