Oxybutynin

Oxybutynin

Systematic (IUPAC) name
4-Diethylaminobut-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylethanoate
Clinical data
Trade names	Ditropan
AHFS/Drugs.com	monograph
MedlinePlus	a682141
Pregnancy cat.	B
Legal status	Rx Only (CA)[1], Rx Only (US)
Routes	oral, transdermal
Pharmacokinetic data
Protein binding	91%-93%
Half-life	12.4-13.2 hours
Identifiers
CAS number	5633-20-5 Y
ATC code	G04BD04
PubChem	CID 4634
IUPHAR ligand	359
DrugBank	APRD00427
ChemSpider	4473 Y
UNII	K9P6MC7092 Y
KEGG	D00465 Y
ChEBI	CHEBI:7856 N
ChEMBL	CHEMBL1231 Y
Chemical data
Formula	C22H31NO3
Mol. mass	357.486 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C22H31NO3/c1-3-23(4-2)17-11-12-18-26-21(24)22(25,19-13-7-5-8-14-19)20-15-9-6-10-16-20/h5,7-8,13-14,20,25H,3-4,6,9-10,15-18H2,1-2H3 Y Key:XIQVNETUBQGFHX-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Oxybutynin (Ditropan, Lyrinel XL) is an anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination (urge incontinence), by decreasing muscle spasms of the bladder.^[2] It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor. It also has direct spasmolytic effects on bladder smooth muscle as a calcium antagonist and local anesthetic, but at concentrations far above those used clinically. It is available orally in generic formulation and as the brand-names Ditropan and Lyrinel XL, as a transdermal patch under the brand name Oxytrol, and as a topical gel under the brand name Gelnique. Also Ditrospam by Avenzor Syria.

Oxybutynin is also a possible treatment of hyperhidrosis, or hyper-active sweating.^[3][4][5]

Chemistry

Oxybutynin contains one stereocenter. Commercial formulations are sold as the racemate. The (R)-enantiomer is a more potent anticholinergic than either the racemate or the (S)-enantiomer, which is essentially without anticholinergic activity at the doses used in clinical practice.^[6][7] However, (R)-oxybutynin administered alone offers little or no clinical benefit above and beyond the racemic mixture. The other actions (calcium antagonism, local anesthesia) of oxybutynin are not stereospecific. (S)-Oxybutynin has not been clinically tested for its spasmolytic effects, but may be clinically useful for the same indications as the racemate, without the unpleasant anticholinergic side effects.

Clinical efficacy

In two trials of patients with overactive bladder, transdermal oxybutynin 3.9mg/day decreased the number of incontinence episodes and increased average voided volume to a significantly greater extent than placebo. There was no difference in transdermal oxybutynin and extended-release oral tolterodine.^[8]

Adverse effects

Common adverse effects associated with oxybutynin and other anticholinergics include: dry mouth, difficulty in urination, constipation, blurred vision, drowsiness and dizziness.^[9] Anticholinergics have also been known to induce delirium.^[10] These are dose-related and sometimes severe; in one population studied, after six months more than half of the patients had stopped taking the medication due to side effects and calcium defects. An intake of calcium of 800 to 1000 mg is suggested.^{[citation needed]} Dry mouth may be particularly severe; one estimate is that over a quarter of patients who begin oxybutynin treatment may have to stop because of dry mouth.^{[citation needed]}

N-Desethyloxybutynin is an active metabolite of oxybutynin that is thought to be responsible for much of the adverse effects associated with the use of oxybutynin.^[11] N-Desethyloxybutynin plasma levels may reach as much as six times that of the parent drug after administration of the immediate-release oral formulation.^[12] Alternative dosage forms have been developed in an effort to reduce blood levels of N-desethyloxybutynin and allow for a more steady concentration of oxybutynin to be achieved than is possible with the immediate release form. The long-acting formulations also allow once-daily administration instead of the twice-daily dosage required with the immediate-release form. The transdermal patch, in addition to the benefits of the extended-release oral formulations, bypasses the first-pass hepatic effect that the oral formulations are subject to.^[13] In those with overflow incontinence due to diabetes or neurological diseases like multiple sclerosis or spinal cord trauma, oxybutin can worsen overflow incontinence since the fundamental problem is the bladder is not contracting.

