3. EFFECTOFCOMBINATIONOFDRUGS
Combinations of two/more drugs, simultaneously or
in quicksuccession
1. No interference with each otherāseffects.
2. May oppose each otherās actions(antagonism)
3. May produce similar actions on the sameorgan
(synergism)
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
ā¢ Final effect is sameasthe algebraic sum of the
magnitude of individualsdrugs
ā¢ 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
++
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.
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
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
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 āsurmountableantagonismā.
4. Parallel rightward shift of DRC
31. Examples: Atropine andAcetylcholine at Muscarinic-R
Naloxone and Morphine at opioid-R
Propranolol and NEat Ī²2- 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
36. ā¢ DOAof irreversible antagonist islonger
ā¢ Equilibrium between Antagonist - Agonist
cannot be established even after increasing
the dose of agonist hence the term āNon-
equilibrium competitiveantagonismā
ā¢ E.g.Dibenamine and NEat Ī±1adrenoceptors
37. Pseudo-reversible Antagonism:
ā¢ Lesserdegree of receptor occupancy bythe
antagonist & availability ofspare receptors
ā¢ Increasing conc. of agonist- shift LDRtoright
ā¢ Increasing conc. of antagonist- reductionin
maximal response.
ā¢ Hencethe term āPseudo-reversible
Antagonismā
42. Non Competitive Antagonism
ā¢ ViaAllosteric Modulation
ā¢ Receptor-Effector pathway
modulation
(Down-stream regulation)
NO Competition
for Agonist site
43
44. ā¢
ā¢
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:
47. Receptor-Effector pathway modulation
(Down-stream regulation)
48
AT1-R
NE
Ag II
Prazosin
Comp. Ant
Losartan
Comp. Ant
IP3,
DAG
Ī±1-R
Ca2+
channel Activation
Free Ca2+ entry
Ca2+ Channel blocker
(eg., Nifedipine,
non-competitive antagonist
Vasoconstriction
48. Effectsonlog DRC
ā¢
ā¢
ā¢
There is downward shift .The slope isreduced
and maximum response is diminished
Theparallelism is not maintained
No shift of curve on doseaxis
49. 50
ā¢ 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
ā¢ 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
ā¢ Basedon the physical property of drugse.g.
Charcoal adsorbs alkaloids and can prevent
their absorption- used in alkaloidalpoisonings
53
