Selegiline

Mechanism

Chemical and Commercial Profile

Common trade names: Plurimen, Selgisin, Emsam (transdermal patch).
Group: Irreversible MAO-B inhibitor (in low doses), phenylethylamine derivative.

Mechanism of Action

Selectivity on monoamine oxidase isoenzymes is dose-dependent:

• At low standard doses (<10 mg/day orally): It irreversibly and selectively inhibits MAO-B in the striatum, the enzyme responsible for the catabolism of extracellular dopamine. Increases the availability and permanence of this neurotransmitter without interfering with the degradation of intestinal tyramine or systemic serotonin.
• At high doses (>10 mg/day orally or through high-dose transdermal systems): It loses selectivity, irreversibly blocking both MAO-A and MAO-B. Massively enhances peripheral and central levels of norepinephrine and serotonin.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid oral administration but with low bioavailability (<10%) due to an extensive first-pass metabolic phenomenon. The transdermal patch system provides continuous and direct absorption into the general circulation with a bioavailability of 75%.
• Metabolism: Oxidative liver via CYP2B6 and CYP2C19, giving rise to the active metabolites L-amphetamine and L-methamphetamine (partly responsible for the stimulant effect and associated insomnia). The transdermal patch drastically reduces the formation of these metabolites.
• Excretion: Renal (75%) in the form of demethylated and conjugated metabolites.
• Half-life (t_1/2): 2 to 10 hours, however, the biological inhibitory effect persists for weeks until the de novo synthesis of the MAO enzyme by the neural tissue.

Indicators and dose

Indications

• Idiopathic Parkinson's disease (as an adjuvant to levodopa/carbidopa to alleviate "off" motor fluctuations).
• Major depression resistant to multiple lines of treatment (preferably used in transdermal patch format at high doses).

Dosage and Settings

• Parkinson's disease (Oral): 5 mg to 10 mg/day divided into two doses (breakfast and lunch to avoid nocturnal insomnia).
• Resistant depression (Transdermal): Start with 6 mg/24 hours; increase from 3 mg by 3 mg every two weeks to a maximum of 12 mg/24 hours.
• Adjustments in Renal / Liver Failure: Not recommended in terminal stages of liver or kidney failure (Cl_Cr < 15 ml/min). In moderate stages, reduce the theoretical dose by half and avoid oral formulations.

Security

Contraindications

Hypertensive crisis alert ("Cheese Effect")

At doses where the selectivity of MAO-B is lost (>10 mg/day orally), the inhibition of intestinal MAO-A prevents the catabolism of exogenous tyramine ingested in fermented foods (aged cheese, red wine, sausages, unfiltered beer). Tyramine displaces norepinephrine from the sympathetic adrenergic vesicles, inducing hypertensive crises of extreme severity. The low-dose transdermal patch (6 mg/24h) avoids this effect by bypassing the gastrointestinal tract.

Adverse Effects (ADR)

• CNS: Sleep insomnia (due to amphetamine metabolites), psychomotor agitation, visual hallucinations, tension headache.
• Cardiovascular: Severe orthostatic hypotension (especially in the elderly and parkinsonians), hypertensive crises of dietary origin, cardiac arrhythmias in association with sympathomimetics.

Clinical Interactions

• Opioids: Absolute contraindication to coadministration with pethidine, methadone, tramadol and dextromethorphan due to critical risk of malignant hyperthermia and cardiovascular collapse.
• Indirect sympathomimetics: Nasal decongestants such as pseudoephedrine or phenylephrine can trigger fatal hypertensive emergencies.

Pregnancy and Breastfeeding

FDA Category: C. Potential risk of intrauterine growth retardation and fetal sympathetic toxicity. Breastfeeding: Not recommended. It is unknown whether it passes into breast milk and due to its amphetamine precursor structure, there is a high risk of irritability and tachycardia in the infant.