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General Principles of Pharmacology

Course Number: 580

Conceptual Basis of Drug Action

Drugs achieve their desirable (therapeutic) and undesirable (adverse) effects by interacting with specific molecular components of cells known as receptors. The various mechanisms of drug-receptor binding are illustrated in Figure 1.7 Bond strength associated with van der Waals forces, caused by shifting electron density in a molecule resulting in transient positive or negative charges that interact with transient areas of opposite charges on another molecule, is quite weak.

Hydrogen bonds between positively charged hydrogen atoms and negatively charged oxygen, nitrogen, or sulfur atoms and ionic bonds between atoms with an excess of electrons imparting an overall negative charge and atoms with a deficiency of electrons imparting an overall positive charge, are of intermediate strength. Covalent bonds, resulting from the sharing of a pair of electrons between two atoms, are so strong that they are essentially irreversible.

Chart showing hydrogen bonding and ionic bonding are the most common in drug-receptor interactions

Figure 1.

Hydrogen bonding and ionic bonding are the most common in drug-receptor interactions as they require little energy and may be easily broken.

There are six major groups of drug receptors (Figure 2).7 Drugs can bind to transmembrane ion channels and alter channel conductance. Voltage-gated channel conductance is regulated by the voltage across plasma membrane, e.g., action potentials in neurons permitting the selective passage of Na+ ions into cells, which, incidentally, may be blocked by lidocaine. Ligand-gated channel conductance can be controlled by endogenous ligands, e.g., acetylcholine, or exogenous drugs.

Illustrations showing the major types of drug-receptor interactions

Figure 2. Major types of drug-receptor interactions.

Drugs can bind to (A) transmembrane ion channels, (B) transmembrane G protein-coupled receptors, (C) transmembrane receptors with linked enzymatic domains, or (D) following diffusing across the plasma membrane, to cytoplasmic or nuclear receptors. Additionally, drugs can target extracellular and adhesion receptors (not shown).

Transmembrane G protein-coupled receptors convey information provided by endogenous ligands or exogenous drugs, e.g., epinephrine, from its extracellular surface to intracellular regions and activate signaling molecules called G proteins: G-stimulatory (Gs) activates Ca2++ channels and adenylyl cyclase, G-inhibitory (Gi) activates K+ channels and inhibits adenylyl cyclase, Go inhibits Ca2++ channels, Gq activates phospholipase C, and G12/13 affects diverse ion transporters.

Phosphorylation is a ubiquitous mechanism of protein signaling. Transmembrane receptors with linked enzymatic domains modify proteins by adding or removing phosphate groups to or from amino acids. The largest group of transmembrane receptors with enzymatic domains is the receptor tyrosine kinases family. These receptors transduce signals from many hormones and growth factors by phosphorylating tyrosine residues on the cytoplasmic side of the receptor.

Small, lipophilic (lipid-soluble) drugs that can cross the plasma membrane, along the concentration gradient, by passive diffusion and other drugs that are transported into the cell by facilitated transport or active transport target intracellular receptors. There are many such drugs that by activating or inhibiting intracellular enzymes and signal transduction molecules, transcription factors, structural proteins, and nucleic acids, have profound effects on cellular function.

Some drug receptors are located outside the plasma membrane. Extracellular receptors may be structural proteins, signaling molecules, or soluble cytokines such as TNF-α. Cells also interact directly; for example, when immune cells interact with cells in an inflamed tissue. The region of contact between two cells is called an adhesion. Cell-to-cell adhesion interactions are mediated by pairs of adhesion receptors, which may be inhibited by a class of drugs known as integrins.