DRUG RECEPTORS AND PHARMACODYNAMICS

DRUG RECEPTORS AND PHARMACODYNAMICS

Most drugs are effective in extremely low concentrations and generally elicit very predictable responses that are dependent upon the concentration of the drug at the receptor sites. These reactions are usually mediated through the interaction of the drug with specific macromolecules (receptors) in the target cell activating or inhibiting 1 or more of the various mechanisms discussed above. Only the basic tenets of modem receptor theory, as they apply to clinical pharmacology, are briefly reviewed here to provide a foundation for the under­standing of drug action and reactions.

Nature of Drug Receptor Interactions: The selective action of a drug depends on its combination with a specific set of receptors. The receptor sites are almost invariably composed of proteins. They may be regulatory proteins, enzymes, transport proteins, and even structural proteins in rare cases. Drug-receptor interactions are usually reversible and are governed by the Law of Mass Action schematically represented as follows:

Receptor + Drug  ---------> Drug-Receptor complex -------> effect

The binding of drugs to receptors may involve all types of molecular interac­tions - Van der Waals forces, hydrophobic interactions, and hydrogen, dipole, ionic, and covalent bonds.

Covalent bond – High energy; cannot be broken; drug-receptor interaction is considered to be irreversible. Recovery from drug exposure usually depends on the body producing new receptors.

Electrostatic bond – Medium energy; occur between opposite charges; can act over a great distance; reversible; may be involved in attracting the drug to the receptor and lining it up properly prior to actual docking.

Hydrogen bond - Medium energy; occur when two molecules share a hydrogen atom. Usually between aminoacids with the H+ being shared between nitrogen (N) residue on one and an oxygen (O) residue on the other.

Van der Waals bond – When drug and receptor are in close proximity a dipole is induced in the non-polar regions that are closest. Each induced dipole has + and – charges that are attracted to the opposite charges in the other molecule’s dipole. Very weak, but may be many dipoles that interact, increasing drug-receptor specificity greatly.

Hydrophobic bond – Weak bonds between highly fat soluble (hydrophobic) regions of drug and receptor; these weak bonds are usually involved in very selective drug-receptor binding.

Bond Energy                                                    Bond Type

           

High                             N=C                              Covalent

                                                N~O-C                          Ionic

                                                N-H…O=C                     Hydrogen

                                                                                    Hydrophobic

            Low                              C-H                   H-N       Van der walls

Besides receptor proteins, drugs may also become bound in a similar fash­ion to other proteins. However, in these cases, no pharmacodynamic response is initiated ("silent receptors"). Examples of such drug acceptors include plasmaproteins, intracellular proteins, and membrane protein fractions. These macromolecules represent sites of drug loss or storage.

Drugs that are capable of reacting with specific receptors and which then produce a defined response are said to possess affinity as well as intrinsic ac­tivity and are termed "agonists". On the other hand, certain drugs are capable of combining with the same receptor complex, thus possessing affinity, but they lack intrinsic activity and no response occurs. These agents are termed pharma­cological "antagonists". Antagonists may act in several different ways. It is also possible for some drugs to interact with the same receptors as a full agonist but the response may be limited and less than maximal. These agents then possess affinity for the receptor but only intermediate activity and are termed "partial agonists". Finally, there are some special drugs that at certain concentrations act as agonists on 1 type of receptor population but as antagonists on other subsets of the receptor. These agents are known as "agonist-antagonists". Some of the drugs produce exactly opposite effect as seen with pure agonists, by acting on the same receptors and are called as “Inverse agonists”.

Properties of Agonists: Several typical properties of receptor agonists require further definition. The affinity of a ligand (drug or endogenous substance) for a receptor is a measure of its capacity to bind to the receptor. Affinity may vary greatly between agonists (as well as antagonists).

Intrinsic activity is a measure of the ability of the agonist-receptor complex to initiate the observed biological response. A full agonist has an intrinsic ac­tivity value (α) of 1.

Maximal efficacy reflects the upper limit of the dose-response relationship without toxic effects being evident. Agonists differ from each other in this re­gard.

Potency refers to the range of concentrations over which an agonist pro­duces increasing responses. Highly potent drugs produce their effects at lower concentrations and this may impart an advantage to their clinical use, provided the increase in potency is not accompanied by an increase in toxicity.

Selectivity and specificity: Few agonists are so specific that they interact only with a single subtype of receptor. However, several agonists (and antago­nists) do show evidence of selectivity for certain subpopulations of receptors.

