Pilocarpine

Pilocarpine
Names
Trade namesIsopto Carpine, Salagen, others
IUPAC name
  • (3S,4R)-3-Ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)dihydrofuran-2(3H)-one
Clinical data
Drug classMiotic (cholinergic)[1]
Main usesIncreased eye pressure, dry mouth[1][2]
Side effectsIrritation of the eye, increased tearing, headache, blurry vision[1]
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		topical (eye drops), by mouth
    Defined daily dose0.4 ml (ophthalmic drop)
    40 mg (ointment)[3] and
    15 mg (by mouth)
    10 mg (parenteral)[4]
    External links
    AHFS/Drugs.comMonograph
    US NLMPilocarpine
    MedlinePlusa608039
    Legal
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetics
    Elimination half-life0.76 hours (5 mg), 1.35 hours (10 mg)[5]
    Excretionurine
    Chemical and physical data
    FormulaC11H16N2O2
    Molar mass208.261 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C2OC[C@H](Cc1n(cnc1)C)[C@@H]2CC
    InChI
    • InChI=1S/C11H16N2O2/c1-3-10-8(6-15-11(10)14)4-9-5-12-7-13(9)2/h5,7-8,10H,3-4,6H2,1-2H3/t8-,10-/m0/s1 checkY
    • Key:QCHFTSOMWOSFHM-WPRPVWTQSA-N checkY

    Pilocarpine is a medication used to reduce pressure inside the eye and treat dry mouth.[1][2] As eye drops it is used to manage angle closure glaucoma until surgery can be performed, ocular hypertension, primary open angle glaucoma, and to bring about constriction of the pupil following its dilation.[1][6][7] However, due to its side effects it is no longer typically used in the long term management.[8] Onset of effects with the drops is typically within an hour and lasts for up to a day.[1] By mouth it is used for dry mouth as a result of Sjögren syndrome or radiation therapy.[9]

    Common side effects of the eye drops include irritation of the eye, increased tearing, headache, and blurry vision.[1] Other side effects include allergic reactions and retinal detachment.[1] Use is generally not recommended during pregnancy.[10] Pilocarpine is in the miotics family of medication.[11] It works by activating cholinergic receptors of the muscarinic type which cause the trabecular meshwork to open and the aqueous humor to drain from the eye.[1]

    Pilocarpine was isolated in 1874 by Hardy and Gerrard and has been used to treat glaucoma for more than 100 years.[12][13][14] It is on the World Health Organization's List of Essential Medicines.[15] The wholesale cost in the developing world is about US$1.61–4.88 per 10 ml bottle.[16] In the United States a month of the drops costs less than $25 as of 2015.[9] It is one of the lowest cost medications for glaucoma.[17] It was originally made from the South American plant Pilocarpus.[12]

    Medical uses

    Pilocarpine stimulates the secretion of large amounts of saliva and sweat.[18] It is used to prevent or treat dry mouth, particularly in Sjögren syndrome, but also as a side effect of radiation therapy for head and neck cancer.[19]

    It may be used to help differentiate Adie syndrome from other causes of unequal pupil size.[20][21]

    It may be used to treat a form of dry eye called aqueous deficient dry eye (ADDE)[22]

    Surgery

    Pilocarpine is sometimes used immediately before certain types of corneal grafts and cataract surgery.[23][24] In ophthalmology, pilocarpine is also used to reduce symptomatic glare at night from lights when the patient has undergone implantation of phakic intraocular lenses; the use of pilocarpine would reduce the size of the pupils, partially relieving these symptoms. The most common concentration for this use is pilocarpine 1%. Pilocarpine is shown to be just as effective as apraclonidine in preventing intraocular pressure spikes after laser trabeculoplasty.[25]

    Other

    Pilocarpine is used to stimulate sweat glands in a sweat test to measure the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis.[26]

    Dosage

    The defined daily dose is 0.4 ml (eye drop) or 40 mg (eye ointment)[3] and 15 mg (by mouth) or 10 mg (by injection).[4]

    Side effects

    Use of pilocarpine may result in a range of side effects, most of them related to its non-selective action as a muscarinic receptor agonist. Pilocarpine has been known to cause excessive salivation, sweating, bronchial mucus secretion, bronchospasm, bradycardia, vasodilation, and diarrhea. Eye drops can result in brow ache and chronic use in miosis.

