Abstract
β-Adrenergic blockers, particularly atenolol, are often recommended for the tachycardia and hypertension that accompany hyperthyroidism; however, the effects of monotherapy with atenolol on both systolic blood pressure (SBP) and heart rate (HR) have not been reported. Twenty hyperthyroid cats with SBP ≥160 mmHg were studied retrospectively to investigate the SBP and HR lowering effects of atenolol. Median pre-treatment SBP and HR for all cats were 186.5 mmHg and 231 beats/min, respectively. All cats were treated with atenolol at a dosage of 1–2 mg/kg PO q 12 h for a minimum of 5 days prior to reassessment and treatment with radioactive iodine. SBP and HR both decreased following atenolol therapy in this group of cats to median values of 171.5 mmHg (P=0.0088) and 185/min (P=0.0003). However, when successful clinical control of hypertension was defined as a post-treatment SBP <160 mmHg, atenolol monotherapy was ineffective in 70% of the cases. There was no statistically significant difference in baseline serum total thyroxine or atenolol dosage between clinical responders and non-responders. While atenolol effectively reduces HR in most cats with hyperthyroidism, elevated SBP is poorly controlled, and the addition of another vasodilator such as amlodipine or an angiotensin converting enzyme inhibitor is needed to treat associated hypertension.
Systemic hypertension is a commonly recognized medical condition in cats with chronic renal disease or hyperthyroidism. Although a number of drugs have been investigated for control of hypertension in cats, the calcium channel blocking drug amlodipine has been considered the antihypertensive of choice due to efficacy, once daily dosing, and low incidence of side effects (Henik et al 1994, Henik 1997, AAFP/AFM 2005, Tissier et al 2005). In the case of hypertension associated with hyperthyroidism, however, β-blocking drugs such as atenolol have been advocated to slow HR and block additional effects of thyroid hormone excess on the cardiovascular system (Mooney and Thoday 2000, Atkins 2004, Trepanier 2006).
In a previous study, atenolol administration to cats with hypertension associated with renal disease was ineffective in adequately lowering SBP (Jensen et al 1997). However, the effects of atenolol as a sole antihypertensive agent in hyperthyroid cats have not been reported.
Materials and methods
Records of hyperthyroid cats presented to the University of Wisconsin-Madison Veterinary Medical Teaching Hospital (VMTH) Internal Medicine Service for radioiodine (131I) treatment between September 2004 and September 2006 were studied retrospectively. Owners were instructed to withdraw methimazole treatment for a minimum of 10 days prior to presentation. Only cats that were non-azotemic were considered acceptable candidates for 131I treatment. Screening tests performed prior to 131I treatment included: complete blood count (CBC), serum total thyroxine (TT4), serum biochemical analysis, urinalysis, thoracic radiographs, and Doppler SBP measurement. Doppler SBP (Parks Model 811-B, Parks Medical Electronics, Aloha, OR) was measured with the cat unsedated and lightly restrained. Cuff width was 30–40% of the circumference of the forelimb, and six measurements were taken, with the first being discarded and the remainder averaged (Henik et al 2005). HR was recorded between successive SBP measurements. Cats that had an average SBP ≥160 mmHg (and were at moderate or higher risk of target organ damage) (Brown et al 2007) were classified as hypertensive and prescribed atenolol within the dosage range of 1–2 mg/kg PO q 12 h, beginning that evening.
Cats were scheduled for 131I injection 5 days after the initial screening tests. Owners were instructed to give the atenolol on the morning of the cat's admission, and Doppler SBP measurement was repeated (approximately 2–3 h post-dosing) prior to isolation of the cat and treatment with 131I.
Descriptive statistics were performed on the signalment data, atenolol dosage, baseline TT4, and HR and SBP pre- and post-atenolol treatments (Table 1). Subgroups were assigned based on response of SBP to atenolol treatment. Group 1 included cats whose SBP decreased to <160 mmHg while receiving atenolol, group 2 included cats in which SBP decreased >10 mmHg but did not decrease to <160 mmHg and group 3 included cats with ≤10 mmHg change or absolute increase in SBP. SBP pre- and post-treatments and HR pre- and post-treatments were compared with a Wilcoxon test for all cats and within each subgroup. Atenolol dosage in mg/kg body weight and baseline TT4 were compared among the three response subgroups using Kruskal–Wallis analysis. A Spearman correlation analysis was performed on changes in HR and SBP with atenolol dosage, and change in HR with change in SBP. For all tests, P<0.05 was considered significant.
