Selegiline


Article Author:
Jacob Moore


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
Rhonda Coffman
Lindsay Iverson
Heather Templin


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
1/29/2019 7:46:31 AM

Indications

Selegiline, a monoamine oxidase (MAO) inhibitor, is FDA-approved as an adjunct treatment in the management of patients with Parkinson disease and as a treatment for a major depressive disorder (MDD) in adults. Selegiline is also used off-label for early Parkinson disease,[1] and the treatment of attention-deficit/hyperactivity disorder (ADHD).[2]

Mechanism of Action

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), an enzyme that catabolizes norepinephrine, serotonin, and dopamine. Blockage of this enzyme prevents reuptake of these neurotransmitters in the CNS, conferring increased levels of the biologically active monoamines at the synaptic cleft. With lower doses, selegiline exhibits selective B-type monoamine oxidase (MAO-B) inhibition. Loss of dopamine-containing neurons in the substantia nigra of the midbrain and resultant depletion of dopamine in the striatum is the cause of Parkinson disease. Therefore, the selective inhibition of MAO-B is desired for the treatment of Parkinson disease because MAO-B primarily metabolizes dopamine.[3] In contrast, selective inhibition of MAO-B is not the desired outcome when using selegiline to treat MDD. In fact, inhibition of both MAO-A and MAO-B is implicated as selegiline's effective mechanism of action when utilized as a treatment for MDD. The monoamine hypothesis of depression predicts the underlying pathophysiologic basis of depression as a depletion in the levels of serotonin, norepinephrine, and dopamine in the central nervous system.[4] Because increasing the levels of all three of these monoamines is often the targeted outcome for treating MDD, nonselective inhibition of both MAO subtypes is preferred.

As with most psychotropic medications, the mechanism of action of selegiline is not fully understood. Although the above-proposed mechanisms are widely accepted, other proposed mechanisms may contribute to selegiline's clinical efficacy. It is hypothesized that selegiline's metabolites, which include amphetamine, may play a role in its mechanism of action by augmenting the release of monoamine neurotransmitters.[5] Additionally, selegiline is speculated to have neuroprotective effects that prevent progression in Parkinson disease through increases in production of neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) that protect neurons from the inflammatory process. This induction and activation of multiple factors for anti-oxidative stress and anti-apoptosis may preserve healthy brain tissue.[6]

Administration

Selegiline is administered via two different routes and in three different forms. The oral route, in either capsule or oral disintegrating tablet (ODT) form, produces the low plasma concentration levels which bestow the selective inhibition of MAO-B that is desired for the treatment of Parkinson disease. The other route of administration of selegiline is transdermal, in which a patch is applied to the patient's skin to facilitate absorption of the medication directly into the blood, bypassing first pass metabolism. The transdermal route achieves greater plasma concentration levels than the oral route; the elevated levels of selegiline produce the anti-depressive effect, nonselective MAO inhibition, desired for treatment of MDD.

Adverse Effects

Selegiline may cause a hypertensive crisis, a severe elevation of blood pressure, when the medication is concurrently consumed with food, drink, or supplements that are rich in tyramine. Other dangerous adverse effects include sudden sleep episodes, orthostatic hypotension, arrhythmias, mental status alteration, hallucinations, extrapyramidal symptoms, dyskinesia, and serotonin syndrome. Common adverse effects of selegiline are predominantly due to the drug's anticholinergic effects, xerostomia, and constipation. The most commonly reported are headache, dizziness, insomnia, and nausea. Abrupt cessation of selegiline is advised against because of the risk of antidepressant and antiparkinsonian discontinuation syndromes.[7]

Adverse effects specific to the form of administration exist. For the transdermal route, a black box warning for the antidepressant use of selegiline cautions the use of antidepressants in pediatric and young adult populations due to an increase in the risk of suicidal thoughts and behaviors. Selegiline is not FDA-approved for bipolar depression as it may precipitate a manic episode. Transdermal use commonly causes skin irritation at the site of application. The ODT form can cause buccal mucosa irritation.[7]

Contraindications

Use of selegiline within 10 days before elective surgery is contraindicated due to adverse effects on blood pressure. Transdermal selegiline is contraindicated for use in children younger than 12 years and in patients of any age who have pheochromocytoma. Transdermal selegiline should be discontinued for at least 2 weeks before starting any of the following medications: carbamazepine, serotonin reuptake inhibitors, clomipramine, imipramine, tramadol, propoxyphene, methadone, pentazocine, and dextromethorphan. Conversely, transdermal selegiline should not be started within five half-lives of the previously listed medications. Oral selegiline should not be concomitantly used with cyclobenzaprine, dextromethorphan, St John's wort, methadone, propoxyphene, tramadol and other MAO inhibitors. Selegiline, in any form, should not be used if previous hypersensitivity to selegiline has been identified, and all forms are contraindicated with concomitant use of the medication, meperidine.[8]

Selegiline is metabolized by many subunits of the cytochrome P450 system. The 2B6 subunit plays the major role in metabolism, so interactions and impairments with this enzyme should be noted. Patients with hepatic impairment may need adjustment of selegiline dosage, and selegiline ODT is not recommended for patients with severe hepatic impairment. Likewise, selegiline ODT should be avoided in patients with creatinine clearance less than 30 mL/min.

Monitoring

Patients taking selegiline should be educated about the risks that the medication carries and for specific symptoms that they can self-monitor. Prescribers do not have the luxury of continuous monitoring; therefore, patient awareness is a key aspect of medication safety. Blood pressure should be monitored in patients taking selegiline to decrease falls that are associated with orthostatic hypotension and to prevent hypertensive crisis and long-term effects of elevated blood pressure. Patients require monitoring for symptoms of Parkinsonism and serotonin syndrome. Behavior, mood, and suicidality should be assessed in patients taking selegiline to prevent psychiatric disturbances and death. Periodic skin examinations are warranted, especially in patients using the transdermal form of selegiline. The importance of close monitoring is heightened when the medication is initiated or when the dosage is adjusted.

