Pilocarpine

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Pilocarpine
Pilocarpine.svg
Pilocarpine ball-and-stick model.png
Clinical data
Trade names Isopto Carpine, Salagen, Vuity, others
AHFS/Drugs.com Monograph
MedlinePlus a608039
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		Topical eye drops, by mouth
Drug class
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 0.76 hours (5 mg), 1.35 hours (10 mg) [3]
Excretion urine
Identifiers
  • (3S,4R)-3-Ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)dihydrofuran-2(3H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.936 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H16N2O2
Molar mass 208.261 g·mol−1
3D model (JSmol)
  • O=C2OC[C@H](Cc1n(cnc1)C)[C@@H]2CC
  • 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 Yes check.svgY
  • Key:QCHFTSOMWOSFHM-WPRPVWTQSA-N Yes check.svgY
   (verify)

Pilocarpine is a lactone alkaloid originally extracted from plants of the Pilocarpus genus. [4] It is used as a medication to reduce pressure inside the eye and treat dry mouth. [1] [5] As an eye drop it is used to manage angle closure glaucoma until surgery can be performed, ocular hypertension, primary open angle glaucoma, and to constrict the pupil after dilation. [1] [6] [7] However, due to its side effects, it is no longer typically used for 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]

Contents

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 [15] It was originally made from the South American plant Pilocarpus . [12]

Medical uses

Pilocarpine stimulates the secretion of large amounts of saliva and sweat. [16] 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. [17]

It may be used to help differentiate Adie syndrome from other causes of unequal pupil size. [18] [19]

It may be used to treat a form of dry eye called aqueous deficient dry eye (ADDE) [20]

Surgery

Pilocarpine is sometimes used immediately before certain types of corneal grafts and cataract surgery. [21] [22] It is also used prior to YAG laser iridotomy. 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.[ dubious – discuss ] The most common concentration for this use is pilocarpine 1%.[ citation needed ] Pilocarpine is shown to be just as effective as apraclonidine in preventing intraocular pressure spikes after laser trabeculoplasty. [23]

Presbyopia

In 2021, the U.S. Food and Drug Administration (FDA) approved pilocarpine hydrochloride as an eyedrop treatment for presbyopia, age-related difficulty with near-in vision. It works by causing the pupils to constrict, increasing depth of field, similar to the effect of pinhole glasses. Marketed as Vuity, the effect lasts for more than 6 hours. [24] [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]

Adverse effects

Use of pilocarpine may result in a range of adverse 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. It can also cause temporary blurred vision or darkness of vision, temporary shortsightedness, hyphema and retinal detachment.

Pharmacology

Pilocarpine is a drug that acts as a muscarinic receptor agonist. 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 leaves of Pilocarpus microphyllus in a multi-step process : the sample is moistened with dilute sodium hydroxide to transform the alkaloid into its free-base form then extracted using chloroform or a suitable organic solvant. Pilocarpine can then be further purified by re-extracting the resulting solution with aqueous sulfuric acid then readjusting the pH to basic using ammonia and a final extraction by chloroform. [29] [30] [31]

It can also be synthesized from 2-ethyl-3-carboxy-2-butyrolactone in a 8 steps process from the acyl chloride (by treatment with thionyl chloride) via a Arndt–Eistert reaction with diazomethane then by treatment with potassium phthalimide and potassium thiocyanate. [4]

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), Timpilo (Merck Frosst), and Vuity (AbbVie).

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. [32] [33] 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.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Glaucoma</span> Group of eye diseases

Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of sight" because the loss of vision usually occurs slowly over a long period of time. A major risk factor for glaucoma is increased pressure within the eye, known as intraocular pressure (IOP). It is associated with old age, a family history of glaucoma, and certain medical conditions or the use of some medications. The word glaucoma comes from the Ancient Greek word γλαυκός, meaning 'gleaming, blue-green, gray'.

