Treatment of Feline Hypertension With Transdermal Amlodipine: A Pilot Study

Introduction

Systolic hypertension, a well-recognized disease of cats, has been associated with chronic renal failure, hyperthyroidism, diabetes mellitus, and hyperaldosteronism.¹ It should be considered as a differential diagnosis for cats with acute onset of blindness, retinal edema, retinal hemorrhage, retinal detachment, cardiac disease, or neurological abnormalities.¹ In 1997, Henik suggested that any feline patient with an indirect blood pressure consistently over 170/100 mm Hg should be treated with antihypertensive medication.² Uncontrolled hypertension can result in damage to ophthalmic, renal, cardiovascular, and cerebrovascular tissues.² In most cases of suspected hypertension, reliable blood pressure measurement can be obtained with doppler-sonographic methods.^3,4 A quiet environment and adequate patient acclimation are necessary to obtain reliable blood pressure results.⁵ In cats found to be hypertensive, oral amlodipine administered once daily is a highly effective antihypertensive agent.^6–9

Oral administration of medications in cats is often problematic for clients and patients, resulting in compliance issues and dysregulation of hypertension control. Additionally, the stress of administering oral medications may result in a transient increase in the animal’s blood pressure. Transdermal drug administration holds promise as an alternative drug-delivery method.^10–12 While dermal delivery may circumvent the hepatic first-pass effect, most drugs, in their native form, cannot penetrate the stratum corneum.¹³ The molecular weight and n-octanol/water partition coefficient of the drug in question are important determinants of the drug’s ability to breach this dermal barrier.^13–18 The development of permeation enhancers and a greater understanding of the effects of these enhancers on the stratum corneum have resulted in a greater interest in transdermal drug delivery.^14,17,19,20 This advancement allows the transdermal administration of drugs that otherwise would be unsuitable for such therapy. Some drugs undergo dermal metabolism after transdermal administration, and their systemic absorption may be less than predicted. ¹³ Without pharmacokinetic data from transdermal studies, one should not assume that any transdermally administered drug will have a bioequivalence or duration of action similar to the same dose of drug administered orally.

Transdermal drug delivery studies in cats are limited. Published single-dose feline transdermal administration studies with methimazole, dexamethasone, fluoxetine, amitriptyline, buspirone, and glipizide have shown low to undetectable bioavailability compared to oral dosing.^21–25 However, in the methimazole and glipizide studies, clinical response was seen with chronic dosing, suggesting that single- dose kinetics are insufficient to determine clinical responses.^25–27

No studies exist that examine clinical responses of blood pressure to transdermally administered amlodipine in hypertensive cats. This prospective, open-label study evaluated the clinical response of hypertensive cats treated with transdermal amlodipine, and it assessed the relative bioavailability of transdermal administration compared to oral dosing of amlodipine.

Materials and Methods

Six privately owned cats evaluated at a referral institution and subsequently diagnosed with systolic hypertension were included in this prospective study. The diagnosis of hypertension was made using the following criteria:

1. Any cat with retinal lesions and an average Doppler^a-measured systolic blood pressure of >180 mm Hg was diagnosed with hypertension.²⁸

2. Any cat with an average systolic blood pressure >220 mm Hg was diagnosed with hypertension.

3. Any cat with an average systolic blood pressure between 180 and 220 mm Hg was evaluated at a second visit. If the cat’s average systolic blood pressure was still >180 mm Hg on the second visit, hypertension was diagnosed.

The minimum database for these cats included a complete blood count, serum biochemical panel, urinalysis, and total thyroxine level (T4). These tests were completed at the time of initial evaluation. Cats were enrolled in the study from November 2002 to June 2003 with informed owner consent. Hyperthyroid cats were excluded from the study until they had undergone radioactive iodine therapy (¹³¹I), were euthyroid (T4 range of 1.0 to 4.0 μg/dL), and were determined to be persistently hypertensive in their euthyroid state. Cats on antihypertensive medications at the time of initial examination were excluded from the study.