Summary of SBP and HR changes with atenolol treatment in hyperthyroid, hypertensive cats
Median values are listed with 25% and 75% quartiles in parentheses. See text for group classifications.
Significantly different from pre-treatment BP (P=0.0088).
Significantly different from pre-treatment HR (P=0.0003).
Significantly different from group 1 pre-treatment BP (P=0.0312).
§Significantly different from group 1 pre-treatment HR (P=0.0312).
Significantly different from group 2 pre-treatment BP (P=0.0156).
Significantly different from group 3 pre-treatment HR (P=0.0156).
Results
Twenty hyperthyroid, hypertensive cats treated with atenolol had follow-up SBP measurement prior to 131I treatment and restoration of euthyroidism. Fifteen (75%) had SBP measurement repeated and were admitted for radioiodine treatment after 5 days of atenolol (as described). In five cats there was a 1-week (n=2) or 2-week (n=3) period of atenolol administration prior to repeat SBP measurement and 131I treatment.
Breeds included 16 domestic shorthairs, one domestic longhair, one domestic medium-hair, one Siamese, and one Himalayan. Fourteen cats (70%) were spayed females, and six were neutered males. Median age was 13 years (range, 10–15 years), and median body weight was 3.4 kg (range, 2.2–6.7 kg).
Median SBP for all cats at initial presentation was 186.5 mmHg (mean, 184.7 mmHg; range, 166–208 mmHg), and median HR was 231 beats/min (mean, 232.2 beats/min; range, 178–270 beats/min) (Fig. 1Table 1). Median TT4 in the 20 cats prior to radioiodine therapy was 15.05 μg/dl (range, 5.5–30.9 μg/dl; reference range, 1.9–4.8 μg/dl) (Table 1).
HR and SBP responses in 20 hyperthyroid, hypertensive cats treated with atenolol. Target SBP (ie, controlled hypertension) post-atenolol treatment is <160 mmHg. Arrows represent median values. HRpre, HR at baseline evaluation; HRpost, HR after a minimum of 5 days of atenolol treatment; BPpre, systolic BP at baseline measurement; BPpost, systolic BP after a minimum of 5 days of atenolol treatment.
Atenolol was administered at a median dosage of 1.39 mg/kg PO q 12 h (mean, 1.45 mg/kg; range, 1.01–1.95 mg/kg) (Table 1). Following a minimum of 5 days of atenolol treatment, median SBP significantly decreased to 171.5 mmHg (mean, 170.1 mmHg; range, 120–199 mmHg; Fig. 1 and Table 1) (P=0.0088). Percentage change in median SBP compared to baseline was −8.2% (range, −41.5% to +12.1%). Median HR after ≥5 days of atenolol was 185 beats/min (mean, 190.9 beats/min; range, 150–240 beats/min; Fig 1 and Table 1) (P=0.0003). Percentage change in median HR was −20.3% (range, −34.1% to +16.8%).
Six of 20 cats (30%) were classified as group 1 (ie, those with SBP <160 mmHg post-treatment). Median SBP in group 1 cats significantly decreased from 171.5 mmHg pre-treatment to 151 mmHg post-treatment (Table 1; P=0.0312). The percentage change in median SBP in six cats successfully treated with atenolol was −11.6% (range, −7.02 to −41.5%) with a median atenolol dose of 1.6 mg/kg PO q 12 h (range, 1.07–1.93 mg/kg). Median HR significantly decreased in group 1 cats from 248 beats/min to 188.5 beats/min (Table 1; P=0.0312), a change of −20.25% (range, −9.1 to −28.1%). Median baseline TT4 in cats responding to atenolol was 18.05 μg/dl (range, 5.7–30.1 μg/dl).
