1. Drug combinations can have additive, synergistic, or antagonistic effects depending on how the drugs interact. Additive effects are when the combined effect is equal to the sum of the individual drug effects. Synergistic effects occur when the combined effect is greater than the sum. Antagonistic effects are when the combined effect is less than the sum. 2. There are different types of drug antagonism including competitive (reversible or irreversible), non-competitive, chemical, physiological, and physical. Competitive antagonism occurs when drugs bind to the same receptor site, while non-competitive antagonism involves effects downstream of the receptor. 3. Rightward shifts of dose-response curves indicate competitive antagon

1. COMBINEDEFFECTSOFDRUGS
Deepankar Ratha
AssistantProfessor
Department ofPharmacology
CUTM,Rayagada

2. Protocol:
Summation
Additive effects
Synergism
Drug antagonism
2

3. EFFECTOFCOMBINATIONOFDRUGS
Combinations of two/more drugs, simultaneously or
in quicksuccession
1. No interference with each other’seffects.
2. May oppose each other’s actions(antagonism)
3. May produce similar actions on the sameorgan
(synergism)

4. Interaction
Pharmacokinetic Pharmacodynamic

5. DrugSynergism
Syn-together ; ergon-work

6. Drug Synergism:
This is facilitation of the effects of one drug
by another when giventogether
Types:
a. Additive (summation)
b. Supra-additive (Potentiation)

7. Summation/Addition
Effect of drugsA+B=Effect of drug A+Effect of drugB
• Final effect is sameasthe algebraic sum of the
magnitude of individualsdrugs
• Sideeffects do not addup
Examplesof Summation:Different MOA
Aspirin : (-) PGsynthesis analgesia +
Codeine : Opioid agonist analgesia +
Examplesof Addition: SameMOA
Ibuprofen: (-) PGsynth analgesia +
Paracetamol: (-) PGsynth analgesia+
Analgesia
++
Analgesia
++

8. Other Additive DrugCombinations
Drug Effect
Combination
Amlodipine + Antihypertensive
Atenolol
Glibenclamide +
Metformin
Hypoglycemic

9. Supraadditive( Potentiation)
Effectof drugA+B>Effectof drugA+Effectof drugB
When two drugs are given together the final effect is much
more than the simple algebraic sum of the magnitude of
individuals drugs.
Examples:
Sulphamethoxazole & Trimethoprim--- sequentialblockade
of two steps in synthesis of folic acid in micro-organisms.

11. Synergism by altering Pharmacokinetics
of theother:
• Levodopa +Carbidopa

12. Other supraadditivedrug
combinations
DRUG PAIR BASIS OF POTENTIATION
Ach + Physostigmine
Adrenaline + Cocaine
Tyramine + MAO
inhibitors
Inhibition of break
down
Inhibition of neuronal
uptake
Increasing
releaseable CAT
store

13. DrugAntagonism

14. DrugAntagonism
Definition:
Combined effect of two drugs is lessthan thesum of
the effects of the individualdrugs
Effect of drugsA+B<Effect of drug
A+Effect of drug B
One drug decreases / opposes / reverses / counters
the effect of other drugby different mechanisms

15. Types:
a. PharmacologicalAntagonism :
i. Competitive (Reversible)
ii. Non-competitive (Irreversible)
b. ChemicalAntagonism
c. PhysiologicalAntagonism
d. Physicalantagonism

16. PharmacologicalAntagonism:
Irreversibly
Reversibly
competitive competitive
Pseudo-
reversibly
competitive
Interfere “Down-stream events” Act on
“allosteric site”
PHARMACODYNAMIC ANTAGONISM
Competitive NonCompetitive

17. Competitive
Antagonism
18

18. D-Rinteractions
R
B
B
D
B
19

19. 1
20
1
00
80
60
40
20
0
= Agonist = Antagonist
-1
0.5 -1
0 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6

20. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

21. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

22. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

23. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

24. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

25. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

26. Reversible-Competitive
B
D
R
27
• Weak bond
• Sameagonist
site
• Short duration

27. LDRCshift toR
B
R
D
D
D
D
D
28
Reversible-Competitive
Conc dependant Dynamic Equilibrium

28. Competitive (Reversible)Antagonism/Competitive
(Equilibrium ) Antagonism
1. Samereceptor byformingWeak bonds
2.Maximal response depends on concentration of
both agonist andantagonist
3. Theeffect of antagonist can be overcome by
increasing the concentration of agonist. Thesame
maximal responsecanbeattained by increasing
dose of agonist---It is “surmountableantagonism”.
4. Parallel rightward shift of DRC

29. 120
100
80
60
40
20
0
= Agonist = Antagonist
-11 -10 -9 -8 -7 -6

30. = Agonist = Antagonist

31. Examples: Atropine andAcetylcholine at Muscarinic-R
Naloxone and Morphine at opioid-R
Propranolol and NEat β2- R
%
Response
50
ED 50 ED 50 ED 50

