Published on

Published in: Education, Technology
  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide


  1. 1. Hiba Hamid PHARMACOLOGY GENERAL PHARMACOLOGY PHARMACODYNAMICS  Describes the actions of the drug on the body  Influence of drug concentrations on the magnitude of the response Receptor 1. A biologic molecule to which a drug binds to bring about a change in function of the biologic system. 2. It is a specific drug-binding site in a cell or on its surface that mediates drug action. Nature of drug receptors 1. Regulatory proteins that mediate actions of neurotransmitters, autacoids or hormones 2. Enzymes, e.g. dihydrofolate reductase 3. Transport proteins, e.g. Na+-K+-ATPase 4. Structural proteins, e.g. tubulin Note: some drugs, e.g. mannitol, do not have a specific receptor. Major receptor families 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 1. Transmembrane ligand-gated ion channels a) Responsible for the regulation of the flow of ions across cell membranes b) Activity of these channels regulated by the binding of a ligand to the channel c) Response is very rapid, enduring for a few milliseconds d) Receptors mediate diverse functions, including neurotransmission, cardiac conduction, and muscle contraction e) For e.g., stimulation of nicotinic receptor by ACh results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle f) Benzodiazepines, on the other hand, enhance stimulation of γ-aminobutyric acid (GABA) receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. 1
  2. 2. Hiba Hamid g) Ion-channels such as the voltage-gated sodium channels are important drug receptors for several drug classes, including local anesthetics. 2. Transmembrane G protein-coupled receptors a) Consists of G protein-coupled receptors. G-protein Receptors Effector/mechanism Gs β-adrenergic amines Adenylyl cyclase → ↑ cAMP (2nd messenger) → vasoconstriction of smooth muscle blood vessels → ↑bp Gi α2-adrenergic amines Adenylyl cyclase → ↑ cAMP (2nd messenger) → open K+ channels → ↓ heart rate Gq Acetylcholine IP3 Phospholipase C DAG ↑ Ca2+ released from storage vesicles → binds with calmodulin → ↑ Ca2+ dependent protein kinase 3. Enzyme-linked receptors a) Consists of a protein that spans once and may form dimers or multi-subunit complexes. b) Also have cytosolic enzyme activity as an integral component of their structure and function. c) Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. d) Duration of responses to the stimulation of these receptors is on the order of minutes to hours. e) Metabolism, growth, and differentiation are important biological functions controlled by these types of receptors. 4. Intracellular receptors a) The receptor is entirely intracellular, therefore, the ligand must diffuse into the cell to interact with the receptor. b) Ligand must have sufficient lipid solubility to be able to move across the target cell membrane. Because the receptor ligands are lipid-soluble, they are transported in the body attached to plasma proteins such as albumin. c) 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
  3. 3. Hiba Hamid d) For e.g., steroid hormones exert their action on target cells via this receptor mechanism. e) The time course of activation and response of these receptors is much longer than that of the other mechanisms described above. Regulation of receptors: 1. Down-regulation (desensitization): in this, number of receptors is decreased. 2. Up-regulation: in this, number of receptors is increased. Spare receptors  When maximal response can be elicited by an agonist at a conc. that does not result in occupancy of all available receptors, the receptors that are not occupied are called spare receptors.  Spare receptors are neither hidden nor unavailable. They are simply not occupied because maximum response can be achieved by occupying less number of receptors. Affinity Ability of a drug to bind to a receptor. Intrinsic activity Ability of the drug to elicit a response after binding to a receptor. Quantal dose-response relationships  A graph of the fraction of a population that shows a specified response at progressively increasing doses.  When the minimum dose required to produce a specified response is determined in each member of a population, the quantal dose-response relationship is defined. EC50, ED50, TD50, etc.:  Median effective (ED50), median toxic (TD50), and (in animals), median lethal (LD50)  In graded dose-response curves, the concentration or dose that causes 50% of the maximal effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a specified response in 50% of the population under study Efficacy  Often called maximal efficacy, is the greatest effect an agonist can produce if the dose is taken to the highest tolerated level. 3
  4. 4. Hiba Hamid  Determined mainly by the nature of the drug, and the receptor and its associated effector system.  Can be measure with a graded dose-response curve but not with a quantal dose-response curve.  Partial agonists have lower maximal efficacy than full agonists. Potency  Denotes amount of drug needed to produce a given effect.  Potency is determined mainly by the affinity of the receptor for the drug and the number of receptors available.  In graded dose-response measurements, the effect usually chosen is 50% of the maximal effect and the concentration or dose causing this effect is called EC50 or ED50.  In quantal dose-response measurements, ED50, TD50, and LD50 are also potency variables (median effective, toxic, and lethal doses, respectively, in 50% of the population studied).  