Drug-Receptor Interactions

Introduction to Pharmacology

Pharmacology is the study of how drugs interact with biological systems. Drugs are defined as substances that have an effect on a biological system, such as paracetamol for pain relief. The field encompasses both the body's reaction to drugs (pharmacokinetics) and the drug's action on the body (pharmacodynamics), as well as pharmacogenetics and genomics.

• Pharmacokinetics: How the body absorbs, metabolizes, and excretes drugs.

• Pharmacodynamics: The action of drugs on cellular, molecular, organ, and organism levels.

• Bioassay: Measurement of drug activity using living material, such as organ baths.

Drug-Receptor Binding

Agonists and Antagonists

Drugs interact with receptors to elicit biological responses. The nature of this interaction determines whether the drug acts as an agonist or antagonist.

• Agonist: Binds to a receptor, activates it, and causes a biological effect. Example: Salbutamol for asthma binds to lung receptors and opens airways.

• Antagonist: Binds to a receptor but does not activate it; instead, it blocks the receptor. Example: Ibuprofen binds to enzyme receptors and prevents their action.

Partial agonists bind to receptors but produce less than the maximal response even at high concentrations.

Law of Mass Action and Drug-Receptor Binding

The interaction between drugs and receptors follows the law of mass action, which describes reversible binding and the influence of drug concentration on response.

• Magnitude of response depends on:

  • Number of drug molecules present

  • Proportion of available receptors occupied

  • Rate of formation and dissociation of drug-receptor complexes

Affinity and Efficacy

Affinity Constants: KD and KA

Drug-receptor binding is characterized by two key constants:

• KD (Dissociation constant): The concentration at which 50% of receptors are occupied by the ligand. Lower KD indicates higher affinity.

• KA (Association constant): The equilibrium constant for binding; higher KA means stronger binding affinity. KA is the inverse of KD.

Relationship:

Where [D] is drug concentration, [R] is receptor concentration, and [DR] is drug-receptor complex concentration.

Drug Binding and Activation

• Step 1: Agonist binds to receptor (Occupation).

• Step 2: Receptor changes shape and is activated (Activation).

Measuring Drug Response

• EC50: Concentration of drug required to produce 50% of the maximum effect.

• Emax: Maximum measured efficacy of a drug.

• ED50: Dose that produces half of the maximum effect in a population.

Potency, Efficacy, and Affinity

Definitions and Relationships

• Affinity: Tendency of a drug to bind a receptor.

• Efficacy: Ability of a drug to activate the receptor after binding.

• Potency: Amount of drug required to produce a given effect; more potent drugs require lower concentrations.

Graphical representation: On a log scale, increasing drug concentration increases receptor occupancy. Lower KD means higher potency.

Antagonists: Competitive and Non-Competitive

Competitive Antagonists

Competitive antagonists bind reversibly to the same site as agonists. High concentrations of agonist can displace the antagonist, restoring efficacy but reducing potency.

• pA2: Negative logarithm of the molar concentration of antagonist required to produce a two-fold shift in the agonist concentration-response curve.

• Ki: Inhibition constant; concentration of competing ligand that occupies 50% of receptors in a competition assay.

• IC50: Concentration required to inhibit 50% of the response; varies with experimental conditions.

Cheng-Prusoff equation relates IC50 to Ki:

Non-Competitive (Irreversible) Antagonists

Non-competitive antagonists bind permanently to the receptor, preventing activation by agonists regardless of their concentration. This reduces both potency and efficacy (Emax).

• Affinity but no efficacy (0).

• Cannot be displaced by agonist.

Summary Table: Agonists vs Antagonists

Key Equations and Concepts

• : Concentration for 50% maximal effect

• : Maximum effect

• : Dose for 50% effect in population

• : Negative log of antagonist concentration for two-fold shift

Applications and Examples

• Asthma: Salbutamol (agonist) binds to bronchi receptors, opens airways; salmeterol (longer acting agonist) binds for 12 hours.

• Antagonists: Used to block excessive receptor activation, e.g., in asthma, antagonists block acetylcholine receptors to reduce bronchial contraction.

Additional info:

• Avogadro's constant: mol-1, defines the number of molecules per mole.

• Pharmacological principles are foundational for understanding drug action, receptor theory, and therapeutic applications.