The technique for blood pressure measurement was consistent for each cat. All cats were acclimated to the room, the animal holder, the primary investigator, and the Doppler device prior to blood pressure measurement. Coupling gel was applied liberally over the plantar metatarsal arteries, and the Doppler piezoelectric crystal was positioned until a good Doppler signal was heard. Clipping of hair was avoided unless a Doppler signal could not be obtained by the aforementioned method. Cuff size was selected to approximate 40% of the circumference of the limb proximal to the tarsus. Each cat was positioned in right lateral recumbency; the cuff was then applied proximal to the left tarsus, and a systolic blood pressure reading was measured. At least five measurements were taken in succession over a span of a couple of minutes, and the average of three middle values was recorded in the patient chart as the systolic blood pressure. Repeat blood pressure measurements at subsequent examinations were completed using the same cuff size and leg for each cat.

The transdermal amlodipine for this study, prepared by an independent compounding pharmacist,^b consisted of 0.625 mg of amlodipine besylate in 0.1 mL of Lipoderm base ointment.^c The amlodipine was obtained from commercially available 5-mg amlodipine tablets.^d

Results

One neutered male and five spayed female cats were included in the study. The cats ranged from 9 to 16 years of age (median 13.2 years) and weighed 2.41 to 5.91 kg (median 3.4 kg). Domestic shorthair (n=5) and Persian (n=1) were the only breeds represented in the study. Concurrent disease was present in all cats and included controlled hyperthyroidism ([n=2] pre¹³¹I T4 of 14.8 μg/dL and 10.2 μg/dL; post¹³¹I T4 of 1.6 μg/dL and 1.2 μg/dL, respectively [normal reference range 0.8 to 4.0 μg/dL]); renal insufficiency ([n=1] blood urea nitrogen [BUN] 50 mg/dL [reference range 14 to 36 mg/dL], creatinine 3.0 mg/dL [reference range 0.6 to 2.4 mg/dL], and urine specific gravity 1.024 [reference range 1.018 to 1.050]); renal insufficiency and seizures ([n=1] BUN 45 mg/dL, creatinine 3.5 mg/dL, and urine specific gravity 1.018); bilateral retinal detachment and acute onset of blindness (n=1); and inflammatory bowel disease based on endoscopic biopsy (n=1). No dermal irritation of the pinna was noted on any cat during the transdermal administration period. The Doppler device used for this study could not measure systolic blood pressures >300 mm Hg. For cats with a presenting systolic blood pressure >300 mm Hg (n=1), a systolic pressure of 300 mm Hg was used for calculation purposes.

The median pretreatment systolic blood pressure was 242.5 mm Hg, with a range of 192 to 300 mm Hg [Table 1]. After 7 days of oral antihypertensive therapy with a median dose of 0.285 mg/kg q 24 hours, blood pressure dropped by a median of 73.5 mm Hg (range 48 to 122 mm Hg; relative change=32%, P<0.05). After 7 days of transdermal therapy at the same dose, blood pressure remained 51.5 mm Hg lower than pretreatment pressures (range 20 to 90 mm Hg; relative change=22%, P<0.05). The relative decrease in blood pressure after oral amlodipine was greater than that after transdermal amlodipine (P<0.05). When the oral and transdermal data were combined and pharmacodynamically modeled using simple Emax, the calculated effect (percent change in blood pressure, R) for a given plasma level demonstrated a good correlation to the observed effect (measured percent change in blood pressure) [see Table 2, Figure]. The mean difference between the calculated and observed effects was 3.35±1.83 mm Hg.

Discussion

Transdermal amlodipine application for 7 days to clinically hypertensive cats resulted in a substantial reduction in systolic blood pressure, despite a low relative bioavailability (31%), when compared to oral amlodipine. As expected, transdermal amlodipine resulted in a lesser magnitude of change (51.5 mm Hg versus 73.5 mm Hg; relative change of 21% versus 33%). All six were able to maintain systolic pressures at ≤220 mm Hg, but only three of six cats maintained systolic blood pressures ≤180 mm Hg on transdermal amlodipine, as compared to all cats on oral amlodipine. These data suggest that transdermal amlodipine at doses comparable to oral doses may result in clinical control of hypertension.

