Abstract
Objectives
Alpha-adrenergic antagonists are commonly used to prevent recurrent urethral obstruction in cats with mixed reports of efficacy. No published data on tamsulosin use in cats are available. The objective of this study was to measure changes in urodynamic parameters and blood pressure in five healthy male cats before and after administration of tamsulosin orally for 4 and 10 days.
Methods
Five young healthy adult male cats from a research colony were administered tamsulosin at 0.1 mg/cat PO q24h for 10 days. Urethral pressure profile and blood pressure measurements were performed before treatment and approximately 6 h after treatment on days 4 and 10. Maximum urethral closure pressure (MUCP) for the prostatic and penile urethra, functional urethral length (FPL), functional area (FA) and systolic blood pressures were recorded and compared between the time points.
Results
Significant changes in blood pressure on day 4 (121.1 mmHg ± 20.2 mmHg) and on day 10 (112.6 mmHg ± 14.9 mmHg) compared with day 0 (141.1 mmHg± 33.4 mmHg) were not detected (P = 0.18) in anesthetized cats. No significant difference in MUCP, FA or FPL measurements were detected among baseline, day 4 and day 10 of treatment. Hematuria and transient pollakiuria were induced in two cats with 3.5 Fr urethral catheters.
Conclusions and relevance
Tamsulosin at 0.1 mg/cat PO q24h did not induce hypotension in healthy cats. Urodynamic testing performed 6 h after the tamsulosin pill was administered did not detect consistent decreases in urodynamic functions induced by tamsulosin. Repeated catheterization of tom cats with 3.5 Fr catheters may induce significant urethral trauma.
Introduction
Feline idiopathic cystitis (FIC) is the final diagnosis in approximately two-thirds of young adult cats of both sexes with clinical signs of lower urinary tract (LUT) infection.1,2 The definitive cause of FIC is unknown and is likely multifactorial. Male cats are prone to urethral obstruction (UO) from urethral plugs due to the narrow penile urethra. Even though the presence of urethral plugs is not always evident (hence the term ‘idiopathic’), it is possible the urethral plugs disintegrate during the ‘unblocking’ process. Feline UO is one of the most common feline emergency presentations. Even though the survival to discharge rate is excellent,3–5 recurrent UO is common (in the range of 15–65%), and recurrent and refractory cases might ultimately lead to euthanasia in up to 20% of cases. 6
Anecdotally, urethral spasm may contribute to the pathogenesis of UO in cats with FIC. Alpha1 adrenergic antagonists, such as prazosin, are routinely prescribed in clinical practice as an attempt to lessen urethral smooth muscle tone and decrease recurrent UO (rUO). In the past few decades, several studies have been conducted to evaluate the effects of prazosin in cats with UO, and none of these studies found compelling evidence of its clinical efficacy.6–12 Tamsulosin belongs to a newer generation of selective alpha1 adrenergic antagonists. In humans, tamsulosin has greater selectivity for alpha1A adrenoreceptors (the predominant receptor type in LUT tissues) than alpha1B adrenoreceptors (the predominant receptor type in vascular tissues). 13 Tamsulosin has been shown to have better uroselectivity and lower incidence of hypotension compared with other alpha1 adrenergic antagonists, such as prazosin, in human patients with benign prostatic obstruction. 13 To the authors’ knowledge, no studies have been conducted on the presence of alpha 1 receptor subtypes in the urinary system in cats. In one study, tamsulosin was administered at 0.004–0.006 mg/kg, in an attempt to relieve ureteral obstruction of stones in cats and this is the dose reported in veterinary drug handbooks (www.vin.com). 14 However, there are no published data available that describe the effect of tamsulosin on urethral urodynamic findings or LUT clinical responses in cats.
Urodynamic evaluation by performing a urethral pressure profile is a standard procedure in humans. 15 Although UPPs are not routinely performed in cats, standardized protocols have been established. 16 The aim of this study was to evaluate urodynamic parameters as well as blood pressure changes in five healthy male cats being administered tamsulosin at 0.1 mg PO q24h with pre-treatment data compared with data collected after 4 days and 10 days of treatment.
