Drug- Receptor Interactions and Pharmacodynamic

Lecture (4) Pharmacology Dr. Dalia A. Muhsin
Drug- Receptor Interactions and Pharmacodynamic
Pharmacodynamics describes the actions of a drug on the body and the influence of drug concentrations on the magnitude of the response. Most drugs exert their effects, both beneficial and harmful, by interacting with receptors.
Receptor : a specialized target macromolecule present on the cell surface or intracellularly that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects or “pharmacologic response”(Figure 2.1).
Cells have different types of receptors, each of which is specific for a particular ligand and produces a unique response. The heart, for example, contains membrane receptors that bind and respond to epinephrine or norepinephrine as well as muscarinic receptors specific for acetylcholine. These receptors dynamically interact to control the heart’s vital functions. The magnitude of the response is proportional to the number of drug–receptor complexes:
Drug + Receptor ? Drug–receptor complex ? Biologic effect
Major receptor families
Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes, nucleic acids, and structural proteins can be considered to be pharmacologic receptors. However, the richest sources of therapeutically exploitable pharmacologic receptors are proteins that are responsible for transducing extracellular signals into intracellular responses.
These receptors may be divided into four families:
1) ligand-gated ion channels
2) G protein–coupled receptors,
3) enzyme–linked receptors,
4) intracellular receptors (Figure 2.2).


1- Transmembrane ligand-gated ion channels:
• responsible for regulation of the flow of ions across cell membranes.
• The activity of these channels is regulated by the binding of a ligand to the channel.
• Response to these receptors is very rapid, enduring for only a few milliseconds.
• For example, nicotinic receptor ,?-aminobutyric acid (GABA)
2- Transmembrane G protein–coupled receptors:
• These receptors comprise single helical peptide that has seven membrane spanning regions.The extracellular domain of this receptor usually contains the ligand-binding area . Intracellularly, these receptors are linked to a G protein having three subunits, an ? subunit and a ?? subunit .
• Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein and dissociation of the G protein occurs, and both the ? - subunit and the ?? subunit subsequently interact with other cellular effectors, usually an enzyme, a protein, or an ion channel. These effectors then activate second messengers that are responsible for further actions within the cell.
• Stimulation of these receptors results in responses that last several seconds to minutes.
• Examples : ? and ? adrenoceptors
Second messengers: These are essential in conducting and amplifying signals coming from G protein–coupled receptors.
Examples:
? cyclic adenosine monophosphate (cAMP) ,
? inositol-1,4,5-trisphosphate
? diacylglycerol.
? cyclic guanosine monophosphate (cGMP)
These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well
• Enzyme-linked receptors: A third major family of receptors consists of a protein that spans the membrane and have cytosolic enzyme activity as an integral component of their structure and function .
• Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity.
• Duration of responses to stimulation of these receptors is on the order of minutes to hours.
• ( e.g. insulin receptor) .
Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting kinases from their inactive forms to active forms. The activated receptor autophosphorylates and then phosphorylates tyrosine residues on specific proteins . The addition of a phosphate group can substantially modify the three-dimensional structure of the target protein, thereby acting as a molecular switch.
4. Intracellular receptors:
• differs considerably from the other three types in that the receptor is entirely intracellular, and, therefore, The ligand must diffuse into the cell to interact with the receptor (Figure 2.5).
• the ligand, must have sufficient lipid solubility to be able to move across the target cell membrane.
• For example, steroid hormones receptor.
• The activated ligand–receptor complex migrates or translocates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression.
• Because gene expression and, therefore, protein synthesis is modified, cellular responses are not observed until considerable time has elapsed (30 minutes or more), and the duration of the response (hours to days) is much greater than that of other receptor families.