Pharmacology of Selegiline

1. Introduction/Overview

Selegiline, also known internationally as L-deprenyl, represents a cornerstone agent in the therapeutic management of neurodegenerative and neuropsychiatric disorders. As a selective and irreversible inhibitor of monoamine oxidase B (MAO-B), its introduction marked a significant advancement in the symptomatic treatment of Parkinson’s disease. The drug’s unique pharmacological profile, which extends beyond simple enzyme inhibition to include putative neuroprotective effects, has sustained clinical and research interest for decades. Its development was rooted in the understanding of monoamine neurotransmitter metabolism and the role of oxidative deamination in both disease pathophysiology and the metabolism of exogenous amines.

The clinical relevance of selegiline is multifaceted. Primarily, it is employed as an adjunctive therapy in Parkinson’s disease, where it may enhance and prolong the response to levodopa while potentially modifying disease progression. Furthermore, the transdermal formulation of selegiline has secured approval for the treatment of major depressive disorder, exploiting a different dosing paradigm to achieve broader monoamine oxidase inhibition. This dual utility across neurological and psychiatric domains underscores its importance in the medical pharmacopeia. The drug also serves as a prototypical example of how pharmacokinetic manipulation, such as route of administration, can fundamentally alter pharmacodynamic outcomes and therapeutic indications.

The learning objectives for this chapter are:

• To delineate the molecular mechanism of action of selegiline, focusing on its irreversible inhibition of monoamine oxidase B and the subsequent effects on dopaminergic neurotransmission.
• To analyze the pharmacokinetic properties of selegiline, including the significant differences between oral and transdermal administration and their clinical implications.
• To evaluate the approved therapeutic applications of selegiline in Parkinson’s disease and major depressive disorder, including its role as monotherapy and adjunctive treatment.
• To identify the major adverse effect profile and serious drug interactions associated with selegiline, with particular emphasis on the risk of serotonin syndrome and hypertensive crisis.
• To apply knowledge of selegiline’s pharmacology to special patient populations, including those with hepatic impairment, the elderly, and pregnant individuals.

2. Classification

Selegiline can be classified according to several pharmacological and chemical schemas, each highlighting different aspects of its clinical use and mechanism.

2.1. Therapeutic Classification

The primary therapeutic classification of selegiline is as an anti-Parkinson agent. Within this broad category, it is specifically an adjunctive treatment used to potentiate the effects of levodopa. Its second major classification is as an antidepressant, specifically when delivered via the transdermal patch system. This dual classification is unusual and directly tied to its dosage form and resultant pharmacodynamics.

2.2. Pharmacological Classification

Pharmacologically, selegiline is defined as a monoamine oxidase inhibitor (MAOI). More precisely, it is a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B). This selectivity is dose-dependent. At low oral doses typical for Parkinson’s disease (e.g., 10 mg/day), it preferentially inhibits MAO-B. At higher doses achieved via the transdermal route (e.g., 6 mg/24 hours and above), it loses selectivity and inhibits both MAO-A and MAO-B. It is also classified as a propargylamine, a chemical feature critical to its irreversible mechanism of action.

2.3. Chemical Classification

Chemically, selegiline is (R)-N,α-dimethyl-N-2-propynylphenethylamine hydrochloride. It is a synthetic derivative of phenethylamine with a propargyl group (-C≡C-CH₃) attached to the nitrogen atom. This propargyl moiety is essential for its irreversible binding to the flavin adenine dinucleotide (FAD) cofactor within the active site of MAO. The molecule is chiral, and the commercially available form is the levorotatory enantiomer (L- or R-selegiline), which possesses the desired MAO-B inhibitory activity. The dextrorotatory enantiomer is largely inactive against MAO-B.

3. Mechanism of Action

The therapeutic effects of selegiline are primarily mediated through the inhibition of monoamine oxidase (MAO), a mitochondrial outer membrane-bound enzyme responsible for the oxidative deamination of endogenous and exogenous monoamines. The human body expresses two major isoenzymes, MAO-A and MAO-B, which differ in substrate preference, inhibitor sensitivity, and tissue distribution.

