(1 mg/kg BW, ql2h), an anticonvulsant, is another possible option (3-5). Megestrol acetate has also been employed, but its side effects should preclude its use in.
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Clomipramine-induced urinary retention in a cat Erika Pfeiffer, Norma Guy, Alastair Cribb Abstract A 10-year-old, female, spayed shorthair with presumed psychogenic alopecia was treated with clomipramine (1 mg/kg body weight/day). The cat developed urinary retention within 2 days. Clomipramine was discontinued. Clinical signs resolved over the next 7 days. The urinary retention was attributed to the anticholinergic effects of clomipramine. Resume Retention urinaire provoquee par la clomipramine chez un chat. Une femelle de 10 ans, castree, 'a poils courts, presentant une presumee alopecie psychogene a ete traitee 'a la clomipramine (1 mg/kg de poids corporel, par jour). La chatte a fait une retention urinaire dans les deux jours. La clomipramine a ete interrompue. Les signes cliniques ont disparus dans les sept jours suivants. La retention urinaire a ete attribuee aux effets anticholinergiques de la clomipramine. (Traduit par docteur Andr6 Blouin) Can Vet J 1999; 40: 265-267
A 10-year-old, female, spayed and declawed short-hair was presented for ventral abdominal alopecia of 2 years' duration. The cat was reported to have been irritable and aggressive since 1 y of age. She appeared to be disturbed by any change in her routine, such as visitors to the house or the absence of the owner. She would hiss at or attack strangers and would groom her abdomen excessively when upset. No specific event could be linked to the onset of the alopecia. Previous therapies, including changing the bedding and feed and treatment with prednisone (10 mg, PO, q24h, for 3 d; 5 mg, q24h, for 5 d; 5 mg, q48h, for 10 d), had failed to resolve the problem. There was no evidence of flea infestation. Results of complete blood cell count (CBC) and serum thyroxine concentrations were within normal limits. Apart from hair loss, there were no apparent skin lesions. Although a conclusive diagnosis would have required additional diagnostic procedures, including skin scrapings, fungal culture, and biopsy, a working diagnosis of psychogenic alopecia was made. Treatment with clomipramine hydrochloride (Anafranil, Geigy, Mississauga, Ontario) at 1 mg/kg body weight (BW)/d was initiated (1). Two days after initiating therapy, the cat was returned to the clinic with a client complaint of apparent urinary obstruction. She had been straining to urinate for several hours without voiding any urine. She was depressed and anorexic. On abdominal palpation, an enlarged urinary bladder approximately 10 to 12 cm in diameter South Central Veterinary Clinic, Box 149, Notre-Dame, Manitoba ROG IMO (Pfeiffer), Department of Anatomy and Physiology, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island CIA 4P3 (Cribb, Guy). Address correspondence to Dr. Alastair Cribb. Can Vet J Volume 40, April 1999
could be felt. No other abnormalities were noted on physical examination, except for the previously reported abdominal alopecia. The cat was sedated (ketamine, atropine, xylazine) to permit cystocentesis and urinary catheterization. After a urine sample had been obtained by cystocentesis, the cat spontaneously voided approximately 200 ml of urine. Urinary catheterization was not performed. The animal was hospitalized and given 100 mL 0.9% normal saline, SC. Urinalysis revealed a specific gravity of 1.029, pH 7.0, trace protein, a few squamous cells, and a few hippuric acid-resembling crystals. A urine sample was submitted for bacterial culture. A CBC obtained the following morning was within normal limits and a serum chemistry profile did not reveal any clinically significant abnormalities. A tentative diagnosis of clomipramine-induced urinary retention was made. Treatment with clomipramine was discontinued. Additional diagnostic tests that could have been performed to assist in the establishment of a conclusive diagnosis through the elimination of other possible causes include abdominal ultrasound, abdominal radiographs, contrast cystography or urethrography, repeat urinalyses, and cystourethrometry (bladder and urethral pressure profiles). However, some of these specialized diagnostic tests were not available in the general practice setting where this cat was treated, and since there was no evidence of physical obstruction, referral for additional invasive tests was not felt to be indicated. Pending urinary culture results, treatment with enrofloxacin (Baytril, Bayer, Etobicoke, Ontario; 2.5 mg/kg BW, ql2h) had been initiated. However, urinary tract infection is uncommon in cats with lower urinary tract disease and indiscriminate use of antibiotics should be avoided in this condition. Therefore, enrofloxacin was discontinued when a negative urine culture was returned on Day 2 of hospitalization. 265
