Atenolol is a β1-receptor antagonist commonly prescribed in cats affected with hypertrophic obstructive cardiomyopathy. The traditional oral dose is 6.25 to 12.5 mg per cat q12-24h. The oral tablet is highly bioavailable (90 ± 9%) with peak atenolol concentration occurring 1-2 hours post administration in cats. However results from several studies indicate owner compliance may be poor with long-term oral treatment, and feline disposition can present specific challenges to owners with chronic oral medication administration. Previous veterinary studies investigating transdermal atenolol at equivalent oral atenolol dosages have found the majority of cats receiving transdermal atenolol did not have therapeutic plasma atenolol concentrations 2 hours after administration, and none had therapeutic plasma atenolol concentrations 12 hours after administration. These results raise questions regarding the direct substitution of transdermal doses at equivalent oral doses, and the inherent variability of compounded medications. Therefore the goals of this study were to optimize a non-patented transdermal atenolol formulation and assess atenolol dosage amount and frequency in healthy cats using this formulation. We hypothesized that an optimized transdermal atenolol formula at a higher transdermal dosage rate administered q12h will result in therapeutic ( > 260 ng/mL) atenolol concentrations in healthy cats.
We collaborated with Oregon State University (OSU) College of Pharmacy researchers to create a transdermal atenolol formulation that had optimal drug release and good permeation in a steady-state manner. Different concentrations of atenolol gels in a hypomellose carrier and carbomer base were evaluated by an in vitro diffusion study using Franz-Chin upright diffusion cells. The samples were subsequently analyzed for atenolol content using a high-performance liquid chromatography. Candidate gels with the highest in vitro perfusion rates through polymer membranes were applied to post-mortem samples obtained from the nape and ears of 8 cats. The samples were placed on Franz-Chin diffusion cells to measure skin permeability of atenolol through the excised skin between the half cells. The results indicated that application of the atenolol gel to the ear gave significantly greater permeation, and one topical formulation suggested optimized performance for transdermal applications in vivo. The optimized atenolol formulation with a concentration of 125 mg/mL was then applied to healthy cats enlisted from the OSU veterinary community. Enrolled cats had no abnormalities noted on physical examination, blood pressure measurement, electrocardiogram (ECG), echocardiography, baseline complete blood count and chemistry evaluation. Cats received an escalating dose of transdermal atenolol over 10 days. On the 10th day of treatment, transdermal atenolol was administered and blood samples were collected for atenolol serum concentrations at 3, 6, and 12 hours after topical application. After phlebotomy at 3 and 6 hours post-atenolol administration, an ECG was also performed and average heart rate (HR) measured. Gradual tapering of transdermal atenolol subsequently occurred over 4 days.
All enrolled cats successfully completed the drug trial and no cats experienced any adverse side-effects. Two cats initially received a maximum transdermal dose of 12.5 mg q12h and serum atenolol concentrations were subtherapeutic ( < 260 ng/mL) at 3, 6, and 12 hours post-atenolol. The transdermal atenolol dose was increased to 25 mg q12h, and the same 2 cats were re-enrolled in the study using the higher atenolol dosage after a 4 week washout period. Three cats have completed this updated study protocol at the higher atenolol dosage. Two of the 3 cats had therapeutic serum atenolol concentrations 3 hours post-atenolol; the 3rd cat had a near therapeutic concentration of 255 ng/mL (target ≥ 260 ng/mL) at 3 hours post-atenolol. At the 6 hours post-atenolol timepoint, 1 of the 3 cats had a therapeutic serum atenolol concentration and the other 2 cats had near therapeutic serum atenolol concentrations. At 12 hours post-atenolol dosing, 2 of the 3 cats had therapeutic serum atenolol concentrations. For the HR data post-phlebotomy, all cats had a reduction in HR compared to baseline HR at 3 hours post-atenolol (average reduction of 40 bpm), and 2 of the 3 cats had a reduction in HR at 6 hours post-atenolol (average reduction of 25 bpm) compared to baseline HR.
The results of this pilot study suggest this formulation of transdermal atenolol administered at 25 mg q12h provides therapeutic serum atenolol concentrations and attendant HR reduction in most clinically healthy cats. This preliminary data requires validation in a larger cohort of cats.
Assistant Professor of Cardiology
Oregon State University
Dr. Nicole LeBlanc is currently an Assistant Professor of Cardiology at Oregon State University. Nicole is a 2010 graduate of the University of Wisconsin, and after graduation completed a rotating small animal internship at North Carolina State University, followed by a residency in cardiology at the Oregon State University. Nicole became a Diplomate in the American College of Veterinary Internal Medicine in 2014. Nicole has a clinical research focus on advanced three-dimensional imaging modalities to diagnose acquired and congenital cardiac disorders, as well as minimally invasive therapeutic interventions.
Thursday, June 14
5:00 PM – 5:15 PM
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