3.1. Monoamine Oxidase Inhibition

Selegiline acts as a mechanism-based irreversible inhibitor, also termed a “suicide substrate.” The drug is initially recognized as a substrate by MAO-B. The enzyme’s catalytic cycle then activates the propargylamine group, leading to the formation of a highly reactive intermediate. This intermediate forms a stable, covalent adduct with the N⁵ atom of the enzyme’s FAD cofactor, permanently inactivating the enzyme. Because the inhibition is irreversible, recovery of MAO-B activity depends on the synthesis of new enzyme protein, a process that may take several weeks.

The selectivity for MAO-B at low oral doses is a key feature. MAO-B preferentially metabolizes dopamine, phenethylamine, and benzylamine. In the human brain, MAO-B is the predominant form in glial cells and serotonergic neurons, while MAO-A is found in catecholaminergic neurons. By selectively inhibiting MAO-B in the striatum, selegiline reduces the catabolism of dopamine, thereby increasing its synaptic availability. This is particularly effective in Parkinson’s disease, where dopaminergic neurons in the substantia nigra are degenerated, and synaptic dopamine levels are critically low.

At higher systemic exposures, such as those achieved with transdermal administration, selegiline loses its selectivity and inhibits both MAO-A and MAO-B. MAO-A preferentially metabolizes serotonin, norepinephrine, and tyramine. Inhibition of MAO-A in the gut and liver is responsible for the classic “cheese reaction” (hypertensive crisis) associated with non-selective MAOIs, as it prevents the first-pass metabolism of dietary tyramine. The transdermal route bypasses significant hepatic and intestinal MAO-A, mitigating this risk at therapeutic doses.

3.2. Effects on Dopaminergic Neurotransmission

In Parkinson’s disease, the primary mechanism is the potentiation of dopaminergic signaling. By inhibiting striatal MAO-B, selegiline decreases the breakdown of both endogenous dopamine and exogenous dopamine derived from levodopa therapy. This leads to increased dopamine concentration in the synaptic cleft, enhanced stimulation of post-synaptic D₁ and D₂ receptors, and improved motor function. The effect is synergistic with levodopa, often allowing for a reduction in levodopa dose and mitigating end-of-dose motor fluctuations (“wearing-off”).

3.3. Putative Neuroprotective and Neurorescue Effects

Beyond symptomatic relief, preclinical evidence suggests selegiline may have disease-modifying properties, though clinical proof remains inconclusive. Proposed mechanisms include:

• Reduction of Oxidative Stress: MAO catalyzes the oxidation of amines, producing hydrogen peroxide (H₂O₂) as a byproduct. By inhibiting MAO-B, selegiline may reduce the generation of these reactive oxygen species, thereby attenuating oxidative damage to vulnerable neurons.
• Anti-apoptotic Activity: The propargylamine moiety may independently promote neuronal survival. It is hypothesized to stabilize mitochondrial membrane potential and prevent the opening of the mitochondrial permeability transition pore, a key step in the intrinsic apoptotic pathway. This action may involve the activation of Bcl-2 and the downregulation of pro-apoptotic factors like Bax and Bad.
• Induction of Neurotrophic Factors: Some studies indicate that selegiline and its metabolites can upregulate the expression of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF).

It is critical to note that while these mechanisms are pharmacologically plausible and supported by in vitro and animal models, their clinical significance in altering the progression of Parkinson’s disease in humans has not been definitively established in long-term trials.

3.4. Antidepressant Mechanism

The antidepressant efficacy of the transdermal formulation is attributed to broader monoamine oxidase inhibition. By inhibiting both MAO-A and MAO-B in the brain, selegiline increases the synaptic levels of serotonin, norepinephrine, and dopamine. This broad spectrum of monoaminergic enhancement is similar to that of older, non-selective MAOIs but with a superior safety profile regarding dietary tyramine restrictions due to the route of administration.