Clinical pharmacology

Oxybutynin hydrochloride exerts direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. It exhibits one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).

Contraindications

Oxybutynin chloride is contraindicated in patients with untreated angle closure glaucoma and in patients with untreated narrow anterior chamber angles since anticholinergic drugs may aggravate these conditions. It is also contraindicated in partial or complete obstruction of the gastrointestinal tract, hiatal hernia, gastroesophageal reflux disease, paralytic ileus, intestinal atony of the elderly or debilitated patient, megacolon, toxic megacolon complicating ulcerative colitis, severe colitis and myasthenia gravis. It is contraindicated in patients with obstructive uropathy and in patients with unstable cardiovascular status in acute hemorrhage. Oxybutynin chloride is contraindicated in patients who have demonstrated hypersensitivity to the product.

References

1. ^ = eng&code = 67903 "Product Information". Drug Product Database. http://webprod3.hc-sc.gc.ca/dpd-bdpp/info.do?lang = eng&code = 67903. Retrieved 2011-08-13. 
2. ^ Chapple CR. "Muscarinic receptor antagonists in the treatment of overactive bladder". Urology (55)5, Supp. 1:33-46, 2000.
3. ^ Tupker RA, Harmsze AM, Deneer VH (2006). "Oxybutynin therapy for generalized hyperhidrosis.". Arch Dermatol 142 (8): 1065–6. doi:10.1001/archderm.142.8.1065. PMID 16924061. 
4. ^ Mijnhout GS, Kloosterman H, Simsek S, Strack van Schijndel RJ, Netelenbos JC. (2006). "Oxybutynin: dry days for patients with hyperhidrosis.". Neth J Med 64 (9): 326–8. PMID 17057269. 
5. ^ Schollhammer M, Misery L. (2007). "Treatment of hyperhidrosis with oxybutynin.". Arch Dermatol. 143 (4): 544–5. doi:10.1001/archderm.143.4.544. PMID 17438194. 
6. ^ Kachur JF, et al. "R and S enantiomers of oxybutynin: pharmacological effects in guinea pig bladder and intestine." Journal of Pharmacology and Experimental Therapeutics 247:867-72, 1988.
7. ^ Noronha-Blob L, Kachur JF. "Enantiomers of oxybutynin: in vitro pharmacological characterization at M₁, M₂ and M₃ muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs." Journal of Pharmacology and Experimental Therapeutics 256:562-7, 1991.
8. ^ Baldwin C, Keating GM.[1].Drugs 2009;69 (3):327-337.doi: 10.2165/00003495-200969030-00008.
9. ^ Mehta D (Ed.) 2006. British National Formulary 51. Pharmaceutical Press. ISBN 0-85369-668-3
10. ^ Andreasen NC and Black DW, "Introductory Textbook of Psychiatry." American Psychiatric Publishing Inc. 2006
11. ^ Allen B. Reitz, Suneel K. Gupta, Yifang Huang, Michael H. Parker, and Richard R. Ryan (2007). "The preparation and human muscarinic receptor profiling of oxybutynin and N-desethyloxybutynin enantiomers". Med Chem 3 (6): 543–5. doi:10.2174/157340607782360353. PMID 18045203. 
12. ^ Zobrist RH, et al. "Pharmacokinetics of the R- and S-Enantiomers of Oxybutynin and N-Desethyloxybutynin Following Oral and Transdermal Administration of the Racemate in Healthy Volunteers". Pharmaceutical Research 18:1029-1034, 2001.
13. ^ Oki T, et al. "Advantages for Transdermal over Oral Oxybutynin to Treat Overactive Bladder: Muscarinic Receptor Binding, Plasma Drug Concentration, and Salivary Secretion". Journal of Pharmacology and Experimental Therapeutics Fast Forward 316:1137-1145, 2006.

External links

• http://health.yahoo.com/urinary-medications/oxybutynin-oral/healthwise--d00328a1.html
• http://www.mayoclinic.com/health/drug-information/DR601047
• http://www.medicinenet.com/oxybutynin_er-oral/article.htm