Veterinary : Cardiology/Hypertension
 
 
 

Compounding For Feline Hypertension

Therapies for feline hypertension have not often been systematically evaluated. Therapies that have been employed and reported include diuretics (furosemide and spironolactone), angiotensin-converting enzyme inhibitors (ACE-I; captopril, enalapril, lisinopril, and benazepril), beta-blockers (propranolol and atenolol), and calcium channel blockers (diltiazem and amlodipine). Littman retrospectively evaluated 24 cats with chronic renal failure (CRF) and found that the most effective antihypertensive therapy was the combination of a beta-blocker and an ACE-I and that there was a poor response to furosemide. Jensen prospectively studied 12 similarly affected cats and found that the response to an ACE-I or beta-blocker alone was poor. A North Carolina State University study retrospectively found amlodipine to lower blood pressure ≥ 20% in 30 of 32 hypertensive cats with 28 of 32 becoming normotensive. Diltiazem and beta-blockers alone or with ACE-I also lowered blood pressure in the majority of cats so treated. The literature and clinical experience would, nevertheless, lead one to appropriately conclude that amlodipine is the single best agent for the management of feline systemic hypertension, and that the adjunct therapies mentioned above may be added if indicated.

To reduce stress to the cardiovascular system of the feline patient and to preserve the owner-pet bond, palatable, non-invasive therapy is mandatory for treatment of feline hypertension. Amlodipine is dosed at 0.3mg – 0.625mg orally once to twice daily, and has also been shown to be effective when applied transdermally at approximately twice the effective oral dose. Amlodipine is only FDA approved for human use and is available in tablet sizes far too large to afford safe and effective therapy in cats. Our compounding pharmacists can compound amlodipine into oral suspensions, capsules, treats, and powders to sprinkle on food, as well as into transdermal gels for application to the pinnae. Diltiazem may also be utilized to lower feline blood pressure and is available in several human-approved dosage forms that are, again, far too large for use in cats. Diltiazem controlled-delivery (Cardizem CD®) is the only dosage form of diltiazem that demonstrates pharmacokinetics to support once daily dosing in cats. Available as a capsule containing a 40/60 mixture of immediate release and sustained release beads of diltiazem, compounding pharmacists can reformulate these capsules into 45mg (total) doses for once daily administration to cats. Diltiazem has not been sufficiently evaluated to determine whether or not transdermal administration is effective; however, there are many anecdotal reports of efficacy. Atenolol may be useful in reducing heart rate in hypertensive cats and is dosed empirically at 6.25mg – 12.5mg per cat orally once daily. Again, our compounding pharmacists can provide palatable dosage forms of atenolol that are voluntarily accepted by feline patients. For feline patients requiring multiple therapies, we can also provide combination therapies in a single dosage form. For example, we can compound a single capsule or treat that contains amlodipine, diltiazem and atenolol, further reducing the stress to both patient and owner. We invite veterinarians wishing to explore palatable and non-invasive therapies for cats with hypertension to consult with our compounding pharmacists.

J Vet Intern Med. 1994 Mar-Apr 1994;8(2):79-86.
Spontaneous systemic hypertension in 24 cats.
Littman MP.
Click here to access the PubMed abstract of this article.


Am J Vet Res. May 1997;58(5):535-540.
Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease.
Jensen J, Henik RA, Brownfield M, Armstrong J.
Click here to access the PubMed abstract of this article.

J Am Vet Med Assoc. Sep 2000;217(5):695-702.
Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998).
Maggio F, DeFrancesco TC, Atkins CE, Pizzirani S, Gilger BC, Davidson MG.
Click here to access the PubMed abstract of this article.

J Am Anim Hosp Assoc. 2007 May-Jun 2007;43(3):149-156.
Treatment of feline hypertension with transdermal amlodipine: a pilot study.
Helms SR.
Click here to access the PubMed abstract of this article.

 


 

Low Dose Anti-platelet Therapies for Feline Arterial Thromboembolism (FATE)

