Overview Of Pharmacodynamics 04.15.09


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  • Overview Of Pharmacodynamics 04.15.09

    2. 2. PHARMACODYNAMICS <ul><li>What the drug does to the body </li></ul><ul><li>Receptor binding </li></ul><ul><li>Agonist, antagonist or partial agonist </li></ul><ul><li>What effect it has (beta blocker, H2 antagonist) </li></ul><ul><li>What side effects it has </li></ul>
    3. 3. <ul><li>Receptor interactions </li></ul><ul><li>Non-receptor mechanisms </li></ul>MECHANISMS OF DRUG ACTION
    4. 5. RECEPTORS <ul><li>A macromolecular component of the organism that binds the drug and initiates its effect. </li></ul><ul><li>Have specific sites that neurotransmitters and drugs recognize specific interaction </li></ul>
    5. 6. RECEPTOR INTERACTIONS Agonist Receptor Agonist-Receptor Interaction Lock and key mechanism
    6. 7. RECEPTOR INTERACTIONS Receptor Perfect Fit! Induced Fit
    7. 8. RECEPTOR INTERACTIONS Antagonist Receptor Antagonist-Receptor Complex DENIED! Competitive Inhibition
    8. 9. RECEPTOR INTERACTIONS Agonist Receptor Antagonist ‘ Inhibited’-Receptor DENIED! Non-competitive Inhibition
    9. 10. AGONISTS, ANTAGONISTS AND PARTIAL AGONISTS <ul><li>Agonists occupy receptors, produce a conformational change which leads to receptor activation and thus efficacy </li></ul><ul><li>Antagonists occupy receptors, produce no conformational change and prevent the action of agonists </li></ul>
    10. 11. AGONISTS, ANTAGONISTS AND PARTIAL AGONISTS <ul><li>Partial agonists occupy receptors, produce an effect which is less than the maximum obtainable with a full agonist </li></ul>
    11. 12. <ul><li>Partial agonists can act as agonists or antagonists depending on the circumstances </li></ul><ul><li>Low efficacy partial agonists (e.g. beta blockers with ISA) almost always act clinically as antagonists </li></ul>LOW EFFICACY PARTIAL AGONISTS
    12. 13. <ul><li>Moderate efficacy partial agonists (e.g. xamoterol) act as agonists with low and moderate underlying (sympathomimetic) activity (e.g. moderate heart failure) BUT as antagonists with high underlying (sympathomimetic) activity (e.g. severe heart failure) </li></ul>MODERATE EFFICACY PARTIAL AGONISTS
    13. 14. HIGH EFFICACY PARTIAL AGONISTS <ul><li>High efficacy partial agonists (e.g. buprenorphine) almost always act as full agonists except following excessive dose of agonist when they act as antagonists </li></ul>
    14. 15. <ul><li>Whether the agonist be a direct agonist, a co-agonist or an indirect agonist, in order for the drug to stimulate the receptor, transporter or enzyme, the agonist must have affinity and efficacy </li></ul>AGONIST
    15. 16. <ul><li>Affinity </li></ul><ul><ul><li>How well the compound binds to a receptor </li></ul></ul><ul><ul><li>Drugs with higher affinity tend to exert greater or longer lasting effects </li></ul></ul><ul><ul><li>e.g., Morphine has a higher affinity for the muopioid receptor than does methadone </li></ul></ul><ul><li>Efficacy </li></ul><ul><ul><li>How well the compound activates the receptor </li></ul></ul><ul><ul><li>Drugs with higher efficacy produce greater effects </li></ul></ul><ul><ul><li>e.g., Methamphetamine is more efficacious at reversing the serotoinin transporter than is amphetamine </li></ul></ul>AFFINITY VERSUS EFFICACY
    16. 17. <ul><li>Competitive antagonism </li></ul><ul><ul><li>The antagonist binds to the same site as the agonist (they compete for the same site) </li></ul></ul><ul><ul><li>Blockade will depend upon the amount of neurotransmitter you have competing with the antagonist at that site </li></ul></ul><ul><ul><li>Lots of neurotransmitter less </li></ul></ul><ul><ul><li>Antagonism more antagonist </li></ul></ul>ANTAGONISM
    17. 18. <ul><li>Non-competitive antagonism </li></ul><ul><ul><li>The antagonist binds to a different site than the agonist but still prevents the activation of the receptor (they are not competing for the same site) </li></ul></ul><ul><ul><li>Sometimes non-competitive antagonism physically blocks the activation of the receptor (PCP and Special K & NMDA receptor) </li></ul></ul><ul><ul><li>Sometimes non-competitive antagonism changes the shape of the receptor so it does not activate (alcohol & the NMDA receptor) </li></ul></ul>ANTAGONISM
