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Combined Effect of Drugs: Synergism, Antagonism, etc.


  • Two drugs produce same response with different mechanisms.

  • Combined effect is algebraic sum of individual effects.

  • e.g. aspirin + Codeine for analgesic action.

Additive effect

  • Two drugs produce same response with same mechanism.

  • Combined effect is algebraic sum of individual effects.

  • e.g. paracetamol + ibuprofen for analgesic action.


  • Combined effect is more than algebraic sum of individual effects.

Sequential Block
  • Both drugs inhibit different steps of the same biochemical pathway.

  • e.g. Sulfamethoxazole + trimethoprim combination to inhibit folic acid synthesis:

    • Sulfamethoxazole inhibits folate synthase.

    • Trimethoprim inhibits dihydrofolate reductase.

    • Individually these drugs are bacteriostatic but the combination is bactericidal.

One Drug Alters the Pharmacokinetics of the Other Drug
  • e.g. levodopa + carbidopa for Parkinsonism:

    • Levodopa alone is degraded in periphery โ†’ no or very less action.

    • Levodopa + carbidopa โ†’ carbidopa prevents peripheral degradation of levodopa โ†’ more levodopa enters CNS โ†’ better antiparkinsonian action.

Drug Antagonism

  • One substance decreases effect of the other substance.

  • Usually in such cases, only one is an actual drug. The other is usually endogenous molecule or sometimes poison whose activity we want to decrease.

Chemical Antagonism
  • One is simply a chemical antidote of the other i.e. they neutralize each other even without involvement of any living thing from our body.

  • e.g.

    • Gastric acid + Antacids: Antacids like aluminum hydroxide neutralize gastric acid.

    • Heavy metals + chelating agents: chelating agents like BAL and calcium sodium edetate form inactive insoluble complexes with heavy metals like arsenic or lead โ†’ prevents the effects of heavy metals

    • Heparin + protamine: Highly positively charged protamine neutralizes strongly negative heparin

Physiological or Functional Antagonism
  • Both drug act by different receptors or different mechanisms.

  • Produce opposite effects on same physiological parameter.

  • Example 1. Adrenaline + histamine on bronchial muscles:

    • Histamine โ†’ histamine receptors โ†’ Broncho-constriction.

    • Adrenaline โ†’ adrenergic receptors โ†’ Broncho-dilatation.

  • Example 2. Glucagon + Insulin on blood sugar:

    • Glucagon โ†’ glucagon receptors โ†’ increase blood sugar level.

    • Insulin โ†’ insulin receptors โ†’ decrease blood sugar level.

Pharmacological Antagonism or Receptor Antagonism

Competitive Antagonism

  • Both drugs compete with each other for same site on receptor.

  • Reversible or Equilibrium Type

    • Antagonist makes a weak bond โ†’ binding of antagonist is reversible โ†’ by increasing concentration of agonist โ†’ antagonists can be displaced โ†’ maximum response can be achieved.

    • E.g. atropine is reversible competitive antagonist of acetylcholine on muscarinic receptors.

  • Irreversible or Non-equilibrium Type

    • Antagonist binds with strong covenant bond โ†’ binding is irreversible โ†’ if agonist concentration is increased โ†’ effect of antagonist cannot be overcome โ†’ maximum response cannot be achieved.

    • E.g. dibenamine is irreversible competitive antagonist of norepinephrine on ฮฑ1 receptors.

    • Pseudo-reversible antagonism

      • Its a type of irreversible antagonism seen if spare receptors are present.

      • For certain physiological responses, occupying some receptors it's enough to achieve maximum response. So we have spare receptors.

      • At low antagonist concentration โ†’ fewer receptors are occupied by antagonists โ†’ increasing agonist concertation can achieve maximum response by using spare receptors โ†’ its like reversible inhibition โ†’ but if we increase antagonist concentration also, more or all the receptors are occupied by antagonist โ†’ spare receptors are also blocked โ†’ increasing agonist concentration cannot overcome antagonist's effect โ†’ irreversible antagonism.

      • e.g. phenoxybenzamine is pseudo-reversible antagonist of ฮฑ1 receptor

Non-Competitive Antagonism

  • The antagonist does not compete for the binding site for agonist.

  • By binding at allosteric site:

    • Allosteric site is a site different from that where agonist binds.

    • Binding of antagonist at allosteric site โ†’ prevents receptor activation by agonist

  • Through interfering downstream events:

    • e.g. norepinephrine โ†’ ฮฑ1 receptor โ†’โ†’โ†’ opening of Ca channels โ†’ entry of Ca โ†’ vasoconstriction. Here verapamil blocks Ca channel and prevent the effect of noradrenaline. So verapamil can be said to be non-competitive antagonist.


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