ANALYSIS OF DOSE RESPONSE RELATIONSHIP

by Lee Eun Jin

 DOSE = amount of drug administered to the patient

RESPONSE = effect in the body produced by

Drug + Receptor Drug-Receptor Complex Response

the drug

Dose-response relationship

Depends on multiple factors

A drug usually has one desired effect that causes a change in a target organ or structure It will also have secondary effects because it will be absorbed by other areas of the body

Main effects and side effects

Main effect the effect you want the drug to hav e Side effects secondary effects that may or may not be desirable or helpful Goal is to use a dose of a drug that is effective, bu t has minimal side effects

Dosage-response curve

Making dosage decision Compare dosage to the percentage of people showing different effects ED10- effective dose where 10% of people show respo nse of interest Example dosages of a drug used to increase attentio n (main effect) but also has 2 side effects
Heart palpitations death

 The dose-response relationships for drugs may be Graded or quantal. Graded dose-response curve can be constructed for responses that are measured on a continuous scale Eg, heart rate. Graded dose-response curves relate the intensity of response to the size of the dose, and hence are useful for characterizing the actions of drugs. Quantal dose-response curve can be constructed for drugs that elicit an all-or-none response Eg, presence or absence of epileptic seizures. For most drugs, the doses that are required to produce a specified quantal effect in a population are log normally distributed, so that the frequency distribution of responses plotted against log dose is a gaussian normal distribution curve. The percentage of the population requiring a particular dose to exhibit the effect can be determined from this curve. When these data are plotted as a cumulative frequency distribution, a sigmoidal dose-response curve is generated.

Graded dose response

means that a slight increase of drug should bring about a small increase in the response For example, increase doses of histamine cause gradual contraction of the guinea-pig ileum. Very low doses of histamine have virtually no effect and responses can be observed, only beyond a threshold does of about 20ng. Again, very high doses of more than 50g have no additional effects, and the response remains constant at this maximal level. Graded dose response means the pharmacological effects of the drugs expressed in quality or number, such as the heart rate by beat, blood pressure by mmHg, also the contract of ileum in height effected by the drugs.

ED50 GRADED DOSERESPONSE CURVE

ED50

 An all-or-none response to a drug and relates to the f requency with which a specific dose of a drug produc es a specific response in a population. Indicates that a given dose of a drug has or has not evo ked a certain effect in the various subject under investiga tion, that is the pharmacological effects are expressed in passive or negative. For example, to test either presence or absence of hypn osis for a sedative. (e.g., death among the mice in a preclinical study or effective among the patients in a clinical trial.)

Cumulative Frequency Distribut ion

QUANTAL DOSE-RES PONSE CURVE

Frequency Distribut ion

Graded

Continuous scale Measured in a single biologic unit Relates dose to intensity of effect
Dose

rate (%) Quantal

rate (%)

All-or-none pharmacologic effect Population studies Relates dose to frequency of effect

Dose

Dose-Response Curve Information

4 Important Values: Potency Efficacy Slope Variability

o Absolute amount of drug required to produce an effect

o More potent drug is the one that requires lower do to cause same effect

o Measure of amount of drug required for effect (ED50)

Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drug's maximal effect as depicted by a graded dose-response curve. EC50 equals KD when there is a linear relationship between occupancy and response. Often, signal amplification occurs between receptor occupancy and response, which results in the EC50 for response being much less (ie, positioned to the left on the abscissa of the log dose-response curve) than KD for receptor occupancy. Potency depends on both the affinity of a drug for its receptor, and the efficiency with which drug-receptor interaction is coupled to response. The dose of drug required to produce an effect is inversely related to potency. In general, low potency is important only if it results in a need to administer the drug in large doses that are impractical. Quantal dose-response curves provide information on the potency of drugs that is different from the information derived from graded dose-response curves. In a quantal dose-response relationship, the ED50 is the dose at which 50% of individuals exhibit the specified quantal effect

Potency

B
Therapeutic Effect

Effect

Dose

Efficacy (Intrinsic activity) THE Ability of the drug to elicit a response when it binds to the receptor. Conformational changes in receptors as a result of drug occupancy initiate biochemical and physiologic events that characterize the drug's response. In some tissues, agonists demonstrating high efficacy can result in a maximal effect, even when only a small fraction of the receptors is occupied

