Pharmacodynamics: Drug-receptors

Intracellular Receptors

• Located in the cytoplasm or nucleus of cells
• Bind to small, hydrophobic ligands, such as steroids
• Receptor-ligand complex binds to specific DNA sequences
• This interaction activates or inhibits specific genes

Cell-Surface Receptors

• Embedded in the plasma membrane
• Bind to ligands that are too large or hydrophilic to pass through the membrane
• Three main types: ligand-gated ion channels, enzyme-coupled receptors, and G-protein coupled receptors

Ligand-gated Ion Channels (Ionotropic Receptors)

• Form channels or pores that are closed in the absence of a ligand
• Binding of a ligand opens the channel, allowing ions (chloride, calcium, sodium, potassium) to pass through
• Ions flow passively down their concentration gradients
• This triggers downstream signaling pathways

Enzyme-coupled Receptors

• Usually single-pass transmembrane proteins
• Extracellular domain binds to ligands
• Intracellular domain has enzymatic activity, typically protein kinase (tyrosine kinase)
• Ligand binding triggers conformational changes, creating high-affinity binding sites for second messengers
• Tyrosine kinases phosphorylate second messengers, activating other proteins in the signaling pathway

G-protein Coupled Receptors (Seven-Pass Transmembrane Receptors)

• Long proteins with one end outside the cell and seven transmembrane segments
• Ligand binding on the extracellular end activates guanine nucleotide-binding proteins (G proteins)
• G proteins have alpha, beta, and gamma subunits
• Alpha subunit binds to GDP in the inactive state
• Ligand binding causes the alpha subunit to release GDP and bind GTP
• This activation causes the alpha subunit to detach and trigger other proteins in the signaling pathway

Types of G Proteins

• Gq, Gi, and Gs
• Each type has a unique alpha subunit
• Gq activates phospholipase C
• Gs and Gi stimulate or inhibit adenylate cyclase, respectively

Second Messengers

• IP3, DAG, and cAMP
• Produced by the action of G proteins and their target enzymes
• IP3 and DAG are produced by phospholipase C
• cAMP is produced (or inhibited) by adenylate cyclase
• Activate or inhibit various enzymes and molecular pathways

Medication-Receptor Interactions

• Three key principles: affinity, potency, and efficacy

Affinity

• Strength of the binding interaction between a medication and its receptor
• Determined by the chemical bond between the two molecules
• Higher affinity generally corresponds to a stronger interaction

Potency

• Amount of medication needed to produce a specific effect
• High potency requires a lower dose for a given effect
• Affinity is directly proportional to potency

Efficacy

• Maximum effect a medication can produce
• Measured by the Emax (maximum response) on a dose-response curve
• Higher efficacy corresponds to a greater maximum response

Dose-Response Curve

• Graph showing the relationship between medication concentration (dose) and the response produced
• Typically S-shaped (sigmoidal)
• X-axis: medication concentration (logarithmic scale)
• Y-axis: response

EC50

• Median effective concentration
• Concentration of medication that produces 50% of the maximum effect (Emax)
• EC50 is inversely proportional to potency

Comparing Medications

• Higher potency corresponds to a lower EC50 on the dose-response curve (curve shifted left)
• Higher efficacy corresponds to a higher Emax on the dose-response curve (curve shifted upward)