    18. 19. DRUG RECEPTORS Nuclear receptors Steroid hormones Thyroid hormone 4 Enzyme-linked receptors Insulin Growth factors 3 G-Protein coupled receptors Slow transmission e.g. norephinephrine 2 Ligand gated ion chanels Fast neurotransmittors e.g. acetylcholine 1 STRUCTURE ENDOGENOUS LIGAND SUPERFAMILY
    19. 20. DRUG RECEPTORS <ul><li>Ion channel </li></ul><ul><ul><li>Nicotinic (II) cholinergic for Na + ions </li></ul></ul><ul><ul><li>GABA A for chloride ions (e.g. benzodiazepines) </li></ul></ul>
    20. 24. DRUG RECEPTORS <ul><li>G proteins (guanine nucleotide) coupled receptors </li></ul><ul><ul><li>Stimulating intracellular enzymes (e.g. beta adrenoceptor agonists and adenyl cyclase) or by ion channels </li></ul></ul>
    21. 25. <ul><li>In addition to ionotropic receptors , there exist also metabotropic receptors ( G protein-coupled ) </li></ul><ul><li>When metabotropic receptors are activated, they release a protein complex called a G-protein that breaks apart and the subunits of the G-protein produce a variety of effects inside the cell </li></ul>DRUG RECEPTORS
    22. 27. <ul><li>Some subunits activate K+ channels from the inside IPSP </li></ul><ul><li>Some subunits activate Ca2+ release from the inside EPSP </li></ul><ul><li>Some subunits activate second messengers (other enzymes involved in transmitting the neurotransmitter signal; e.g., cAMP-in text) and they can, in turn, alter ion channels, receptors, gene transcription etc. </li></ul>G PROTEINS
    23. 28. <ul><li>G-protein coupled receptors, (GPCRs) are a major focus of pharmaceutical drug discovery. </li></ul><ul><ul><li>18 are directed at GPCRs among the top 100 drugs </li></ul></ul><ul><ul><li>60% of all commercial drugs GPPCR acting drugs </li></ul></ul><ul><ul><li>There are a lot of human GPCRs of pharmaceutical interest </li></ul></ul><ul><li>GCPRs are targeted by 12 of the top 20 selling drugs </li></ul><ul><ul><li>Coreg for congestive heart failure </li></ul></ul><ul><ul><li>Cozaar for high blood pressure </li></ul></ul><ul><ul><li>Zoladex for breast cancer </li></ul></ul><ul><ul><li>Buspar for anxiety </li></ul></ul><ul><ul><li>Clozaril for schizophrenia </li></ul></ul><ul><ul><li>Claritin for allergies </li></ul></ul><ul><ul><li>Zantac for ulcers </li></ul></ul><ul><ul><li>Paxil for depression </li></ul></ul><ul><ul><li>Vasotec for hypertension </li></ul></ul>SIGNIFICANCE OF G PROTEINS
    24. 30. DRUG RECEPTORS <ul><li>Enzyme-linked receptors </li></ul><ul><ul><li>Transmembrane receptor where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. </li></ul></ul><ul><ul><li>Tyrosine kinase receptors </li></ul></ul><ul><ul><li>Activation of tyrosine kinase causes movement of ions or nutrients across membranes </li></ul></ul><ul><ul><li>e.g. insulin and glucose </li></ul></ul>
    25. 34. DRUG RECEPTORS <ul><li>Nuclear receptors </li></ul><ul><ul><li>Interact with cell nucleus to enhance DNA genetic transcription </li></ul></ul>
    26. 36. D 2 DPA 5HT 2A 5HT 1A <ul><li>Partial agonist activity: D2 receptors and serotonin 5-HT1A receptors </li></ul><ul><li>Antagonist activity: </li></ul><ul><li>serotonin 5-HT2A receptors </li></ul>h
    27. 37. <ul><li>Actions on Enzymes </li></ul><ul><ul><li>Enzymes = Biological catalysts </li></ul></ul><ul><ul><ul><li>Speed chemical reactions </li></ul></ul></ul><ul><ul><ul><li>Are not changed themselves </li></ul></ul></ul><ul><ul><li>Drugs altering enzyme activity alter processes catalyzed by the enzymes </li></ul></ul><ul><ul><li>Examples </li></ul></ul><ul><ul><ul><li>Cholinesterase inhibitors </li></ul></ul></ul><ul><ul><ul><li>Monoamine oxidase inhibitors </li></ul></ul></ul>NON-RECEPTOR INTERACTIONS
    28. 38. <ul><li>Changing Physical Properties </li></ul><ul><ul><li>Mannitol </li></ul></ul><ul><ul><li>Changes osmotic balance across membranes </li></ul></ul><ul><ul><li>Causes urine production (osmotic diuresis) </li></ul></ul>NON-RECEPTOR INTERACTIONS
