Transdermal dosing results in significantly higher exposure to selegiline and lower exposure to all metabolites when compared to oral dosing; this is due to the extensive first-pass metabolism of the pill form and low first-pass metabolism of the patch form. The site of application is not a significant factor in how the drug is distributed. In humans, selegiline does not accumulate in the skin, nor is it metabolized there. Chemistry
Selegiline belongs to the phenethylamine and amphetamine chemical families. It is also known as L-deprenyl, as well as (R)-(–)-N,α-dimethyl-N-(2-propynyl)phenethylamine or (R)-(–)-N-methyl-N-2-propynylamphetamine. The compound is a derivative of levomethamphetamine (L-methamphetamine) with a propargyl group attached to the nitrogen atom. This detail is borrowed from pargyline, an older MAO-B inhibitor of the phenylalkylamine group. Selegiline is the levorotatory enantiomer of the racemic mixture deprenyl. Selegiline is synthesized by the alkylation of (–)-methamphetamine using propargyl bromide.Another clinically used MAOI of the amphetamine class is tranylcypromine. History
Following the discovery that the tuberculosis drug iproniazid elevated the mood of people taking it, and the subsequent discovery that the effect was likely due to inhibition of MAO, many people and companies started trying to discover MAO inhibitors to use as antidepressants. Selegiline was discovered by Zoltan Ecseri at the Hungarian drug company, Chinoin (part of Sanofi since 1993), which they called E-250.
Side effects
Side effects of the tablet form in conjunction with levodopa include, in decreasing order of frequency, nausea, hallucinations, confusion, depression, loss of balance, insomnia, increased involuntary movements, agitation, slow or irregular heart rate, delusions, hypertension, new or increased angina pectoris, and syncope. Most of the side effects are due to a high dopamine signaling, and can be alleviated by reducing the dose of levodopa.The main side effects of the patch form for depression include application-site reactions, insomnia, diarrhea, and sore throat. The selegiline patch carries a black box warning about a possible increased risk of suicide, especially for young people, as do all antidepressants since 2007. Interactions
Both the oral and patch forms come with strong warnings against combining selegiline with drugs that could produce serotonin syndrome, such as SSRIs and the cough medicine dextromethorphan. Selegiline in combination with the opioid analgesic pethidine is not recommended, as it can lead to severe adverse effects. Several other synthetic opioids such as tramadol and methadone, as well as various triptans, are contraindicated due to potential for serotonin syndrome.Birth control pills containing ethinylestradiol and a progestin increase the bioavailability of selegiline by 10- to 20-fold. High levels can lead to loss of MAO-B selectivity, and selegiline may begin inhibiting MAO-A as well. This increases susceptibility to side effects of non-selective MAOIs, such as tyramine-induced hypertensive crisis and serotonin toxicity when combined with serotonergic medications.Both forms of the drug carry warnings about food restrictions to avoid hypertensive crisis that are associated with MAO inhibitors.