<span class="mw-page-title-main">Aqueous humour</span> Fluid in the anterior segment of the eye

The aqueous humour is a transparent water-like fluid similar to blood plasma, but containing low protein concentrations. It is secreted from the ciliary body, a structure supporting the lens of the eyeball. It fills both the anterior and the posterior chambers of the eye, and is not to be confused with the vitreous humour, which is located in the space between the lens and the retina, also known as the posterior cavity or vitreous chamber. Blood cannot normally enter the eyeball.

Carbachol, also known as carbamylcholine and sold under the brand name Miostat among others, is a cholinomimetic drug that binds and activates acetylcholine receptors. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery. It is generally administered as an ophthalmic solution.

<span class="mw-page-title-main">Ciliary body</span> Part of the eye

The ciliary body is a part of the eye that includes the ciliary muscle, which controls the shape of the lens, and the ciliary epithelium, which produces the aqueous humor. The aqueous humor is produced in the non-pigmented portion of the ciliary body. The ciliary body is part of the uvea, the layer of tissue that delivers oxygen and nutrients to the eye tissues. The ciliary body joins the ora serrata of the choroid to the root of the iris.

<span class="mw-page-title-main">Intraocular pressure</span> Fluid pressure inside the eye

Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated to measure pressure in millimeters of mercury (mmHg).

<span class="mw-page-title-main">Red eye (medicine)</span> Eye that appears red due to illness or injury

A red eye is an eye that appears red due to illness or injury. It is usually injection and prominence of the superficial blood vessels of the conjunctiva, which may be caused by disorders of these or adjacent structures. Conjunctivitis and subconjunctival hemorrhage are two of the less serious but more common causes.

<span class="mw-page-title-main">Ciliary muscle</span> Eye muscle which is used for focussing

The ciliary muscle is an intrinsic muscle of the eye formed as a ring of smooth muscle in the eye's middle layer, the uvea. It controls accommodation for viewing objects at varying distances and regulates the flow of aqueous humor into Schlemm's canal. It also changes the shape of the lens within the eye but not the size of the pupil which is carried out by the sphincter pupillae muscle and dilator pupillae.

<span class="mw-page-title-main">Betaxolol</span> Chemical compound

Betaxolol is a selective beta1 receptor blocker used in the treatment of hypertension and angina. It is also a adrenergic blocker with no partial agonist action and minimal membrane stabilizing activity. Being selective for beta1 receptors, it typically has fewer systemic side effects than non-selective beta-blockers, for example, not causing bronchospasm as timolol may. Betaxolol also shows greater affinity for beta1 receptors than metoprolol. In addition to its effect on the heart, betaxolol reduces the pressure within the eye. This effect is thought to be caused by reducing the production of the liquid within the eye. The precise mechanism of this effect is not known. The reduction in intraocular pressure reduces the risk of damage to the optic nerve and loss of vision in patients with elevated intraocular pressure due to glaucoma.

<span class="mw-page-title-main">Latanoprost</span> Chemical compound

Latanoprost, sold under the brand name Xalatan among others, is a medication used to treat increased pressure inside the eye. This includes ocular hypertension and open-angle glaucoma. Latanaprost is applied as eye drops to the eyes. Onset of effects is usually within four hours, and they last for up to a day.

<span class="mw-page-title-main">Timolol</span> Chemical compound

Timolol is a beta blocker medication used either by mouth or as eye drops. As eye drops it is used to treat increased pressure inside the eye such as in ocular hypertension and glaucoma. By mouth it is used for high blood pressure, chest pain due to insufficient blood flow to the heart, to prevent further complications after a heart attack, and to prevent migraines.

<i>Pilocarpus</i> Genus of flowering plants

Pilocarpus is a genus of about 13 species of plants belonging to the family Rutaceae, native to the Neotropics of South America. Various species are important pharmacologically as a source of the parasympathomimetic alkaloid pilocarpine. Many of the species have the common name jaborandi.

Ocular hypertension is the presence of elevated fluid pressure inside the eye, usually with no optic nerve damage or visual field loss.

