Analysis of Ditropan XL

3PM3: Pharmacology

 Ditropan XL also known as Oxybutynin chloride, is an antimuscarinic drug that consists of various formulations to treat specific conditions. In addition to being an antimuscarinic drug, it is also an anticholinergic drug and produces direct muscle relaxant effects. (Abrams, Andersson, Buccafusco, Chapple, Groat, & Fryer, et al., 2006) The drug first became available in the United Kingdom in 1980 where it was an extremely effective treatment for overactive bladder (OAB). (Pharmaceutical Journal, 2011) Ditropan XL however was not approved until 1999 in America. (Arisco, 2009)

 At first the drug was only prescribed to patients specifically however after completing clinical trials of various users viewing side effects, new formulas were considered. In 1998, researchers looked at producing an immediate release (IR) formula as well as an extended release (ER) formula, where they saw an improvement with dry mouth symptoms with the Oxybutynin ER. (Arisco, 2009) The two formulas were also compared in urgency where it was seen that the extended release formula of Oxybutynin was more effective while still reducing incontinence episodes. (Pharmaceutical Journal, 2011) In 1999, a Ditropan XL Study Group was completed where it was found that the new formula was effective and reduced side effects such as dry mouth. (Gleason, 1999)

 Oxybutynin is a tertiary amine, (refer to Figure 1.1) which skips the first step of metabolism by completing the first pass effect. By doing this, it can convert to its primary active metabolite which is N-desthyloxybutynin. (Chapple, Yamanishi & Chess-Williams, 2002) This process allows for the drug to be more effective as the active metabolite contains the same antimuscarinic and anaesthetic effects as Oxybutynin. The active metabolite is very similar to the parent compound however it tends to be more effective as a drug and produces greater antimuscarinic effects. For this reason, there are more side and adverse effects associated with Oxybutynin due to the predominant nature of its active metabolite. Various other methods of administration have been explored to reduce side and adverse effects such as intravesical, rectal, vaginal and patches. These routes are expected to do so by reducing the peak levels of Oxybutynin as well as the concentration of N-desthyloxybutynin which is found in the plasma. (Chapple, Yamanishi & Chess-Williams, 2002) Oxybutynin is very widely used for OAB as well as many other conditions due to its ability to effectively treat many bladder conditions. (Pharmaceutical Journal, 2011)

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 Chemically related compounds include Tolterodine which is also an antimuscarinic agent which is used for the treatment of overactive bladder. Similar to Oxybutynin, it can be both administered as immediate-release and as extended-release formulas. There exists a lot of similarities between the two drugs however it was found that Oxybutynin proved to be more effective, but Tolterodine was better tolerated in the body and produces less side effects. (Harvey, 2001) It produces less side effects due to its slightly different mechanism of action as it acts on M2 and M3 muscarinic receptors, where as Oxybutynin acts on M1 and M3. (Drug Bank, 2018) The main side effect of Oxybutynin which is dry mouth is caused by the action of the M3 receptors which are found in the mouth. (Nasir & Schonwald, 2009)

 The primary use of Ditropan XL is for the treatment of overactive bladder, but it can also be used in the treatment of other bladder related complications. Overactive bladder occurs due to the contraction of muscles of the bladder at a low urine volume as though an individual has high urine volume.  As seen in Figure 1.2, when the sympathetic nervous system is inactivated the detrusor muscle, sphincter closure and bladder filling all become relaxed. (Schroeer, 2012) As the volume in the bladder reaches around 200mL (where the average maximum volume is around 400mL) the voiding sensation is passed through the spinal cord to the brain centres. Where voiding refers to the poor coordination between the muscles of the bladder and the urethra. When this process is controlled, the parasympathetic nervous system and the voluntary somatic nervous system are both stimulated which causes contractions of muscles. (George & DeMaagd, 2012) The muscles contracted include the detrusor muscle which leads to sphincter relaxation. (George & DeMaagd, 2012) The effective use of Oxybutynin is due to its ability to decrease the urgency and frequency of urination in individuals. Not only is it effective in doing this but it can increase bladder volume which alleviates some of the pressure exerted on the detrusor. (Yarker, Goa & Fitton, 1995)