    Mechanism of action

    It acts on a subtype of muscarinic receptor (M3) found on the iris sphincter muscle, causing the muscle to contract - resulting in pupil constriction (miosis). Pilocarpine also acts on the ciliary muscle and causes it to contract. When the ciliary muscle contracts, it opens the trabecular meshwork through increased tension on the scleral spur. This action facilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure. Paradoxically, when pilocarpine induces this ciliary muscle contraction (known as an accommodative spasm) it causes the eye's lens to thicken and move forward within the eye. This movement causes the iris (which is located immediately in front of the lens) to also move forward, narrowing the Anterior chamber angle. Narrowing of the anterior chamber angle increases the risk of increased intraocular pressure.[27]

    Society and culture

    Preparation

    Plants in the genus Pilocarpus are the only known sources of pilocarpine, and commercial production is derived entirely from the leaves of Pilocarpus microphyllus (Maranham Jaborandi). This genus grows only in South America, and Pilocarpus microphyllus is native to several states in northern Brazil.[28]

    Pilocarpine is extracted from the powdered leaf material in a multi-step process. First the material is treated with ethanol acidified with hydrochloric acid, and the solvents removed under reduced pressure. The resultant aqueous residue is neutralized with ammonia and put aside until the resin has completely settled. It is then filtered and concentrated by sugar solution to a small volume, made alkaline with ammonia, and finally extracted with chloroform. The solvent is removed under reduced pressure.

    Cost

    The wholesale cost in the developing world is about US$1.61–4.88 per 10 ml bottle.[16] In the United States a month of the drops costs less than $25.[9] It is one of the lowest cost medications for glaucoma.[17]

    Trade names

    Pilocarpine is available under several trade names such as: Diocarpine (Dioptic), Isopto Carpine (Alcon), Miocarpine (CIBA Vision), Ocusert Pilo-20 and -40 (Alza), Pilopine HS (Alcon), Salagen (MGI Pharma), Scheinpharm Pilocarpine (Schein Pharmaceutical), and Timpilo (Merck Frosst).

    Research

    Pilocarpine is used to induce chronic epilepsy in rodents, commonly rats, as a means to study the disorder's physiology and to examine different treatments.[29][30] Smaller doses may be used to induce salivation in order to collect samples of saliva, for instance, to obtain information about IgA antibodies.

    Veterinary

    Pilocarpine is given in moderate doses (about 2 mg) to induce emesis in cats that have ingested foreign plants, foods, or drugs. One feline trial determined it was effective, even though the usual choice of emetic is xylazine.

    See also

    • Cevimeline—a similar parasympathomimetic medication for dry mouth (xerostomia)
    • Bethanechol—a similar muscarinic parasympathomimetic with longer lasting effect

