Acute beta-blockade changes the extracellular distribution of thyroid hormones. - PDF Download Free (2023)

J. Endocrinol. Invest. 13: 277 -281, 1990

Acute beta-blockade changes the extracellular distribution ofthyroid hormones L. Kayser*, H. Perrild*, P. H. Petersen**, L. Skovsted*, and J. E. M. Hansen* * Department of Internal Medicine and Endocrinology F, Herlev hospital, 2730 Herlev, Denmark and ** Department of Clinical Chemistry, Odense Hospital, 5000 Oden se C, Denmark ABSTRACT. The acute (within hours) changes in the concentrations of T4' T3' reverse-T3 (rT3) and T3 resin uptake test (T 3RU) were studied in 31 hyperthyroid patients for 4 h after po treatment with either acebutolol, oxprenolol, pindolol or timolol. In 21 of the patients, the changes were compared to changes in the serum concentrations of a 2 -macroglobulin (a macromolecule) and two middle-sized molecules; thyroid hormone-binding globulin (TBG) and albumin in order to calculate the changes in extracellular distribution of the thyroid hormones and to distinguish between changes due to a changed metabolism and changes due to a changed distribution of the thyroid hormones. Acebutolol, oxprenolol and timolol

caused a decrease in serum T3 after 1/2 h, and acebutolol and oxprenolol also a decrease in rT3 after 1/2 - 1 h, the changes reversed within 2 h. A concomitant decrease in serum albumin and TBG suggests a change in the extracellular distribution of middlesized molecules to wh ich thyroid hormones are attached, as an explanation of the acute decrease (1 h) of the thyroid hormones. The small and insignificant change in a 2 -macroglobulin indicates that the changes are mainly extravascular, but the difference of a 2 -macroglobulin changes between the drugs (acebutolol/timolol vs pindolol/oxprenolol) could depend on the intrinsic sympathomimetic activity of the drugs.

INTRODUCTION Propranolol given over days and weeks causes a fall in serum T3 and a rise in serum reverse -T3 (rT3 ) (1,2). This is probably due to an interaction between the hepatically metabolized propranolol and the liver 5'-monodeiodinase reducing the deiodination of T4 to T3 and rT 3 (3). Regarding the effect of other betablockers, differing in metabolie pathway and cardioselectivity, on the thyroid hormone concentrations, data are conflicting (1 , 2, 4, 5). After an oral dose of 40 mg propranolol, a decrease in serum T3 have been reported already after 60 min (6). Since the halflife of T3 in thyrotoxic subjects is approximately 12-18 h (7), this acute effect is not likely to be due to drug interaction with the T3 metabolism.

Thus another mechanism, e.g. a changed distribution of the protein bound hormones must be considered. Albumin, as TBG, is a middlesized moleeule (MW = 69 kD) with a slow turnover rate (Iess than 0.3% per h (8)) distributed in the extracellular compartment (both the intravascular and the extravascular volume). Changes in serum albumin concentrations (within h) reflects changes in the distribution of middlesized molecules in the extracellular compartment. a 2 -Macroglobulin (a 2 -M) is a large moleeule (MW = 820 kD) distributed in the intravascular compartment, hence changes in the serum-concentration of a2 -M (within h) reflects changes in the intravascular volume. The difference between the changes in the albumin and a2-M serum concentrations reflects the changes in the extracellular, extravascular compartment. Thus comparing the changes in the thyroid hormones with the changes in serum proteins enables us to describe the changes in the distribution of the protein bound thyroid hormones in the different extracellular compartments.

Key-words:Thyroid. beta-adrenergic blockade. albumin. a 2 -macroglobulin. acute changes. Correspondence: Dr. Lars Kayser. Department of Internal Medicine and Endocrinology E. Frederiksberg Hospital. 2000 Frederiksberg. Denmark.

Received June 20. 1989; accepted January 10. 1990.

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We have measured serum concentrations ofthyroid hormones, TBG, albumin and a2-M during 4-h treatment with one of 4 betablockers differing in pharmacokinetic and pharmacodynamic properties (acebutolol, oxprenolol, pindolol or timolol).

