2. dose resp relationsp presentsn copy - copy

by Lee Eun Jin

ANALYSIS OF DOSE RESPONSE RELATIONSHIP

• DOSE = amount of drug administered to the patient

• RESPONSE = effect in the body produced by the drug

• Drug + Receptor Drug-Receptor Complex Response

Dose-response relationshipDose-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 effectsMain effects and side effects

Main effect – the effect you want the drug to have

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, but has minimal side effects

Dosage-response curveDosage-response curve Making dosage decision

Compare dosage to the percentage of people showing different effects

ED10- effective dose where 10% of people show response of interest

Example – dosages of a drug used to increase attention (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.

GRADED DOSE-RESPONSE CURVE

ED50

ED50

• An all-or-none response to a drug and relates to the frequency with which a specific dose of a drug produces a specific response in a population. • Indicates that a given dose of a drug has or has not evoked a certain effect in the various subject under investigation, that is the pharmacological effects are expressed in passive or negative. •For example, to test either presence or absence of hypnosis for a sedative. (e.g., death among the mice in a pre-clinical study or effective among the patients in a clinical trial.)

QUANTAL DOSE-RESPONSE CURVE

Frequency Distribution

CumulativeFrequency Distribution

GradedGraded

QuantalQuantal

•• Measured in a single biologic unitMeasured in a single biologic unit•• Relates dose to intensity of effectRelates dose to intensity of effect

•• All-or-none All-or-none

pharmacologic effectpharmacologic effect

•• Population studiesPopulation studies

•• Relates dose to Relates dose to

frequency of effectfrequency of effect

• • Continuous scaleContinuous scale

Dose

Dose

rate(%)

rate(%)

Dose-Response Curve InformationDose-Response Curve Information

4 Important Values: Potency Efficacy Slope Variability

oAbsolute amount of drug required to produce an effect

oMore 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

PotencyPotency

Effect

Dose

A B

TherapeuticEffect

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

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

Response

Log Drug Concentration [Molar]

0

100

50

ED501

2

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

Effect

Dose

A

B

TherapeuticEffect

Dosage (mg/kg)

Th

era

peu

tic

re

sp

on

se

%

100

50

ED50

Death

100

50

LD50

MED M

TD

ED50- dose which will be therapeutically effective in 50% of animals (median effective dose)LD50- dose which will, on average, kill 50% of animals in a populationMED- minimum effective dose (the least dose that is likely to be effective).Also called toxic dose-low(TDL)MTD- maximum tolerated dose (or minimum toxic dose) (more than this will produce signs of toxicity).Also called highest nontoxic dose (HNTD)

Therapeutic Range

Toxic

Co

nce

ntr

atio

nC

on

cen

trat

ion

Subtherapeutic

ED50

TI ＝ LD50 ／ ED50

LD50

Therapeutic index (TI): The index used forjudging drug's safety.

Factors Altering Drug ResponsesFactors 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 ResponsesFactors Altering Drug Responses

Environment◦ Heat or cold◦ Presence or real or perceived threats

Fever Shock

• Toxicology is the science that deals with the amount of an agent that causes an adverse action in some living system

•‘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 applied to the body outwardly, or in any way introduced into it, can destroy life by its own inherent qualities, without acting mechanically, and irrespective of temperature.’

• Toxicity is the degree to which a substance can damage an organism

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-effectse.g. immunosuppression by corticosteroids – opportunistic infections

a. the predictable

Pharmacokinetic Drug interactions:

• absorption e.g. gastric emptying, gut motility

Atropine and metoclopramide

•distribution e.g. displacement from plasma proteins

aspirin and warfarin

•metabolism e.g. increased by enzyme induction

barbiturates and steroids

• excretion e.g. active transport competition

NSAIDS and methotrexate

a. the predictable

• Age- most drugs tested on young to middle-aged volunteers-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 fatdeclined renal functionreduced hepatic blood flowreduced 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 dosingMultiple dosing On continuous steady administration of a drug,

plasma concentration will rise fast at first then more slowly 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

0

1

2

3

4

5

6

7

0 5 10 15 20 25 30

Time

Pla

sm

a C

on

cen

trati

on

Repeated doses –Maintenance dose

Therapeutic level

Single dose – Loading dose

• 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

Margin of Safety = LD1

ED99

ED50AED99A

LD1

A

Desired vs undesired effects: Indices of drug safety.

• Safety Index• Therapeutic Index

Safety index: LD1/ED99

-20

0

20

40

60

80

100

0.00

010.

001

0.01 0.

1 1 10 100 1K 10

K10

0K

Sleep Death

LDLD11

EDED9999

Therapeutic index: LD50/ED50

-20

0

20

40

60

80

100

0.00

010.

001

0.01 0.

1 1 10 100 1K 10

K10

0K

Sleep Death

Causes of Variability in Drug Response

Those related to the biological system1. Body weight and size2. Age and Sex3. Genetics - pharmacogenetics4. Condition of health5. Placebo effect

Causes of Variability in Drug Response

• Those related to the conditions of administration1. 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.

DoseDose EffectEffectEffect site Effect site ConcentrationConcentration

Pharmacokinetics Pharmacodynamics

AbsorptionAbsorption

DistributionDistribution

MetabolismMetabolism

Elimination Elimination

Drug interactionsDrug interactions

Tissue/organ sensitivity Tissue/organ sensitivity (target status)(target status)

Monitoring drug responsesMonitoring drug responses

LevelLevel Molecular (e.g., enzyme inhibition, receptor Molecular (e.g., enzyme inhibition, receptor

binding assay)binding assay) Cellular (Cellular (in vitroin vitro tissue culture, blood cells) tissue culture, blood cells) Tissue or organ (Tissue or organ (in vitroin vitro or or in vivoin vivo)) Animal disease modelAnimal disease model

Endpoint used to measure the effect may be different Endpoint used to measure the effect may be different at each levelat each level

Overall effect = Sum of multiple drug effects and Overall effect = Sum of multiple drug effects and physiological responses to drug effectsphysiological responses to drug effects

Endpoints to monitor drug effectsEndpoints to monitor drug effects

LEVEL ENDPOINT

Molecular Enzyme e inhibition

Cellular Proliferation rate, Apoptosis

Tumor 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 =*Effect =EffectEffectMaxMax • [Drug] • [Drug]

KKDD + [Drug] + [Drug]

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


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

Bio

logi

c ef

fect

Log dose

potency

efficacy

0

50

100

Bio

logi

c ef

fect

(%)

Log dose (mg)

1 10 100

MorphineCodeine

Aspirin


Typical dose-response curve

for drugs showing differences in potency and efficacy.


Effects of drug antagonists.


Effects of partial agonists.

-1 0 1 2

RE

SPO

NS

E

Full Agonist

Partial Agonist

Antagonist

Log([A]/KA)

QUANTAL DOSE-RESPONSE RELATIONSHIPS

Therapeutic Index

Therapeutic index =

toxic dose(LD50)/effective dose(EC50)

This is a measure of a drug’s safety• A large number = a wide margin of safety• A small number = a small margin of safety





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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2. dose resp relationsp presentsn copy - copy