    References

    1. 1 2 3 4 5 6 7 8 9 "Pilocarpine". The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 8 December 2016.
    2. 1 2 Tarascon Pocket Pharmacopoeia 2019 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2018. p. 224. ISBN 9781284167542. Archived from the original on 2021-08-28. Retrieved 2019-09-19.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 24 July 2020. Retrieved 16 September 2020.
    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 4 November 2020. Retrieved 16 September 2020.
    5. ↑ Gornitsky M, Shenouda G, Sultanem K, Katz H, Hier M, Black M, Velly AM (July 2004). "Double-blind randomized, placebo-controlled study of pilocarpine to salvage salivary gland function during radiotherapy of patients with head and neck cancer". Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 98 (1): 45–52. doi:10.1016/j.tripleo.2004.04.009. PMID 15243470.
    6. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 439. hdl:10665/44053. ISBN 9789241547659.
    7. ↑ "Glaucoma and ocular hypertension. NICE guideline 81". National Institute for Health and Care Excellence. November 2017. Archived from the original on 28 August 2021. Retrieved 19 September 2019. Ocular hypertension... alternative options include carbonic anhydrase inhibitors such as brinzolamide or dorzolamide, a topical sympathomimetic such as apraclonidine or brimonidine tartrate, or a topical miotic such as pilocarpine, given either as monotherapy or as combination therapy.
    8. ↑ Lusthaus J, Goldberg I (March 2019). "Current management of glaucoma" (PDF). The Medical Journal of Australia. 210 (4): 180–187. doi:10.5694/mja2.50020. PMID 30767238. Archived (PDF) from the original on 2020-10-31. Retrieved 2019-09-16. Pilocarpine is no longer routinely used for long term IOP control due to a poor side effect profile
    9. 1 2 3 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. pp. 254, 412. ISBN 9781284057560.
    10. ↑ "Pilocarpine ophthalmic Use During Pregnancy | Drugs.com". www.drugs.com. Archived from the original on 28 December 2016. Retrieved 28 December 2016.
    11. ↑ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 769. ISBN 9780857111562.
    12. 1 2 Sneader, Walter (2005). Drug Discovery: A History. John Wiley & Sons. p. 98. ISBN 978-0-471-89979-2. Archived from the original on 2016-12-29.
    13. ↑ Rosin A (1991). "[Pilocarpine. A miotic of choice in the treatment of glaucoma has passed 110 years of use]". Oftalmologia (in Romanian). 35 (1): 53–5. PMID 1811739.{{cite journal}}: CS1 maint: unrecognized language (link)
    14. ↑ Holmstedt, B; Wassén, SH; Schultes, RE (January 1979). "Jaborandi: an interdisciplinary appraisal". Journal of Ethnopharmacology. 1 (1): 3–21. doi:10.1016/0378-8741(79)90014-x. PMID 397371.
    15. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    16. 1 2 "Pilocarpine". International Drug Price Indicator Guide. Archived from the original on 22 January 2018. Retrieved 8 December 2016.
    17. 1 2 Schwab, Larry (2007). Eye Care in Developing Nations. CRC Press. p. 110. ISBN 9781840765229. Archived from the original on 2021-08-28. Retrieved 2019-09-19.
    18. ↑ "Pilocarpine". MedLinePlus. U.S. National Library of Medicine. Archived from the original on 2010-03-06.
    19. ↑ Yang, WF; Liao, GQ; Hakim, SG; Ouyang, DQ; Ringash, J; Su, YX (1 March 2016). "Is Pilocarpine Effective in Preventing Radiation-Induced Xerostomia? A Systematic Review and Meta-analysis". International Journal of Radiation Oncology, Biology, Physics. 94 (3): 503–11. doi:10.1016/j.ijrobp.2015.11.012. hdl:10722/229069. PMID 26867879.
    20. ↑ Kanski, Jack J.; Bowling, Brad (2015-03-24). Kanski's Clinical Ophthalmology E-Book: A Systematic Approach. Elsevier Health Sciences. p. 812. ISBN 9780702055744. Archived from the original on 2021-08-28. Retrieved 2019-09-16.
    21. ↑ Bartlett, Jimmy D.; James, Siret D. (October 2013). "Drug Affect the Autonomous Nervous System". Clinical Ocular Pharmacology. Elsevier. p. 118. Archived from the original on 2021-08-28. Retrieved 2019-09-18.
    22. ↑ Mannis, Mark J; Holland, Edward J (September 2016). "Chapter 33: Dry Eye". Cornea E-Book. Elsevier Health Sciences. p. 388. ISBN 978-0-323-35758-6. OCLC 960165358. Archived from the original on 2021-08-28. Retrieved 2019-09-18.
    23. ↑ Parker, Jack (2017). Descemet Membrane Endothelial Keratoplasty (DMEK): A Review (PDF). Leiden University. Archived (PDF) from the original on 2020-10-31. Retrieved 2019-09-16.
    24. ↑ Ahmed, E.; E, Ahmed (2010). Comprehensive Manual of Ophthalmology. JP Medical Ltd. p. 345. ISBN 9789350251751. Archived from the original on 2021-08-28. Retrieved 2019-09-16.
    25. ↑ Zhang L, Weizer JS, Musch DC (February 2017). "Perioperative medications for preventing temporarily increased intraocular pressure after laser trabeculoplasty". The Cochrane Database of Systematic Reviews. 2 (2): CD010746. doi:10.1002/14651858.CD010746.pub2. PMC 5477062. PMID 28231380.
    26. ↑ Prasad, Raj K. (2017-07-11). Chemistry and Synthesis of Medicinal Agents: (Expanding Knowledge of Drug Chemistry). BookRix. ISBN 9783743821415. Archived from the original on 2021-08-28. Retrieved 2017-11-24.
    27. ↑ Shaarawy, Tarek M.; Sherwood, Mark B.; Hitchings, Roger A.; Crowston, Jonathan G. (September 2014). "Lsser Peripheral Iridoplasty". Glaucoma E-Book. Elsevier Health Sciences. p. 718. Archived from the original on 2021-08-28. Retrieved 2019-09-18.
    28. ↑ De Abreu, Ilka Nacif; Sawaya, Alexandra Cristine H. F.; Eberlin, Marcos Nogueira; Mazzafera, Paulo (November–December 2005). "Production of Pilocarpine in Callus of Jaborandi (Pilocarpus microphyllus Stapf)". In Vitro Cellular & Developmental Biology. Plant. Society for In Vitro Biology. 41 (6): 806–811. doi:10.1079/IVP2005711. JSTOR 4293939.
    29. ↑ Károly, Norbert (2018). Immunohistochemical investigations of the neuronal changes induced by chronic recurrent seizures in a pilocarpine rodent model of temporal lobe epilepsy (Thesis). University of Szeged. doi:10.14232/phd.9734.
    30. ↑ Morimoto K, Fahnestock M, Racine RJ (May 2004). "Kindling and status epilepticus models of epilepsy: rewiring the brain". Progress in Neurobiology. 73 (1): 1–60. doi:10.1016/j.pneurobio.2004.03.009. PMID 15193778.
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