<span class="mw-page-title-main">Brimonidine</span> Chemical compound

Brimonidine is an α2 agonist medication used to treat open-angle glaucoma, ocular hypertension, and rosacea. In rosacea it improves the redness. It is used as eye drops or applied to the skin. It is also available in the fixed-dose combination medication brimonidine/timolol along with timolol maleate.

<span class="mw-page-title-main">Apraclonidine</span> Chemical compound

Apraclonidine (INN), also known under the brand name Iopidine, is a sympathomimetic used in glaucoma therapy. It is an α2 adrenergic receptor agonist and a weak α1 adrenergic receptor agonist.

<span class="mw-page-title-main">Dorzolamide</span> Chemical compound

Dorzolamide, sold under the brand name Trusopt among others, is a medication used to treat high pressure inside the eye, including in cases of glaucoma. It is used as an eye drop. Effects begin within three hours and last for at least eight hours. It is also available as the combination dorzolamide/timolol.

<span class="mw-page-title-main">Levobunolol</span> Chemical compound

Levobunolol is a non-selective beta blocker. It is used topically in the form of eye drops to manage ocular hypertension and open-angle glaucoma.

A spasm of accommodation is a condition in which the ciliary muscle of the eye remains in a constant state of contraction. Normal accommodation allows the eye to "accommodate" for near-vision. However, in a state of perpetual contraction, the ciliary muscle cannot relax when viewing distant objects. This causes vision to blur when attempting to view objects from a distance. This may cause pseudomyopia or latent hyperopia.

<span class="mw-page-title-main">Scleral spur</span> Annular structure composed of collagen in the human eye

The scleral spur in the visual system is a protrusion of the sclera into the anterior chamber. The spur is an annular structure composed of collagen in the human eye.

<span class="mw-page-title-main">Secondary glaucoma</span> Eye disorder

Secondary glaucoma is a collection of progressive optic nerve disorders associated with a rise in intraocular pressure (IOP) which results in the loss of vision. In clinical settings, it is defined as the occurrence of IOP above 21 mmHg requiring the prescription of IOP-managing drugs. It can be broadly divided into two subtypes: secondary open-angle glaucoma and secondary angle-closure glaucoma, depending on the closure of the angle between the cornea and the iris. Principal causes of secondary glaucoma include optic nerve trauma or damage, eye disease, surgery, neovascularization, tumours and use of steroid and sulfa drugs. Risk factors for secondary glaucoma include uveitis, cataract surgery and also intraocular tumours. Common treatments are designed according to the type and the underlying causative condition, in addition to the consequent rise in IOP. These include drug therapy, the use of miotics, surgery or laser therapy.

Ocular hypotony, or ocular hypotension, or shortly hypotony, is the medical condition in which intraocular pressure (IOP) of the eye is very low.

