Dose-Effect Relationships

• Dose-Response Curves:

• 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

• 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

• 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