Toxicity

A hypertensive crisis caused by selegiline is due to toxic levels of adrenergic metabolites. Recommended treatment includes intravenous phentolamine, labetalol, or nitroprusside to decrease noxious blood pressure levels rapidly. Signs of end-organ damage should be assessed and treated accordingly.[9]

Enhancing Healthcare Team Outcomes

While selegiline is usually prescribed by the neurologist, the patient is often followed by the primary care provider or nurse practitioner. Patients taking selegiline should be educated about the risks that the medication carries and for specific symptoms that they can self-monitor.  Blood pressure should be monitored in patients taking selegiline to decrease falls that are associated with orthostatic hypotension and to prevent hypertensive crisis and long-term effects of elevated blood pressure. Patients require monitoring for symptoms of Parkinsonism and serotonin syndrome. Behavior, mood, and suicidality should be assessed in patients taking selegiline to prevent psychiatric disturbances and death. Periodic skin examinations are warranted, especially in patients using the transdermal form of selegiline. The importance of close monitoring is heightened when the medication is initiated or when the dosage is adjusted.


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Selegiline - Questions

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Which is true of selegiline when used in the treatment of Parkinson disease?



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Selegiline is used in the treatment of Parkinson disease. What is its mechanism of action?



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Which monoamine oxidase inhibitor is widely used to treat Parkinson disease?



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Which is correct about the use of selegiline in the treatment of Parkinson disease?



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Which is false about the treatment of Parkinson disease?



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Which one of the following medications work by selectively inhibiting MAO-B enzyme?



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Which of the following anti Parkinsonian medications works by inhibiting the enzyme monoamine oxidase B (MAO-B)?



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Parkinson disease can be treated with which of the following monoamine oxidase inhibitors?



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Which of the following is false regarding selegiline?



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A patient presents with moderate signs and symptoms of Parkinson disease that are progressively getting worse. Current therapy is carbidopa/levodopa alone. The patient is advised to continue current therapy and start a new medication that requires adherence to dietary restrictions of foods containing high levels of tyramine, which includes aged cheeses and smoked meats. Which of the following medications is the patient being advised to start?



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Aged cheese and aged, smoked, or fermented meats should be avoided in patients taking which of the following drugs?



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A 45-year-old female presents to the emergency department in acute distress. She complains of confusion, blurry vision, and headache. She has a past medical history of treatment-resistant major depressive disorder and allergic rhinitis. The first day of her last menstrual period was approximately 12 weeks ago, and she is a G2P2, both children delivered by Cesarean section. She denies abdominal pain and shortness of breath. She reports irregular periods for the past few years, is sexually active with her husband of 20 years, and she celebrated her wedding anniversary last night by going wine tasting. Her current medications are loratadine and a new anti-depressant but she cannot recall the name. She does state that it is a transdermal patch that she applies once per day. Vitals reveal a blood pressure of 204/118 mmHg; all other vitals are within normal limits. Pregnancy test is negative, and EKG is within normal limits. Additional labs are pending. What is the most likely cause of her current symptoms?



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A 68-year-old male with past medical history of Parkinson disease presents to the emergency department in a stuporous state. His Parkinson disease has been well managed on carbidopa-levodopa and selegiline. Workup reveals severe hypertension and subarachnoid hemorrhage. The patient eventually dies. His caregiver later reports that he was not following his dietary restrictions that were encouraged by his neurologist following the start of selegiline. Death was attributed to hypertensive crisis. What is the role of the structure that is inhibited by selegiline?



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Selegiline - References

References

Abrams JH,Schulman P,White WB, Successful treatment of a monoamine oxidase inhibitor-tyramine hypertensive emergency with intravenous labetalol. The New England journal of medicine. 1985 Jul 4     [PubMed]
Aboukarr A,Giudice M, Interaction between Monoamine Oxidase B Inhibitors and Selective Serotonin Reuptake Inhibitors. The Canadian journal of hospital pharmacy. 2018 May-Jun     [PubMed]
Mazumder MK,Paul R,Phukan BC,Dutta A,Chakrabarty J,Bhattacharya P,Borah A, Garcinol, an effective monoamine oxidase-B inhibitor for the treatment of Parkinson's disease. Medical hypotheses. 2018 Aug     [PubMed]
Delgado PL, Depression: the case for a monoamine deficiency. The Journal of clinical psychiatry. 2000     [PubMed]
Nagatsu T,Sawada M, Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson's disease: possible implications of glial cells. Journal of neural transmission. Supplementum. 2006     [PubMed]
Akhondzadeh S,Tavakolian R,Davari-Ashtiani R,Arabgol F,Amini H, Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial. Progress in neuro-psychopharmacology     [PubMed]
Mizuno Y,Hattori N,Kondo T,Nomoto M,Origasa H,Takahashi R,Yamamoto M,Yanagisawa N, A Randomized Double-Blind Placebo-Controlled Phase III Trial of Selegiline Monotherapy for Early Parkinson Disease. Clinical neuropharmacology. 2017 Sep/Oct     [PubMed]
Bundgaard C,Montezinho LP,Anderson N,Thomsen C,Mørk A, Selegiline induces a wake promoting effect in rats which is related to formation of its active metabolites. Pharmacology, biochemistry, and behavior. 2016 Nov - Dec     [PubMed]
Shulman KI,Herrmann N,Walker SE, Current place of monoamine oxidase inhibitors in the treatment of depression. CNS drugs. 2013 Oct     [PubMed]

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