MAO-B inhibitors in the treatment of Parkinson's Disease

Monoamine Oxidase B Inhibitors, such as Selegiline and Rasagiline, are commonly used by patients with PD because of their potential disease modifying and neuroprotective effects [1]. This drug class is considered a potential disease modifier due to its ability to inhibit the monoamine oxidase type B (MAO-B) enzyme, which naturally breaks down dopamine in the brain[1].By inhibiting the breakdown of the MAO-B enzyme, these drugs are able to extend the effects of dopamine at the CNS synapse [2][3]). However, more research needs to be done on the ability of MAO-B inhibitors to slow the progression of PD. MAO-B inhibitors exhibit neuroprotection by decreasing dopamine oxidation, therefore preventing excessive production of free radicals, while prolonging the effects of endogenous dopamine [4][5]). MAO-B inhibitors can be used as an initial drug in the treatment of Parkinson’s Disease or can be combined with Levodopa in order to reduce motor fluctuations[1].

The prototypical selective, irreversible MAO-B inhibitor, Selegiline, is absorbed in the GI tract and then distributed to tissues throughout the body, including the brain[6]. Selegiline is metabolized to L-amphetamine-like metabolites which may promote insomnia [1]. This drug is primarily metabolized in the liver and then excreted by the kidneys [6]. Selegiline has an oral bioavailability of 10% and an oral clearance rate of 59 L/min [7].  This drug is given at a therapeutic dose of 10mg/day and has a half-life of 10 hours[1]. Selegiline is typically administered twice per day as a 5mg oral tablet [8]. If this dose is increased Selegiline will lose it’s selective ability[1].

Rasagiline, another selective, irreversible MAO-B inhibitor, is metabolized into aminoindan in the liver by cytochrome p450 type 1A2, which means it does not have the amphetamine-like effects that Selegiline displays and may be preferred [9]. Its oral bioavailability is 35% and it reaches its therapeutic maximum after 0.5-1 hour [9]. The oral clearance rate of Rasagiline is 94.3 L/day[9]. This drug is given at a recommended dose of 0.5-1 mg/day and has a half-life or 1.5-3.5 hours [9]. It is typically administered once per day as a 0.5mg or 1mg oral tablet [8].

When used in adjunct with Levodopa both Selegiline and Rasagiline have been known to decrease motor fluctuations in patients with PD [1]. These two drugs are relatively safe compared to other MAO inhibitors due to their selective ability [10]. Common adverse effects of other MAO-B Inhibitors may include dizziness, headache, GI distress, and sedation [10].    

References:

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Teo, K. C., & Ho, S. Monoamine Oxidase-B (MAO-B) Inhibitors: Implications for Disease-modification in Parkinson’s Disease. NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847108/. September 8, 2013. Accessed November 5, 2018.
  2. Fabbrini G, Abbruzzese G, Marconi S, Zappia M. Selegiline: a reappraisal of its role in Parkinson disease. NCBI. https://www.ncbi.nlm.nih.gov/pubmed/22592509. 2012. Accessed November 5, 2018.
  3. Magyar K. The pharmacology of selegiline. NCBI.  https://www.ncbi.nlm.nih.gov/pubmed/21971003. 2011. Accessed November 5, 2018.
  4. Aluf Y, Vaya J, Khatib S, et al. (2013). Selective inhibition of monoamine oxidase A or B reduces striatal oxidative stress in rats with partial depletion of the nigro-striatal dopaminergic pathway. NCIB. https://www.ncbi.nlm.nih.gov/pubmed/22982254. February 2013. Accessed November 5, 2018.
  5. Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. NCBI. https://www.ncbi.nlm.nih.gov/pubmed/20600573. November, 2010. Accessed November 5, 2018.  
  6. 6.0 6.1 H., K, S., S, S. J., A., S., K., & K, R. U. Pharmacokinetics and metabolism of selegiline. Wiley Online Library. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0404.1989.tb01788.x. January 29, 2009. Accessed November 5, 2018.
  7. Mahmood, I.Clinical pharmacokinetics and pharmacodynamics of selegiline. An update. NCBI. https://www.ncbi.nlm.nih.gov/pubmed/9260033. August, 1997. Accessed November 5, 2018.
  8. 8.0 8.1 Parkinson's Disease Clinic and Research Center. UCSF School of Medicine. http://pdcenter.neurology.ucsf.edu/patients-guide/parkinson’s-disease-medications/monoamine-oxidase-b-mao-b-inhibitors. 2010. Accessed November 5, 2018.
  9. 9.0 9.1 9.2 9.3 Lecht, S., Haroutiunian, S., Hoffman, A., & Lazarovici, P. Rasagiline – A Novel MAO B Inhibitor in Parkinson’s Disease Therapy. NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386362/. June, 2007. Accessed November 5, 2018.
  10. 10.0 10.1 Chen JJ, Wilkinson JR. The monoamine oxidase type B inhibitor rasagiline in the treatment of Parkinson disease: is tyramine a challenge? PubMed. https://www.ncbi.nlm.nih.gov/pubmed/21628600. May, 2012. Accessed November 5, 2018.