Selegiline

Absorption

Rapidly absorbed from the gastrointestinal tract.

Toxicity

LD50=63 mg/kg (rats, IV)

Description

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 and the treatment of attention-deficit/hyperactivity disorder (ADHD). 

The Uses of Selegiline

This drug is a selective inhibitor of monoaminooxidase B, which suppresses dopamineinactivation processes and facilitates an increase of its level in the brain. In treating Parkinsonism, selegiline is usually used in combination with levodopa.

The Uses of Selegiline

Antidyskinetic; antiparkinsonian (in combination with levodopa/carbidopa).

Background

A selective, irreversible inhibitor of Type B monoamine oxidase. It is used in newly diagnosed patients with Parkinson's disease. It may slow progression of the clinical disease and delay the requirement for levodopa therapy. It also may be given with levodopa upon onset of disability. (From AMA Drug Evaluations Annual, 1994, p385) The compound without isomeric designation is Deprenyl.

Indications

Monotherapy for initial treatment of Parkinson's disease, as well as an adjunct therapy in patients with a decreased response to levodopa/carbadopa. Also used for the palliative treatment of mild to moderate Alzheimer's disease and at higher doses, for the treatment of depression.

Definition

ChEBI:(-)-selegiline is a selegiline and a terminal acetylenic compound. It has a role as a geroprotector. It is a conjugate base of a (-)-selegiline(1+).

brand name

Emsam (Somerset).

World Health Organization (WHO)

Selegiline was introduced in the early 1990s. It is a monoamine oxidase inhibitor and is used in the management of Parkinson's disease. A symptomatic effect of selegiline in Parkinson's disease has been shown, but longer follow-up failed to provide any definitive evidence of ability to retard the loss of dopaminergic neurons (Parkinson's Study Group, 1993).

Biological Functions

Another drug used in the treatment of Parkinson’s disease is selegiline (also known as deprenyl, or Eldepryl). It is an irreversible inhibitor of MAO-B, an important enzyme in the metabolism of dopamine (Fig. 33.2). Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors. Selegiline, as monotherapy, may be effective in the newly diagnosed patient with parkinsonism because its pharmacological effect enhances the actions of endogenous dopamine.
Selegiline is also used in conjunction with levodopa– carbidopa in later-stage parkinsonism to reduce levodopa dosage requirements and to minimize or delay the onset of dyskinesias and motor fluctuations that usually accompany long-term treatment with levodopa. It has also been proposed that selegiline may slow the progression of the disease by reducing the formation of toxic free radicals produced during the metabolism of dopamine. However, any neuroprotective effect of selegiline in parkinsonian patients remains to be established.
Most of the adverse reactions to selegiline are related to actions of increased levels of dopamine, as discussed earlier. At recommended doses, and unlike the nonselective MAO inhibitors used in the treatment of depression, selegiline has little effect on MAO-A and therefore generally does not cause the hypertension associated with the ingestion of tyramine-enriched foods. However, at doses higher than those usually recommended, MAO-A may be inhibited, which increases the risk of a tyramine reaction.
Selegiline should not be coadministered with tricyclic antidepressants or selective serotonin uptake inhibitors because of the possibility of a severe adverse drug reaction (e.g., hyperpyrexia, agitation, delirium, coma).

Pharmacokinetics

Dopamine is an essential chemical that occurs in many parts of the body. It is the premature degradation of dopamine that results in the symptoms of Parkinson's disease. Monoamine oxidase (MAO) is an enzyme which accelerates the breakdown of dopamine. Selegiline can prolong the effects of dopamine in the brain by preventing its breakdown through seletively blocking MAO-B. It also may prevent the removal of dopamine between nerve endings and enhance release of dopamine from nerve cells.

Synthesis

Selegiline, N-methyl-N-(2-propinyl)-2-methyl-1-phenylethylamine (10.1.14), is synthesized by the alkylation of (-)methyamphetamine (8.1.2.3) using propargylbromide [20¨C23].

Metabolism