tizanidine
{{Short description|Muscle relaxant medication}}
{{Use American English|date=September 2017}}
{{Use dmy dates|date=February 2024}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 470611127
| image = Tizanidine.svg
| image_class = skin-invert-image
| width = 190
| image2 = Tizanidine-from-xtal-3D-bs-17.png
| image_class2 = bg-transparent
| pronounce = {{IPAc-en|t|aɪ|ˈ|z|æ|n|ᵻ|d|iː|n}} {{respell|tye|ZAN|i-deen}}
| tradename = Zanaflex, Sirdalud, and others
| Drugs.com = {{drugs.com|monograph|tizanidine-hydrochloride}}
| MedlinePlus = a601121
| DailyMedID = Tizanidine
| pregnancy_category =
| routes_of_administration = By mouth
| ATC_prefix = M03
| ATC_suffix = BX02
| ATC_supplemental =
| class = α2-adrenergic receptor agonist
| legal_US = Rx-only
| protein_bound = ~30%
| metabolism = Liver (CYP1A2, 95%)
| elimination_half-life = 2.54 hours (tizanidine), 20–40 hours (inactive metabolites)
| excretion = Urine (60%), feces (20%)
| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 51322-75-9
| PubChem = 5487
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00697
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5287
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6AI06C00GW
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08611
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00776
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1079
| synonyms = 4-Chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-8-thia-7,9-diazabicyclo[4.3.0]nona-2,4,6,9-tetraen-5-amine
| IUPAC_name = 5-Chloro-N-(4,5-dihydro-1H-imidazol-2-yl)benzo[c] [1,2,5]thiadiazol-4-amine
| C=9 | H=8 | Cl=1 | N=5 | S=1
| smiles = Clc1ccc3nsnc3c1NC/2=N/CCN\2
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H8ClN5S/c10-5-1-2-6-8(15-16-14-6)7(5)13-9-11-3-4-12-9/h1-2H,3-4H2,(H2,11,12,13)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XFYDIVBRZNQMJC-UHFFFAOYSA-N
|drug_name=|alt=|caption=|type=|legal_status=|licence_EU=|pregnancy_AU=|licence_US=|legal_UK=POM
}}
Tizanidine, sold under the brand name Zanaflex among others, is an alpha-2 (α2) adrenergic receptor agonist, similar to clonidine, that is used to treat muscle spasticity due to spinal cord injury, multiple sclerosis, and spastic cerebral palsy.{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=1094|edition= 76}} Effectiveness appears similar to baclofen or diazepam.{{cite journal | vauthors = Kamen L, Henney HR, Runyan JD | title = A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury | journal = Current Medical Research and Opinion | volume = 24 | issue = 2 | pages = 425–439 | date = February 2008 | pmid = 18167175 | doi = 10.1185/030079908X261113 | s2cid = 73086671 }} It is taken by mouth.
Common side effects of tizanidine include dry mouth, sleepiness, weakness, and dizziness. Serious side effects may include low blood pressure, liver problems, psychosis, and QT prolongation. It is unclear if use in pregnancy and breastfeeding is safe.{{cite web |title=Tizanidine Pregnancy and Breastfeeding Warnings |url=https://www.drugs.com/pregnancy/tizanidine.html |website=Drugs.com |access-date=3 March 2019 }} It is an α2-adrenergic agonist, but how it works is not entirely clear.{{cite web |title=Tizanidine Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/tizanidine-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=3 March 2019 }}
Tizanidine was approved for medical use in the United States in 1996. It is available as a generic medication. In 2022, it was the 94th most commonly prescribed medication in the United States, with more than 6{{nbsp}}million prescriptions.{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}{{cite web | title = Tizanidine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Tizanidine | access-date = 30 August 2024 }}
Medical uses
Tizanidine has been found to be as effective as other antispasmodic drugs and is more tolerable than baclofen and diazepam.
