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 Parkinson's Disease 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 KC, Ho SL. Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Translational neurodegeneration 2013 Dec;2(1):19.
  2. Fabbrini G, Abbruzzese G, Marconi S, Zappia M. Selegiline: a reappraisal of its role in Parkinson disease. Clinical neuropharmacology 2012 May 1;35(3):134-40.
  3. Magyar K. The pharmacology of selegiline. In: International review of neurobiology. Academic Press, 2011 (Vol. 100, pp. 65-84).
  4. Aluf Y, Vaya J, Khatib S, Loboda Y, Finberg JP. Selective inhibition of monoamine oxidase A or B reduces striatal oxidative stress in rats with partial depletion of the nigro-striatal dopaminergic pathway. Neuropharmacology 2013;65:48-57.
  5. Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Progress in neurobiology 2010;92(3):330-44.  
  6. 6.0 6.1 Heinonen EH, Myllylä V, Sotaniemi K, Lamintausta R, Salonen JS, Anttila M, Savijärvi M, Kotila M, Rinne UK. Pharmacokinetics and metabolism of selegiline. Acta neurologica Scandinavica. Supplementum 1989;126:93-9.
  7. Mahmood I. Clinical pharmacokinetics and pharmacodynamics of selegiline. Clinical pharmacokinetics 1997;33(2):91-102.
  8. 8.0 8.1 UCSF School of Medicine. Parkinson's Disease Clinic and Research Center. Available from: http://pdcenter.neurology.ucsf.edu/patients-guide/parkinson’s-disease-medications/monoamine-oxidase-b-mao-b-inhibitors (accessed 5 November 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. Therapeutics and clinical risk management 2007;3(3):467.
  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? The Journal of Clinical Pharmacology 2012 May;52(5):620-8.