This document describes key concepts related to dose-response relationships and drug interactions. It defines dose-response relationships and curves, and explains how drug potency, efficacy, selectivity, and therapeutic index are determined based on these curves. It also discusses how drugs can have synergistic or antagonistic effects when combined, including competitive and non-competitive receptor antagonism. The overall intent is to explain important pharmacological concepts for understanding how drug effects are produced at varying doses both alone and when administered together with other drugs.

1. Dose-Response
Relationship
Dr. Sanooz Raheem

2. Objectives
1. Describe dose response relationship
2. Explain therapeutic window phenomenon
3. Define a. drug potency b. drug efficiency
4. Define therapeutic index and its clinical importance

3. Dose-Response Relationship
• When a Drug administered systemically
• Dose-plasma concentration relationship (determined by pharmacokinetic
properties)
• Plasma concentration (dose)-response relationship
• Intensity of response increases with increase in dose / concentration at the
receptor
• Drug-receptor interaction obeys law of mass action

4. Emax * [D]
E=
KD +[D]
E- observed effect
D- dose
Emax- maximal response
Kd- dissociation constant of the drug-receptor complex

5. Dose-Response Curve
E =
Emax X [D]
Kd + [D]
Dose-response and log dose-response
curves

6. Dose- Response curve
• Response is proportional to an exponential function(log) of the dose
• Advantages:
- A wide range of drug doses can be easily displayed on a graph
- Comparison between agonists and study of antagonists becomes
easier

7. Drug Potency and efficacy
• Potency: amount of drug required to produce a certain response
DRC positioned rightward indicates a lower potency
Relative potency is more meaningful than absolute potency
Relative potency: comparing the dose of two agonists at which they elicit half
maximal response (EC50)
Ex: 10mg of morphine= 100 mg pethidine as analgesic , morphine is potent
• Potency for therapeutic effect should increase over the potency for adverse effects
• Potency of a drug important to choose a dose

8. • Efficacy:
Maximal response that can be elicited by the drug
Ex: morphine produces analgesia not reached with any dose of aspirin.
Morphine is more efficacious than aspirin.
Efficacy is an important factor in the choice of a drug

9. Illustration of drug potency and drug efficacy.
Dose-response curve of four drugs producing the same
qualitative effect
Potency and efficacy
1.Compare drug A&B
2.A&C
3.D vs A,B,C

10. Note:
Drug B is less potent but equally efficacious as drug A.
Drug C is less potent and less efficacious than drug A
Drug D is more potent than drugs A, B, & C, but less
efficacious
than drugs A & B, and equally efficacious as drug C

11. Potency and efficacy - Examples
• Aspirin is less potent as well as less efficacious than Morphine
• Pethidine is less potent analgesic than Morphine but equally efficacious
• Diazepam is more potent but less efficacious than pentobarbitone
• Furosemide is less potent but more efficacious than metolazone
• Depending on the type of drug, both higher efficacy or lower efficacy could be
clinically advantageous.

12. Slope of DRC
• Steep slope – moderate increase in dose markedly increase the response (dose needs
individualization)
• Flat DRC – little increase in response occurs in wide range of doses (standard dose can be given to
most patients)
• Example: Hydralazine and Hydrochlorothiazide DRC in Hypertension
Steep and flat dose-response curves illustrated
by antihypertensive effect of hydralazine and
hydrochlorothiazide

13. Therapeutic efficacy
• Depends on
- Relative potency and efficacy
- Pharmacokinetic variables
- Pathophysiological variables
• Expressed in terms of
a.Degree of benefit/ relief afforded by the drug or
b.Success rate in achieving a defined therapeutic end point
Ex: a drug which makes a higher percentage of epileptic patients totally
seizure free than another drug is the more therapeutically effective
antiepileptic.

14. Drug Selectivity
• Some drugs may produce different actions
• DRCs for different effects of drug may be different
• Extent of separation of DRCs of a drug for different effects is a
measure of its selectivity
Ex: Isoprenaline vs salbutamol

15. Illustration of drug selectivity.
Log dose-response curves of salbutamol for bronchodilatation
(A) and cardiac stimulation (D)
Log dose-response curves of isoprenaline for bronchodilatation
(B) and cardiac stimulation (C)

16. Therapeutic index (TI)/ Safety margin
Gap between the therapeutic effect DRC and adverse effect DRC
Median effective dose- dose which
produces the Specified effect in 50%
individuals
Median lethal dose- dose which kills
50% of the recipients