Side effects
Side effects include dizziness, drowsiness, weakness, nervousness, confusion, hallucinations, strange dreams, depression, vomiting, dry mouth, constipation, diarrhea, stomach pain, heartburn, increased muscle spasms, back pain, rash, sweating, and a tingling sensation in the arms, legs, hands, and feet.{{cite web |url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000106/ |title = Page not available |website = PubMed Health |access-date = 4 September 2017 |url-status = dead |archive-url = https://web.archive.org/web/20121111213511/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000106/ |archive-date = 11 November 2012 |df = dmy-all }}
Symptoms of overdose in 45 cases reported to a poison control center included: lethargy, bradycardia, hypotension, agitation, confusion, vomiting and coma.{{cite journal | vauthors = Spiller HA, Bosse GM, Adamson LA | title = Retrospective review of Tizanidine (Zanaflex) overdose | journal = Journal of Toxicology. Clinical Toxicology | volume = 42 | issue = 5 | pages = 593–596 | date = January 2004 | pmid = 15462150 | doi = 10.1081/CLT-200026978 | s2cid = 38946270 }}
Interactions
Concomitant use of tizanidine and moderate or potent CYP1A2 inhibitors (such as zileuton, certain antiarrhythmics (amiodarone, mexiletine, propafenone, verapamil), cimetidine, famotidine, aciclovir, ticlopidine and oral contraceptives) is contraindicated. Concomitant use of tizanidine with fluvoxamine, a potent CYP1A2 inhibitor in humans, resulted in a 33-fold increase in the tizanidine AUC (plasma drug concentration-time curve).{{cite web |title = Zanaflex (tizanidine hydrochloride) Capsules and Tablets for Oral Use. Full Prescribing Information |url = http://www.acorda.com/assets/docs/zanaflexpi-final-fda-approved-subm111813.pdf |publisher = Acorda Therapeutics Inc. Ardsley, NY 10502 |access-date = 1 September 2016 }} For this reason both fluvoxamine and tizanidine should not be taken at the same time. Fluoroquinolone antibiotics such as moxifloxacin, levofloxacin, and ciprofloxacin should also be avoided due to an increased serum concentration of tizanidine when administered concomitantly.{{cite web |url = https://www.drugs.com/tizanidine.html |title = Tizanidine Uses, Dosage, Side Effects – Drugs.com |website = drugs.com |access-date = 4 September 2017 }} Tizanidine has the potential to interact with other central nervous system depressants. Alcohol should be avoided, particularly as it can upset the stomach. The CNS-depressant effects of tizanidine and alcohol are additive. Caution with the following interactions:{{Cite web|url=http://www.wales.nhs.uk/sites3/Documents/814/TIZANIDINE-GwentGuidelines%5BJan08%5D.pdf|title=Tizanidine (Zanaflex) Gwent Primary Care Prescribing Guidance|last=NHS Wales|date=2011|publisher=Aneurin Bevan University Health Board}}{{Cite web|url=http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1496381982517.pdf|title=Tizanidine package leaflet: Information for the user|date=2016|publisher=Medicines and Healthcare products Regulatory Agency (UK)|access-date=16 September 2018|archive-date=16 September 2018|archive-url=https://web.archive.org/web/20180916202506/http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1496381982517.pdf|url-status=dead}}{{Cite web|url=http://www.pdr.net/drug-summary/Zanaflex-tizanidine-hydrochloride-811|title=Zanaflex (tizanidine hydrochloride) dose, indications, adverse effects, interactions... from PDR.net|website=www.pdr.net|language=en|access-date=16 September 2018}}
- antibiotics such as enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, or norfloxacin;
- blood pressure medications such as clonidine, guanabenz, guanfacine (Tenex), or methyldopa;
- heart rhythm medications such as amiodarone (Cordarone, Pacerone), mexiletine (Mexitil), propafenone (Rhythmol), and verapamil (Calan, Covera, Isoptin).
Pharmacology
Tizanidine is an α2 receptor agonist closely related to clonidine. It has approximately one-tenth to one-fifteenth of the blood pressure-lowering effect of clonidine. The relation between the α2 receptor agonism and the spasmolytic action is still not fully understood.{{Cite book|title=Basic & clinical pharmacology|isbn=9781259641152|edition=14th |location=New York|publisher=McGraw Hill Education|page=487|oclc=1015240036| vauthors = Katzung BG |date = 30 November 2017}}
| class="wikitable"
|+ !Site !Ki (nM) !Species !Ref |
| α2A
|62 |Human |
| α2B
|75 |OK |
| α2C
|76 |Rat |
=Route of administration=
Tizanidine is available as a tablet or capsule. Capsules may be opened and sprinkled on food. However, this may change the absorption of the medication compared to taking the capsule whole.{{cite web |title=Tizanidine: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a601121.html |website=medlineplus.gov |publisher=U.S. National Library of Medicine |access-date=29 October 2019 |language=en}} It has a volume of distribution of 2.4 L/kg following intravenous administration.
Chemistry
Tizanidine is a derivative of 2,1,3-benzothiadiazole and its first published synthesis was reported in a patent.{{cite patent |country=US |number=3843668 |status=patent |pubdate=1974-10-22 |fdate=1973-05-08 |pridate=1972-05-09 |invent1 = Neumann P |title=Certain 4-substituted amino-2,1,3-benzothiadiozoles |assign1=Sandoz AG }} The 5-chloro-2,1,3-benzothiadiazol-4-amine intermediate was a known compound, produced in three steps from 4-chlorophenylenediamine as shown.{{cite journal |doi=10.1007/BF00468340 |title=Research on 2,1,3-thia- and selenadiazole |year=1969 | vauthors = Pesin VG, Sergeev VA |journal=Chemistry of Heterocyclic Compounds |volume=3 |issue=5 |pages=662–666 |s2cid=98830770 }} Treatment with two equivalents of thionyl chloride in pyridine formed the heterocycle, which was nitrated with sodium nitrate in sulfuric acid and reduced using iron and acetic acid.
:File:Tizanidine synthesis US3843668.svg
The amine intermediate was treated with benzoyl chloride and ammonium thiocyanate followed by alkaline hydrolysis to form a thiourea. This was activated as its isothiuronium salt before being treated with ethylene diamine to give tizanidine.{{cite web |url=https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-20-0115 |title=Pharmaceutical Substances: Tizanidine |publisher=Thieme |access-date=16 February 2023 }}{{Dead link|date=February 2025 |bot=InternetArchiveBot |fix-attempted=yes }}
References
{{reflist}}
{{Muscle relaxants}}
{{Adrenergic receptor modulators}}
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Category:Alpha-2 adrenergic receptor agonists