Seven of 20 cats (35%) had >10 mmHg decrease in SBP with atenolol, but SBP remained ≥160 mmHg (ie, hypertensive), and were classified as group 2. Median SBP in group 2 cats decreased significantly from 191 mmHg pre-treatment to 172 mmHg post-treatment (Table 1; P=0.0156). The percentage change in median SBP in the seven group 2 cats was −9% (range, −6.8 to −17.8%). Median atenolol dose in these seven cats was 1.2 mg/kg PO q 12 h (range, 1.01–1.81 mg/kg). Median baseline TT4 in group 2 cats was 16.6 μg/dl (range, 5.5–30.9 μg/dl). The decrease in median HR was 38 beats/min (Table 1), but this change did not achieve significance (P=0.1094). The percentage change in median HR was −10.3% (range, −29.9 to +16.8%). One cat had an increase in HR at re-evaluation compared to baseline; SBP in this cat, however, decreased from 202 mmHg to 172 mmHg.
Seven cats (35%) had no change (≤10 mmHg) or an absolute increase in SBP (percentage change in median SBP, +1.8%; range, −5.2 to +12.1%) and were classified as group 3. Pre-treatment median SBP in group 3 cats was 180 mmHg, and post-treatment median SBP was 190 mmHg (Table 1; P=0.2969). Median atenolol dose in group 3 cats was 1.5 mg/kg PO q 12 h (range, 1.07–1.95 mg/kg). Median HR decreased significantly from 230 beats/min to 180 beats/min post-treatment (Table 1; P=0.0156), which was a change of −23.5% (range, −5.2 to −34.1%), and included cats in which SBP increased. Median baseline TT4 in group 3 cats was 12.5 μg/dl (range, 6.5–21.8 μg/dl).
None of the five cats that received atenolol for a longer period (ie, 1–2 weeks) prior to repeat SBP measurement had SBP in the target range (ie, <160 mmHg) after treatment. Overall, 70% of hyperthyroid cats remained hypertensive when administered atenolol at a dosage of 1–2 mg/kg PO q 12 h for a minimum of 5 days.
There was no statistical difference in baseline TT4 (P=0.5129) or median atenolol dosage (P=0.64) among the three treatment–response groups. There was no correlation between percent change in HR and percent change in SBP (P=0.4581), atenolol dosage and percent change in HR (P=0.0675) or atenolol dosage and percentage change in SBP (P=0.7168).
Discussion
Systemic hypertension is well documented in hyperthyroid cats, with reported prevalence rates ranging from 87% (Kobayashi et al 1990) in an early study to 17 (Elliott et al 2001) to 23% (Stiles et al 1994). Although hypertension is reversible with restoration of normal thyroid hormone concentrations (Kobayashi et al 1990), high SBP should be treated to minimize damage to end-organ tissues (ie, renal, cardiac, ocular, and neurologic).
Arterial blood pressure is the product of cardiac output (CO) and systemic vascular resistance (SVR), so conditions that affect either CO or SVR will alter blood pressure. CO is the product of HR, which is under autonomic control, and stroke volume (SV), which is determined by multiple factors including the inotropic state of the myocardium and the circulating intravascular volume. β-Blockers, such as atenolol, would be expected to exert an antihypertensive effect primarily by decreasing HR and the inotropic state of the myocardium, and therefore CO. β-Blockers also prevent the adrenergic nerve-mediated release of renin from the renal juxtaglomerular cells. The effects of atenolol on HR are more profound than those on SBP (Fig. 1).
The cardiovascular changes in hyperthyroidism result from T3-induced activation of nuclear receptors and subsequent increased mRNA coding of proteins (Polikar et al 1993). Changes include a hyperdynamic circulation with increased CO, HR, pulse pressure, and blood pressure (especially systolic) (Prisant et al 2006) with decreased SVR (Klein and Ojamaa 2001, Vargas et al 2006). Both systolic and diastolic functions are increased with hyperthyroidism as a result of changes in the expression of contractile and calcium-regulating proteins (Kiss et al 1994, Klein and Ojamaa 2001). These changes are all suited to meet the increased metabolic needs of the body. The decline in SVR stimulates renin release (Resnick and Laragh 1982) and sodium reabsorption by the kidney, resulting in an expansion of plasma volume and increase in venous return to the heart. Thyroid hormone also stimulates erythropoietin secretion, which contributes to increased blood volume (Klein and Ojamaa 2001).
