The document discusses key concepts related to dose-response relationships for drugs. It defines important terms like dose, response, and dose-response curves. It explains that the dose-response relationship depends on multiple factors and describes the difference between main and side effects. Additionally, it provides details about graded and quantal dose-response curves and their characteristics. Metrics like potency, efficacy, slope, and variability that are used to analyze dose-response relationships are also outlined.

1. ANALYSIS OF
DOSE RESPONSE RELATIONSHIP
by Lee Eun Jin

2. • DOSE = amount of drug administered to the patient
• RESPONSE = effect in the body produced by the drug
• Drug + Receptor ⇔ Drug-Receptor Complex
⇓
Response

3. 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

4. Main 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

5. Dosage-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

10. • 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.

11. 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 50µg 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.

12. ED50
GRADE D
DOSE-
RE ONSE
SP
CURVE
ED50

13. • 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.)

14. Cumulative
Frequency
Distribution
QUANT AL
DOSE-
RE ONSE
SP
CURVE
Frequency
Distribution

15. Graded • Continuous scale
• Measured in a single biologic unit
• Relates dose to intensity of effect
rate
(% Dose
) Quantal
• All-or-none pharmacologic effect
rat • P opulation studies
e
(%) • Relates dose to frequency of
effect
Dose

16. Dose-Response Curve Information
4 Important Values:
 Potency
 Efficacy
 Slope
 Variability

17. 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)

18. 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 K D 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 ED 50 is the dose at which 50% of
individuals exhibit the specified quantal effect

19. Potency
A B
Therapeutic
Effect
Effect
Dose

20. 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

21. Efficacy
• Efficacy – how large an effect the drug produces
• Maximum effect obtained with drug (not potency)
100
Response 50 2
0
1
E 50
D
L Drug Concentration [M
og olar]

22.  Slope: Effect of incremental increase in dose
 change in effect from change in dose

23.  Variability: Reproducibility of data
 different for different people

24.  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

25. E 50- dose which will be
D
therapeutically effective in
100 100
50% of animals (median
effective dose)
T rapeutic
response %
L 50- dose which will, on
D
average, kill 50% of
Death
50 50 animals in a population
M D- minimum effective dose
E
he
(the least dose that is likely
E 5
D L 5
D to be effective).
Also called toxic dose-
0 low(T )
DL
0
Dosage (mg/
kg) M D- maximum tolerated
T
dose (or minimum toxic
ME dose) (more than this will
D MT produce signs of toxicity).
D Also called highest nontoxic
dose (H D)
NT

26. Concen tration Toxic
Therapeutic Range
Subtherapeutic

27. Therapeutic index (TI): The index used for
judging drug's safety.
TI ＝ LD 50 ／ ED 50
ED 50
LD 50

28. 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

29. Factors Altering Drug Responses
 Environment
◦ Heat or cold
◦ Presence or real or perceived threats
 Fever
 Shock

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

31. Principle causes of drug toxicity/side effects
a. the predictable
b. the less predictable
c. the unpredictable

32. 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 –
opportunistic infections

33. a. the predictable
Pharmacokinetic Drug interactions:
bsorption Atropine and
.g. gastric emptying, gut motility
metoclopramide
tribution aspirin and warfarin
. displacement from plasma proteins
etabolism barbiturates and steroids
g. increased by enzyme induction
xcretion NSAIDS and
g. active transport competition methotrexate

34. 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 fat
declined renal function
reduced hepatic blood flow
•Gender
reduced activities of cytochrome P450 enzymes
- a relative increase of body fat in females

35. 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)

36. Multiple 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

37. Single dose
–
7 Loading
6 dose
Therapeutic
lasma Concentration
5 level
4
3
Repeated doses
2 –M aintenance
dose
P
1
0
0 5 10 15 20 25 30
Time

38. • 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)

40. Morphine
Aspirin

41. T E
H RAP UT INDE – AN INDE OF
E IC X X
SAF T
EY
Hypnosis Death

42. E 99A
D
E 50A
D
L 1A
D
L 1
D
Margin of Safety =
ED99

43. Desired vs undesired effects: Indices
of drug safety.
• Safety Index
• Therapeutic Index

44. Safety index: LD1/ED99
ED 99
100
80 Sleep Death
60
40
LD 1
20
0
0
K
01
01
1
1
10
0K
1
-20 1K
10
0.
00
10
0.
00
10
0.
0.

45. Therapeutic index: LD50/ED50
100
80 Sleep Death
60
40
20
0
0
K
01
01
1
1
10
0K
1
-20 1K
10
0.
00
10
0.
00
10
0.
0.

46. 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

47. 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.

48. Effect site
Dose Concentration
Effect
Pharmacokinetics Pharmacodynamics
Absorption Tissue/organ sensitivity
Distribution (target status)
Metabolism
Elimination
Drug interactions

49. 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

50. Endpoints 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

51. DOSE-RESPONSE RELATIONSHIPS
The effect of dose on the
magnitude of
pharmacologic
response.
Panel A is a linear graph.
EffectMax • [Drug]
*Effect =
KD + [Drug]
* E 50=drug dose that shows fifty
C
percent of maximal response.

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

53. 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
Morphine
Biologic effect
Codeine
efficacy 100
Biologic effect(%)
Aspirin
50
potency
0
1 10 100
Log dose Log dose (mg)

54. DOSE-RESPONSE RELATIONSHIPS
Typical dose-response
curve
for drugs showing
differences in
potency and efficacy.

55. DOSE-RESPONSE RELATIONSHIPS
Effects of drug
antagonists.

56. DOSE-RESPONSE RELATIONSHIPS
Effects of partial
agonists.
Full Agonist
Partial Agonist
ES NOPS E R
Antagonist
-1 0 1 2
Log([A]/KA)

57. 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

58. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Effects of partial
agonists.

59. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Effects of partial
agonists.

62.  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

63. THANK YOU