References

  1. 1 2 3 4 5 6 7 "Pilocarpine". The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 8 December 2016.
  2. ↑ "Vuity- pilocarpine hydrochloride solution/ drops". DailyMed. Retrieved 19 December 2021.
  3. ↑ Gornitsky M, Shenouda G, Sultanem K, Katz H, Hier M, Black M, et al. (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.
  4. 1 2 Vardanyan RS, Hruby VJ (2006). "Cholinomimetics". Synthesis of Essential Drugs. pp. 179–193. doi:10.1016/B978-044452166-8/50013-3. ISBN   978-0-444-52166-8.
  5. ↑ Tarascon Pocket Pharmacopoeia 2019 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2018. p. 224. ISBN   978-1-284-16754-2.
  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. 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". The Medical Journal of Australia. 210 (4): 180–187. doi:10.5694/mja2.50020. PMID   30767238. S2CID   73438590. Pilocarpine is no longer routinely used for long term IOP control due to a poor side effect profile
  9. ↑ Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 415. 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 W (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): 53–55. PMID   1811739.
  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. ↑ "Pilocarpine". MedLinePlus. U.S. National Library of Medicine. Archived from the original on 2010-03-06.
  17. ↑ Yang WF, Liao GQ, Hakim SG, Ouyang DQ, Ringash J, Su YX (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): 503–511. doi:10.1016/j.ijrobp.2015.11.012. hdl: 10722/229069 . PMID   26867879.
  18. ↑ Kanski JJ, Bowling B (2015-03-24). Kanski's Clinical Ophthalmology E-Book: A Systematic Approach. Elsevier Health Sciences. p. 812. ISBN   978-0-7020-5574-4.
  19. ↑ Jaanus SD, Pagano VT, Bartlett JD (1989). "Drugs Affecting the Autonomic Nervous System". Clinical Ocular Pharmacology. pp. 69–148. doi:10.1016/B978-0-7506-9322-6.50011-8. ISBN   978-0-7506-9322-6.
  20. ↑ Mannis MJ, Holland EJ (September 2016). "Chapter 33: Dry Eye". Cornea E-Book. Elsevier Health Sciences. p. 388. ISBN   978-0-323-35758-6. OCLC   960165358.
  21. ↑ Parker J (2017). Descemet Membrane Endothelial Keratoplasty (DMEK): A Review (Thesis). Leiden University. hdl:1887/50484.
  22. ↑ Ahmed E (2010). Comprehensive Manual of Ophthalmology. JP Medical Ltd. p. 345. ISBN   978-93-5025-175-1.
  23. ↑ 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. 2017 (2): CD010746. doi:10.1002/14651858.CD010746.pub2. PMC   5477062 . PMID   28231380.
  24. ↑ Grzybowski A, Ruamviboonsuk V (March 2022). "Pharmacological Treatment in Presbyopia". Journal of Clinical Medicine. 11 (5): 1385. doi: 10.3390/jcm11051385 . PMC   8910925 . PMID   35268476.
  25. ↑ "Vuity Label Revised: 10/2021" (PDF). Allergan, an AbbVie Company. U.S. Food and Drug Administration.
  26. ↑ Prasad RK (2017-07-11). Chemistry and Synthesis of Medicinal Agents: (Expanding Knowledge of Drug Chemistry). BookRix. ISBN   978-3-7438-2141-5.
  27. ↑ Teekhasaenee C (2015). "Laser Peripheral Iridoplasty". Glaucoma. pp. 716–721. doi:10.1016/B978-0-7020-5193-7.00073-X. ISBN   978-0-7020-5193-7.
  28. ↑ De Abreu IN, Sawaya AC, Eberlin MN, Mazzafera P (November–December 2005). "Production of Pilocarpine in Callus of Jaborandi (Pilocarpus microphyllus Stapf)". In Vitro Cellular & Developmental Biology - Plant. 41 (6). Society for In Vitro Biology: 806–811. doi:10.1079/IVP2005711. JSTOR   4293939. S2CID   26058596.
  29. ↑ Avancini G, Abreu IN, Saldaña MD, Mohamed RS, Mazzafera P (May 2003). "Induction of pilocarpine formation in jaborandi leaves by salicylic acid and methyljasmonate". Phytochemistry. 63 (2): 171–175. Bibcode:2003PChem..63..171A. doi:10.1016/S0031-9422(03)00102-X. PMID   12711138.
  30. ↑ Sawaya AC, Abreu IN, Andreazza NL, Eberlin MN, Mazzafera P (July 2008). "HPLC-ESI-MS/MS of imidazole alkaloids in Pilocarpus microphyllus". Molecules. 13 (7): 1518–1529. doi: 10.3390/molecules13071518 . PMC   6245396 . PMID   18719522.
  31. ↑ Schwab L (2007). "Glaucoma". In Fourth (ed.). Eye Care in Developing Nations. pp. 99–116. doi:10.1201/b15129-14 (inactive 2024-11-12). ISBN   978-1-84076-103-0.{{cite book}}: CS1 maint: DOI inactive as of November 2024 (link)
  32. ↑ Károly N (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 .
  33. ↑ 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. S2CID   36849482.
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