Because tachycardia is a common clinical finding in hyperthyroid cats, the optimal treatment of hypertension in this disorder would include a drug that is also a negative chronotrope. The cats of this study were given atenolol at standard initial doses (ie, 6.25 mg/cat PO q 12 h), which resulted in a dosage of 1–2 mg/kg. Small cats (ie, <3.2 kg) received reformulated preparations within the dosage range of 1–2 mg/kg q 12 h.
Pharmacokinetic studies of atenolol in young healthy cats receiving 3 mg/kg PO q 12 h showed a 90% oral bioavailability, and a significant decrease (20±16%) in resting HR at 12 h that was gone by 24 h (Quinones et al 1996). Plasma concentrations of atenolol peaked 1 h after oral administration when cats were fasted. Half-life after oral atenolol administration in the cat is 3.66±0.39 h (Quinones et al 1996), therefore, steady state would be expected in the cats of this study prior to SBP measurement after 5 days of treatment. In the current study, median HR decreased at least 20% in two subgroups (groups 1 and 3). Group 2 cats had a median decrease in HR of 10.3%. A possible explanation for one cat that had an increase in HR compared to baseline may have been inadequate medication administration prior to SBP and HR measurement, although SBP was decreased compared to pre-treatment values. Decrease in HR in the remaining 19 cats, however, suggests that lack of compliance cannot explain the variable SBP response to atenolol.
A higher dose of atenolol (eg, 3 mg/kg) might be more effective in restoring normal SBP in hyperthyroid cats, but studies in rats have not supported this (Amos et al 1994). In a rat model of severe hyperthyroidism, atenolol treatment attenuated the increases in HR, rectal temperature, and oxygen consumption but did not alter cardiac hypertrophy, hypertension, or increased β-adrenergic density (Amos et al 1994). Administration of β-adrenergic receptor antagonists to human patients with hyperthyroidism slows HR but does not alter systolic or diastolic contractile performance of the heart (Mintz et al 1991). Mintz et al 1991 concluded that important cardiovascular risk factors are not altered by atenolol and cardiac function does not return to normal in hyperthyroid patients.
The addition of amlodipine or angiotensin converting enzyme inhibitors (ACEI) to β-adrenergic receptor blockers may be promising in the management of hyperthyroid cats with both hypertension and tachycardia. Past studies of ACEI have demonstrated poor efficacy when given to hypertensive cats with chronic renal disease (Steele et al 2002) but data regarding antihypertensive effects in hyperthyroid cats is lacking. Future studies to evaluate hyperthyroid cats for activation of the renin angiotensin aldosterone system (RAAS), in addition to response to ACEI, may assist in determination of the best therapeutic protocol for hypertension. The administration of ACEI to cats with activation of the RAAS, however, does not reliably result in adequate control of SBP (Jensen et al 1997).
Limitations of the study include small sample size and the retrospective evaluation of the data. The authors felt that a placebo-controlled trial for treatment of hypertension would not be ethical based on current ACVIM guidelines (Brown et al 2007). In the authors' institution, hypertensive cats are evaluated by the cardiology service, and are prescribed medications by one of three clinicians. Blood pressure measurements are obtained by one of two technicians and, therefore, all cats are treated similarly.
In summary, treatment of 20 hypertensive, hyperthyroid cats with atenolol at a dosage of 1–2 mg/kg PO q 12 h was ineffective in decreasing SBP to <160 mmHg hypertension in 70% of the cats. Atenolol did significantly decrease median SBP and HR compared to pre-treatment values, but its effect on SBP was not sufficient to reliably reduce SBP to the minimal to moderate risk category for target organ damage (ie, successful treatment). Baseline TT4 or atenolol dosage did not predict response to therapy. β-Adrenergic blockers, such as atenolol, are still recommended for the tachycardia that accompanies hyperthyroidism but are not reliable antihypertensive agents in these patients. The addition of another vasodilator, such as amlodipine or an ACEI, may be necessary to control hypertension associated with feline hyperthyroidism.