Materials and methods
Animals
Five apparently healthy adult male cats with normal physical examinations from a contract research facility were used in this study with Institutional Animal Care and Use Approval (protocol number 170-070). A complete blood count and serum biochemistry panel were performed before the study to ensure there were no clinically significant abnormalities. Urine samples for urinalysis were obtained by urinary bladder catheterization immediately before the first UPP study under anesthesia to ensure that there was no overt evidence of inflammation or infection. Tamsulosin hydrochloride (compounded from 0.4 mg tamsulosin capsules; Zydus) was dosed at 0.1 mg/cat PO q24h for 10 days. All cats were monitored at least once daily for side effects of the drug as well as adverse effects from the urinary tract procedures.
Anesthesia
A previously established anesthesia protocol used in a previous feline UPP study was followed. 16 Briefly, the cats were placed in an anesthesia chamber infused with 100% oxygen and 3–5% isoflurane for 3–5 mins until sedation was adequate for catheterization of a cephalic vein. Once the cephalic vein catheter was placed, a bolus (2 mg/kg) of propofol (Abbott Animal Health) was administered, followed by a propofol constant rate infusion (CRI) at 0.2 mg/kg/min. If this degree of anesthesia was not adequate, the CRI was increased to a maximum of 0.3 mg/kg/min until the cat was adequately sedated and then decreased to 0.2 mg/kg/min. Cats were maintained on a propofol CRI for at least 15 mins to allow the isoflurane to dissipate before the urodynamic procedures. Oxygen (2 l/min) was delivered via a face mask during the procedures.
Heart rates, respiratory rates and depth of anesthesia were monitored in all cats by an assistant throughout the procedure. Body temperatures were assessed at the beginning and end of the procedures via a rectal thermometer.
Doppler blood pressure
Blood pressure was obtained via a Doppler ultrasonic device as soon as the cats reached the stable plane of anesthesia. Three readings were obtained, and the mean was reported.
Urodynamic evaluations
All procedures were performed using the Goby Urodynamics System (Laborie) used by the internal medicine service at Colorado State University Veterinary Teaching Hospital. In short, after adequate anesthesia was established, the penis was gently exteriorized, cleaned by a lavage of 0.5–2% chlorhexidine followed by a sterile saline lavage, and carefully catheterized with a sterile 3.5 Fr polyurethane infant feeding tube (Kangaroo Neonatal Feeding Tube; CardinalHealth) by the same veterinarian experienced in placing urinary catheters (ZW). After the catheter was placed into the bladder (15 cm from the penile orifice) for all cats, the bladder was emptied and 10 ml of sterile saline was instilled into the bladder. A three-way stopcock was inserted between the catheter and pressure transducer, to allow for infusion of sterile saline at 1 ml/min. The pressure was set to zero while the catheter was in the bladder. The urinary catheter was connected to the urodynamic ‘puller’ and the catheter was mechanically withdrawn at a constant rate of 1.0 mm/s. The UPP tracing was recorded until the urinary catheter was pulled out of the urethra. After the catheter was removed, the propofol infusion was discontinued and the cat was monitored until it had fully recovered from the anesthesia.
The urinary procedures were performed on days 0, 4 and 10 of tamsulosin treatment. On days 4 and 10, data were recorded 6 h after oral administration of the tamsulosin pill.
Areas of the feline urethra (pre-prostatic, prostatic and post-prostatic) were estimated by evaluation of characteristic pressure peaks that have previously been reported, 17 combined with the distance from the external meatus to the post-prostatic area as estimated on the first UPP performed before the administration of tamsulosin.
