Lecture 1 Pharmacodynamics
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Lecture 1 Pharmacodynamics

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  • Sorry 'Agonist are the drugs that block the response' I don't quite understand this doesn't an agonist elicit the same response that the receptor would otherwise have done? For example Pilocarpine stimulates muscarinic receptors
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Lecture 1 Pharmacodynamics Lecture 1 Pharmacodynamics Presentation Transcript

  • Pharmacodynamics Dr Rizwan Ashraf
  • Lecture Objectives
    • To understand the basic concepts regarding
    • pharmacodynamics
    • To define agonist and antagonists and other
    • terms in relation to pharmacodynamics
    • To explain the mechanism of drug receptor
    • interaction
    • Define spare receptors
    • To differentitate between different tyes of
    • antagonism
  • WHAT IS PHARMACODYNAMICS ?
  •  
    • Action of a drug on the body
    • receptor interactions,
    • mechanisms of therapeutic
    • dose-response phenomena,
    • toxic action .
  • RECEPTOR INTERACTION
    • A drug will not work unless it is bound
    • AGREED or NOT AGREED
    • BOUND WITH WHAT ?
    • PARTICULAR CONSTITUENTS OF
    • CELLS & TISSUES IN ORDER TO
    • PRODUCE AN EFFECT
    • PROTEINS
    • LIPIDS
    • DNA
    • RECEPTORS ?
  • ARE THERE DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE CONSTITUENTS
    • YES
    • OR
    • NO
  • YES
    • OSMOTIC DIURETICS
    • OSMOTIC PURGATIVES
    • ANTACIDS
    • HEAVY METALS CHELATING AGENTS
  • BUT
    • PRINCPLES REMAIN TRUE FOR GREAT MAJORITY
    • THAT IS _____________________
    • ______________________________.
  • Most drugs act through Receptors
  • Receptors
  • Drug Receptor
    • A macromolecular component of a cell with which a drug interacts to produce a response
    • Usually a protein
    • Receptors must be biologically important molecules
    • Receptors must have structural features that permit drug specificity
    • Receptors must have a drug-binding site and a biologically active site
  • Characteristics of Receptors       a. specificity       b. selectivity of response       c. sensitivity
  • Molecules capable of serving as Receptors
    • Enzymes
    • Membrane proteins
    • glycoproteins, lipoproteins)
    • Nucleic acids
    • Complex polysaccharides
    • Many drugs inhibit enzymes
      • in the patient (ACE inhibitors)
      • in microbes (sulfas, Penicillins)
      • in cancer cells (5-FU, 6-MP)
  • Types of Protein Receptors
    • Regulatory – mediate the action of endogenous chemicals e.g. hormones, NT,autocoids
    • Enzymes – may be inhibited or activated e.g. dihydrofolate reductase receptor for methotrexate
    • Transport – e.g. Na + /K + ATP’ase for digitalis glycosides
    • Structural – e.g. tubulin,receptor for colchicine
    • some drugs bind to:
      • the genome (cyclophosphamide)
      • microtubules (vincristine)
    • Non-receptor Mediated Effects
    • Interaction with small molecules (e.g. binding of heavy metals)
    • Interaction with enzymes (e.g. sulfonamides, digitalis)
    • Incorporation into a macromolecule (e.g. some anticancer agents - purine and pyrimidine analogues)
    • Nonspecific effects (e.g. membrane perturbation by general anesthetics)
    • Receptor-independent drug actions
    • Chemically reactive agents
      • Disinfectants
      • Alkylating anticancer drugs
    • Physically active agents
      • Mannitol
      • Hydrogen peroxide
    • Counterfeit biochemical constituents
      • 5-bromouracil
  • Antagonists tend to up regulate receptors   Receptor regulation    1.   Homeostasis    2. Up and down regulation    3. Desensitization    4. Tolerance
    • agonists desensitize receptors
    • homologous
    • (decreased receptor number)
    • heterologous
    • (decreased signal transduction
  • Pharmacodynamics Drug receptor interaction
    • D + R DR Complex
    Drug - Receptor Binding Affinity
  • Drug Receptor Interaction DR Complex Effect
  • Theories of the  relationship between  binding and response
  •      a. Occupation theory       D + R  DR  RESPONSE :response is proportional to the fraction of occupied  receptors :maximal response occurs when all the receptors are occupied