Potency can thus be determined from graded or quantal dose-response curves, but the numbers obtained are not identical. Agonists A drug that binds to a receptor and produces a biologic response. Full agonists  Drug capable of fully activating the effector system when it binds to the receptor.  Drugs occupying the receptor can stabilize the receptor in a given conformational state, that is, in the active or inactive state  For e.g., phenylephrine is an agonist of α1-adrenoreceptors, because it produces the effects that resemble the action of the endogenous ligand, norepinephrine. Upon binding to α1adrenoreceptors on the membranes of vascular smooth muscle, phenylephrine stabilizes the receptor in its active state. This leads to mobilization of intracellular Ca2+, causing interaction of the smooth muscle actin and myosin. Shortening of muscle cells decreases diameter of arteriole, causing increase in blood pressure. In general, a full agonist has a strong affinity for its receptor and good efficacy. Partial agonists  A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist.  Partial agonists have efficacies (intrinsic activities) greater than zero but less than that of a full agonist.  Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist.  It may have an affinity which is greater than, less than, or equivalent to that of a full agonist. 4
  5. 5. Hiba Hamid  Under appropriate conditions, a partial agonist may act as an antagonist of a full agonist.  For e.g., consider what would happen to the Emax of a receptor saturated with a full agonist in the presence of increasing concentrations of partial agonist. As the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist.  The potential of partial agonist to act both as an agonist and antagonist can be fully exploited. For e.g., aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine receptors. As a result, dopaminergic pathways that were overactive tend to be inhibited by the partial agonist, whereas pathways that were underactive may be stimulated. This might explain the ability of aripiprazole to improve many symptoms of schizophrenia, with a small risk of causing extrapyramidal adverse effects. Inverse agonists  A drug that binds to the inactive state of receptor molecules and decreases constitutive activity. (Activity in the absence of a ligand is called constitutive activity.)  Usually, unbound receptors are inactive and require interaction by an agonist to assume an active conformation.  However, some receptors show spontaneous conversion from inactive to active state in the absence of agonist. These receptors thus show constitutive activity.  Inverse agonists, unlike full agonists, stabilize the inactive form of the receptors. All of the constitutively active receptors are forced to remain inactive in the presence of an inverse agonist.  This decreases number of activated receptors to below that observed in the absence of a drug. Thus, inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists. Antagonists  Drugs that decrease or oppose the actions of another drug or endogenous ligand.  Has no effect if an agonist is not present.  Many antagonists act on the identical receptor macromolecule as the agonist.  Antagonist, however, have no intrinsic activity. They are still able to bind avidly to target receptors because they possess strong affinity. Competitive antagonists  A pharmacologic antagonist that can be overcome by increasing the concentration of agonist.  If both antagonist and agonist bind to the same site, they are said to be “competitive”.  The competitive antagonist will prevent the agonist from binding to its receptor and maintain the receptor in the inactive state. 5
  6. 6. Hiba Hamid Irreversible antagonists  A pharmacologic antagonist that cannot be overcome by increasing the concentration of the agonist.  The effects of competitive antagonists can be overcome by increasing the concentration of the agonist. In contrast, the effects of irreversible antagonist cannot be overcome with increasing the agonist concentration.  Competitive antagonists increase ED50, whereas irreversible antagonists do not (unless spare receptors are present).  The antagonist can bind covalently or with very high affinity to the active site of the receptor (irreversible antagonist). This irreversibility in binding to the active site reduces the amount of receptors available to the agonist.  The second type of antagonist binds to a site (“allosteric site”) other than the agonist binding site. This allosteric antagonist prevents the receptor from being activated even when the agonist is attached to the active site.  Competitive antagonists reduce agonist potency, whereas noncompetitive antagonists reduce agonist efficacy. Functional (physiological) and chemical antagonism  Functional antagonism: a drug that counters the effect of another by binding to a different receptor and causing opposite effects.  A classic example is the functional antagonism by epinephrine to histamine-induced bronchoconstriction. Histamine binds to H1 histamine receptor on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at β2adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax.  Chemical antagonism: a drug that counters the effects of another by binding the agonist drug (not the receptor).  For e.g., protamine sulfate is a chemical antagonist for heparin. It is a basic (positively charged) protein that binds to the acidic heparin (negatively charged), rapidly preventing its therapeutic as well as toxic effects. Allosteric agonist / antagonist A drug that binds to the receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist. 6