    29. 39. <ul><li>Changing Cell Membrane Permeability </li></ul><ul><ul><li>Lidocaine </li></ul></ul><ul><ul><ul><li>Blocks sodium channels </li></ul></ul></ul><ul><ul><li>Verapamil, nefedipine </li></ul></ul><ul><ul><ul><li>Block calcium channels </li></ul></ul></ul><ul><ul><li>Bretylium </li></ul></ul><ul><ul><ul><li>Blocks potassium channels </li></ul></ul></ul><ul><ul><li>Adenosine </li></ul></ul><ul><ul><ul><li>Opens potassium channels </li></ul></ul></ul>NON-RECEPTOR INTERACTIONS
    30. 40. <ul><li>Combining With Other Chemicals </li></ul><ul><ul><li>Antacids </li></ul></ul><ul><ul><li>Antiseptic effects of alcohol, phenol </li></ul></ul><ul><ul><li>Chelation of heavy metals </li></ul></ul>NON-RECEPTOR INTERACTIONS
    31. 41. <ul><li>Anti-metabolites </li></ul><ul><ul><li>Enter biochemical reactions in place of normal substrate “competitors” </li></ul></ul><ul><ul><li>Result in biologically inactive product </li></ul></ul><ul><ul><li>Examples </li></ul></ul><ul><ul><ul><li>Some anti-neoplastics </li></ul></ul></ul><ul><ul><ul><li>Some anti-infectives </li></ul></ul></ul>NON-RECEPTOR INTERACTIONS
    32. 42. <ul><li>Time Response </li></ul><ul><li>Dose Response </li></ul>DRUG - RESPONSE RELATIONSHIPS
    33. 43. TIME - RESPONSE RELATIONSHIPS Latency Duration of Response Maximal (Peak) Effect Effect/ Response Time
    34. 44. TIME - RESPONSE RELATIONSHIPS Effect/ Response Time IV SC IM
    35. 45. <ul><li>Potency </li></ul><ul><ul><li>Absolute amount of drug required to produce an effect </li></ul></ul><ul><ul><li>More potent drug is the one that requires lower dose to cause same effect </li></ul></ul>DOSE - RESPONSE RELATIONSHIPS
    36. 46. POTENCY Effect Dose A B Which drug is more potent? A! Why? Therapeutic Effect
    37. 47. <ul><li>Threshold (minimal) dose </li></ul><ul><ul><li>Least amount needed to produce desired effects </li></ul></ul><ul><li>Maximum effect </li></ul><ul><ul><li>Greatest response produced regardless of dose used </li></ul></ul>DOSE - RESPONSE RELATIONSHIPS
    38. 48. DOSE - RESPONSE RELATIONSHIPS Which drug has the lower threshold dose? Effect Dose A B Which has the greater maximum effect? A B Therapeutic Effect
    39. 49. <ul><li>Loading dose </li></ul><ul><ul><li>Bolus of drug given initially to rapidly reach therapeutic levels </li></ul></ul><ul><li>Maintenance dose </li></ul><ul><ul><li>Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels </li></ul></ul>DOSE - RESPONSE RELATIONSHIPS
    40. 50. <ul><li>Drug’s safety margin </li></ul><ul><li>Must be >1 for drug to be usable </li></ul><ul><li>Digitalis has a TI of 2 </li></ul><ul><li>Penicillin has TI of >100 </li></ul>THERAPEUTIC INDEX
    41. 51. THERAPEUTIC INDEX Why don’t we use a drug with a TI <1? ED50 < LD50 = Very Bad!
    42. 52. PHASES AFFECTING DRUG ACTIVITY Absorption Distribution Metabolism Excretion I – Pharmaceutical Phase II – Pharmacokinetic Phase III – Pharmacodynamic Phase Administration Drug available for absorption Drug available for action EFFECT Disintegration of dosage form Dissolution of drug Drug-receptor Interaction Dose of formulated drug
    43. 53. <ul><li>Bourne HR, von Zastrow M. Drug receptors & pharmacodynamics. In: Katzung BG, editor. Basic and clinical pharmacology. 10 th ed. NY: The McGraw-Hill Companies, Inc.; 2007. </li></ul><ul><li>Cagayan MSFS. Receptors classification structure [lecture].27 Nov 2007. </li></ul><ul><li>Jimeno C. Pharmacodynamics & pharmacokinetics of drugs acting on the endocrine system: focus on insulin and oral antidiabetic agents [lecture]. 19 Sep 2006. </li></ul><ul><li>Makalinao IR. Pharmacology: an introductory lesson on pharmacodynamics and pharmacokinetics [lecture]. 22 Aug 2006. </li></ul><ul><li>Pascual JC. What’s all about ARI: a symphony in psychopharmacology [lecture]. 2 Sep 2007. </li></ul><ul><li>Pharmacology: pharmacokinetics pharmacodynamics. Available from URL: http://www.templejc.edu/dept/ems/documents/Presentations/1stSemesterParamedic/Pharmacology/DrugActions.ppt#379,1,Pharmacology . [Accessed on: 10 Apr 2008]. </li></ul><ul><li>Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale’s pharmacology. 6th ed. Edinburgh: Churchill Livingstone; 2007. </li></ul>SOURCES
    44. 54. THANK YOU.