Fluoxetine

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Mechanism of Action

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) which functions by inhibiting the reuptake of serotonin in the pre-synaptic neuron. This inhibition of uptake of reuptake of 5-HT1A into pre-synaptic neurons is highly selective and does not affect noradrenaline, dopamine, acetylcholine, histaminic or alpha-1 adrenergic receptors. 5-HT1A receptors have an effect on mood and behaviour. SSRIs are derived from TCAs, such as Clomipramine. SSRIs act to bring about changes in conformation of receptors, this can take 3-5 weeks[1]. Regulation of second messengers (cAMP, Ca2+, cGMP, IP3) is responsible for the major effect. Their actions on protein kinases then act to change neuronal metabolism and receptor protein transcription[2].

Fluoxetine is largely metabolised in the liver by the cytochrome P450 enzyme system to norfluoxetine, also an SSRI.


Uses

  • Licensed (dog)
  • Treatment of canine separation anxiety[3][4][5][6][7][8][9] in conjunction with behaviour modification in dogs over 6 months old.
  • Unlicensed
  • Compulsive disorders[10]
  • Aggression
  • Panic and anxiety disorders[11]
  • Feline Urine Marking

As with other drugs used to treat behavioural problems it is recommended that fluoxetine be used in conjunction with behavioural modification techniques [9][12][13][14][15][16][17]. Fluoxetine has a long half-life and therefore a minimum of 6-8 weeks should be allowed before making an assessment of efficaciousness. Due to the long half-life of fluoxetine it is not necessary to gradually reduce or taper the dose. Once treatment with fluoxetine has ceased continued behavioural modification is advisable to avoid the reappearance of clinical signs. The long half-life of fluoxetine and its metabolites also mean that a period of at least 6 weeks should be allowed to pass before administration of any drugs which may interact adversely.

Adverse Effects[18]

  • Decreased appetite
  • Depression/lethargy
  • Shaking/shivering/tremor
  • Vomiting and diarrhoea
  • Restlessness and anxiety
  • Seizures
  • Aggression
  • Mydriasis
  • Vocalisation
  • Weight loss
  • Panting
  • Confusion
  • Incoordination
  • Hypersalivation

Caution should be taken in if the animal suffers from any of the following pre-existing medical conditions:

  • Contraindicated for animals with a history of epilepsy or seizures

Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:

  • Fluoxetine should not be given at the same time as drugs which lower seizure threshold eg. phenothiazines such as acepromazine or chlorpromazine.
  • Monoamine oxidase inhibitors (MAOI), or within a period of 2 weeks after discontinuation of treatment with a MAOI due to the risk of serotonin syndrome[19]
  • Fluoxetine has not been evaluated with drugs that affect the cytochrome P450 enzyme, care should therefore be taken with any drug that affects the enzyme system eg. ketoconazole.

References

  1. ↑ Overall, K.L., 2004. Paradigms for pharmacologic use as a treatment component in feline behavioural medicine. Journal of Feline Medicine and Surgery 6, 29–42
  2. ↑ Overall, K.L., 2001. Pharmacological Treatment in Behavioural Medicine: The Importance of Neurochemistry, Molecular Biology and Mechanistic Hypotheses. The Veterinary Journal, 162, 9–23
  3. ↑ Landsberg, G.M., Melese, P., Sherman, B.L., Neilson, J.C., Zimmerman, A., Clarke, T.P., 2008. Effectiveness of fluoxetine chewable tablets in the treatment of canine separation anxiety. Journal of Veterinary Behavior 3, 12-19
  4. ↑ Dodman, N.H., Shuster, L., 1994. Pharmacologic approaches to managing behaviour problems in small animals. Vet. Med. 89, 960-969.
  5. ↑ Beaver, B.V., 1999. Canine Behavior: A Guide for Veterinarians. W.B. Saunders Company, Philadelphia, PA, pp. 26-28.
  6. ↑ Overall, K.L., 2001. Pharmacological treatment in behavioral medicine: the importance of neurochemistry, molecular biology and mechanistic hypotheses. Vet. J. 162, 9-23.
  7. ↑ Landsberg, G., Hunthausen, W., Ackerman, L., 2003. In: Handbook of Behavior Problems of the Dog and Cat, 2nd ed. Elsevier Saunders, Philadelphia, pp. 258-267.
  8. ↑ Simpson, B.S., Papich, M.G., 2003. Pharmacologic management in veterinary behavioral medicine. Vet. Clin. North Am.: Small Anim. Pract. 33, 365-404.
  9. ↑ 9.0 9.1 Simpson, B.S., Landsberg, G.M., Reisner, I.R., Ciribassi, J.J., Horwitz, D., Houpt, K.A., Kroll, T.L., Luescher, A., Moffat, K.S., Douglass, G., Robertson-Plouch, C., Veenhuizen, M.F., Zimmerman, A., Clark, T.P., 2007. Effects of Reconcile (fluoxetine) chewable tablets plus behavior management for canine separation anxiety. Vet. Ther. 8, 18-31. Sonawalla, S.
  10. ↑ Altemus, M., Glowa, J. R. & Murphy, D. L., 1993. Attenuation of food restriction-induced running by chronic fluoxetine treatment. Psychopharmacology Bulletin 29, 397–400.
  11. ↑ Meltzer-Brody, S., Connor, K. M., Churchill, E. & Davidson, J. R. T., 2000. Symptom-specific effects of fluoxetine in post-traumatic stress disorder. International Clinical Psychopharmacology 15, 227–31.
  12. ↑ Petit, S., Pageat, P., Chaurand, J.P., Heude, B., Beata, C., 1999. Efficacy of clomipramine in the treatment of separation anxiety in dogs: clinical trial. Rev. Med. Vet. 2, 133-140.
  13. ↑ King, J.N., Simpson, B.S., Overall, K.L., Appleby, D., Pageat, P., Ross, C., Chaurand, J.P., Heath, S., Beata, C., Weiss, A.B., Muller, G., Paris, T., Bataille, B.G., Parker, J., Petit, S., Wren, J., 2000. Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomized, double-blind, placebo controlled, parallel-group, multicenter clinical trial. Appl. Anim. Behav. Sci. 67, 255-275.
  14. ↑ Seksel, K., Lindeman, M.J., 2001. Use of clomipramine in treatment of obsessive-compulsive disorder, separation anxiety and noise phobia in dogs: a preliminary, clinical study. Aust. Vet. J. 79, 252-256.
  15. ↑ Horwitz, D., 2000. Diagnosis and treatment of canine separation anxiety and the use of clomipramine hydrochloride. J. Am. Anim. Hosp. Assoc. 36, 107-109.
  16. ↑ Takeuchi, Y., Houpt, K.A., Scarlett, J.N., 2000. Evaluation of treatments for separation anxiety in dogs. J. Am. Vet. Med. Assoc. 217, 342-345.
  17. ↑ Landsberg, G., Hunthausen, W., Ackerman, L., 2003. In: Handbook of Behavior Problems of the Dog and Cat, 2nd ed. Elsevier Saunders, Philadelphia, pp. 258-267.
  18. ↑ Fluoxetine hydrochloride data sheet
  19. ↑ Brown, T.M., Skop, B.P., Mareth, T.R., 1996. Pathophysiology and management of the serotonin syndrome. The Annals of Pharmacotherapy 30, 527–533.


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