Efficacy

Efficacy how large an effect the drug produces Maximum effect obtained with drug (not potency)

100

Response

50

ED50 Log Drug Concentration [Molar]

Slope: Effect of incremental increase in dose change in effect from change in dose

Variability: Reproducibility of data different for different people

Threshold (minimal) dose

Least amount needed to produce desired effects

Maximum effect
Greatest response produced regardless of dose used

B A
Therapeutic Effect

Effect

Dose

100

100

ED50- dose which will be therapeutically effective in 50% of animals (median effe ctive dose) LD50- dose which will, on average, kill 50 % of animals in a population

50

50

ED50

LD50 Dosage (mg/kg)

MED- minimum effective dose (the least dose that is likely to be effective). Also called toxic dose-low(TDL)

ME D

MT D

MTD- maximum tolerated dose (or minimu m toxic dose) (more than this will produce s igns of toxicity). Also called highest nontoxic dose (HNTD)

Toxic

Therapeutic Range Subtherapeutic

Therapeutic index (TI):

judging drug's safety.

The index used for

TILD50ED50 ED50

LD50

Factors Altering Drug Responses

Age
Pediatric or geriatric Immature or decreased hepatic, renal function

Weight
Big patients spread drug over larger volume

Gender
Difference in sizes Difference in fat/water distribution

Factors Altering Drug Responses

Environment
Heat or cold Presence or real or perceived threats

Fever Shock

 Toxicity is the degree to which a substance can damage an organism Toxicology is the science that deals with the amount o

f an agent that causes an adverse action in some living s ystem All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.- Paracelus (16th century physician-alchemist) A poison is any substance or matter which, when appl ied to the body outwardly, or in any way introduced int o it, can destroy life by its own inherent qualities, witho ut acting mechanically, and irrespective of temperature.

Principle causes of drug toxicity/side effects

a. the predictable

b. the less predictable

c. the unpredictable

a.

the predictable
excessive action at a primary site (over dosage) e.g. anaesthetics, warfarin non-selectivity: acting at unrelated sites (more likely with over dosage) e.g. chlorpromazine

incomplete selective toxicity: acts against the host as well as the target organism or cell e.g. protein synthesis inhibitors, antimicrobials, antifungal

tolerance (dependence & abuse potential) e.g. benzodiazepines, opioids unavoidable side-effects e.g. immunosuppression by corticosteroids opportuni stic infections

a. the predictable Pharmacokinetic Drug interactions:

absorption Atropine and e.g. gastric emptying, gut motility metoclopramide distribution aspirin and warfarin e.g. displacement from plasma proteins metabolism barbiturates and ster e.g. increased by enzyme induction
excretion NSAIDS and e.g. active transport competition methotrexate

a. the predictable

Age - most drugs tested on young to middle-aged vol unteers

-causing problems such as: -drug clearance mechanisms (renal and hepatic) are limited in newborns -clearance is reduced in elderly (increasing half life) reduction in lean body mass, serum albumin, total body water. increased body fat declined renal function reduced hepatic blood flow reduced activities of cytochrome P450 enzymes

Gender

- a relative increase of body fat in females

b. the less predictable Genetic factors e.g. polymorphism in NAT2 in the liver (N-acetyltransferase2). -metabolises about 16 common drugs (phenytoin, hydralazine) Plasma esterase suxamethonium (about 1 in 3000 individuals)

c. the unpredictable
untoward adverse reactions drug allergies and anaphylactic reactions e.g. penicillin (1 in 50,000 patients exposed)

Multiple dosing

On continuous steady administration of a drug, plas ma concentration will rise fast at first then more slo wly and reach a plateau, where: rate of administration = rate of elimination i.e.steady state is reached.

