Pharmacodynamics: Drug Targets

Receptors

• Essential components of cellular communication
• Four major families:
  • G-protein coupled receptors
  • Ligand-gated ion channels
  • Kinase linked receptors
  • Nuclear receptors
• Often named after their ligands (endogenous or pharmacological)

G-protein Coupled Receptors

• Largest receptor family, with 865 known human GPCRs
• Ligand-activated receptors, consisting of a single polypeptide with 7 transmembrane domains
• Linked to intracellular effectors known as G-proteins
• Activate enzymatic signalling cascades, resulting in metabotropic responses, which are slow and long-lasting (induction takes over 100 milliseconds; initial effects last seconds to minutes)

Gs proteins

• Stimulate adenylate cyclase, increasing cAMP and PKA activity

Gi proteins

• Inhibit adenylate cyclase, decreasing cAMP and PKA activity

Gq proteins

• Activate phospholipase C, leading to increased PKC activity and intracellular calcium levels

Examples of GPCRs

• Muscarinic acetylcholine receptors: found in the CNS, lungs, and GI tract
• Adrenergic receptors: present in the heart, vasculature, lungs, and CNS
• Histamine receptors: located in the heart, vasculature, GI tract, and nociceptive pathways
• Prostaglandin receptors: involved in inflammation, GI function, and CNS activity

General Information

• Drugs target proteins; this is important to understand the mechanism of action of a drug
• Common drug targets include: receptors, enzymes, ion channels, and transporters

Enzymes

• Vital for metabolism, including:
  • Regulation of metabolism
  • Intracellular and intercellular signaling
  • Gene activation and suppression
  • Drug metabolism

Ion Channels

• Often selective for cations (K+, Na+, Ca2+) or anions (Cl-)
• Cation channels may be specific for one ion, or permeable to several

Voltage-gated Ion Channels

• Example: voltage-gated sodium channel (VGNaC)
• Closed at resting membrane potential (-70 mV)
• Depolarization of the membrane (-40 mV) causes the channel to open

Local Anesthetics

• Block the inside of the VGNaC pore, preventing Na+ flux
• Examples: lidocaine

Transporters ("Pumps")

• Move ions and small molecules across cell membranes
• May utilize electrochemical gradient or ATP hydrolysis
• Types include:
  • Symporters: co-transport
  • Antiporters: exchange

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Inhibit the serotonin transporter (SERT), preventing reuptake of serotonin from the synapse

Tolerance

• Reduced drug effect over time
• Mechanisms include:
  • Increased expression of proteins mediating opposite activity
  • Receptor internalization by endocytosis

Withdrawal

• Symptoms experienced upon discontinuation of a drug
• Caused by the body's adaptation to the drug's presence
• Example: corticosteroids
  • Suppress endogenous cortisol production
  • Discontinuation leads to cortisol deficit

Summary of Drug Targets

• Drugs affect molecules to alter physiological activity
• Understanding the cellular and physiological systems targeted by drugs is crucial for comprehending pharmacology

Explore the essential roles and mechanisms of G-protein coupled receptors (GPCRs) in cellular communication. This quiz covers the four major families of receptors, the specific types of G-proteins, and their signaling pathways. Test your knowledge on how these receptors influence various physiological processes.