Structure-activity relationships (SAR): The affinity of an agonist (or antago­nist) for a receptor as well as the agonist's intrinsic activity are intimately related to the chemical structure of the drug. The relationship is usually quite stringent and minor modifications in the drug molecule can result in significant differences in its pharmacological properties. Often, congeners of a parent drug molecule are developed for therapeutic use because of advantages in their therapeutic effects or reductions in the incidence of toxicity.

Drug-receptor theories: Whatever its actual nature, the conformational change that occurs when a receptor is occupied by an agonist is only 1 of several steps necessary for the expression of a full pharmacological response. The transduction process between occupancy of receptors and the drug re­sponse is called "coupling". Receptor-effector coupling is influenced by the ionic environment, several coupling factors, and the receptor itself. A number of theories have been advanced to explain how agonist-receptor interactions lead to effective receptor-effector coupling and the specific pharmacological response observed.

1. Occupancy theory: This is proposed by Clark (1937) after he studied the quantitative aspects of drug action. This theory is based on the Law of Mass action i.e. the drug action based on occupation of receptors by specific drugs and that the pace of a cellular function can be altered by interaction of these receptors with drugs. This theory postulated

i. The intensity of response is directly proportional to the fraction of acceptors occupied by a drug and maximal response occurs when all receptors are occupied.

ii. Drugs exert an "all or none" action on each receptor, i.e. either a receptor is fully activated or not at all there is no partial activation and

iii. A drug and its receptor have complementary structural features and stand in rigid "Lock and kev" relationship.

This theory gave the fundamental concept but the postulates were later found to be only partially correct and need to be modified.

2. Rate theory: This is introduced by W.D.M.Paton at 1961. This suggested that agonist action depended on the rate of agonist - receptor association and / or dissociation and this in turn decides the magnitude of drug effects. Paton suggested that the rate of receptor occupation rises sharply to start with, reaches a peak and  then there is a fall to steady state or equilibrium or the phenomenon of fade. This theory explains many aspects of the time-course of drug ejects.

3. Induced fit theory: This proposes that in the process of agonist - receptor interaction, a conformational change occurs that generates the active receptor site.

4. Perturbation theory: This differentiates between specific conformationaI chages indued by agonists Vs nonspecific perturbations produced by antagonists.

5. Activation - Aggregation theory: This proposes that receptors exist in dynamic equilibrium between different functional states and that agonists shift the equilibrium towards the activated form the receptor.

Properties of Antagonists: Many receptor antagonists are used therapeutically. However, a number of different forms of drug antagonism occur that need to be understood because of direct clinical implications.

Competitive antagonists combine reversibly with the same receptor site as agonists and progressively inhibit the response to agonists. Competitive antago­nists may even possess greater affinity for the receptor site than pure agonists. Typically, the blockade can be overcome by increasing the concentration of the agonist in the biophase.

Noncompetitive antagonists may act reversibly, or, more commonly, irre­versibly. Characteristically, high concentrations of agonist cannot completely overcome the antagonism and a maximal response cannot be produced. Several types of noncompetitive antagonism are recognized. The binding may oc­cur to the same receptor producing blockade. If covalent bonds are formed, receptor inhibition becomes permanent and the de novo synthesis of receptors is required for complete reversal of the antagonist's effects. This form of irre­versible noncompetitive antagonism is encountered with some organophosphates and cholinergic receptors. Binding of noncompetitive antagonists to a different part of a receptor macromolecule may lead to deformation of the active receptor site leading to a diminution in the affinity for the usual agonists. This effect is similar to allosteric inhibition of enzymes. Antagonists may also bind to an extrareceptor area in a membrane but, because of their molecular configuration, may obscure the receptor sites for 1 or more agonists. The phenothiazine neuroleptics appear to be multipotent receptor blockers of this type.

Physiological or functional antagonists are, in fact, agonists that elicit physiological responses that directly oppose those of the first drug adminis­tered, by stimulating a different class of receptors. Examples of physiological antagonism include the reversal of histamine's effects (histaminergic receptors) by epinephrine (adrenergic receptors) and the stimulation of intestinal smooth muscle by acetylcholine (cholinergic receptors) following its inhibition by nor-epinephrine (adrenergic receptors).

Properties of Partial Agonists and Agonist-Antagonists: Partial agonists pro­duce a lower than maximal response at full receptor occupancy notwithstand­ing high receptor affinities in many cases. They will also act as competitive antagonists in the presence of pure agonists. Nalorphine and pentazocine are partial agonists used in veterinary medicine. Agonist-antagonists that are used clinically include the opioid analgesics that possess selective affinity and intrin­sic activity for certain of the opioid receptor types but act as competitive an­tagonists at others, thus reducing some of the undesirable features of full opioid agonists. Butorphanol and nalbuphine are regarded as opioid agonist-antagonists.