DOSE RESPONSE

RELATIONSHIP
Prof.DR.H.J.MUKONO, dr.,MS.,MPH.
FAKULTY OF PUBLIC HEALTH
AIRLANGGA UNIVERSITY
SURABAYA
INDONESIA
 Definitions
DOSE - amount of exposure to an agent.
RESPONSE - the reaction to the dose.

For example, eating one green apple

may be just fine but eating five green
apples at one time may produce a very
undesirable response.
 Definitions
HAZARD – the possibility that an agent can cause harm
EXPOSURE – contact with an agent
RISK – the probability of harm or adverse effect (injury,
disease, death) following exposure to an agent

Reff. R.Woodraw Setzer (US EPA, 2010)

 DOSE
Similar to drug‘s
effectiviness , drug’s
toxicity e.g. lethality
(mortality) also shows
dose-response relationship,
typical S-shape curve.
LD50 (the dosage of a
substance that kills 50% of
the animals over a set period
of time following an acute
exposure).
Reff:Frank.M.Balis (2007)
 Dose & Drug Effects
• Pharmacodynamics what the drug does to the
body
• Effects of drug depends on dose
• In general...
as dose increases, effects increase
to a maximum
then effects decrease
 Dose / Response

Hazard + Exposure = Risk

Individual Sensitivity
HUBUNGAN DOSIS RESPON
PENINGKATAN DOSISMENINGKATKAN EFEK SAMPAI
EFEK MAKSIMAL TERCAPAI

MACAM RESPON:
RESPON MEMATIKAN (LETHAL RESPONE)
RESPON TDK MEMATIKAN (NON-LETHAL RESPONE)
PENGGUNAAN HUBUNGAN
DOSIS RESPON
HARUS MEMPERHATIKAN BEBERAPA
ASUMSI DASAR :

RESPON TERGANTUNG PADA CARA MASUK

BAHAN
DAN
RESPON TERGANTUNG PADA DOSIS
 Log Dose-Effect Curve
100

80

60
% of Maximal
Effect
40

20

EC50
0
1 10 100 1000
[Drug] Reff. Megan Phillips (2006)
Dose-Response Curve
• How response changes as function of dose
– S-shaped curves
– Slope important
• Gradual
–  dose  small response change
• Steep
–  dose  large response change ~
 Dose-response Relationship
• Weight of individual important
• Dose
–amount of drug per body weight
–mg/kg (milligrams/kilogram)
• Helps achieve equal blood concentrations
–often not tightly controlled in humans
Dose-response Relationship
• Drug effects are variable
– Probability statements
• Group dose-response curves
– % of population responding
– Response magnitude
• Different for each individual effect
• i.e., temperature, respiration, euphoria, etc. ~
Dose-Effect Parameters
POTENCY: The sensitivity of an organ or
tissue to the drug

EFFICACY: The maximum effect

 Graded Dose-Effect Analysis
• Identify the therapeutic dose/concentration
• Define site of drug action (receptor)
• Classify effect produced by drug-receptor interaction
(agonist, antagonist)
• Compare the relative potency and efficacy of drugs that
produce the same effect
• Assess mechanism of drug interactions
 Relating Dose to Effect
In Vivo
Dose Effect site Effect
Concentratio
Pharmacokinetics
n Pharmacodynamics

Age Tissue/organ
Absorption sensitivity
Distribution (receptor status)
Elimination
Drug interactions Reff. R.Woodraw Setzer (US EPA, 2010)
Therapeutic Index
• Margin of safety
– % population responding
• Compare effective dose (ED50) to
– Lethal dose (LD50)
– Or toxic dose (TD50)
LD50
 TI: 10mg/10mg = 1
100mg/10mg = 10
ED50
1000mg/10mg = 100 ~
Therapeutic Index: Side Effects
• Drug effects other than desired effects
–Drugs have multiple effects!
–TD50 : toxic dose
• TI for side effects

TD50 side effect

Reff. Megan Phillips (2006)
ED50 desired effect
Role of Dose-Effect Studies
• 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)
 Evaluating the toxicity:
time factor
• Acute basis over a 14-d period,
• subchronic /subacute, 90-d period (daily given), additional
information gained, target organ, major toxic effects,
slower onset,
• chronic , life time of animal, post-mortem examination.
• Story on an antiviral drug for hepatitis- a delayed toxic
reaction occurred after administration was discontinued.
5/5 died suddenly, liver failure.
 GENDER
• Ethanol consumption, first-pass metabolism, in female LDH
lower,
• Dinitrotoluene-induced hepatic tumor, higher incidence in
male: male glucuronide conjugation, biliary excretion,
hydrolyzed and reabsorption; urinary excretion
predominates in female  better clearance;
• Chloroform-induced kidney damage, higher incidence in
male : androgen effect, testosterone-mediated, castration
diminished
 AGE
• Age related change: 1. liver metabolism; 2. renal elimination; 3. body
composition
• Liver metabolism- less amount of drug metabolizing enzymes in
newborn infants.
– Therapeutic disorders
• (1) gray baby syndrome : inadequate glucuronidation of
chloramphenicol  [chloramphenicol] 
• (2) sulfonamide induced icterus: displacement of bilirubin from
plasma by sulfonamide;
In general, reduced binding of drug to plasma proteins in neonatal
period.
 ALLERGY
•not follow dose-response
relationship
• e.g. chronic beryllium disease,
hypersensitivity lung disorder, exposure
to beryllium, lack of dose-response
relationship
THANKS VERYMUCH
FOR YOUR ATTENTION
TERIMA KASIH ATAS PERHATIANNYA