Therefore, at steady state: Dose (Rate of Administration) = clearance x plasma conc.

steady state conc. = Dose/clearance

7 6 5

Single dose Loading dose

Therapeutic level

Plasma Concentration

4 3 2 1 0 0 5 10 15 20 25 30

Repeated doses Maint enance dose

Time

 Drug development - Site of action - Selection of dose and schedule - Potency, efficacy and safety - Drug interactions Patient management -Therapeutic drug monitoring -Risk benefit (therapeutic indices)

Morphine Aspirin

THERAPEUTIC INDEX AN INDEX OF SAFETY

Hypnosis

Death

ED99A ED50A

LD1A

Margin of Safety =

LD1 ED99

Desired vs undesired effects: Indices of drug safety.

Safety Index Therapeutic Index

Safety index: LD1/ED99

ED99
100 80 60 40 20 0

Sleep

Death

LD1

10 0

0. 00 01 0. 00 1 0. 01

10 K

0. 1

10

-20

10 0K

1K

Therapeutic index: LD50/ED50

100 80 60 40 20 0

Sleep

Death

10 0

0. 00 01 0. 00 1 0. 01

10 K

0. 1

10

-20

10 0K

1K

Causes of Variability in Drug Response

Those related to the biological system 1. Body weight and size 2. Age and Sex 3. Genetics - pharmacogenetics 4. Condition of health 5. Placebo effect

Causes of Variability in Drug Response

Those related to the conditions of administration 1. Dose, formulation, route of administration. 2. Resulting from repeated administration of drug:
drug resistance; drug tolerance-tachyphylaxis; drug allergy

3. Drug interactions:
chemical or physical; GI absorption; protein binding/distribution; metabolism (stimulation/inhibition); excretion (pH/transport processes); receptor (potentiation/antagonism); changes in pH or electrolytes.

Dose

Effect site Concentration

Effect

Pharmacokinetics Absorption Distribution Metabolism Elimination Drug interactions

Pharmacodynamics Tissue/organ sensitivity (target status)

Monitoring drug responses

Level Molecular (e.g., enzyme inhibition, receptor binding assay) Cellular (in vitro tissue culture, blood cells) Tissue or organ (in vitro or in vivo) Animal disease model Endpoint used to measure the effect may be different at each level Overall effect = Sum of multiple drug effects and physiological responses to drug effects

Endpoints to monitor drug effects

LEVEL Molecular Cellular Tumor

ENDPOINT Enzyme e inhibition Proliferation rate, Apoptosis Response (Change in tumor size)

Organism

Survival, Quality of life

DOSE-RESPONSE RELATIONSHIPS

The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph.

*Effect =

EffectMax [Drug] KD + [Drug]

*EC50=drug dose that shows fifty percent of maximal response.

DOSE-RESPONSE RELATIONSHIPS

The effect of dose on the magnitude of pharmacologic response. Panel B is a semi-logarithmic plot of the same data.

Determinants of Drug Activity

1. Potency: the amount of drug to produce an effect of a given magnitude
2. Efficacy: the maximal response (effect) produced by drug
Biologic effect
Morphine Biologic effect(%) Codeine Aspirin

efficacy

100

50 0

potency Log dose

10

100

Log dose (mg)

DOSE-RESPONSE RELATIONSHIPS

Typical dose-response curve for drugs showing differences in potency and efficacy.

DOSE-RESPONSE RELATIONSHIPS

Effects of drug antagonists.

DOSE-RESPONSE RELATIONSHIPS

Effects of partial agonists.

RESPONSE

Full Agonist Partial Agonist

Antagonist

-1

Log([A]/KA)

QUANTAL DOSE-RESPONSE RELATIONSHIPS

Therapeutic Index
Therapeutic index = toxic dose(LD50)/effective dose(EC50) This is a measure of a drugs safety
A large number = a wide margin of safety A small number = a small margin of safety

QUANTAL DOSE-RESPONSE RELATIONSHIPS

Effects of partial agonists.

QUANTAL DOSE-RESPONSE RELATIONSHIPS

Effects of partial agonists.

 Drugs- receptor- response Some drugs can act without binding to a receptor spare receptors allow maximum response without full receptor occupancy Efficacy is the amount of drug needed to produce an effect. Affinity is the attractiveness between 2 drug molecules. Agonist are the drugs that block the response. Partial agonist has affinity and maximum efficacy. Antagonist has efficacy but no affinity. Competitive antagonist decreases potency Non competitive antagonist decreases efficacy

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