The following parameters were measured from the UPP tracing using the SketchAndCalc website tool (https://www.sketchandcalc.com/) (Figure 1): ● Functional profile length (FPL): the portion of the UPP tracing during which urethral pressure exceeds intravesical pressure. ● Maximal urethral closure pressure (MUCP): the maximal pressure generated in the urethra. ● Functional area (FA): the area under the FPL curve. FA (whole) indicates the area under the entire FPL curve. FA (pre-prostatic and prostatic) indicates the area under the FPL curve for the section of pre-prostatic and prostatic urethra.
Demonstration of maximal urethral closure pressure (MUCP) and functional profile length (FPL) on a urethral pressure profile (UPP) tracing (a) and measuring urodynamic parameters – whole functional area (FA), (b) and pre-prostatic and prostatic FA (c) using SketchAndCalc tool
Statistical analysis
The normality of the data was tested using the Jarque-Bera test at a 5% significance level and confirmed normal distribution of all data. Blood pressure and urodynamic parameter results on days 0, 4 and 10 of tamsulosin administration were reported as mean ± SD and a repeated measure ANOVA was used to compare the values. A value of P <0.05 was considered significant.
Results
Animals
The mean age of the five cats was 5.9 years (range 5.7–6.3) and the mean body weight was 6.4 kg (range 5.5–7.3). All cats were castrated males. Based on the 0.1 mg of tamsulosin per cat, the doses administered were 0.020, 0.017, 0.018, 0.018 and 0.014 mg/kg. No anesthesia complications were observed during the study. Gross hematuria, stranguria and pollakiuria were observed 36 h after the day 10 UPP in one cat. The clinical signs lasted for 72 h and resolved with robenacoxib (Onsior; Elanco) at 12 mg PO q24h for 3 days. Microscopic hematuria was observed in another cat that lasted for less than 24 h with no treatment. Urinalysis was performed on the urine collected on the day 10 UPP study for all cats. Microscopic hematuria and pyuria were observed in one cat that had transient hematuria. Urine culture revealed coagulase negative Staphylococcus (1000–10,000 cfu/ml). Antibiotic treatment was not initiated due to the spontaneous resolution of clinical signs according to the International Society for Companion Animal Infectious Diseases (ISCAID) guidelines for the diagnosis and management of bacterial urinary tract infections in dogs and cats. 18 No LUT signs or active urinary sediments were noted on urinalysis in other cats.
Blood pressure
No significant differences (P >0.05) in blood pressure or heart rate among data collected on days 0, 4 and 10 were detected (Table 1). However, the effect size for the mean blood pressure comparisons for day 0 and day 10 was 1.1.
Blood pressure (BP) and heart rate (HR) values
Data are mean ± SD
Urethral pressure profiles
UPPs were obtained from the five cats without complications (Table 2, Figure 2). No significant differences in MUCP, FA and FPL were detected among the data collected on days 0, 4 and 10 from the five cats (P >0.05). Compared with day 0, the FA (whole) was lower in all five cats on day 4 (P = 0.01) but the mean values were not significantly lower by ANOVA. Compared with day 0, the FA (whole) was still decreased in 3/5 cats on day 4 (P = 0.17) but the mean values were not significantly different by ANOVA.
Maximal urethral closure pressure (MUCP), functional area (FA) and functional profile length (FPL) values
Data are mean ± SD
Urodynamic parameter changes over the course of the study. The short horizontal line depicts the mean value. No statistical differences were identified in any comparison: (a) prostatic maximal urethral pressure, (b) penile maximal urethral pressure, (c) whole functional area, (d) pre-prostatic and prostatic functional area and (e) functional profile length. MUCP = maximal urethral closure pressure; FA = functional area; FPL = functional profile length
Discussion
In the present study, tamsulosin administered at 0.1 mg/cat (mean = 0.017 mg/kg) PO q24h for 10 days did not induce hypotension in healthy anesthetized cats 6 h after the drug was administered. However, this protocol also failed to induce a measurable difference in urodynamic parameters 6 h after administration on day 4 and day 10 of treatment in comparison with baseline. It was also found that repeated catheterization of young healthy male cats with a 3.5 Fr polyurethane catheter, even for the short period of time needed to collect urodynamic information, may induce urethral trauma and cause transient LUT signs. This finding may have masked an effect of the drug on UPP measurements in this study.