4. Pharmacokinetics

The pharmacokinetics of selegiline are complex and highly dependent on the route of administration, which fundamentally dictates its metabolic fate, selectivity, and clinical use.

4.1. Absorption

Oral Administration: Selegiline hydrochloride is rapidly absorbed from the gastrointestinal tract, but it undergoes extensive first-pass metabolism. Its oral bioavailability is low, estimated at approximately 10% or less. Peak plasma concentrations (C_max) are typically reached within 0.5 to 2 hours post-dose. Absorption is not significantly affected by food.

Transdermal Administration: The transdermal system delivers selegiline continuously through the skin and directly into the systemic circulation. This bypasses the portal circulation and pre-systemic intestinal and hepatic metabolism. Steady-state plasma concentrations are achieved within 24-48 hours of initial application. The bioavailability via this route is significantly higher relative to oral dosing, though absolute values are not precisely defined. The patch is typically applied once daily, providing consistent drug delivery over 24 hours.

4.2. Distribution

Selegiline is a lipophilic base and distributes widely throughout the body. It readily crosses the blood-brain barrier, which is essential for its central nervous system effects. The volume of distribution is large, exceeding total body water, indicating extensive tissue binding. The drug is approximately 85-90% bound to plasma proteins, primarily albumin. Its distribution into human breast milk has been documented.

4.3. Metabolism

Metabolism is the most critical pharmacokinetic aspect, generating active metabolites and determining the drug’s selectivity profile. Selegiline is extensively metabolized by the hepatic cytochrome P450 system, primarily CYP2B6 and CYP2C19, and also via non-P450 pathways.

The major metabolic pathways include:

• N-Desalkylation: This is the primary pathway, producing L-amphetamine and L-methamphetamine. These metabolites are levorotatory, which confers weaker sympathomimetic activity compared to their dextrorotatory counterparts (e.g., illicit D-methamphetamine). Nevertheless, they may contribute to the drug’s side effects, such as insomnia, agitation, and cardiovascular stimulation. Their role in the therapeutic effect is considered minimal.
• N-Depropargylation: Leads to the formation of the primary amine, desmethylselegiline.

The extent of first-pass metabolism after oral administration is substantial. When the drug is absorbed transdermally, a much lower proportion is converted to these amphetamine metabolites, as it avoids initial hepatic passage. Instead, a greater proportion of the parent drug reaches the systemic circulation and, subsequently, the brain.

4.4. Excretion

The metabolites of selegiline are eliminated primarily via the kidneys. Less than 5% of an oral dose is excreted unchanged in the urine. The elimination of the parent drug is rapid, with a half-life of approximately 1.5 to 2 hours for the oral formulation. However, the pharmacological effect persists far longer due to the irreversible nature of MAO-B inhibition. The recovery of enzyme activity depends on de novo synthesis, with a turnover rate of about 2-4 weeks. The pharmacokinetics of the transdermal system are best described by the rate of delivery from the patch rather than the plasma half-life of the drug.

4.5. Half-life and Dosing Considerations

The short plasma half-life of the parent compound necessitates specific dosing strategies. For Parkinson’s disease, the standard oral dose is 5 mg twice daily (taken at breakfast and lunch) or a single 10 mg dose. Dosing is typically confined to earlier in the day to minimize the risk of insomnia caused by the amphetamine metabolites. The avoidance of evening doses is a standard clinical pearl. For the transdermal patch used in depression, dosing is once daily, with strengths ranging from 6 mg/24 hours to 12 mg/24 hours. The continuous delivery maintains stable plasma concentrations, making the short plasma half-life irrelevant for this formulation.

5. Therapeutic Uses/Clinical Applications

Selegiline has established roles in two major therapeutic areas, with the indication strictly tied to the formulation and dosing regimen.

