top of page

Combined Effect of Drugs: Synergism, Antagonism, etc.



Summation

  • 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.

Synergism

  • 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 → no or very less action.

    • Levodopa + carbidopa → carbidopa prevents peripheral degradation of levodopa → more levodopa enters CNS → 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 → 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 → histamine receptors → Broncho-constriction.

    • Adrenaline → adrenergic receptors → Broncho-dilatation.

  • Example 2. Glucagon + Insulin on blood sugar:

    • Glucagon → glucagon receptors → increase blood sugar level.

    • Insulin → insulin receptors → 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 → binding of antagonist is reversible → by increasing concentration of agonist → antagonists can be displaced → 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 → binding is irreversible → if agonist concentration is increased → effect of antagonist cannot be overcome → maximum response cannot be achieved.

    • E.g. dibenamine is irreversible competitive antagonist of norepinephrine on Îą1 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 → fewer receptors are occupied by antagonists → increasing agonist concertation can achieve maximum response by using spare receptors → its like reversible inhibition → but if we increase antagonist concentration also, more or all the receptors are occupied by antagonist → spare receptors are also blocked → increasing agonist concentration cannot overcome antagonist's effect → irreversible antagonism.

      • e.g. phenoxybenzamine is pseudo-reversible antagonist of Îą1 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 → prevents receptor activation by agonist

  • Through interfering downstream events:

    • e.g. norepinephrine → Îą1 receptor →→→ opening of Ca channels → entry of Ca → vasoconstriction. Here verapamil blocks Ca channel and prevent the effect of noradrenaline. So verapamil can be said to be non-competitive antagonist.

 

Next >>






Comments


bottom of page