 Ditropan XL is typically used for the treatment of bladder conditions such as these due to it’s antimuscarinic effects and their influence on muscarinic receptors. Oxybutynin is an anticholinergic agent and it contains antispasmodic properties which make it effective in the treatment of idiopathic detrusor instability or detrusor hyperlexia as well. (Yarker, Goa & Fitton, 1995) These conditions are both very similar to an overactive bladder, as they involve urge incontinence which refers to the immediate need to urinate.  (Yarker, Goa & Fitton, 1995) Ditropan XL can be used as an anticholinergic and antimuscarinic drug for various other conditions, however the drug is most effective in the treatment of bladder related issues.

 Although Ditropan XL is a very effective drug in the treatment of overactive bladder, there have been many documented side and adverse effects. Certain adverse effects associated with this drug include dry mouth, constipation and blurred vision. The main effect being dry mouth due to the blocking of the M3 receptor which is found in the mouth. (Nasir & Schonwald, 2009) All these effects are due to the drug being of the anticholinergic nature and other side effects include urinary retention due to the muscarinic receptors blocked by this drug. Individuals who are sensitive to anticholinergic drugs are not recommended as this drug may prove to show no therapeutic effects. (Yarker, Goa & Fitton, 1995) There are a few psychological effects associated with this drug due to its ability to easily cross the blood-brain barrier by the presence of the HCl group in its structure (refer to Figure 1.1). It produces effects such as sedation, insomnia, confusion and cognitive issues due to the blocking of the M1 receptor. (Nasir & Schonwald, 2009)

 Antimuscarinic agents such as Ditropan XL are effective as they block specifically the muscarinic receptors that are found on detrusor smooth muscle cells. Detrusor muscles cells are contracted upon acetylcholine acting on muscarinic receptors which stimulates the parasympathetic nervous system. (Abrams et al., 2006) The receptors primarily responsible for detrusor contractions are Muscarinic M3 receptors which are blocked by Ditropan XL. (Abrams et al., 2006)

  Oxybutynin is a muscarinic receptor agonist that also has a secondary mechanism of action and especially high affinity for M1 and M3 muscarinic receptors. (Chapple, Yamanishi & Chess-Williams, 2002) The main effects of Oxybutynin are due to the antimuscarinic properties; however, it produces local anesthetic effects by blocking the calcium channel and affects smooth bladder muscles allowing for an increased urinary bladder capacity. (Hesch, 2007) The active metabolite N-desethyl-oxybutynin also has a high affinity in the bladder, aiding in treatment of bladder conditions. (Chapple, Yamanishi & Chess-Williams, 2002)

 Ditropan is absorbed in the gastrointestinal tract upon administration and then it is metabolized by the cytochrome P450 enzymes, specifically in the liver and gut by CYP3A4 isoenzyme. (DrugBank, 2018) 0.1% of the Ditropan dose is then excreted via urine as well as 0.1% of the active metabolite N-desethyloxybutynin where it is expected to clear the system at a rate of 26L per hour. (DrugBank, 2018)

 As Oxybutynin is metabolized by CYP3A4 isoenzyme, immediately any drugs which are CYP3A4 inhibitors should be avoided. (Hesch, 2007) The administration of Oxybutynin with a CYP3A4 inhibitor such as itraconazole, would increase the plasma concentration of Oxybutynin during distribution. (Rebecca & McCrery, 2006) When consuming Oxybutynin orally, there may be drug interactions with bisphosphonates. This may cause issues in the esophagus as this drug also is active in that region. (Hesch, 2007) In addition to this, alcohol and other sedatives are not recommended during the administration of Oxybutynin as they may enhance side effects such as drowsiness and dizziness sourced from the brain. This is due to the nature of the interaction of anticholinergics and antimuscarinics with sedatives producing more severe side effects.