The cat was observed in hospital for 5 d. Initially, she was stranguric with only a single large micturition in each 24- to 36-hour period. By the 4th day of hospitalization, she was eating and drinking normally and appeared more comfortable. The cat was discharged on day 5, at which time, she had a more normal micturition pattern but still voided large volumes infrequently. No further obstructive problems at home were reported by the owner. Clomipramine is a tricyclic antidepressant used in human medicine to treat depression and obsessivecompulsive disorders (2). The primary mechanism of action of tricyclic antidepressants is to block norepinephrine and serotonin presynaptic neurotransmitter reuptake in the brain, reducing turnover and thus effectively increasing the action of these neurotransmitters. Clomipramine is distinguished from the other tricyclic antidepressants by its potent serotonin reuptake-inhibiting properties, which resemble those of the selective serotoninreuptake inhibitors such as fluoxetine (2). The tricyclic antidepressants as a class have been prescribed in companion and captive animals as anxiolytics and to treat obsessive-compulsive disorders (3-5). Only limited clinical trials have been conducted in dogs, but they have shown successful treatment in some cases of stereotypical behavior, separation anxiety, or self-mutilation (3). Descriptions of the use of these drugs in cats is limited primarily to anecdotal reports. There is limited information not only on the pharmacological profile of these drugs in cats and dogs, but on potential adverse reactions as well. All tricyclic antidepressants have varying degrees of anticholinergic, anti-oti-adrenergic, and antihistaminic effects that account for many of their common side
effects, including urinary retention, hypotension, and sedation. The antimuscarinic (anticholinergic) properties of clomipramine likely accounted for the observed side effects in this cat. Muscarinic blockade decreases the tone of the bladder musculature, which decreases the intraluminal pressure that can be achieved and allows collapse of the trigone area, obstructing urinary outflow. Increased adrenergic activity through inhibition of norepinephrine reuptake may also contribute to urinary retention (2), but this effect may be decreased through the anti-ao1-adrenergic properties. There were several factors that led us to the presumptive diagnosis of clomipramine-induced urinary retention. First, urinary retention is an effect that could be attributed to the known pharmacological properties of clomipramine (2). Although there are no published reports in cats, urinary retention is known to occur in other species, and there are unlikely to be significant differences in antimuscarinic properties of clomipramine among species. Further, the temporal association with the drug was appropriate. The signs appeared 2 d after initiating therapy and were not present prior to treatment. There were no other drugs being administered at the onset of clinical signs and neither physical examination nor laboratory evaluation revealed any other explanation for the clinical signs. Finally, the clinical signs resolved on drug withdrawal and in the absence of any other treatment. Reexposure to the drug at the same dose would have confirmed the diagnosis but to do so was considered unethical. 266
Upon withdrawal of the drug, we estimated that up to 1 wk might be required for resolution of clinical signs. This estimate was based on the reported pharmacokinetics of clomipramine in humans because no data are available in cats. The plasma half-life of clomipramine in humans is 21 h following a single oral dose; clomipramine is metabolized primarily by hydroxylation, demethylation, and N-oxidation (2,6). Many of the metabolites retain pharmacological activity and have even longer half-lives than the parent compound. Although extrapolations between species can be erroneous, we estimated that it could take S to 7 d or longer (5 times the estimated half-life) for the patient to clear the parent drug and its active metabolites, and hence alleviate the clinical signs. This is indeed what was observed. We did not attempt to intervene pharmacologically in this adverse reaction. The urinary retention, although uncomfortable, was not life threatening to the cat, and we did not wish to introduce other possible adverse