To the authors’ knowledge, this is the first study utilizing UPPs to evaluate the effect of alpha antagonists on urodynamic findings in male cats. The UPP is intrinsically challenging to perform in male cats due to difficulty in catheterization and possible UO secondary to urethral trauma. Before the present study, we had performed a pilot experiment using the same methods, except that 5 Fr polyurethane catheters were used for the procedures. In that pilot experiment, significant urethral inflammation and penile swelling were noted in all five cats after catheterization on day 0, only two cats could be re-catheterized on day 4 and only 1/4 cats could be catheterized on day 10. Clinical abnormalities resolved in all cats with supportive care and the study was amended to use 3.5 Fr catheters with the group of five cats described herein. As described, the 3.5 Fr catheters were easily passed to collect the UPP measurements. However, mild distal penile swellings and lower urinary signs were still observed in 2/5 cats. Our findings add to the body of literature indicating that the size of urethral catheter used in tom cats has a significant effect on trauma of the LUT and rates of rUO. Similar findings were noted in a retrospective case series evaluating 192 male feline UO cases; rOU rates were >2.5 times higher in cats catharized with 5 Fr than those catheterized with 3.5 Fr catheters. 8 The 5 Fr catheters have more forcible contact with the urethral mucosa and are therefore more likely to incite urethral trauma and inflammation, which can contribute to UO or rUO. Clinical treatment for UO usually consists of placement of indwelling urinary catheters for 24–72 h. Previous studies identified either no association between rUO and duration of catheterization 8 or decreased risk of UO with a longer duration of catheterization. 12 Such findings, along with our results, suggest the LUT trauma associated with catheterization most likely happens during placement and removal of the catheter. The mere presence of the catheter in the urinary tract may contribute less to iatrogenic LUT inflammation.
The significant distal urethritis seen in the present study was not observed in a similar study performed in female cats with idiopathic cystitis using 6 Fr double-lumen urinary catheters for UPP. 16 The differences may arise from anatomic differences, the ease of catheterization in female cats (even though no forceful catheterization was perceived in the present study) and differences in catheter material. In the present study, polyurethane catheters were used for catheterization. Among the types of urinary catheters commonly available in veterinary medicine (polypropylene, polyvinyl, polytetrafluorethylene and polyurethane), polyurethane is considered to be less reactive and irritating to the urethra mucosa compared with polypropylene or polyvinyl. 19 Polyurethane catheters also have the benefit of being stiff in room temperature, which aids in the ease of catheterization, and they soften when warmed up to body temperature. 19 Therefore, it is reasonable to deduce that even more severe urethritis would have been induced in this group of cats if a different type of catheter had been used.
With such findings in mind, it is reasonable to suspect the later series of UPP measurements reported herein likely reflect both the effects of tamsulosin (potential decrease in urethral tone) and iatrogenic cystitis/urethritis from catheterization (increasing urethral tone). The FA (whole) was consistently decreased in all five cats on day 4 and remained decreased on day 10 in 3/5 cats, even though the results were not statistically different to baseline. MUCP (prostatic) and MUCP (penile) were numerically elevated on day 4 and day 10 in comparison with baseline, but again, the findings were not statistically significant.
In male cats, the pre-prostatic urethra is composed of smooth muscle. Smooth muscle begins to transition to striated muscle at the prostatic urethra, and the post-prostatic urethra is composed of striated muscle. 17 In order to specifically assess the tamsulosin-targeted area and eliminate the impact of iatrogenic distal urethral inflammation from clinical observation, we further evaluated the FA of the pre-prostatic and prostatic areas separately. The findings were similar to those from the FA (whole) and showed no statistically significant decrease with tamsulosin.
