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Muscarinic Agonists        &   AntagonistsBrian J. Piper, Ph.D., M.S.
Objectives• Similarities & differences in muscarinic  receptors• Agonists  – Synthetic: methacholine  – Natural: pilocarpi...
** Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmac...
Acetylcholine• This neurotransmitter does not make a good  drug because:  – Limited penetration (quaternary ammonium) of  ...
Muscarinic Receptors• Metabotropic   – M1, M3 & M5 via Gq   – M2 & M4 via Gi• Orthosteric binding site (ACh) highly conser...
12 Cranial Nerves   • On Old Olympic Towering Tops A Finn And     German Viewed Some Hops   • Once One Openly Told Tourist...
Overall Receptor          Distribution    • Cranial Nerve         – III: oculomotor         – VII: facial         – IX: gl...
Immunocytochemistry (ICC)• Uses immune system to generate antibodies• Antibodies are applied to tissue to localize  protei...
M1 to M4 ICC Localization for I3               M1                                           M2                M3          ...
Neural LocalizationStahl, S. (2008). Essential Psychopharmacology, p. 916.
Tissue Distribution   Receptor            Organs   M1                  salivary glands, enteric nerves   M2               ...
Muscarinic Agonists                          Origin        Nicotinic    BBB              Uses                             ...
Bethanechol• Short-acting muscarinic  agonist• Used to treat non-obstructive  urinary retention
Atropa belladona• Atropos: Greek god of life• Belladona: dilation of pupils• Contains nonselective muscarinic  antagonists...
Atropine1875 - 1968                  Rang et al. (2007). Pharmacology. p. 145.
Pharmacological Actions of Atropine• Heart: decrease (low-dose)/increase (high-dose)• Lungs: inhibit histamine induced  br...
Relative Physiological EffectsKatzung et al. (2009). Basic & Clinical Pharmacology. p. 120.
Red as a beet (heat compensation)Dry as a bone (decreased salivation)Blind as a bat (mydriasis)Hot as firestone (decreased...
Scopolamine                                                                • Crosses BBB                                  ...
Datura stramonium•   Plant found in North America, Europe, Asia•   Jimsom weed, witch’s brew, thornapple•   Plant contains...
Are seeds special?                     >                     >                                                   >Miraldi ...
Homeopathy  • Atropa belladona used for centuries including as a tincture “like    treats like”  • 30C (centesimal) diluti...
“Deadly nightshade”Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
Conclusion:   Pro: no side effect   Con: not harmlessBrien et al. (2003). British Journal of Clinical Pharmacology, 56, 56...
Atropine Induced Coma Therapy   • Physical withdrawal is unpleasant   • Coma Therapy has a long-history (1930s) but     li...
Summary• Muscarinic agonists used to treat urinary  retention & xerostomia. Muscarinic  antagonists useful for OAB, COPD, ...
Future: Selective Muscarinic Allosteric             Modulators?
Future: Selective Muscarinic Allosteric                Modulators?PQCA: M1 positive allosteric modulator; donepezil: acety...
Goodwin Terminology (Refresher)orthosteric: site where the ligand binds to a receptor or enzymeallosteric: the other site ...
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Muscarinic agonists and antagonists

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An overview of muscarinic receptor agonists and antagonists. This presentation was delivered to 2nd year pharmacy students enrolled in a pharmacology & toxicology class and accompanies Goodman & Gilman's (12e) chapter 9.

Veröffentlicht in: Gesundheit & Medizin
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Muscarinic agonists and antagonists