5.1. Approved Indications

Parkinson’s Disease (Oral Formulation): Selegiline is approved as an adjunct to levodopa/carbidopa in the treatment of Parkinson’s disease. It is used to reduce “off” time in patients experiencing motor fluctuations. It may also be used as monotherapy in early Parkinson’s disease in some regions, though this is less common. In the adjunctive setting, it can permit a reduction in the total daily dose of levodopa, potentially mitigating long-term levodopa-induced dyskinesias.

Major Depressive Disorder (Transdermal Formulation): The selegiline transdermal system is approved for the treatment of major depressive disorder in adults. It is indicated for patients who have not achieved an adequate response to other antidepressant therapies. Its efficacy is believed to be comparable to other classes of antidepressants, including SSRIs and TCAs, but with a distinct mechanism of action.

5.2. Off-Label Uses

Several off-label applications have been explored, supported by varying degrees of evidence:

• Attention-Deficit/Hyperactivity Disorder (ADHD): The potential utility stems from its ability to increase dopaminergic and noradrenergic tone. Evidence is limited and not sufficient to support routine use.
• Negative Symptoms of Schizophrenia: As an adjunct to antipsychotics, based on the dopamine-enhancing hypothesis for negative symptoms. Results from clinical trials have been mixed.
• Neuroprotection in Parkinson’s Disease: As discussed, this remains a theoretical and investigational area. Large clinical trials like the DATATOP study initially suggested a delay in the need for levodopa, but whether this represented true disease modification or merely symptomatic effects has been debated for years.
• Smoking Cessation: Explored due to its effects on dopamine reward pathways, but it is not a standard therapy.

6. Adverse Effects

The adverse effect profile of selegiline differs somewhat between the oral (Parkinson’s) and transdermal (depression) formulations, reflecting differences in metabolism, selectivity, and concomitant medications.

6.1. Common Side Effects

Associated with Oral Selegiline (Parkinson’s Disease):

• Gastrointestinal: Nausea, abdominal pain, dry mouth.
• Neurological: Dizziness, lightheadedness, insomnia, vivid dreams, and hallucinations (particularly in elderly patients or those with advanced disease). The insomnia is often attributed to its amphetamine metabolites.
• Psychiatric: Confusion, agitation.
• Cardiovascular: Orthostatic hypotension, which can be significant in patients with autonomic dysfunction associated with Parkinson’s disease.

Associated with Transdermal Selegiline (Depression):

• Application Site Reactions: The most frequent adverse effect, including erythema, pruritus, rash, or irritation. Rotating application sites is recommended.
• Gastrointestinal: Diarrhea.
• Neurological: Headache, insomnia.
• Other: Pharyngitis.

6.2. Serious/Rare Adverse Reactions

Serotonin Syndrome: This is a potentially life-threatening condition caused by excessive serotonergic activity in the central nervous system. The risk is highest when selegiline, especially at non-selective (transdermal) doses, is combined with other serotonergic agents (e.g., SSRIs, SNRIs, TCAs, tramadol, meperidine). Symptoms include mental status changes (agitation, confusion), autonomic hyperactivity (tachycardia, hyperthermia, diaphoresis), and neuromuscular abnormalities (hyperreflexia, myoclonus, tremor).

Hypertensive Crisis (Tyramine Reaction): With non-selective MAO inhibition, ingestion of tyramine-rich foods (aged cheeses, cured meats, fermented products, tap beers, etc.) can lead to a sudden, severe increase in blood pressure. Tyramine, a pressor amine, is normally metabolized by MAO-A in the gut. When this is inhibited, tyramine enters the systemic circulation and causes a massive release of norepinephrine from sympathetic nerve endings. Symptoms include severe headache, palpitations, neck stiffness, nausea, vomiting, and hypertensive emergency. The risk with the transdermal formulation at recommended doses (≤ 6 mg/24 hours) is considered low, and strict dietary restrictions are not typically mandated, though caution is advised. At higher transdermal doses (9 mg/24 hours, 12 mg/24 hours), dietary modifications are recommended. The risk with low-dose oral selegiline is minimal due to its MAO-B selectivity.