Our UPP tracings revealed that the post-prostatic urethra is predominantly responsible for urethral pressure, which is similar to previous reports. 17 This suggests that skeletal muscle relaxants may have larger effects for urethral relaxation than alpha antagonists, and not only tamsulosin but all alpha antagonists may not have an effect on UO in male cats. However, the side effects of skeletal muscle relaxants, including lethargy, weakness and ataxia, may be less tolerable for patients.
Hypotension is the major side effect for alpha antagonists. In our study, we evaluated blood pressure before and after the administration of tamsulosin. Doppler blood pressure measurements when the cats were awake were attempted initially but failed due to excessive stress and/or excitement in this group of research colony cats. Therefore, blood pressure was measured when the cats first reached the stable plane of anesthesia. Because the same anesthesia protocol was used consistently throughout the study, we suggest the results are comparable. No significant changes in blood pressure or heart rate were observed in our study. However, it is possible that the effect of anesthesia may have completely overridden the effect of tamsulosin. In addition, while the difference in HR and BP were not statistically significant in the present study, it may be clinically relevant. No other clinical side effects of tamsulosin were observed during study period, suggesting tamsulosin administered at 0.1 mg per cat PO q24h is likely safe.
There is no pharmacokinetics study of tamsulosin that is available for cats. In humans, it takes approximately 4–7 days for tamsulosin to reach a steady-state plasma concentration. 13 A study in dogs revealed that after oral tamsulosin dosing, the drug was retained in LUT tissues, displayed peak urethral effects 1–2 h after dosing and those effects lasted at least 6–8 h. 20 Based on that study, we chose to perform UPP measurements 6 h after the tamsulosin pill was administered. The administration of tamsulosin at 0.004–0.006 mg/kg to cats with ureteral calculi showed potential beneficial effects 14 and so we hypothesize that the dose used in this study (mean 0.017 mg/kg, range 0.014–0.020 mg/kg) should have had an effect on the urethral smooth muscle. However, it is possible that even higher doses of tamsulosin would achieve better efficacy. Further pharmacokinetic and pharmacodynamic studies are needed to investigate the functional effects of tamsulosin and the concentration of the drug in LUT tissues in cats.
The present study has some limitations. First, the small sample size that was approved by the IACUC for this study may have been an important limiting factor and the results must be interpreted with caution. While the day 4 FA (whole) was lower than that of day 0 in all five cats, the mean values were not significantly different and there were no differences in other parameters. Further study with a larger number of cats is needed to provide more definitive information about the potential benefits of tamsulosin in managing feline UO. Second, our study was conducted on a group of healthy adult male cats; the findings may differ in cats with FIC. Third, our study only evaluated tamsulosin at one anecdotal dose that was tested only at 6 h after administration. Future pharmacokinetic and pharmacodynamic studies are needed to help explore the optimal dosing for this medication in cats. Finally, it is possible the induction of anesthesia created some stress for the cats involved in this study; however, it was considered the safest and most stress-free choice for this group of research colony cats due to their resistance for handling without sedation. Utilization of other sedatives may have interfered with the UPP results.
Conclusions
Tamsulosin at 0.014–0.020 mg/kg PO q24h for 10 days did not induce hypotension in anesthetized cats nor consistent changes in urodynamic functions in healthy male cats. Repeated catheterization of tom cats with 5 Fr catheters may induce significant urethral damage and this may not be totally avoided by using 3.5 Fr catheters.
Footnotes
Acknowledgements
The authors would like to thank Megan Slaughter, Maya Swiderski, Kara Maslyn and Patricia Lopes Sicupira Franco for their assistance with this study.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
Ethical approval
The work described in this manuscript involved the use of experimental animals and the study therefore had prior ethical approval from an established (or ad hoc) committee as stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). For any animals or people individually identifiable within this publication, informed consent (verbal or written) for their use in the publication was obtained from the people involved.