  1. 1. Muscarinic Agonists & AntagonistsBrian J. Piper, Ph.D., M.S.
  2. 2. Objectives• Similarities & differences in muscarinic receptors• Agonists – Synthetic: methacholine – Natural: pilocarpine• Antagonists – atropine – scopalomine
  3. 3. ** Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.
  4. 4. Acetylcholine• This neurotransmitter does not make a good drug because: – Limited penetration (quaternary ammonium) of the Blood Brain Barrier – Peripheral enzymes (butyrylcholinesterase) degrade it quickly
  5. 5. Muscarinic Receptors• Metabotropic – M1, M3 & M5 via Gq – M2 & M4 via Gi• Orthosteric binding site (ACh) highly conserved, allosteric binding site moderately conserved• Non-selectivity within M1-M5• Co-expression Amanita muscaria
  6. 6. 12 Cranial Nerves • On Old Olympic Towering Tops A Finn And German Viewed Some Hops • Once One Openly Told Tourists About Fighting Vampires Gobling Various Antelope Herds • Oh Once One Takes The Anatomy Final Very Good Vacations Are Heavenlyhttp://en.wikipedia.org/wiki/List_of_mnemonics_for_the_cranial_nerves
  7. 7. Overall Receptor Distribution • Cranial Nerve – III: oculomotor – VII: facial – IX: glossopharyngeal – X: vagushttp://flipper.diff.org/app/items/info/4260
  8. 8. Immunocytochemistry (ICC)• Uses immune system to generate antibodies• Antibodies are applied to tissue to localize protein (receptor, enzyme)
  9. 9. M1 to M4 ICC Localization for I3 M1 M2 M3 M4 Levey (1993). Life Sciences, 52, 441-448.
  10. 10. Neural LocalizationStahl, S. (2008). Essential Psychopharmacology, p. 916.
  11. 11. Tissue Distribution Receptor Organs M1 salivary glands, enteric nerves M2 heart, smooth muscle M3 smooth muscle, salivary glands M4 brain (diffuse), lung M5 brain (substantia nigra), eyeAndersson, K. E. http://www.medscape.org/viewarticle/487222
  12. 12. Muscarinic Agonists Origin Nicotinic BBB Uses Effect PermeabilityMethacholine synthetic low low challenge for asthmaCarbachol synthetic high low miosis glaucomaMuscarine natural no low research hallucinoginPilocarpine natural no high xerostomia Brown & Laiken (2011). In Pharmacological Basis of Therapeutics, p. 219-237.
  13. 13. Bethanechol• Short-acting muscarinic agonist• Used to treat non-obstructive urinary retention
  14. 14. Atropa belladona• Atropos: Greek god of life• Belladona: dilation of pupils• Contains nonselective muscarinic antagonists atropine & scopolamine• Overdose = dry Carl Linnaeus mouth, confusion, seizures 1707 - 1778
  15. 15. Atropine1875 - 1968 Rang et al. (2007). Pharmacology. p. 145.
  16. 16. Pharmacological Actions of Atropine• Heart: decrease (low-dose)/increase (high-dose)• Lungs: inhibit histamine induced bronchoconstriction• Eyes: mydriasis but long-lasting• Salivation: reduced• Sweating: reduced
  17. 17. Relative Physiological EffectsKatzung et al. (2009). Basic & Clinical Pharmacology. p. 120.
  18. 18. Red as a beet (heat compensation)Dry as a bone (decreased salivation)Blind as a bat (mydriasis)Hot as firestone (decreased sweating)Mad as a hatter (CNS/hallucinations)
  19. 19. Scopolamine • Crosses BBB • Used prophylactically • Adverse Effects: dry mouth, drowsinessSilly but accurate (1 min): http://www.youtube.com/watch?v=h88Vg3PrKIs&feature=BFa&list=LPq4H22JxqqS4
  20. 20. Datura stramonium• Plant found in North America, Europe, Asia• Jimsom weed, witch’s brew, thornapple• Plant contains atropine & scopolamine• Historical asthma treatment & used to facilitate bone setting
  21. 21. Are seeds special? > > >Miraldi et al. (2001). Fitoterapia, 72, 644-648.
  22. 22. Homeopathy • Atropa belladona used for centuries including as a tincture “like treats like” • 30C (centesimal) dilution involves 30, ten-fold dilutions • Double-blind randomization to Placebo for one-week then (N = 253/206) double-blind randomization to 30C or placebo for more 2 weeks • Daily questionnaire of belladona symptoms (My pupils are unusually dilated, especially when I feel hot) • Independent verification that 30C versus placebo blinding was successful. Samuel Hahnemann, MD Nadu, IndiaBrien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568. 1755 - 1843
  23. 23. “Deadly nightshade”Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
  24. 24. Conclusion: Pro: no side effect Con: not harmlessBrien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
  25. 25. Atropine Induced Coma Therapy • Physical withdrawal is unpleasant • Coma Therapy has a long-history (1930s) but limited data on safety & efficacy • Drug addiction involves both physical & psychological components1.5 min: http://www.youtube.com/watch?v=r7HSokv8A5M&feature=player_detailpageForrer, G. (1956). J Nervous Mental Disease, 124(3), 256-259.
  26. 26. Summary• Muscarinic agonists used to treat urinary retention & xerostomia. Muscarinic antagonists useful for OAB, COPD, and in ophthalmology with local application.• Lack of selectivity results in difficulty with patient adherence.
  27. 27. Future: Selective Muscarinic Allosteric Modulators?
  28. 28. Future: Selective Muscarinic Allosteric Modulators?PQCA: M1 positive allosteric modulator; donepezil: acetylcholinesterase inhibitorUslaner et al. (in press-2012). Psychopharmacology.
  29. 29. Goodwin Terminology (Refresher)orthosteric: site where the ligand binds to a receptor or enzymeallosteric: the other site (non-active site)positive allosteric modulation: binding of ligand to allosteric site increases binding between substratemolecules & other binding sitenegative allosteric modulation: binding of ligand to allosteric site decreases binding between substratemolecule & other binding sitedystonia: involuntary muscle contractions that cause slow repetitive movements or abnormal posturescycloplegia: inability to focus eye for near visiondiaphoresis: excessive sweatingdiverticulitis: formation of small bulging pouches in the lining of intestine that become inflamedmiosis (myosis): constriction of the pupil of eyemydriasis: dilation of pupil of eyesialagogue: any drug or agent that can stimulate the flow of salivaxerostomia: dry mouthsyncope: fainting

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