Pharmacology: Drug-Receptor Interactions

Law of Mass Action

• Drug-receptor interactions are governed by the law of mass action; response correlates with drug and receptor concentrations.
• Full occupancy of receptors results in maximal response; nonetheless, some tissues can reach maximum response with unoccupied receptors, known as spare receptors.
• Spare receptors mean that effective responses can occur at lower drug concentrations.

Types of Receptors

• Intracellular Receptors: Reside within the cell and require drugs to penetrate the cell membrane. Examples include steroid hormone receptors like cortisol and estrogen.
• Ligand-Gated Ion Channels: Binding of drugs leads to opening or closing of channels, allowing ion movement. These receptors enable rapid processes, e.g., GABA_A receptor allows chloride ions through when activated.
• G-Protein Coupled Receptors (GPCRs): Characterized by seven transmembrane domains, activated by ligands to initiate signaling via G-proteins. GPCRs are targets for approximately half of therapeutic drugs; an example includes beta-adrenergic receptors.
• Enzyme-Linked Receptors: Ligand binding activates associated enzymes, triggering cellular responses. A notable example is the insulin receptor, which regulates glucose uptake.

Selectivity, Affinity, and Intrinsic Activity

• Selectivity: Describes a drug's ability to selectively affect specific receptors, minimizing side effects.
• Affinity: Measures the strength of interaction between a drug and its receptor.

Therapeutic Index (TI)

• TI is calculated as the ratio of lethal dose (LD50) to effective dose (ED50).
• LD50: Dose that results in death for 50% of a population.
• ED50: Dose that produces the desired therapeutic effect in 50% of a population.
• A high TI indicates a safer drug with a larger margin between effective and lethal doses, while a low TI suggests closer lethal and therapeutic doses, indicating a higher risk.

GPCR and G-Protein Signaling

• GPCRs are single proteins with seven transmembrane domains interacting with ligands.
• Activation leads to rapid responses through second messengers such as PKA and PKC, typically reversible within seconds to minutes.
• Long-term signaling affects gene expression and can modulate cell function over extended periods.

Rhodopsin and Gαt Signaling Pathway

• Rhodopsin functions as a GPCR in rod cells of the retina, activated by light.
• Light induces a conformational change in rhodopsin, activating transducin (Gαt) by promoting GTP binding.
• Gαt activation leads to stimulation of phosphodiesterase (PDE), reducing cGMP levels, which in turn causes closure of cGMP-gated ion channels and hyperpolarizes photoreceptor cells.

Signal Amplification in GPCR Signaling

• GPCR signaling amplifies signals; one ligand-bound receptor can activate multiple G-proteins.
• Each activated G-protein can trigger various downstream effectors, leading to extensive second messenger production.

First-Pass Metabolism

• Orally administered drugs undergo first-pass metabolism in the liver via the hepatic portal vein before systemic circulation.
• This process may significantly reduce the active drug concentration reaching the target site, exemplified by drugs like propranolol.

Blood Flow and Drug Distribution

• Tissues with high blood flow (e.g., brain, liver, kidneys) facilitate rapid drug delivery; conversely, poorly perfused tissues (like fat) slow distribution.
• Capillary permeability varies; loose capillaries (e.g., liver) allow easier drug passage, while tight capillaries (e.g., blood-brain barrier) limit access to certain tissues.

Plasma Protein Binding

• Drugs can attach to plasma proteins (e.g., albumin), temporarily inactivating them.
• Only unbound drugs are pharmacologically active and subject to metabolism, affecting their overall efficacy and potency.

Explore the fundamental concepts of drug-receptor interactions and the law of mass action in this pharmacology quiz. Understand the different types of receptors, including intracellular receptors, ligand-gated ion channels, and G-protein coupled receptors. Test your knowledge on how these mechanisms influence drug efficacy and response.