effects. If pharmacological intervention had been desired, low doses of bethanechol, a muscarinic agonist, could have been employed. The role of an aot-adrenergic blocking drug is not clear. Although clomipramine and its metabolites block the reuptake of norepinephrine and could, therefore, have enhanced the adrenergic effects, many of the tricyclic antidepressants, in fact, have aot-adrenergic antagonist properties. Phenoxybenzamine or prazosin, a1-adrenergic antagonist, could have been administered to ensure that there was no enhanced internal sphincter tone due to aL -adrenergic stimulation, but they may be associated with their own adverse effects. The use of diazepam, a centrally acting muscle relaxant, to relax the external urethral sphincter would not have been justified. The starting dose of clomipramine administered in this case was 1 mg/kg BW/d (1). Although there is little information available on appropriate dosing in cats, suggested doses range from 0.5 to 1.5 mg/kg BW/d in cats (1,3,4). Starting at a dose at 1.0 mg/kg BW/d may have contributed to the occurrence of urinary retention in the patient. In general, in dogs or cats, it is recommended to start at the low end of the dose range (0.5 mg/kg BW/d in cats) and slowly increase to an effective dose in order to minimize the likelihood of adverse effects. It may require at least 2 wk of treatment to see the full behavioral effect of a given dose. This delay is related both to the pharmacokinetic properties of the drug (probably requiring up to 1 wk to reach steady state concentrations) and the pharmacodynamic effects on the central nervous system, which may be delayed. Because this was a pharmacologically mediated adverse effect at a nonprimary target receptor, an attempt could have been made to reintroduce clomipramine at a lower starting dose (starting at 0.1-0.25 mg/kg BW/d and increasing to an effective dose). However, we elected not to try treatment again, given the degree of urinary retention previously observed. Alternative pharmacological therapies for psychogenic alopecia are limited. Fluoxetine has been used (5), but there is currently not enough information available to advocate its general use in cats. Diazepam (0.2-0.4 mg/kg BW, q8-12h) and chlorazepate (0.55-2.2 mg/kg BW, q12-24h) have been suggested, although diazepam has been associated Can Vet J Volume 40, April 1999
with hepatoxicity in some cats (3). Phenobarbital (1 mg/kg BW, ql2h), an anticonvulsant, is another possible option (3-5). Megestrol acetate has also been employed, but its side effects should preclude its use in cats. In general, the prognosis remains poor unless the psychogenic factors are resolved. The use of behavior modifying drugs in cats is based largely on anecdotal evidence. Any practitioner considering the use of tricyclic antidepressant drugs should be aware of their possible adverse effects, which may prohibit the use of this class of drugs in some cats. Many of the drugs suggested for the treatment of psychogenic alopecia also have significant potential adverse effects (3-5). Psychogenic alopecia is not a life-threatening problem, and unless there is significant self-trauma associated with it, the treatment may be worse than the disease. Poorly socialized cats may be even more stressed by the struggle of daily medication. Behavior modification and environmental changes designed to produce a more predictable daily routine should be considered the first
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line of therapy in the treatment of compulsive disorders. Pharmacotherapy should ordinarily be reserved for those cases that are refractory to conservative management or that involve self-mutilation. cvi
References 1. Papich M. Table of common drugs: Approximate dosages. In: Kirk RW, Bonagura JD, eds. Kirk's Current Veterinary Therapy XI: Small Animal Practice. Philadelphia: WB Saunders, 1992: 1233-49. 2. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Hardman JE, Limbird LE, Molinoff PB, Ruddon RW, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw-Hill. 1996: 431-60. 3. Landsberg G, Hunthausen W, Ackerman L. Handbook of Behaviour Problems of the Dog and Cat. Oxford: Butterworth-Heinemann, 1997: 45-65; 175-7. 4. Overall KL. Clinical Behavioral Medicine for Small Animals. St. Louis: Mosby-Year Book, 1997: 293-322 5. Simpson BS, Simpson DM. Behavioural pharmacotherapy. Part I. Antipsychotics and antidepressants. Compend Contin Educ Pract Vet 1996; 18: 1067-81. 6. Anafranil Package Insert. In: Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmaceutical Association, 1996: 73-5.
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