Feline hypertrophic cardiomyopathy (HCM) is the most common form of heart disease in cats and is characterized by concentric thickening of the left ventricle. The clinical consequences of ventricular hypertrophy include arrhythmias, congestive heart failure, and feline aortic thromboembolism (FATE). FATE carries an extremely poor prognosis with a 66% mortality rate. The formation of aortic clots in FATE leads to paralysis, severe leg pain and, often, death. There is no cure for HCM; hypertrophy of the heart wall is irreversible. Therapies demonstrating benefit to HCM patients include beta-blockers, diuretics, ACE inhibitors, and antiplatelet drugs. Because systemic warfarin therapy is associated with a high occurrence of hemorrhagic events, aspirin has historically been utilized as the primary oral antiplatelet therapy to prevent FATE in cats with HCM. It was initially dosed at 81mg every 72 hours as this was the smallest commercially available dosage form of aspirin. A study in 2003 revolutionized low dose aspirin therapy in cats through utilization of a compounded 5mg aspirin capsule administered orally every 72 hours. Results of this study indicated that the same degree of antiplatelet activity was achieved but the inhibition of endothelial production of prostacyclin (PGI), an antagonist to platelet aggregation and vasoconstriction, is not affected with the 5mg dose as is seen with the 81mg dose. This study also demonstrated a lower incidence of gastrointestinal adverse effects with the 5mg dose when compared to the 81mg dose of aspirin.
Clopidogrel (Plavix™) has been shown to be more effective than aspirin in preventing myocardial infarction, stroke and peripheral vascular events in humans. Clopidogrel has recently been evaluated in cats and has been shown to significantly inhibit multiple platelet functions. Investigators concluded that a low dose of 18.75mg of clopidogrel (1/4 of a commercially available 75mg tablet) given orally once daily was safe and effective anti-platelet therapy for cats. Investigators also commented that a considerably lower compounded dose of clopidogrel may prove to be as effective, safer, and considerably less expensive than quartering the commercially available tablets and recommended that studies be performed with lower doses of clopidogrel as were done with aspirin in 2003. Some veterinary teaching hospitals are utilizing doses of 6mg and 7mg clopidogrel orally once daily in combination with low dose aspirin therapy although the efficacy of these therapeutic regimens have not been evaluated. The multi-centric Feline Arterial Thromboembolism – Clopidogrel vs. Aspirin Trial (FAT-CAT) initiated at Purdue University College of Veterinary Medicine has been accepting FATE cats for enrollment for the last two years to determine if there is clinical superiority of either agent when prophylaxing against recurrence of FATE. Initial results show a significant (41.6%) reduction of FATE recurrence in one of the two treatment groups; however, study coordinators will not unblind the treatment arms to investigators until the full enrollment of 30 cats per treatment group is achieved. Clinicians interested in learning more about the FAT-CAT study should visit http://www.vin.com/FATCAT/ Veterinarians interested in exploring use of low dose aspirin and low dose clopidogrel therapy can collaborate with our compounding pharmacists regarding formulation of patient-specific doses.

J Vet Intern Med 2003;17:73-83
Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases.
Click here to access the abstract of this article.

J Am Vet Med Assoc 2004;225:1406–1411
Antiplatelet effects and pharmacodynamics of clopidogrel in cats.
Click here to access the PubMed abstract of this article.

Cornell University and NC State University

 


 

Transdermal Diltiazem for Treatment of Hypertrophic Cardiomyopathy in Cats

Diltiazem has direct coronary vasodilating properties, a beneficial therapeutic effect not provided by the beta-adrenergic blocking agents for the management of feline hypertrophic cardiomyopathy (HCM). “Orally administered diltiazem appears to have sustained beneficial effects on left ventricular filling and cardiac performance based on its ability to reduce resting heart rate, decrease blood lactate concentration, increase venous oxygen tension, improve echocardiographic parameters, and resolve radiographic abnormalities. Long-term diltiazem administration may also reverse myocardial hypertrophy in some patients. There appear to be few if any side effects of this drug. Diltiazem, therefore, provides a safe and effective approach for the management of feline HCM.”

At North Carolina State University, College of Veterinary Medicine, analysis of diltiazem in Lipoderm® transdermal gel showed that diltiazem was stable at a concentration of 246 mg/ml for 30 days and at a concentration of 99.6 mg/ml for 60 days, no matter the storage conditions explored in the study.

A formula is available for Diltiazem 5% for veterinary use.

Vet Clin North Am Small Anim Pract. 1991 Sep;21(5):1023-34.
Evidence for or against the efficacy of calcium channel blockers for management of hypertrophic cardiomyopathy in cats.
Click here to access the PubMed abstract of this article.

J Pharm Biomed Anal. 2005 Jun 1;38(1):60-5. Epub 2004 Dec 25.
Analysis of diltiazem in Lipoderm transdermal gel using reversed-phase high-performance liquid chromatography applied to homogenization and stability studies.
Click here to access the PubMed abstract of this article.

International Journal of Pharmaceutical Compounding. Jan/Feb 2008; 12(1):67
Diltiazem 5% in Lipoderm, Veterinary
Click here to access the abstract of this article.

 


 

Transdermal Atenolol and Feasibility of Transdermal Administration

Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.

“In theory, the transdermal route of administering medications has many potential advantages. It is noninvasive and not demanding technically, avoids first-pass hepatic metabolism and gastrointestinal breakdown, has potential for sustained release formulations, and can be administered over a large surface area. Transdermal administration of medication has been shown to achieve blood concentrations of drug that are considered to be therapeutic (eg, fentanyl) or efficaciously affect physiologic surrogates (eg, methimazole, nitroglycerine, and lidocaine). Feasibility of transdermal medication varies on a drug-by-drug basis.”