    •   Ariens
    • response is proportional to the fraction of 
    • occupied receptors  AND  the   intrinsic activity 
    • Stephenson
    • response is a  FUNCTION  of occupancy
    • maximum response can be produced 
    • WITHOUT 100% occupation, 
    • i.e. tissues have   spare receptors
  • BIOLOGICAL STIMULUS PERCENT RECEPTOR OCCUPANCY 0% 100% BIOLOGICAL RESPONSE RECEPTOR RESERVE TRETHOLD 0% 100% Max Effect Threshold Effect Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological response
  • Receptors are said to be spare for a given pharmacological response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors
    • Spare receptors
    • More receptors available than needed
    • to elicit maximum response
    • allow maximal response without total receptor occupancy – increase sensitivity of the system
    • Agonist has to bind only a portion of
    • receptors for full effect
  •  
  • Some terminologies regarding drug receptor interaction
    • Affinity
    • Efficacy
    • Potency
    • Ligand
  • Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor Efficacy: Potential maximum therapeutic response that a drug can produce. Potency: A mount of drug needed to produce an effect.
    • POTENCY
    • OR
    • EFFICACY
    Which one is important while selecting a drug for therapy ?
    • Ligand:
    • Molecules that binds to a receptor
  • Classification of Ligands a.   agonist b.  partial agonist c.  antagonist pharmacological vs. physiological vs. chemical        pharmacological antagonists        -  competitive             surmountable           -  noncompetitive
    • AGONIST
  • Agonists
    • Drugs that cause a response
    • Drugs that interact with and activate receptors;
    • They possess both affinity and efficacy
    • Types
    • Full agonists
    • An agonist with maximal efficacy (response)
    • has affinity plus intrinsic activity
    • Partial agonists
    • An agonist with less then maximal efficacy
    • has affinity and less intrinsic activity
  • Agonists differing in potency and maximum efficacy
  • Response Dose Full agonist Partial agonist Agonist Dose Response Curves
  • [D] (concentration units) % Maximal Effect 0.01 0.10 1.00 10.00 100.00 1000.00 0.0 0.2 0.4 0.6 0.8 1.0 Partial agonist Full Agonist Partial agonist PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ.
  • Antagonists
    • Interact with the receptor but do
    • NOT change the receptor
    • Have affinity but NO efficacy
    • Block the action of other drugs
    • Effect only observed in presence of
    • agonist
  • Types of Antagonists
    • Competitive
    • (Surmountable)
    • decrease apparent
    • Potency
    • Noncompetitive
    • decrease
    • apparent maximum
    • efficacy
  • Competitive Antagonist
    • competes with ________for receptor
    • surmountable with increasing agonist
    • concentration
    • displaces agonist dose response curve to
    • the ___________(dextral shift)
    • reduces the apparent affinity of the
    • __________.
  • Noncompetitive Antagonist
    • drug binds to receptor and stays bound
    • irreversible – does not let go of receptor
    • produces slight dextral shift in the agonist DR curve in the low concentration range
    • but, as more and more receptors are bound (and essentially destroyed),
    • the agonist drug becomes incapable of eliciting a maximal effect
  • AGONIST VS ANTAGONIST
  •  
  • What happen when you increase agonist concentration even higher
  • How do non competitive antagonist affect receptor function
  •  
    • Summary
    • (T or F)
    • Pharmacodynamics is the study of absorption, distribution,
    • metabolism and elimination of drug.
    • Some drugs can act without binding to a receptor
    • spare receptors allow maximum response without
    • full receptor occupancy
    • Efficacy is the amount of drug needed to produce an
    • effect.
    • Affinity is the attractiveness between 2 drug molecules.
    • Agonist are the drugs that block the response.
    • Partial agonist has affinity and maximum efficacy.
    • Antagonist has efficacy but no affinity.
    • Competitive antagonist decreases potency
    • Non competitive antagonist decreases efficacy