The amlodipine bioavailability results and clinical responses in this study mimic those found for other transdermal drug preparations; that is, the transdermal preparation had substantially lower bioavailability but induced a statistically and clinically significant reduction in the clinical parameter being evaluated (blood pressure, blood glucose, serum T4).^25–27 While no data exist for the pharmacokinetics of amlodipine in cats, based on data published for other species, the oral bioavailability of amlodipine is expected to be high in cats.²⁹ Furthermore, it would be extremely unlikely that the relative bioavailability of transdermally administered amlodipine would exceed that of the orally administered preparation.¹³ In this study, the relative bioavailability of the transdermal preparation was considerably lower than the bioavailability of the oral preparation administered [Table 1]. The cause of the lower bioavailability is unknown; however, general hypotheses of transdermal drug bioavailability include dermal metabolism and/or diminished transdermal penetration.^10–13

Clinical response to the transdermal product was noted, and blood levels could be measured after 7 days of transdermal administration. The lower relative percent change in blood pressure after transdermal amlodipine likely resulted from the lower plasma concentrations of amlodipine, as predicted by the pharmacodynamic modeling. While the results obtained from this study should not be considered representative of expected therapeutic plasma levels of amlodipine in the cat, these data suggest that transdermal preparations may require drug concentrations two to three times greater than those used in this study.

Marked drug pharmacokinetic variability is known to exist between various species.²⁹ Until amlodipine pharmacokinetic studies in the cat have been completed, the metabolic fate of amlodipine in this species must be extrapolated based on published information regarding dogs and humans.²⁹ The plasma half-life for amlodipine in the cat has not been established; based on data from dogs, rats, and mice, a 7-day transdermal dosing period was chosen to allow for elimination of previously administered oral drug.²⁹

This study had obvious limitations. Ideally, this study would have included a washout period in which no amlodipine was administered prior to initiation of transdermal therapy in each cat. However, the cats included in the study were being treated for clinically significant hypertension, and withholding therapy would have been clinically inappropriate. Alternatively, a crossover design could have been implemented; however, since the cats in this study were presented for significant hypertension, the initial and clinically appropriate therapy was to administer a proven effective dosage form of amlodipine.⁷ Although the sample size in this study was relatively small, significant changes were observed, providing preliminary evidence for prospective evaluation of transdermal amlodipine.

The bioavailability data should not be used as reference data for therapeutic plasma concentrations, because they were obtained in a small population of cats with hypertension, and true pharmacokinetics were not evaluated. Without pharmacokinetic data, the time of maximum absorption of amlodipine after oral and transdermal administration remains unknown. Potentially, differences in absorption rate between preparations and degradation of drug during storage (some were stored for 2 years) may have affected the results of this study. Additional studies are required to examine single-dose and steady-state pharmacokinetics and pharmacodynamic responses in both healthy and hypertensive cats. Finally, the ability of twice-daily transdermal amlodipine administration to achieve clinical control of the hypertension was not examined. It is possible that more frequent application would result in better control, as has been shown with oral amlodipine in some refractory hypertensive patients. This study does not establish a therapeutic range for amlodipine in the cat; however, the data suggest that many cats given oral amlodipine at a mean dose of 0.28 mg/kg have reductions in blood pressure to normotensive ranges (as documented by previous investigators), and that the same dose administered transdermally produces substantial reductions in blood pressure in hypertensive cats, but may not reach normotensive ranges.^6–8

This study made no attempt to assess the effects of fear or stress on blood pressure measurements. It was also impossible to assess how conditioning the cats to blood pressure measurement may have affected the results in the transdermal arm of the study. It is possible that the reductions observed with the transdermal preparation were greater than what would have been achieved if transdermal preparations were administered to unconditioned (naïve) cats. However, the results of the pharmacodynamic modeling provided strong support for a clinical response to transdermal amlodipine.

Conclusion

This study shows that transdermal amlodipine administered at doses comparable to once-daily oral amlodipine can maintain a reduction in blood pressure in hypertensive cats. The degree of reduction in blood pressure maintained with transdermal amlodipine was less than that achieved by oral amlodipine, but it was clinically important, even in cats whose pressure failed to remain in the normotensive range. The reduced magnitude of effect is predicted by the lower plasma concentrations achieved with the dosing used in this study. Plasma concentrations of amlodipine can be measured in all cats after transdermal amlodipine administration; these plasma concentrations show that the relative bioavailability of transdermally administered amlodipine is less than that of orally administered amlodipine. This study provides the basis for prospective, randomized crossover studies to further assess the potential use of transdermal amlodipine in the treatment of feline hypertension.