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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 Fighting
     Vampires 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            Organs
   M1                  salivary glands, enteric nerves
   M2                  heart, smooth muscle
   M3                  smooth muscle, salivary glands
   M4                  brain (diffuse), lung
   M5                  brain (substantia nigra), eye

Andersson, K. E. http://www.medscape.org/viewarticle/487222
Muscarinic Agonists

                          Origin        Nicotinic    BBB              Uses
                                        Effect       Permeability
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.
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                       Carl Linnaeus
  mouth, confusion, seizures



                                           1707 - 1778
Atropine

1875 - 1968




                  Rang et al. (2007). Pharmacology. p. 145.
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
Are seeds special?



                     >

                     >




                                                   >




Miraldi et al. (2001). Fitoterapia, 72, 644-648.
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, India
Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.   1755 - 1843
“Deadly nightshade”




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

Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
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 enzyme
allosteric: the other site (non-active site)
positive allosteric modulation: binding of ligand to allosteric site increases binding between substrate
molecules & other binding site
negative allosteric modulation: binding of ligand to allosteric site decreases binding between substrate
molecule & other binding site
dystonia: involuntary muscle contractions that cause slow repetitive movements or abnormal postures
cycloplegia: 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
mydriasis: dilation of pupil of eye
sialagogue: any drug or agent that can stimulate the flow of saliva
xerostomia: dry mouth
syncope: fainting

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Muscarinic agonists and antagonists

  • 1. Muscarinic Agonists & Antagonists Brian J. Piper, Ph.D., M.S.
  • 2. Objectives • Similarities & differences in muscarinic receptors • Agonists – Synthetic: methacholine – Natural: pilocarpine • Antagonists – atropine – scopalomine
  • 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 – 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. 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 Heavenly 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. M1 to M4 ICC Localization for I3 M1 M2 M3 M4 Levey (1993). Life Sciences, 52, 441-448.
  • 10. Neural Localization Stahl, S. (2008). Essential Psychopharmacology, p. 916.
  • 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), eye Andersson, K. E. http://www.medscape.org/viewarticle/487222
  • 12. Muscarinic Agonists Origin Nicotinic BBB Uses Effect Permeability 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 Carl Linnaeus mouth, confusion, seizures 1707 - 1778
  • 15. Atropine 1875 - 1968 Rang et al. (2007). Pharmacology. p. 145.
  • 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. Are seeds special? > > > Miraldi et al. (2001). Fitoterapia, 72, 644-648.
  • 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, India Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568. 1755 - 1843
  • 23. “Deadly nightshade” Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
  • 24. Conclusion: Pro: no side effect Con: not harmless Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.
  • 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: M1 positive allosteric modulator; donepezil: acetylcholinesterase inhibitor Uslaner et al. (in press-2012). Psychopharmacology.
  • 29. Goodwin Terminology (Refresher) orthosteric: site where the ligand binds to a receptor or enzyme allosteric: the other site (non-active site) positive allosteric modulation: binding of ligand to allosteric site increases binding between substrate molecules & other binding site negative allosteric modulation: binding of ligand to allosteric site decreases binding between substrate molecule & other binding site dystonia: involuntary muscle contractions that cause slow repetitive movements or abnormal postures cycloplegia: 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 mydriasis: dilation of pupil of eye sialagogue: any drug or agent that can stimulate the flow of saliva xerostomia: dry mouth syncope: fainting

Editor's Notes

  1. Pronunciation: http://dictionary.reference.com/browse/pilocarpine+?s=t
  2. Fig 4.2 on page 44 would be better.
  3. quaternary: four; ammonium: NH4; butyrylcholinesterase is found primarily in the liver and is also known as pseudocholinesterase; similar to acetylcholinesterase which is found in the brain
  4. Ironically,Amanita muscariacontains only trace amounts (0.0003%) of muscarine but this was enough for Henry Dale to differentiate these receptors from those responsive to nicotine.Fly agaric looks like mushrooms from Super Mario Brothers although the creator, Shigeru Miyamoto, claims to have been inspired by Alice in Wonderland.There is a gene for M5 but the receptor hasn’t been identified pharmacologically (yet).There are few selective ligands for the because the M1 to M5orthosteric binding site is so similar. The finding that most cells have at least 2 muscarinic receptors indicates substantial redundancy.Example pronunciation of Amanita muscaria (scare) at: http://www.youtube.com/watch?v=YaGnQZgLtWU
  5. CN III is important for constricting the pupil; CN VII for controlling tears; CN IX for salivation; CN X for cardiac and respiratory function (bronchoconstriction).
  6. Allan Levey conducted ICC with antibodies that target the 3rd intracellular loop of the muscarinic receptors.Coronal views of rat brain showing uniform distribution in the cortex (Cx) and caudate putamen (CP). Note differential binding in the hippocampus (Hi), thalamus (Th), and hypothalamus (Hy). Not shown is binding to M5 in substanianigra.The diffuse neural distribution, especially in the cortex, may account for the hallucinogenic properties of muscarinic antagonists.
  7. M2 acts to slow down heart rate down. M3 is important for vasoconstriction and stimulating salivary secretion.Substantianigra (Latin for black substance) is found in midbrain.
  8. Methacholine is primarily used to diagnose bronchial hyperreactivity, which is the hallmark of asthma and also occurs in COPD. This is accomplished through the bronchial challenge test (methacholine challenge). Methacholine is administered via a nebulizer.Carbachol is used for ophthalmic purposes (glaucoma, eye surgery) and is administered by eyedrops. Carbacholfacilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure.Muscarine is more potent than acetylcholine and is slower but longer acting. This is found in several mushrooms and is consumed for recreational purposes.Pilocarpine causes salivation and is used an an antidote to muscarinic antagonist poisoning.
  9. Bethanechol [be THAN e kole] has a duration of action of about 1 hour and is resistant to cholinesterase. Bethanecholalso stimulates peristalsis in the GI tract and detrusor muscles of bladder. Contraindications: asthma (will make symptoms worse).
  10. The Swedish botanist and father of zoological nomenclature designated this plant Atropabelladona (aka deadly nightshade). Bella dona refers to “beautiful woman” and the practice of dilating the pupils by seductive Italian women. This plant is also associated with witches (hallucination of seeing someone fly).
  11. Acetylcholine at low doses cause vasodilation (mediated by M3) and higher doses cause bradycardia.Muscarinic antagonist atropine blocks the effects of acetylcholine. Higher doses of acetylcholine effect the adrenal gland and increase BP.
  12. The heart rate decrease is often subtle & transient (mediated by presynaptic M1) while the increase is larger and more persistent (mediated by M2 on SA node). The effects on the lung are typically indirect via blocking histamine. Direct administration of atropine to the eye can cause long-lasting pupil dilation. Atropine used in animal surgeries to prevent swallowing saliva.
  13. Chinese used datura to induce unconsciousness during which broken bones were set.
  14. There is a notion that the seeds are the best source of the hallucingenic Jimson weed. Note the substantial variation based on location in plant and age.
  15. A C is a 1/100 parts dilution, 30C is 1/100 done 30 times.
  16. Sample is about half medical and half non-medical students.
  17. Far right column is the N that showed a proving response (i.e. endorsed item on questionairre).