MATERIALS AND METHODS 31 patients (7 males and 24 females), age 49 (3958) yr [mean (interquartile range)] consecutively admitted outpatients, with hyperthyroidism as judged clinically and biochemically (serum T3 , T4 and.T3 RU), were, after informed consent had been obtained, randomized to one of the following betaadrenergic blocking agents for one week: acebutolol (200 mg X 1), oxprenolol (80 mg X 2), pindolol (5 mg X 2) or timolol (5 mg X 2). The doses are equipotent as to the antihypertensive effect to propranolol 40 mg X 2. All four drugs are mainly hepatically metabolized (acebutolol 60%, oxprenolol 95%, pindolol 60%, timolol 80%) (9). Acebutolol is cardioselective whereas oxprenolol, pindolol and timolol are non-cardioselective. Acebutolol, oxprenolol and pindolol are membrane-stabilizing, whereas timolol is not. Oxprenolol and pindolol have the greatest intrinsic sympathomimetic activity (ISA) causing only minor cardiovascular changes compared to acebutolol and timolol (10-12). On the first day of investigation, between 08.00 and 09.00 h, after 20 min at rest in sitting position, pulse rate was measured and blood sampled through an indwelling catheter placed in an arm vein. Then the above mentioned dose of betablocker was given perorally. After 1/2, 1, 2, 3 and 4 h blood was sampled and the pulse rate measured. After being treated for 1 week, blood was sampled and pulse rate measured 4-5 h after the morning dose. The patients did not receive any other antithyroid treatment. Analytical Methods All serum sam pies were analyzed for T4 , T 3 , rT3 and T3RU (4). Serum a2-M, albumin and TBG were measured in sam pies obtained from 21 of the patients 0, 1/2 and 4 h after the first dose of betablocker on the first day. Proteins were determined by electroimmunoassay (13), a2-M and albumin by a modification to obtain high precision (14). The analytical coefficient of variation (CV) was 0.8%. The intraindividual CV during 48 h was 3.8% for albumin and 3.4% for a2-M (15). Sampies from each patient were measured in duplicate within a single run to avoid between run variation.

Correction Procedures Hormone concentrations were corrected for hypothetical changes in both intravascular volume and extravascular extracellular distribution using the changes in serum albumin (alb), assuming the extracellular mass of albumin to be constant according to its slow turnover rate (Iess than 0.3% per h (8)). The formula used was (t 1 time 1, t2 time 2): Formula 1: Corr. hormone(t1 ) = Hormone (t 2 ) * alb(t1 ) / alb(t 2 ) The hypothetical changes in intravascular volume (vol) were expressed as the fractional changes of a2-M concentration (16, 17). The formula (formula 2) used was: Formula 2: Delta(vol) = a 2-M(t 1 ) / a2-M(t2)

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Statistics All results were expressed as mean with range given in brackets. Means are also used in Fig. 1 to calculate the percentual changes. Changes in concentration are tested non-parametrically against the 0 values using Wilcoxons signed ranksum test with a choice of a confidence limit of 95% and correlation of changes in serum albumin, TBG and a2-M was evaluated using Kendalls test. Statistics were performed on an Ii vett i M24 PC using the statistical package STATGRAPH.

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Results In all four groups, a significant reduction of the pulse rate was found within 1/2 hand persisted during the next 4 h. In patients treated with either acebutolol, oxprenolol or timolol, serum T3 decreased within 1/2 h (p< 0.05), accompanied by a decrease in serum rT3 in the oxprenolol treated group after 1/2 h, and in the acebutolol treated group after one h (p< 0.05) (Table 1). Also, though only significant in the timolol treated patients, a decrease in serum T4 was found. Due to the parallel changes in the concentration of hormones, no change was found in the ratios of T3 /T4 or rT3 /T4 . After 2 hall changes had returned to pretreatment values. Concomitant with .changes in hormone concentrations, a decrease was found in serum albumin in the acebutolol, oxprenolol or timolol treated (p< 0.05), with a parallel change of TBG (Kendalls tau 0.454, p< 0.01), whereas serum a2 -M did not change significantly. A comparison, between the change in serum albumin and the change in serum a2-M (Fig. 1), indicate that the changes in

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Acutebeta-blockade and thyroid hormones

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bumin change nearly paralleis the change in a 2-M (according to formula 2). In the oxprenolol treated group, albumin changes are greater than changes of a 2 -M within the first 1 /2 h (Fig. 1), indicating that changes in the thyroid hormones and TBG in these patients are mainly due to a change in their extravascular distribution. After correction for changes in serum albumin (according to formula 1), serum T 3 was unchanged in all four groups, but serum T 4 was increased in the acebutolol [from 208 (180-240) to 220 (189-265) (mean (range)) nrTlOl/I] and oxprenolol treated [from 203 (158-327) to 214 (159-344) nmol/I] within 1/2 h (p< 0.05). After 4 h the only change compared to pretreatment values, was an increase in the concentration of T4 corrected for albumin [219 (161-353) Arb U] and an increase in serum rT 3 corrected for changes in albumin' [from 1.11 (0.69-2.20) to 1.36 (0.78-3.06) Arb U (p 0.05)] in the oxprenolol treated. No change was found in serum T 4 , T 3 , T 3RU, albumin, TBG or a 2-M. After 1 week only a decrease in total T 3 (compared to pretreatment values) in the a-cebutolol treated patients [5.6 to 4.3 nmol/I (p< 0.01)] was fbund .

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Fig. 1 - Percentual changes in serum concentrations of albumin (hatched blocks) and armacroglobulin (clear blocks), 1/2 h after first dose of either acebutolol (n = 6), oxprenolol (n = 5), pindolol (n = 5) or timolol (n = 5) in 21 hyperthyroid patients (* = p < 0.05).