SELEGILINE HCL, L-DEPRENYL

Chemistry - Selegiline HCl, also commonly called l-deprenyl, occurs as a white to off-whitecrystalline powder that is freely soluble in water. It has a pKa of 7.5.

Storage, Stability, Compatibility

Commercially available veterinary tablets should be stored atcontrolled room temperature 20-25°C (68-77°F). The commercially available human-labeled tabletsand capsules are recommended to be stored from 15-30°C.

Pharmacology - SELEGILINE HCL, L-DEPRENYL

Selegiline's mechanism of action for treatment of Cushing's disease (pituitarydependent hyperadrenocorticism¯PDH) is complex; a somewhat simplified explanation follows:
In the hypothalamus, corticotropin-releasing hormone (CRH) acts to stimulate the production of
ACTH in the pituitary and dopamine acts to inhibit the release of ACTH. As dogs get older, there isa tendency for a decrease in dopamine production that can contribute to the development of PDH.
As dopamine is metabolized by monamine oxidase-B (MOA-B) and selegiline inhibits MAO-B, dopamine levels can be increased at receptor sites after selegiline administration. In theory, thisallows the levels of dopamine and CRH to be in balance in the hypothalamus, thereby reducing theamount of ACTH produced and ultimately, cortisol.
Two of three metabolites of selegiline are amphetamine and methamphetamine which maycontribute to both the efficacy and the adverse effects of the drug.

Uses, Indications

At the time of writing, selegiline is approved for use in dogs only for thetreatment of Cushing's Disease, but in Canada it is also approved for the treatment of Canine
Cognitive Dysfunction (so-called "old dog dementia"). In humans, selegiline's primary indicationis for the adjunctive treatment of Parkinson's disease.

Pharmacokinetics - SELEGILINE HCL, L-DEPRENYL

There is only limited information on the pharmacokinetics of selegiline indogs. A study done in 4 dogs showed that selegiline was absorbed rapidly and had an absolutebioavailability of about 10%. The volume of distribution of the central compartment was measuredat approximately 7 l/kg. Terminal half life was about one hour.
In humans, selegiline pharmacokinetics have been demonstrated to have wide interpatient variability. The drug has a high first pass effect where extensive metabolism to L-desmethylselegiline, methylamphetamine and L-amphetamine occur. Each of these metabolites is active. While L-desmethylselegiline does inhibit MAO-B, the others do not, but are CNS stimulants. The drug isexcreted in the urine, primarily as conjugated and unconjugated metabolites.

Contraindications, Precautions, Reproductive Safety

Selegiline is contraindicated in patientsknown to be hypersensitive to it. In human patients, it is contraindicated in patients receivingmeperidine and possibly with other opioids as well.
The manufacturer cautions to perform appropriate diagnostic tests to confirm the diagnosis beforestarting therapy and not to attempt to treat hyperadrenocorticism not of pituitary origin.
Safety of selegiline in pregnant, breeding or lactating animals has not been established. Rat studieshave not demonstrated overt teratogenicity.

Adverse Effects, Warnings

Adverse reports reported thus far in dogs include, vomiting and diarrhea; CNS effects manifested by restlessness, repetitive movements, or lethargy; salivation andanorexia. Diminished hearing/deafness, pruritus, licking, shivers/trembles/shakes have also beenreported. Note that clinical experience with this drug is limited and the adverse effect profile maychange. The manufacturer advises to observe animals carefully for atypical responses.
Adverse effects that have been reported in human patients, include nausea (10%), hallucinations, confusion, depression, loss of balance, insomnia and hypersexuality. These effects are notedbecause of their "subjective" nature and they could help explain untoward behavioral changes incanine patients should they also occur in that species.
Because selegiline could potentially be abused by humans, veterinarians should be alert for drug"shoppers".
Overdosage - Oral LD50 in laboratory animals was approximately 200-445 mg/kg. In limited data, dogs receiving 3X dosages showed signs of decreased weight, salivation, decreased pupillaryresponse, panting, stereotypic behaviors and decreased skin elasticity (dehydration). Overdoses, ifsevere, should be treated with appropriate gut emptying and supportive treatments.

Drug Interactions

In humans, severe agitation, hallucinations and death have occurred in somepatients receiving meperidine and an MAO inhibitor. Until the data can be clarified, it is recommended not use selegiline and meperidine together. A separation of two weeks has been recommended. Other opioids (e.g., morphine) should be safer, but use with extreme caution, if at all.
Potentially, the so-called serotonin syndrome could occur if selegiline is used concurrently withselective serotonin reuptake inhibitors (SSRI's) such as fluoxetine (Prozac®). Concurrent use withthese antidepressants or other tricyclic/tetracyclic antidepressants (e.g., amitriptyline) are notadvised at this time and a 2 week separation between these compounds and selegiline is alsorecommended.
The manufacturer recommends not using selegiline concurrently with amitraz (Mitaban®) orephedrine.