Muscarinic agonists and antagonists

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.

1. Muscarinic Agonists & Antagonists Brian J. Piper, Ph.D., M.S.

2. Objectives Similarities & differences in muscarinic receptors Agonists Synthetic: methacholine Natural: pilocarpine Antagonists a tropine s copalomine

3. * * Acetylcholine & muscarinic receptors for sweat glands Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology , p. 56.

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. Muscarinic Receptors Metabotropic M 1 , M 3 & M 5 via G q M 2 & M 4 via G i Orthosteric binding site ( ACh ) highly conserved, allosteric binding site moderately conserved Non-selectivity within M 1 -M 5 Co-expression Amanita muscaria

6. 12 Cranial Nerves O n O ld O lympic T owering T ops A F inn A nd G erman V iewed S ome H ops O nce  O ne  O penly  T old  T ourists  A bout  F ighting V ampires   G obling   V arious  A ntelope  H erds O h  O nce  O ne  T akes  T he  A natomy  F inal  V ery  G ood   V acations  A re  H eavenly http://en.wikipedia.org/wiki/List_of_mnemonics_for_the_cranial_nerves

7. Overall Receptor Distribution Cranial Nerve III: oculomotor VII: facial IX: glossopharyngeal X: vagus http://flipper.diff.org/app/items/info/4260

8. Immunocytochemistry (ICC) Uses immune system to generate antibodies Antibodies are applied to tissue to localize protein (receptor, enzyme)

9. M 1 to M 4 ICC Localization for I3 M 1 M 2 M 3 M 4 Levey (1993). Life Sciences, 52 , 441-448.

10. Neural Localization Stahl, S. (2008). Essential Psychopharmacology , p. 916.

11. Tissue Distribution Receptor Organs M 1 salivary glands, enteric nerves M 2 heart, smooth muscle M 3 smooth muscle , salivary glands M 4 brain (diffuse), lung M 5 brain ( substantia nigra ), eye Andersson , K. E. http ://www.medscape.org/viewarticle/487222

12. Muscarinic Agonists Origin Nicotinic Effect BBB Permeability Uses Methacholine synthetic low low challenge for asthma Carbachol synthetic high low miosis glaucoma Muscarine natural no low research hallucinogin Pilocarpine natural no high xerostomia Brown & Laiken (2011). In Pharmacological Basis of Therapeutics , p. 219-237.

13. Bethanechol Short-acting muscarinic agonist Used to treat non-obstructive urinary retention

14. Atropa belladona Atropos : Greek god of life Belladona : dilation of pupils Contains nonselective muscarinic antagonists atropine & scopolamine Overdose = dry mouth, confusion, seizures 1707 - 1778 Carl Linnaeus

15. Atropine Rang et al. (2007). Pharmacology. p. 145. 1875 - 1968

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. Relative Physiological Effects Katzung et al. (2009). Basic & Clinical Pharmacology. p. 120.

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. Scopolamine Crosses BBB Used prophylactically Adverse Effects: dry mouth, drowsiness Silly but accurate (1 min): http://www.youtube.com/watch?v=h88Vg3PrKIs&feature=BFa&list=LPq4H22JxqqS4

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. Miraldi et al. (2001). Fitoterapia , 72 , 644-648. Are seeds special? > > >

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. Brien et al. (2003). British Journal of Clinical Pharmacology, 56 , 562-568. 1755 - 1843 Samuel Hahnemann, MD Nadu, India

23. Brien et al. (2003). British Journal of Clinical Pharmacology, 56 , 562-568. “Deadly nightshade ”

24. Brien et al. (2003). British Journal of Clinical Pharmacology, 56 , 562-568. Conclusion: Pro : no side effect Con : not harmless

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 components 1.5 min: http://www.youtube.com/watch?v=r7HSokv8A5M&feature=player_detailpage Forrer , G. (1956). J Nervous Mental Disease, 124(3 ), 256-259.

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. Future: Selective Muscarinic Allosteric Modulators?

28. Future: Selective Muscarinic Allosteric Modulators? PQCA: M 1 positive allosteric modulator; donepezil: acetylcholinesterase inhibitor Uslaner et al. (in press-2012). Psychopharmacology .

29. Goodwin Terminology (Refresher) o rthosteric : site where the ligand binds to a receptor or enzyme a llosteric:   the other site (non-active site) positive a llosteric m odulation : binding of ligand to allosteric site increases binding between substrate molecules & other binding site n egative a llosteric m odulation : binding of ligand to allosteric site decreases binding between substrate molecule & other binding site d ystonia: involuntary muscle contractions that cause slow repetitive movements or abnormal postures c ycloplegia : inability to focus eye for near vision diaphoresis : excessive sweating diverticulitis : formation of small bulging pouches in the lining of intestine that become inflamed miosis ( myosis ): constriction of the pupil of eye m ydriasis : dilation of pupil of eye sialagogue : any drug or agent that can stimulate the flow of saliva xerostomia : dry mouth syncope : fainting