Drug efficacy, potency, and selectivity are crucial concepts in pharmacology. They determine how well a drug works, how much is needed, and how specific its effects are. These properties shape a drug's therapeutic potential and safety profile.

Understanding these concepts is key for developing effective medications. They guide drug design, dosing strategies, and help predict both desired effects and potential side effects. This knowledge is essential for optimizing treatments and minimizing risks to patients.

Drug efficacy, potency, and selectivity

Key Definitions and Importance

• Drug efficacy measures maximum response a drug produces in biological system regardless of dose
  • Determines therapeutic potential and limitations of drug
  • Helps predict clinical effectiveness
• Potency quantifies amount of drug required to produce specific effect
  • Typically expressed as EC50 (half-maximal effective concentration) or IC50 (half-maximal inhibitory concentration)
  • Lower EC50/IC50 values indicate higher potency
• Drug selectivity describes preferential interaction with specific molecular targets
  • Maximizes therapeutic effects (pain relief)
  • Minimizes side effects (nausea)
• Therapeutic index calculates ratio of toxic dose to effective dose
  • Influenced by drug's efficacy, potency, and selectivity
  • Higher index indicates safer drug (penicillin)

Applications in Drug Development and Clinical Practice

• Understanding efficacy, potency, and selectivity crucial for:
  • Optimizing drug development process
    • Screening lead compounds
    • Refining chemical structures
  • Designing dosing strategies
    • Determining appropriate starting dose
    • Adjusting dose for different patient populations
  • Predicting drug interactions
    • Identifying potential synergistic or antagonistic effects
  • Anticipating adverse effects
    • Assessing risk-benefit profile
    • Implementing monitoring protocols

Concentration vs Receptor Occupancy

Occupancy Theory and Mathematical Modeling

• Occupancy theory states drug effect magnitude proportional to fraction of receptors occupied
• Langmuir binding isotherm mathematically describes relationship
  • Assumes 1:1 binding stoichiometry
  • Equation: $\text{Fractional Occupancy} = \frac{[Drug]}{[Drug] + K_d}$
• Receptor occupancy increases non-linearly with drug concentration
  • Follows hyperbolic curve
  • Approaches but never reaches 100% occupancy
• Dissociation constant (Kd) represents drug concentration at 50% receptor occupancy
  • Inversely related to drug's receptor affinity
  • Lower Kd indicates higher affinity

Receptor Reserve and Pharmacological Implications

• Receptor reserve phenomenon allows maximal response with <100% receptor occupancy
  • Influences observed efficacy and potency
  • Examples: beta-adrenergic agonists in cardiac tissue
• Spare receptors contribute to receptor reserve
  • Allow for maintained response despite receptor desensitization or downregulation
• Implications for drug action:
  • Partial agonists may produce full effect in systems with large receptor reserve
  • Inverse agonists more likely to show effects in systems with constitutive receptor activity

Factors Influencing Drug Properties

Biological and Genetic Factors

• Receptor density affects drug efficacy and potency
  • Higher density increases maximum possible response (insulin receptors in adipose tissue)
  • Lower density may require higher drug concentrations for effect (beta-adrenergic receptors in elderly)
• Drug metabolism alters efficacy, potency, and selectivity
  • Changes concentration of active drug at target site
  • Produces active metabolites with different properties (codeine to morphine)
• Genetic polymorphisms cause inter-individual variations
  • Drug targets (warfarin sensitivity and VKORC1 gene)
  • Metabolizing enzymes (CYP2D6 and antidepressant metabolism)

Environmental and Pharmacokinetic Influences

• Allosteric modulators influence drug-receptor interactions
  • Alter receptor conformation and drug affinity
  • Examples: benzodiazepines on GABA receptors
• Environmental factors affect drug-receptor binding
  • pH changes ionization state of drugs (weak acids in stomach)
  • Temperature alters binding kinetics and drug distribution
• Pharmacokinetic properties impact drug concentration at target site
  • Absorption (oral bioavailability of different statins)
  • Distribution (lipophilicity affecting blood-brain barrier penetration)
  • Elimination (renal clearance of aminoglycosides)

Receptor Subtypes and Selectivity

Molecular Basis of Receptor Subtypes

• Receptor subtypes structurally and functionally distinct variants within receptor family
  • Respond to same endogenous ligand
  • Different affinities for drugs
• Molecular cloning and pharmacological studies revealed multiple subtypes
  • Adrenergic receptors (α1, α2, β1, β2, β3)
  • Dopamine receptors (D1-D5)
  • Serotonin receptors (5-HT1-7)

Pharmacological Implications of Receptor Subtypes

• Subtype-selective drugs target specific physiological processes
  • Minimize unwanted effects
  • Example: β1-selective blockers for hypertension without bronchial effects
• Selectivity achieved through:
  • Differences in binding site structure (α1 vs α2 adrenergic antagonists)
  • Allosteric sites (benzodiazepine subtypes)
  • Differential coupling to intracellular signaling pathways (μ vs δ opioid receptors)
• Tissue-specific distribution of subtypes contributes to organ-selective effects
  • Enhances therapeutic utility and safety profile
  • Example: M2 receptors in heart vs M3 receptors in salivary glands
• Understanding subtype pharmacology crucial for:
  • Rational drug design (developing subtype-specific ligands)
  • Development of more selective therapeutic agents (next-generation antipsychotics)