Increased Dyskinesias: In Parkinson’s patients, enhancing dopaminergic tone with selegiline can exacerbate pre-existing levodopa-induced dyskinesias or precipitate their onset.

Mania/Hypomania: As with most antidepressants, selegiline can induce a switch to mania or hypomania in patients with bipolar disorder. It is contraindicated in patients with a history of pheochromocytoma due to the risk of catecholamine crisis.

6.3. Black Box Warnings

The transdermal selegiline system carries a black box warning, the most serious FDA-mandated warning. This warning highlights the risk of suicidal thoughts and behaviors in children, adolescents, and young adults (up to age 24) with major depressive disorder and other psychiatric disorders. This risk is class-wide for antidepressants and necessitates close monitoring for clinical worsening, suicidality, or unusual changes in behavior, especially during initial treatment and dose adjustments. No black box warning exists for the oral formulation used in Parkinson’s disease.

7. Drug Interactions

Drug interactions with selegiline are numerous and can be severe, primarily stemming from its potentiation of monoaminergic systems and irreversible enzyme inhibition.

7.1. Major Drug-Drug Interactions

Contraindicated Combinations (Absolute Avoidance):

• Other MAOIs: Concurrent use with other monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine, linezolid, methylene blue) is contraindicated due to the profound and dangerous increase in monoaminergic activity. A washout period of at least 14 days is required when switching between MAOIs.
• Serotonergic Agents: The combination with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), clomipramine, trazodone, nefazodone, vilazodone, vortioxetine, buspirone, triptans (e.g., sumatriptan), dextromethorphan, tramadol, meperidine (pethidine), methadone, propoxyphene, fentanyl, and St. John’s Wort is contraindicated due to the high risk of serotonin syndrome. A minimum 14-day washout is required when switching from an SSRI to selegiline (5 weeks for fluoxetine due to its long half-life).
• Sympathomimetic Agents: Amphetamines, catecholamines (e.g., epinephrine, norepinephrine, dopamine, isoproterenol), ephedrine, pseudoephedrine, phenylephrine, and phenylpropanolamine can precipitate a hypertensive crisis. This includes both prescription drugs and over-the-counter cold and cough remedies.
• Carbamazepine and Oxcarbazepine: These may lower selegiline levels, but more critically, the combination carries an uncertain risk.
• Bupropion: Contraindicated due to potential synergistic effects lowering seizure threshold and unclear interaction profile.

Significant Interactions Requiring Caution/Dose Adjustment:

• Levodopa: While this is a therapeutic combination, it requires careful titration. Selegiline potentiates the effects of levodopa, often necessitating a 10-30% reduction in the levodopa dose to avoid excessive dopaminergic side effects like dyskinesias, hallucinations, and nausea.
• CYP2B6 and CYP2C19 Inhibitors/Inducers: Drugs that affect these enzymes may alter the metabolism of selegiline. For example, orphenadrine and ticlopidine (CYP2B6 inhibitors) could increase selegiline exposure, while rifampin (an inducer) could decrease it.
• General Anesthetics: Both volatile anesthetics and local anesthetics with vasoconstrictors (e.g., epinephrine-containing dental anesthetics) require extreme caution due to potential pressor responses.

7.2. Contraindications

Selegiline is contraindicated in the following conditions:

• Concomitant use with the medications listed above as contraindicated.
• Known hypersensitivity to selegiline or any component of the formulation.
• Pheochromocytoma (due to risk of hypertensive crisis).
• For the transdermal patch: its use in pediatric patients is not established.

8. Special Considerations

8.1. Use in Pregnancy and Lactation

Pregnancy (Category C): Animal reproduction studies have shown adverse effects, but there are no adequate and well-controlled studies in pregnant women. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The decision requires careful risk-benefit analysis, considering the severity of the maternal condition. Abrupt discontinuation of therapy in pregnant patients with major depression is also not without risk.

