MPharm PHA115: Drug-Receptor Concepts

MPharm Programme - Drug-Receptor Concepts

• This is a module for the MPharm programme (PHA115) at the University of Sunderland.
• The module covers drug-receptor concepts 3 and 4.
• Dr G Boachie-Ansah is the lecturer, and contact details are provided.

Drug-Drug Interactions

• The slides focus on drug-drug interactions, including antagonism, summation/additivity, and synergism/potentiation.

Drug Antagonism

• Drug antagonism occurs when the effect of one drug is diminished or eliminated by another.
• Types of drug antagonism include competitive, non-competitive, chemical, pharmacokinetic, and physiological/functional antagonism.

Competitive Antagonism

• Agonist and antagonist drugs compete for the same receptor binding site.
• Antagonist binding reduces agonist binding, thus reducing agonist effects.
• Two subtypes:
  • Reversible/surmountable: The agonist effect can be restored by increasing the agonist concentration.
  • Irreversible/insurmountable: The antagonist effect cannot be overcome by increasing the agonist concentration.
• Reversible competitive antagonism results in a parallel shift to the right on the agonist log D-R curve, with no reduction in the maximal response.

Irreversible Competitive Antagonism

• The antagonist drug irreversibly binds to the receptor (due to high affinity or covalent bonding).
• A fraction of receptors permanently unavailable for agonist binding.
• The antagonism cannot be overcome by increasing the agonist concentration.
• This leads to two effects on the agonist log D-R curve:
  • Reduction in the slope of the curve.
  • Reduction in the maximal response.

Non-competitive Antagonism

• The antagonist drug does not compete with the agonist for the same receptor binding site.
• The antagonist may bind to a different site on the receptor or interfere with response coupling.
• The antagonism cannot be overcome by increasing the agonist concentration.
• Leads to reduced slope and maximal response on the agonist log D-R curve.

Chemical Antagonism

• Results from direct interaction between antagonist and agonist drugs.
• The antagonist binds to/combines with the active drug (agonist) in solution.
• The active drug is rendered inactive or unavailable to interact with its receptors.
• Examples include protamine vs heparin and dimercaprol vs heavy metals (Hg, Cu, Pb).

Pharmacokinetic Antagonism

• The antagonist drug reduces the effective concentration of the agonist at its site of action.
• Possible mechanisms include:
  • Reduced absorption from the gastrointestinal tract (GIT).
  • Increased metabolic degradation.
  • Increased renal excretion.
• Examples include ferrous salts vs tetracycline antibiotics, phenobarbital vs warfarin, and NaHCO3 vs aspirin.

Physiological/Functional Antagonism

• The interaction of two opposing agonist effects in a single biological system cancels out each other's effect.
• The two drugs elicit opposing responses by acting on different receptors.
• Examples include acetylcholine vs noradrenaline (affecting heart rate) and glucocorticoids vs insulin (affecting blood sugar levels).

Summation/Additivity

• Summation occurs when the combined effect of two drugs eliciting the same overt response is equal to the algebraic sum of their individual effects.
• Additivity happens when the effects of two drugs acting through the same mechanism add up to the predicted expected response based on simple addition.

Synergism/Potentiation

• Synergism or potentiation occurs when the combined effect of two drugs is greater than the algebraic sum of their individual effects.
• The synergist may increase the concentration of the other drug at its receptor sites, or increase the responsiveness of the receptor-effector protein.
• Examples include tyramine & MAO inhibitors, and benzodiazepines & GABA (GABAA receptor).

Variation in Drug Responsiveness

• This section focuses on patient variability in drug response.
  • Scope includes inter-patient and intra-patient variations.
  • Possible consequences include lack of efficacy and unexpected side effects.
  • Possible mechanisms include pharmacokinetic and pharmacodynamic factors.
  • Qualitative and quantitative variations in drug responses are listed.
  • Tolerance, innate vs acquired, and tolerance vs tachyphylaxis are discussed.

Acquired Tolerance

• A progressive, acquired decrease in responsiveness to a drug following exposure.
  • This can be due to a number of mechanisms
    • Pharmacodynamic, including receptor down-regulation and uncoupling.
    • Metabolic tolerance related to induction of enzymes in drug metabolism.
    • Exhaustion/depletion of mediators.
    • Physiological adaptation.

Clinical Selectivity

• This section discusses the concept of clinical selectivity of drugs, specifically focusing on:
  • Absolute vs Relative Selectivity
  • Therapeutic vs undesirable/side effects.
  • Concept of Therapeutic Index (TD50/ED50).
  • The margin of safety, the benefit to risk ratios and examples of drugs are noted.

Recommended Reading

• A list of recommended textbooks and their ISBN numbers is provided.

This quiz covers key concepts from the MPharm programme module on drug-receptor interactions, specifically focusing on drug-drug interactions and various types of drug antagonism. Explore competitive, non-competitive, and other forms of antagonism as outlined in the course material.