Discussion: In spite of these results, investigators did not conclude that transdermally administered atenolol is not feasible.Because two cats did achieve therapeutic blood concentrations of atenolol after transdermal administration, the authors called for further research to find a transdermal formulation and dosing regimen for atenolol that will consistently result in plasma atenolol concentrations of >260ng/ml.Investigators offered several considerations for future studies. This study utilized a hydrophilic carbomer/propylene glycol/glycerin gel vehicle which has been used in human delivery of transdermal medications. As pluronic lecithin organogel (PLO) is the transdermal vehicle used almost exclusively in veterinary medicine, investigators encouraged future transdermal atenolol research utilizing PLO as the vehicle.Investigators also noted that higher doses of atenolol (3mg/kg) have been reported to consistently result in blood levels providing adequate adrenergic blockade at 12 hours in all cats studied.Since the median atenolol dose administered in this study was 1.1mg/kg, researchers suggest studying transdermal atenolol at the 3.3mg/kg dose.

Because daily oral administration of atenolol to cats is challenging and often results in a lack of compliance, a non-invasive dosage form such as transdermal atenolol will most likely result in better compliance, less stress to the cat, and reveal a positive therapeutic effect.

Am J Vet Res. 2008 Jan;69(1): 39-44.
Comparision of pharmacodynamic variables following oral versus transdermal administration of atenolol to healthy cats.
Click here to read the PubMed abstract of this article.

 


 

Enalapril for Cardiomyopathy and CHF


"Enalapril maleate is an angiotensin-converting enzyme (ACE) inhibitor labeled to treat mild to severe heart failure in dogs." Research has shown that enalapril in combination with diuretics - with or without digitalis glycosides - "produces statistically significant clinical improvement in dogs with advanced heart failure due to mitral regurgitation or dilated cardiomyopathy" and has demonstrated "beneficial hemodynamic and clinical effects of adding enalapril to conventional therapy for dogs with CHF... Dogs treated with enalapril and conventional CHF therapy survived two times as long as did those receiving standard therapy alone."

Enalapril has also "been effective in treating cardiomyopathy and CHF in cats and ferrets, and its effects on blood pressure in horses and camels have been studied." Because enalapril is a prodrug and can not be converted to its active form enalaprilat in patients with severe liver dysfunction, captopril or lisinopril might be a better choice in those patients. Renal function should be checked before starting enalapril therapy and at least every two months thereafter. The most common side effects are gastrointestinal, but there have been reports of enalapril-induced cough in dogs and a bird. Hypotension is a major concern if overdose occurs. NSAIDs, including aspirin, may reduce enalapril's effect. The injectable form (enalaprilat) should not be given orally because it is very poorly absorbed.

"The recommended dose for enalapril in dogs is 0.5 mg/kg orally every 12 to 24 hours. The dose for cats is 0.25 to 0.5 mg/kg orally every 12 to 24 hours."

Compendium, Dec. 1999

 


 

Amlodipine to Treat Feline Systemic Hypertension


Amlodipine, a calcium channel blocker, has an antihypertensive effect in cats with coexistent systemic hypertension and renal insufficiency. Its use may improve the prognosis for cats with systemic hypertension by decreasing the risk of ocular injury or neurologic complications induced by high blood pressure (BP). In a retrospective study, medical records from 69 cats with systemic hypertension and hypertensive retinopathy were reviewed. 68.1% of the cats were referred because of vision loss; retinal detachment, hemorrhage, edema, and degeneration were common findings. Amlodipine decreased BP in 31 of 32 cats and improved ocular signs in 18 of 26 cats. Primary hypertension in cats may be more common than currently recognized.

In a study at the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, amlodipine was shown to be a safe and effective once-daily antihypertensive agent when administered to cats at a dosage of 0.18 +/- 0.03 mg/kg daily as monotherapy. Researchers at the Department of Medical Sciences, University of Wisconsin-Madison, administered amlodipine at an oral daily dosage of 0.625 mg per cat (range = 0.08 to 0.23 mg/kg body weight). Average indirect systolic blood pressure measurements in those 12 cases decreased significantly from 198 to 155 mmHg during amlodipine treatment. Significant changes in body weight and serum creatinine and potassium concentrations were not detected.

Relationship between ocular lesions and hypertension
Retinal lesions, caused predominantly by choroidal injury, are common in cats with hypertension. Hypertension should be considered in older cats with acute onset of blindness; retinal edema, hemorrhage, or detachment; cardiac disease; or neurologic abnormalities. Cats with hypertension-induced ocular disease should be evaluated for renal failure, hyperthyroidism, diabetes mellitus, and cardiac abnormalities. Blood pressure measurements and funduscopic evaluations should be performed routinely in cats at risk for hypertension (preexisting renal disease, hyperthyroidism, and age > 10 years).

Am J Vet Res 2002 Jun;63(6):833-9
Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency.
Click here to access the PubMed abstract of this article.

J Am Vet Med Assoc 2000 Sep 1;217(5):695-702
Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998).
Click here to access the PubMed abstract of this article.

J Vet Intern Med 1998 May-Jun;12(3):157-62
Amlodipine: a randomized, blinded clinical trial in 9 cats with systemic hypertension.
Click here to access the PubMed abstract of this article.

J Am Anim Hosp Assoc 1997 May-Jun;33(3):226-34
Treatment of systemic hypertension in cats with amlodipine besylate.
Click here to access the PubMed abstract of this article.