Pharmacology: Affinity vs Efficacy

Drug Efficacy and Agonists

• Full agonists have maximum efficacy (Emax = 1).
• Partial agonists have intermediate efficacy levels.
• Efficacy indicates a drug's ability to activate receptors after binding, which is crucial for producing biological effects.

Affinity vs. Efficacy

• Affinity determines how well a drug binds to receptors.
• Efficacy measures the drug's ability to activate the receptor upon binding.
• Example: Fentanyl acts as a μ-opioid receptor agonist, demonstrating high efficacy.
• Antagonists, such as naloxone, possess zero efficacy and block receptor activation, particularly at μ-opioid receptors.

Potency

• Defined by both affinity and efficacy; relates to the concentration (EC50) or dose (ED50) needed for 50% of maximal effect.
• A drug's potency is represented on a dose-response curve.
• pEC50 is the negative logarithm of EC50, quantifying potency.

Dose-Response Curves

• Describe the relationship between drug dose and physiological response.
• Drugs may have the same efficacy but differing potencies; for instance, Drug A may have a lower EC50 than Drug D.

Pharmacological Targets

• Drugs can affect receptors, ion channels, enzymes, and transporter proteins.
• Most receptors and channels are located on the cell surface; enzymes are typically found in the cytosol.

Specificity and Selectivity of Drug Action

• Selectivity refers to a drug's ability to preferentially bind to one target over another, while specificity indicates a drug's singular effect across biological systems.
• No drug is entirely specific; increasing doses can lead to unintended effects (side effects).
• Side effects can be classified as "on-target," occurring at the principal receptor, or "off-target," affecting alternative mechanisms.

Side Effects and Mechanisms

• Side effects arise from dose-dependent interactions with unintended targets.
• Dimenhydrinate (antiemetic) demonstrates how a drug can produce desired effects (e.g., nausea relief) while also causing side effects (e.g., drowsiness).

Efficacy vs. Potency

• High potency drugs often have high affinity, enabling significant biological effects at lower concentrations.
• A drug can possess low affinity but high efficacy, allowing maximal effect with minimal receptor occupancy.

Receptor Reserve

• Refers to the surplus of receptor sites available compared to signaling capacity.
• Partial agonists may show variable efficacy across different tissues due to differences in receptor reserve.
• Higher receptor reserves generally increase the apparent potency of full agonists.

Summary of Drug Response Characteristics

• Emax indicates the maximum pharmacological effect of a drug.
• EC50 represents the concentration needed for half-maximal response.
• Concentration-effect curves provide insights into drug potency and receptor interaction, but cannot directly measure full agonist affinity.

Pharmacologic Targets

• Molecules binding to proteins can induce pharmacological effects by changing protein structure.
• Pharmacologic targets include protein receptors, ion channels, enzymes, and transporter proteins, each affecting physiological processes via activation or inhibition.

Location of Targets

• Receptors and ion channels are primarily on the cell surface; enzymes typically reside in the cytosol and require drug penetration.
• Nuclear receptors are exceptions, found within the cell nucleus; DNA also serves as a drug target.

Pharmacological Effects on Cells

• Changes in mechanical functions: enhanced cardiac contractility and contraction of bronchiole smooth muscle.
• Biochemical effects: modulation of second messenger levels (e.g., Ca2+, cAMP).
• Inhibition of enzyme activity affects the degradation rate of cellular messengers like cAMP.

Specificity and Selectivity of Drug Interactions

• Selectivity refers to a drug's ability to preferentially bind specific targets; specificity indicates a drug's isolated effect across biological systems.
• No drug achieves complete specificity or selectivity; interactions depend on drug and target classes.

Agonists and Antagonists

• Agonists activate receptors to elicit tissue responses; antagonists bind to the same receptor site but do not activate it, blocking effects of agonists.
• Receptor ligands encompass both agonists and antagonists.

Binding and Receptor Activation

• Drug binding and receptor activation are reversible processes, influenced by various rate constants.
• Antagonists do not initiate receptor activation (β = 0).

Affinity and Equilibrium Constant (KA)

• KA represents a drug's binding affinity to its receptor; a lower KA indicates higher affinity.
• KA is the concentration required to occupy 50% of receptor sites at equilibrium.

Hill-Langmuir Equation

• The proportion of occupied receptors can be quantified; KA marks the concentration needed for 50% receptor occupancy.
• Binding affinity is inversely related to KA’s value.

Dose-Response Curves

• Biological responses to drugs (e.g., heart rate increase, enzyme activation) are measured and plotted in dose-response curves.
• A consistent increase in response corresponds to escalating drug concentrations.

Efficacy and Potency

• Efficacy (Emax) is the maximum expected effect from a drug.
• Efficacy differentiates full agonists (strong tissue response) from partial agonists (limited response).

Drug Affinity vs. Potency

• High affinity often correlates with potency, allowing significant biological effects at lower concentrations.
• Low-affinity drugs can still achieve high efficacy, producing substantial response with fewer receptors occupied.

Receptor Reserve

• The number of receptor sites can exceed a cell's signaling capacity, allowing significant responses even with low occupancy.
• Variations in receptor reserve between tissues can lead to different physiological outcomes from identical agonist concentrations.

Conclusion

• Understanding pharmacological targets, binding interactions, efficacy, and potency is crucial to drug development and therapeutic applications.