Oxybutynin

Oxybutynin
Clinical data
Trade names Ditropan
AHFS/Drugs.com Monograph
MedlinePlus a682141
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration		 By mouth, transdermal gel, transdermal patch
ATC code G04BD04 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: Rx-only/OTC
Pharmacokinetic data
Protein binding 91–93%
Biological half-life 12.4–13.2 hours
Identifiers
CAS Number 5633-20-5 YesY
PubChem (CID) 4634
IUPHAR/BPS 359
DrugBank DB01062 YesY
ChemSpider 4473 YesY
UNII K9P6MC7092 YesY
KEGG D00465 YesY
ChEBI CHEBI:7856 YesY
ChEMBL CHEMBL1231 YesY
ECHA InfoCard 100.158.590
Chemical and physical data
Formula C22H31NO3
Molar mass 357.486 g/mol
3D model (Jmol) Interactive image
  (verify)

Oxybutynin (brand names Ditropan, Lyrinel XL, Lenditro (South Africa), Uripan (Middle East)[1]) 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] Also given to help with symptoms associated with kidney stones.

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.

Oxybutynin is also a possible treatment of hyperhidrosis (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 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 3.9 mg/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 because of side effects and calcium defects. An intake of calcium of 800 to 1000 mg is suggested. 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.

N-Desethyloxybutynin is an active metabolite of oxybutynin that is thought 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 achieve a steadier concentration of oxybutynin 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 because of diabetes or neurological diseases like multiple sclerosis or spinal cord trauma, oxybutynin can worsen overflow incontinence since the fundamental problem is that the bladder is not contracting.

A large study linked the development of Alzheimer's disease and other forms of dementia in those over 65 to the use of oxybutynin, due to its anticholinergic properties.[14]

Clinical pharmacology

Oxybutynin chloride 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).

Sources say the drug is absorbed within one hour and has an elimination half-life of 2 to 5 hours.[15][16][17] There is a wide variation among individuals in the drug's concentration in blood. This, and its low concentration in urine, suggest that it is eliminated through the liver.[16]

Contraindications

Oxybutynin chloride is contraindicated in patients with untreated narrow angle 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.

Formulations

It is available orally in generic formulation or as the brand-names Ditropan, Lyrinel XL, or Ditrospam, as a transdermal patch under the brand name Oxytrol, and as a topical gel under the brand name Gelnique.

A 2009 Weill Cornell Medical College study concluded that patients switched to generic oxybutynin experienced a degradation in therapeutic value: "In women, there was a doubling of daytime frequency of urination, a slight 20% increase in nocturia, and a 46.3% increase in urge incontinence. In men, there was a 2.4-fold increase in daytime frequency, a 40% increase in nocturia, and a 40.6% increase in urge incontinence".[18]

References

  1. ↑ "Uripan Tablets". Adwia Pharmaceuticals. Retrieved 22 November 2015.
  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. (1988). "R and S enantiomers of oxybutynin: pharmacological effects in guinea pig bladder and intestine". Journal of Pharmacology and Experimental Therapeutics. 247: 867–72.
  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 1991; 256:562-7.
  8. ↑ Baldwin C, Keating GM." 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 & 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. (2001). "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.
  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.
  14. ↑ Gray, Shelly L.; Anderson, Melissa L. (January 26, 2015). "Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study". JAMA Intern. Med. 175: 401–7. doi:10.1001/jamainternmed.2014.7663. PMC 4358759Freely accessible. PMID 25621434. Retrieved January 27, 2015.
  15. ↑ "Oxybutynin" Retrieved on 30 August 2012.
  16. 1 2 "The pharmacokinetics of oxybutynin in man. (Abstract)" Retrieved on 30 August 2012.
  17. ↑ "Oxybutynin" Retrieved on 30 August 2012.
  18. ↑ Kerr, Martha (2009-05-03). "AUA 2009: Generics Not Equal to Brand-Name Drugs for Overactive Bladder". American Urological Association (AUA) 104th Annual Scientific Meeting. Medscape. Retrieved 2013-04-20.
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