17. Therapeutic index (TI)

18. Therapeutic window/ therapeutic range
• Bounded by the dose which produces minimal therapeutic effect and
the dose which produces maximal acceptable adverse effect
• Individual variability: effective dose may be toxic for others
• Defining the therapeutic range is difficult
• Few drugs higher therapeutic response and adverse effects in higher
doses
Ex: Prednisolone in Asthma

19. Illustrative dose-response curves for
therapeutic
effect and adverse effect of the same
drug

20. Risk-benefit ratio
• Judgment between estimated harm and the expected advantages
• Estimated harms:
- Adverse effects
- Cost
- Inconvenience
• Expected advantages:
- Relief of symptoms
- Cure
- Reduction in complications/mortality
- Improvement in quality of life

21. • Prescribe when benefit outweighs the risks
• Difficult to measure accurately
• Should rely on pharmacoepidemiology and experience

22. Drug specificity
• Refers to range of actions produced by a drug
• Drugs may show –
- One / limited number of actions
- Widespread effects on many organs of the body
• Depends on:
a.Whether drug acts on single/many receptors/targets and
b.How widely the target is distributed in the body
Ex:
Omeprazole- highly selective
Chlorpromazine- D2, muscarinic cholinergic, H1, 5-HT
Dexamathasone- involves many organs due to receptors widespread in the
body

23. Combined effects of drugs

24. objectives
• Describe the combined effects of drug action
• Explain synergism with few examples
• Explain antagonism with few examples

25. Combined effects of drugs
• If two/ more drugs given simultaneously/ in quick succession, they
may be either indifferent to each other or exhibit synergism/
antagonism.
• Interaction may take place at
- Pharmacokinetic level
- Pharmacodynamic level

26. Synergism
• Action of one drug is facilitated or increased by the other
• In a synergetic pair
- Both drugs can have action in same direction or
- One may be inactive and enhancing the effect of other
• Two types
- Additive
- Supraadditive/ potentiation

27. Additive
• Effect of two drugs in same direction and simply adds up
Effects of drugs A+B= effect of drug A+ effect of drug B
Side effects do not add up
Better tolerance than high dose of one component

28. Supraadditive
• Effect of combination is greater than the individual effects
Effects of drug A+B > effect of drug A+ effect of drug B
When one component given alone produces no effect, but
enhances the effect of the other.

30. Antagonism
• One drug decreases or abolishes the action of the other
Effects of A+B < effect of drug A+ effect of drug B
• One drug is inactive and decreases the effect of the other

31. Drug Antagonism
1. Physical
2. Chemical
3. Physiological antagonism
4. Receptor antagonism:
a. Competitive antagonism (equilibrium)
b. Non-competitive
c. Non-equilibrium

32. Physical antagonism
• Based on the physical property of the drug
- charcoal : adsorbs alkaloids (used in alkaloidal poisonings)

33. Chemical antagonism
• Two drugs react chemically and form an inactive product

34. Physiological/ functional antagonism
• Two drugs act on different receptors or by different mechanisms
• Have opposite effects on the same physiological function

35. Receptor antagonism
• One drug/ antagonist blocks the receptor action of the other
drug/agonist
• Receptor antagonists are relatively selective

36. Receptor antagonism - curves
Competitive:
o Antagonist is chemically similar to agonist and binds to same receptor
molecules
o Affinity (1) but IA (0), Result – no response
o Log DRC shifts to the right
o antagonism is reversible – increase in concentration of agonist overcomes
the block
o Parallel shift of curve to the right side when the concentration of antagonist
increases
o Extent of shift depends on affinity and concentration of antagonist

38. Plot on a DRC for competitive antagonists
A&B. Antagonism A>B, Agonist notify as
C

39. Dose-response curves showing competitive (a) antagonism
A—agonist, B—competitive antagonist,

40. * Partial agonist- have affinity for the same receptor competes with
and antagonizes a full agonist & produces a submaximal response

41. Non-competitive/ allosteric antagonism:
o Allosteric site binding- altering receptor not to bind with
agonist/ unable to transduce the response
o Chemically unrelated to antagonist
o No competition between them – no change of effect even
agonist concentration is increased
o Increasing concentration of antagonist progressively flatten DRC
o Not in clinical use

43. Plot on a graph for non-competitive
antagonists A&B, Antagonism A>B, Agonist
notify as C

45. • Non – equilibrium:
• Antagonists Binds receptor with strong bond
• Dissociation is slow and agonists cannot displace antagonists
• Irreversible antagonism develops
• DRC shifts to the right and Maximal response lowered
• Phenoxybenzamine is a non-equilibrium antagonist of adrenaline
at the alpha adrenergic receptors

46. Plot on a DRC for agonist A and non-
equilibrium antagonist B

47. Compare between competitive and non-
competitive antagonists?

50. THANKYOU