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.

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  • Pronunciation:
  • Fig 4.2 on page 44 would be better.
  • 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
  • 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:
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • Chinese used datura to induce unconsciousness during which broken bones were set.
  • 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.
  • A C is a 1/100 parts dilution, 30C is 1/100 done 30 times.
  • Sample is about half medical and half non-medical students.
  • Far right column is the N that showed a proving response (i.e. endorsed item on questionairre).
  • 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 Heavenly
    7. 7. Overall Receptor Distribution • Cranial Nerve – III: oculomotor – VII: facial – IX: glossopharyngeal – X: vagus
    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.
    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):
    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:, 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