Lactation: Selegiline and its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, including sedation and irritability, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.2. Pediatric and Geriatric Considerations

Pediatric: The safety and effectiveness of oral selegiline in pediatric patients have not been established. The transdermal patch carries a black box warning regarding suicidality in young adults and is not approved for use in children or adolescents.

Geriatric: No overall differences in safety or efficacy have been observed between elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. In elderly patients with Parkinson’s disease, there is an increased susceptibility to drug-induced hallucinations, confusion, and postural hypotension. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

8.3. Renal and Hepatic Impairment

Renal Impairment: The pharmacokinetics of selegiline have not been formally studied in patients with renal impairment. Since the amphetamine metabolites are renally excreted, accumulation could occur in patients with severe renal impairment (creatinine clearance < 30 mL/min), potentially increasing the risk of stimulant-related side effects. Use with caution in this population.

Hepatic Impairment: Selegiline is extensively metabolized by the liver. Patients with hepatic impairment (e.g., cirrhosis) may have significantly reduced first-pass metabolism after oral administration, leading to increased systemic bioavailability and a greater degree of MAO-A inhibition. This could increase the risk of hypertensive reactions even at standard oral doses. Furthermore, impaired metabolism could lead to higher and more prolonged levels of parent drug and metabolites. Selegiline should be used with extreme caution in patients with significant hepatic disease, and dose reduction may be necessary. The transdermal route, by bypassing first-pass metabolism, may present a different risk profile, but caution is still warranted.

9. Summary/Key Points

The pharmacology of selegiline is characterized by its irreversible inhibition of monoamine oxidase, with clinical effects dictated by formulation, dose, and route of administration.

• Selegiline is a selective, irreversible inhibitor of MAO-B at low oral doses (5-10 mg/day), used primarily as an adjunct to levodopa in Parkinson’s disease to enhance dopaminergic signaling and reduce motor fluctuations.
• The transdermal formulation delivers selegiline systemically, bypassing first-pass metabolism. At doses of 6 mg/24 hours and above, it inhibits both MAO-A and MAO-B, providing an effective treatment for major depressive disorder with a reduced risk of dietary tyramine interactions compared to oral non-selective MAOIs.
• Its mechanism involves covalent binding to the FAD cofactor of MAO, leading to long-lasting enzyme inactivation. Putative neuroprotective effects remain of theoretical interest but are not conclusively proven in humans.
• Pharmacokinetics are route-dependent. Oral administration results in low bioavailability and extensive metabolism to L-amphetamine and L-methamphetamine. Transdermal administration yields higher systemic parent drug exposure with less amphetamine metabolite formation.
• The most serious adverse effects are serotonin syndrome (when combined with other serotonergic drugs) and hypertensive crisis (primarily with non-selective inhibition and tyramine ingestion). The transdermal patch carries a black box warning for suicidality in young patients.
• Drug interactions are extensive and potentially severe. Concomitant use with other MAOIs, serotonergic drugs (SSRIs, SNRIs, tramadol, meperidine), and sympathomimetics is contraindicated.
• Special caution is required in patients with hepatic impairment, the elderly (for CNS side effects), and during pregnancy and lactation. Dose adjustments may be necessary when adding selegiline to levodopa therapy.

Clinical Pearls:

1. Oral selegiline for Parkinson’s should be dosed in the morning and at noon to prevent insomnia; avoid evening doses.
2. When initiating transdermal selegiline for depression, start at 6 mg/24 hours. Dietary restrictions are generally not required at this dose but patients should be advised to report immediately any severe headache or other symptoms of hypertensive crisis.
3. Always allow a sufficient washout period (at least 14 days, longer for fluoxetine) when switching from another antidepressant to selegiline, or vice versa, to avoid serotonin syndrome.
4. In Parkinson’s patients, monitor for and be prepared to reduce levodopa dose by 10-30% upon initiation of selegiline to prevent exacerbation of dyskinesias and hallucinations.
5. Educate all patients, regardless of formulation, to avoid over-the-counter cold and cough medications containing sympathomimetics (e.g., pseudoephedrine, phenylephrine).

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