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.

Figure 1.

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.

Figure 2. 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 (G_s) activates Ca²⁺⁺ channels and adenylyl cyclase, G-inhibitory (G_i) activates K⁺ channels and inhibits adenylyl cyclase, G_o inhibits Ca²⁺⁺ channels, G_q activates phospholipase C, and G_12/13 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.

Finally, some drugs can act and affect the actions of enzymes. Drugs can either INHIBIT or STIMULATE (i.e., Induce enzymatic activity)

How can drugs interfere with enzymes? Most common way is by binding to them and inhibiting them

• The type of inhibition that occur is usually of the reversible type, but can also be irreversible

• Irreversible is when the drug binds like "crazy glue" and once the connection is made, it cannot be undone

An example of this can be the Viagra like drugs, the PDE5 inhibitors. This enzyme, PDE5, transforms cGMP into GMP and this process will alter the permeability of blood vessels in certain organs that are very rich in blood vessels which is going to cause problems with the elimination of blood in the blood vessels.

If you close the vessel downstream, the upstream blood vessels will dilate more and more.

If this occurs in a tissue that is very rich in blood vessels, this will cause severe and obvious vasodilation. The size of tissue and the size of organ increases.