32. Irreversibly Competitive or Non
Equilibrium Competitive Antagonism:
1.Haveaffinity for the samereceptor sitesand
bind in an irreversible manner by covalent
bond
2.Effects cannot be overcome even by
increasing the concentration of theagonist
(unsurmountable)
3. LDRcurvesof agonist (in presence of
antagonist) would show reduced efficacybut
unaltered potency

33. Irreversibly- Competitive
B
D
R
• Sameagonist site
• Strong bond
34
• LDRC efficacy
(flatten)
• Longduration

34. 35

35. Irreversible antagonist
+ Agonist
+ Agonist
36

36. • DOAof irreversible antagonist islonger
• Equilibrium between Antagonist - Agonist
cannot be established even after increasing
the dose of agonist hence the term “Non-
equilibrium competitiveantagonism”
• E.g.Dibenamine and NEat α1adrenoceptors

37. Pseudo-reversible Antagonism:
• Lesserdegree of receptor occupancy bythe
antagonist & availability ofspare receptors
• Increasing conc. of agonist- shift LDRtoright
• Increasing conc. of antagonist- reductionin
maximal response.
• Hencethe term “Pseudo-reversible
Antagonism”

38. 39
Pseudo-Reversible Competitive
B
D
R
R
R
R
D
D
• Strong bond
• Sparereceptors
Agonist
overcomes
antagonist
• Sameagonist
site
• LDRC

39. 40
PseudoPresveeurdsoib-leRceovmerpseibtilteivCeompetitive
Inc. dose of agonist

40. at α1adrenoceptor
at 5HTreceptor
41
E.g.
Phenoxybenzamine-
Methysergide -
(5HTreceptor blocker)
Pseudo-Reversible Competitive

41. NonCompetitive
Antagonism
42

42. Non Competitive Antagonism
• ViaAllosteric Modulation
• Receptor-Effector pathway
modulation
(Down-stream regulation)
NO Competition
for Agonist site
43

43. B
D
R
•Different
Receptor site
44
•DR interaction
ineffective
•No Reversal
•LDRC flatten
AntagonismthroughAllosteric
receptor site binding:

44. •
•
i. Binds tosite other than the agonist site
ii. Prevent the receptor activation bythe
agonist
E.g.
Flumazenil by binding to BZDsite
antagonises the effects of BZDby
preventing the binding of GABAtoGABAA
receptor
Bicuculline and BZD
Antagonism through Allosteric
receptor site binding:

45. GABA
46
GABA
binding site
Channel
blocker
(Picrotoxin)
Channel
modulators
(barbiturates)
Inverse
agonists
(β-carbolines)
Flumazenil
(antagonists)
Benzodiazepines
Modulatory Site
Cl-
Cl-
AntagonismthroughAllosteric
receptor site binding:

46. Receptor-Effector pathway modulation
(Down-Stream Regulation)
R
D
47

47. Receptor-Effector pathway modulation
(Down-stream regulation)
48
AT1-R
NE
Ag II
Prazosin
Comp. Ant
Losartan
Comp. Ant
IP3,
DAG
α1-R
Ca2+
channel Activation
Free Ca2+ entry
Ca2+ Channel blocker
(eg., Nifedipine,
non-competitive antagonist
Vasoconstriction

48. Effectsonlog DRC
•
•
•
There is downward shift .The slope isreduced
and maximum response is diminished
Theparallelism is not maintained
No shift of curve on doseaxis

49. 50
• CompetitiveAntagonism
(equilibrium or reversible)
Action of agonist is blocked if
conc. of antagonist is
Antagonism canbe overcome
by conc. of agonist
Agonist can producemax.
response in higherconc.
Competitive antagonist shifts
LDRCof agonist toright
ED50of agonist in presence of
antagonist, e.g., Ach &
atropine; Adr & Prop.;
Morphine & Naloxone
• Non-competitive
(non-surmountable
Antagonist)
site of receptor
Antagonist binds to another
LDRC is flattened + max.
response is
e.g. Diazepamand bicuculline

50. ChemicalAntagonism
Atype of antagonism where a drug counters the effect
of another by simple chemical reaction / neutralization
(not binding to thereceptor)
1. Protamine sulphate & Heparin
2. Calcium sodium edetate form insolublecomplexes
with arsenic / lead
3. Neutralization of gastric acid by antacids like
Aluminium hydroxide, Magnesiumhydroxide,
Sodium bicarbonate

51. PhysiologicalAntagonism
Definition:
Atype of antagonism in whichone drugopposes
/ reverses the effect of another drug by binding
to a different receptor and producing opposite
physiologicaleffects
Examples:
1. Histamine and adrenaline onbronchial
musclesand BP
2. Glucagon and insulin on bloodsugarlevel

52. Physicalantagonism
• Basedon the physical property of drugse.g.
Charcoal adsorbs alkaloids and can prevent
their absorption- used in alkaloidalpoisonings
53