Dose-Effect Relationships

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  • Dose-Response Curves:
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  • Graded Dose-response relationship: A majority of drugs produce graded response i.e. the intensity of effect increases with the dose or concentration of drug. The response can be measured on a continual basis in such cases and it is easy to establish a linear relationship between drug concentration and intensity.
  • Quantal Dose-response relationship: For certain other drugs, the responses are not observed on a continuous basis. Such drugs may either show their effect or not at all – for example, prevention of seizures by phenytoin. Such responses are called quantal or all-or-none.
  • Quantal dose-effects:
  • EC50 - median effective dose - the dose at which 50% of subjects exhibit a quantified effect
  • TD50 - median toxic dose - dose required to produce a toxic effect in 50% of subjects
  • LD50 - median lethal dose - dose required to produce a lethal effect in 50% of subjects
  • Therapeutic index - the ratio of the drug required to produce a desired effect to the dose that produces a toxic effect - ratio of TD50 to ED50

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  • A: Frequency distribution curve - Effective plasma concentration to produce a quantal response determined for 100 individuals and plotted on a chart
  • B: Quantal dose-effect curve - Animals injected with various doses of a drug, responses determined and plotted

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  • Mechanisms of Receptor Antagonism:
  • Competitive Antagonism: Agonist A and antagonist I compete for the same binding site on the receptor
  • Response curves shifted to the right in a concentration dependent manner, EC50 of the agonist increases with the concentration of the antagonist (L, L', L etc)
  • Partial Agonists: Drugs that bind to and activate a receptor, but have only partial efficacy at the receptor relative to a full agonist
  • Act as competitive antagonists by competing for binding sites in a reversible manner
  • Inverse Agonist: An agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.
  • Full agonists have an efficacy of 100%, neutral antagonists have an efficacy of 0%, while inverse agonists have a negative efficacy - <0%
  • Irreversible/pseudo-irreversible (slow dissociation but not covalently bonded) Antagonism:
  • Shifts dose-response curve to the right, and depresses maximal response
  • Allosteric Effects:
  • Allosteric ligand I or P binds to a different site, either inhibiting the response or potentiating the response
  • Saturable - inhibition/potentiation reaches a limiting value when the allosteric site is fully occupied
  • Promoters are referred to as allosteric agonists or co-agonists
  • Mixed Agonist-Antagonists:
  • A drug which has agonist and antagonist activity depending on the tissues it is acting upon

  • Additive Effect: When the combined effect of two drugs equals the sum of the effect of each agent given alone
  • Synergism: When a combination of two drugs produces a combined effect greater than the individual sum of their parts
  • Potentiation: The creation of a toxic effect from one drug due to the presence of another drug