PHARMACODYNAMICS !!!!!

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 (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction. There are two types of drugs actions.

1-    Drug action mediated by the receptor.

2-    Drug action not mediated by the receptor.

1.    DRUG ACTION MEDIATED BY THE RECEPTORS

The drug–receptor complex: 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 hearts vital functions. The magnitude of the response is proportional to the number of drug–receptor complexes:

Drug + Receptor àDrug–receptor complex àBiologic 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.

a.    Transmembrane ligand-gated ion channels: The first receptor family comprises ligand-gated ion channels that are 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. These receptors mediate diverse functions, including neurotransmission, cardiac conduction, and muscle contraction.

b.    Transmembrane G protein–coupled receptors: A second family of receptors consists of G protein–coupled receptors. These receptors comprise a single helical peptide that has seven membrane spanning regions. The extracellular domain of this receptor usually contains the ligand-binding area (a few ligands interact within the receptor transmembrane domain). Intracellularly, these receptors are linked to a G protein (Gs, Gi, and others) having three subunits, an alpha subunit that binds guanosine triphosphate (GTP), and a beta and a gamma subunits. Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α subunit. Dissociation of the G protein occurs, and both the α-GTP subunit and the β 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.

c.    Enzyme-linked receptors: A third major family of receptors consists of a protein that spans the membrane once and may form dimmers or multi subunit complexes. These receptors also 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. Metabolism, growth, and differentiation are important biological functions controlled by these types of receptors. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) are those that have a tyrosine kinase activity as part of their structure. 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.

d.    Intracellular receptors: The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular, and, therefore, the ligand must diffuse into the cell to interact with the receptor. This places constraints on the physical and chemical properties of the ligand, because it must have sufficient lipid solubility to be able to move across the target cell membrane. Because these receptor ligands are lipid soluble, they are transported in the body attached to plasma proteins such as albumin. The primary targets of these ligand-receptor complexes are transcription factors. The activation or inactivation of these factors causes the transcription of DNA into RNA and translation of RNA into an array of proteins.

2.    AGONIST

An agonist binds to a receptor and produces a biologic response. An agonist may mimic the response of the endogenous ligand on the receptor, or it may elicit a different response from the receptor and its transduction mechanism.

o   Full agonists: If a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand, it is known as a full agonist.

o   Partial agonists: Partial agonists have efficacies (intrinsic activities) greater than zero but less than that of a full agonist.

o   Inverse agonist: Inverse agonists, unlike full agonists, stabilize the inactive receptor (R  not R*) form.

3.    ANTAGONIST

Antagonists are drugs that decrease or oppose the actions of another drug or endogenous ligand.

Competitive antagonists: If both the antagonist and the agonist bind to the same site on the receptor, they are said to be “competitive.” The competitive antagonist will prevent an agonist from binding to its receptor and maintain the receptor in its inactive conformational state.

Irreversible antagonists: An irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present. The effects of competitive antagonists can be overcome by adding more agonist. Irreversible antagonists, by contrast, cannot be overcome by adding more agonist.

Functional and chemical antagonism: An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. 

  

4.    DRUG ACTION NOT MEDIATED BY THE RECEPTOR

The followings are the some specific examples of the drugs whose action are not mediated by the receptors

o   Enzymes

o   Metabolic analogues (antimetabolite)

o   Chelation of metallic ions

o   Microcrystal formation

o   Uncoupling of energy mechanism

o   Biochemical and biophysical properties of drugs.

Enzyme: Drugs influencing various enzyme systems, the anti-cholinesterase’s like neostigmine and organic phosphorus insecticide ---inhibition of cholinesterase, monoamine oxidase (MAO) inhibitors like phenelzine--- inhibit oxidation of, epinephrine and nor-epinephrine.

Metabolic analogues (antimetabolite): These are usually closely related chemically to the substrate. For example sulphonamides --- antimetabolites of para aminobenzoic acid (PABA).  PABA is an intermediate in the bacterial synthesis of folate, are structurally similar to PABA, and their antibacterial activity is due to their ability to interfere with the conversion of PABA to folate by the enzyme dihydropteroate synthetase. Thus, bacterial growth is limited through folate deficiency without effect on human cells.

Chelation of metallic ions: Drugs may chelate a metallic ion needed for the normal functioning of an enzyme system. In this way, a parasitic microorganism might be destroyed. The metal ions in chelate form may become fat-soluble and hence penetrate to tissues where they would not normally reach.  The toxicity of antibacterial drugs like 8-hydroxyquoinoline oxime depends on the formation of a copper-oxime complex. Some drugs form readily metal chelates e.g. lead, antimony, copper and arsenic.

Microcrystal formation: Some drugs may form microcrystals with water or other cellular substance which can then affect cellular function.

Uncoupling of energy mechanism: Some drugs effect the intracellular energy relationships of the adenosine phosphate and the regeneration of adenosine triphosphate (ATP) by intracellular oxidative processes without interaction with receptors. Failure of ATP could result in reduction of cessation of certain energy linked reactions. For example narcotic effect of barbiturates—uncoupling of oxidative phosphorylation.

Biochemical and biophysical properties of drugs: These drugs influence any of the steps involved in the maintenance of normal cellular functions, enhance or prevent the entrance of substances into the cell. Transport of glucose into cells is enhanced by insulin permeability of the neuromuscular junction to ions is increased by acetylcholine