Muscarinic Agonists & Antagonists Brian J. Piper, Ph.D., M.S.
Nov 18, 2014
Muscarinic Agonists &
Antagonists
Brian J. Piper, Ph.D., M.S.
Objectives
• Similarities & differences in muscarinic receptors
• Agonists – Synthetic: methacholine– Natural: pilocarpine
• Antagonists– atropine– scopalomine
*
* Acetylcholine & muscarinic receptors for sweat glands
Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.
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
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
12 Cranial Nerves
• On Old Olympic Towering Tops A Finn And German Viewed Some Hops
• Once One Openly Told Tourists About FightingVampires Gobling Various Antelope Herds
• Oh Once One Takes The Anatomy Final Very Good Vacations Are Heavenly
http://en.wikipedia.org/wiki/List_of_mnemonics_for_the_cranial_nerves
Overall Receptor Distribution
• Cranial Nerve– III: oculomotor– VII: facial– IX: glossopharyngeal– X: vagus
http://flipper.diff.org/app/items/info/4260
Immunocytochemistry (ICC)
• Uses immune system to generate antibodies• Antibodies are applied to tissue to localize
protein (receptor, enzyme)
M1 to M4 ICC Localization for I3
M1 M2
M3 M4
Levey (1993). Life Sciences, 52, 441-448.
Neural Localization
Stahl, S. (2008). Essential Psychopharmacology, p. 916.
Tissue Distribution
Receptor OrgansM1 salivary glands, enteric nervesM2 heart, smooth muscleM3 smooth muscle, salivary glandsM4 brain (diffuse), lungM5 brain (substantia nigra), eye
Andersson, K. E. http://www.medscape.org/viewarticle/487222
Muscarinic Agonists
Origin NicotinicEffect
BBB Permeability
Uses
Methacholine synthetic low low challenge for asthma
Carbachol synthetic high low miosisglaucoma
Muscarine natural no low researchhallucinogin
Pilocarpine natural no high xerostomia
Brown & Laiken (2011). In Pharmacological Basis of Therapeutics, p. 219-237.
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 atropine & scopolamine• Overdose = dry mouth, confusion,
seizures
1707 - 1778
Carl Linnaeus
Atropine
Rang et al. (2007). Pharmacology. p. 145.
1875 - 1968
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
Relative Physiological Effects
Katzung 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 sweating)Mad as a hatter (CNS/hallucinations)
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
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
Miraldi et al. (2001). Fitoterapia, 72, 644-648.
Are seeds special?
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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
Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
“Deadly nightshade”
Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
Conclusion: Pro: no side effectCon: not harmless
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.
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.
Future: Selective Muscarinic Allosteric Modulators?
Future: Selective Muscarinic Allosteric Modulators?
PQCA: M1 positive allosteric modulator; donepezil: acetylcholinesterase inhibitor
Uslaner et al. (in press-2012). Psychopharmacology.
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 substrate molecules & other binding sitenegative allosteric modulation: binding of ligand to allosteric site decreases binding between substrate molecule & 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