 Oxybutynin is to be avoided if an individual experiences infectious diarrhea due to the antispasmodic effects the drug exists. The main effect Oxybutynin produces is the inhibition of gastrointestinal activity and motility which impacts the microorganisms naturally existing there. Those with infectious diarrhea contain enterotoxin-producing bacteria which may interact with the administration of Oxybutynin. (Drugs, 2018) Other systems Oxybutynin may affect include autonomic neuropathic conditions such as tachycardia and anhidrosis. (Drugs, 2018) This is due to the antimuscarinic effects the drug produces by acting on the M1 and M3 receptors.

 There are not many complementary drugs that exist that would aid in the treatment of overactive bladder and bladder related malfunctions alongside Oxybutynin. There have been studies that looked at herbal remedies (primarily composed of Chinese herbal medicines) instead of the administration of Oxybutynin however none were found to be as effective. (Bilal, 2013) This is due to the both anticholinergic and antimuscarinic effects produced by Oxybutynin which are difficult to mimic. However, the pairing of herbal remedies with lower doses of Oxybutynin may prove to be effective as they both contain antispasmodic effects on the body, treating bladder conditions.

References

         Abrams, P., Andersson, K., Buccafusco, J., Chapple, C., Groat, W., & Fryer, A. et al. (2006). Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. British Journal Of Pharmacology, 148(5), 565-578. doi:10.1038/sj.bjp.0706780

         AM Arisco, S. (2009). Oxybutynin extended release for the management of overactive bladder: a clinical review. Drug Design, Development And Therapy, 3, 151. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles

         Bilal Chughtai, F. (2013). Use of Herbal Supplements for Overactive Bladder. Reviews In Urology, 15(3), 93. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles

         Chapple, C., Yamanishi, T., & Chess-Williams, R. (2002). Muscarinic receptor subtypes and management of the overactive bladder. Urology, 60(5), 82-88. doi:10.1016/s0090-4295(02)01803-4

         George A. DeMaagd, T. (2012). Management of Urinary Incontinence. Pharmacy And Therapeutics, 37(6), 345. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles

         Gleason DM, e. (1999). Evaluation of a new once-daily formulation of oxybutynin for the treatment of urinary urge incontinence. Ditropan XL Study Group. – PubMed – NCBI . Ncbi.nlm.nih.gov. Retrieved 25 November 2018, from https://www.ncbi.nlm.nih.gov/pubmed/

         Harvey MA, e. (2001). Tolterodine versus oxybutynin in the treatment of urge urinary incontinence: a meta-analysis. – PubMed – NCBI . Ncbi.nlm.nih.gov. Retrieved 26 November 2018, from https://www.ncbi.nlm.nih.gov/pubmed/1

         Hesch, K. (2007). Agents for treatment of overactive bladder: a therapeutic class review. Proceedings (Baylor University. Medical Center), 20(3), 307. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/

         Oxybutynin – DrugBank. (2018). Drugbank.ca. Retrieved 26 November 2018, from https://www.drugbank.ca/drugs/DB01062

         Oxybutynin Disease Interactions – Drugs.com. (2018). Drugs.com. Retrieved 27 November 2018, from https://www.drugs.com/disease-interactions/oxybutynin.html#Infectious_D

         Namzi Nasir, Alison Schonwald (2009). Urinary Fuctions and Enuresis  | ScienceDirect Topics. (2017). Sciencedirect.com. Retrieved 26 November 2018, from https://www.sciencedirect.com/topics/medicine-and-dentistry/oxybutynin

         Rebecca J McCrery, R. (2006). Oxybutynin: an overview of the available formulations. Therapeutics And Clinical Risk Management, 2(1), 19. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PM

         Tolterodine – DrugBank. (2018). Drugbank.ca. Retrieved 26 November 2018, from https://www.drugbank.ca/drugs/DB01036 (Drug Bank, 2018)

         Yarker, Y., Goa, K., & Fitton, A. (1995). Oxybutynin. Drugs & Aging, 6(3), 243-262. doi:10.2165/00002512-199506030-00007

Appendix

Figure 1.1: Chemical Structure of Oxybutynin Chloride

        (New Drug Info, 2018)

Figure 1.2: Anatomy and Physiology of the Human Bladder 

         (Schroeer, 2012)