Molecular Formula: C13H17N HCl
Molecular Weight: 223.75
PHARMACOLOGY: Selegiline is an irreversible inhibitor of monoamine oxidase (MAO).1,2 MAOs are widely distributed throughout the body and are subclassified into 2 types, A and B, which differ in their substrate specificity and tissue distribution. Selegiline is believed to be a selective inhibitor of MAO-B at recommended dosages in the dog due to its greater affinity for type B enzyme active sites compared to type A sites.1 In CNS neurons, MAO plays a role in the catabolism of catecholamines, (dopamine, and, to a lesser extent, norepinephrine and epinephrine) and serotonin.1,2 Selegiline may have pharmacologic effects unrelated to MAO-B inhibition. There is some evidence that it may increase dopaminergic activity by other mechanisms, including increasing synthesis and release of dopamine into the synapse as well as interfering with dopamine re-uptake from the synapse.2-4 Effects resulting from selegiline administration may also be mediated through its metabolites. Two of its 3 principal metabolites, L-amphetamine and L-methamphetamine, have pharmacologic actions of their own. However, the extent to which these metabolites contribute to the effects of selegiline is unknown.
Therapeutic effects of selegiline are thought to result in part from enhanced catecholaminergic nerve function and increased dopamine levels in the CNS.5,6 The pathogenesis of the development of clinical signs associated with cognitive decline is considered to be partly a result of a decrease in the level of catecholamines in the CNS and deficiencies in neurotransmission.7 There is evidence which points to hypothalamic dopamine deficiency playing a role in the pathogenesis of pituitary dependent hyperadrenocorticism in the dog.8,9
Based upon IV administration of selegiline to 4 mixed breed female dogs, the plasma elimination half-life was estimated to be 60 ± 10 minutes (mean ± SD) and the volume of distribution at steady-state (Vss) was estimated to be 9.4 ± 1.6 L/kg (mean ± SD). The relatively large Vss suggests that the selegiline is extensively distributed to body tissues. The absolute bioavailability, F, of an oral solution was less than 10%.10
INDICATIONS: Anipryl tablets are indicated for the control of clinical signs associated with canine cognitive dysfunction syndrome (CDS) and control of clinical signs associated with uncomplicated canine pituitary dependent hyperadrenocorticism (PDH).
CONTRAINDICATIONS: Anipryl is contraindicated in patients with known hypersensitivity to this drug.
In humans, selegiline is contraindicated for use with meperidine and this contraindication is often extended to other opioids.
WARNINGS: Keep out of reach of children. Not for human use.
Anipryl should not be administered at doses exceeding those recommended (0.5-2.0 mg/kg once daily).
In humans, concurrent use of MAO inhibitors with alpha-2 agonists has resulted in extreme fluctuations of blood pressure; therefore, blood pressure monitoring is recommended with concurrent use in dogs.
ADVERSE REACTIONS: In clinical trials, 404 dogs treated with Anipryl for as long as 18 months were monitored for the occurrence of adverse events. Many of the observations listed in the following table may be associated with the underlying disease (PDH or CDS), the advanced age of the patients or the development of unrelated concurrent disease. One index of relative importance, however, is whether or not a reaction caused treatment discontinuation. Eighteen dogs (4%) experienced one or more of the following adverse events that led either to discontinuation of therapy with Anipryl, dismissal from the study, or a reduction in dose: restlessness/agitation, vomiting, disorientation, diarrhea, diminished hearing, possible drug interaction (weakness, confusion, incoordination and “seizure-like” activity while being treated concurrently with metronidazole, prednisone, and trimethoprim sulfa), increase in destructive behavior in a dog with separation anxiety, anorexia, anemia, stiffness and polydipsia.
Percentage of Dogs with Adverse Events Reported in Clinical Field Trials
Adverse Event
|
Anipryl (n=404)
|
Placebo (n=67)
|
vomiting
|
26%
|
21%
|
diarrhea
|
18%
|
10%
|
hyperactive/restless*
|
12%
|
6%
|
anorexia
|
8%
|
1%
|
neurologic**
|
6%
|
1%
|
lethargy
|
6%
|
1%
|
salivation
|
5%
|
4%
|
urinary tract infection
|
4%
|
1%
|
pruritus/dermatologic
|
4%
|
1%
|
weakness
|
4%
|
0
|
pale gums
|
3%
|
1%
|
polyuria/polydipsia
|
3%
|
1%
|
weight loss
|
3%
|
0
|
diminished hearing
|
2%
|
0
|
panting
|
2%
|
1%
|
cardiovascular/respiratory***
|
2%
|
0
|
licking
|
2%
|
1%
|
*This includes hyperactivity, irritability, abnormal repetitive movements, anxiousness, and restlessness.
**This includes ataxia, incoordination, staggering, disorientation, decreased proprioception, and seizure.
***This includes heart murmurs, tachycardia, collapse, dyspnea, pleural effusion, and sneezing.