THYROID Volume 1, Number 3, 1991 Mary Ann Liebert, Inc., Publishers
Propranolol and Thyroid Hormone Metabolism W.M. WIERSINGA
ABSTRACT
Propranolol decreases plasma T3 and increases plasma rT3 in a dose-dependent manner due to a decreased production rate of T3 and a decreased metabolic clearance rate of rT3, respectively, caused by inhibition of the conversion of T4 into T3 and of rT3 into 3,3'-T2. This inhibition of 5'-deiodination is not secondary to inhibition of thyroid hormone transport across the plasma membrane. Propranolol and its major metabolite, 4-hydroxypropranolol, are not directly responsible for these effects, but an unidentified metabolite of propranolol might be involved, ß-blockers ameliorate clinical symptoms and signs of thyrotoxicosis indepen¬ dent of the decrease of plasma 13, that is confined to ß-blockers with membrane-stabilizing activity, such as propranolol and alprenolol. The decrease of plasma T3, however, appears responsible for some of the metabolic responses to ß-blockers.
INTRODUCTION
not change, al¬ of TSH is observed in increase minor though on hypothyroid patients thyroxine, presumably caused by a diminished bioavailability of oral thyroxine due to decreased intestinal absorption.'21" Propranolol does not interfere di¬ rectly with pituitary TSH secretion, nor does it affect thyroidal radioiodine uptake or iodine release."2~14)
volume.'5'9·I0) Plasma TSH in general does in
Propranolol rT3. Although ago,"·2'
T3 and increases plasma this effect was described more than 10 years the mechanism by which propranolol inhibits iodothyronine 5'-deiodination is still unknown. We review the effect of ß-blockers on thyroid hormone metabolism, indicate areas for future research, and discuss the clinical relevance of these decreases plasma
findings.
some
studies
a
EFFECT ON IODOTHYRONINE KINETICS
EFFECT ON PLASMA THYROID HORMONES In hyperthyroid patients, the mean decrease of plasma T3 is 20% after 1 week of treatment with a daily oral dose of 80 mg propranolol and 30% after 1 week of 160 mg propranolol daily.'2' There is a good dose-response relationship between plasma propranolol concentrations and the reciprocal changes in plasma T3 and rT3.'3·4' The magnitude of the response is similar in hypothyroid patients on thyroxine medication, suggesting ah effect on peripheral thyroid hormone metabolism.'2' Changes of plasma T3 and rT3 in euthyroid subjects are qualitatively similar but quantitatively much smaller.'5' Plasma T4 either does not change or increases slightly/5 8) Free thyroid hormone concen¬ trations vary in accordance with total thyroid hormone levels (Table 1 ). These effects cannot be explained by the propranololinduced decrease of plasma TBG nor by changes in plasma
The effect of propranolol on extrathyroidal kinetics of iodothyronines has been evaluated by Lumholtz et al. in T4-treated hypothyroid patients who were studied before and after propra¬ nolol administration in a daily dose of 80 mg for 1 week."5-17' Analysis was by noncompartmental kinetics. The metabolic clearance rates (MCR) of iodothyronines decrease, that of rT3 to a much greater extent than of T4. The production rate (PR) of T3 decreases, and that of rT3 remains unchanged. The conversion rate of T4 into T3 decreases. Conversion of T4 into rT3 and of rT3 into 3',5'-T2 is not affected. Distribution volumes of iodothy¬ ronines remain unchanged. The overall picture is that propra¬ nolol does not interfere with 5-deiodination but inhibits 5'-deiodination (Fig. 1). Inhibition of 5'-deiodination results in a decreased MCR of the substrates of T4, rT3, and3',5'-T2and, consequently, in a rise of their serum levels. On the other hand, inhibition of 5'-deiodination results in a decreased PR of the
Department of Endocrinology, Academisch Medisch Centrum, Amsterdam, The Netherlands. 273
WIERSINGA
274 Table 1. Effect of Propranolol on Plasma Iodothyronines
Hyperthyroidism Plasma T3 Plasma rT3 Plasma T4 Plasma TSH no
Propranolol inhibits the in vitro 5'-deiodination of T4 into T3 in whole cell preparations, such as isolated rat hepatocytes"8' or renal tubules,"91 by acting as a weak noncompetitive inhibitor with a K¡ value of 400-700 µ .'2"' However, the effect of propranolol is absent or only observed with large doses of the drug (2s 1 mM) in studies using rat kidney homogenates."9-2" This suggests that membranes are an important site of action for propranolol. Propranolol is usually administered as the racemic 1:1 mixture of D- and L-propranolol. whereas D-propranolol is devoid of ß-blocking activity but has membrane-stabilizing activity (MSA). Heyma et al."9' demonstrated in vitro inhibi¬ tion of T4 5'-deiodination by D-propranolol and the unrelated drug quinidine (well known for its MSA) but not by ß-blockers without MSA, such as sotalol and atenolol (Table 2). D-Propranolol administered to human subjects decreases plasma T3 and increases plasma rT,,'22'2·" whereas ß-blockers without MSA do not.'24"27' A reduced hepatic blood flow, which by itself might inhibit the conversion of T4 into T3,128' cannot be the causal machanism, since it is induced specifically by ß-blockade
serum*
PR!
Ig
3.
PRl (NS)
FIG. 1.
Effect of
Euthyroidism 1 t
Kt)
change; ( ), minor change.
MECHANISM OF INHIBITION OF 5-DEIODINATION
(NS)
T4
=(t) =(D
=0)
products T3, 3,3'-T2, and, to a lesser extent, 3'-T, and. consequently, in a fall of their serum levels.
PR
on
t
1, decrease; 1, increase; =,
serum
Hypothyroidism
and not by D-propranolol. Thus, the inhibition of 5'-deiodina¬ tion by ß-blockers is dependent on their MSA and not related to the ß-blockade itself. Another membrane effect of propranolol was described by Krenning et al.,(29) who demonstrated inhibition of the active transport of T4 and T3 into rat hepatocytes in primary culture at a rather low dose (50% inhibition by 1 µ of d- or lpropranolol). They hypothesized that inhibition of 5'-deiodination by propranolol could be secondary to an inhibition of thyroid hormone transport across me plasma membrane, result¬ ing in a decreased intracellular substrate concentration available for deiodination. This was tested by kinetic experiments using a three-compartment model in euthyroid volunteers on thyroxine, who were studied before and after D-propranolol administered in a daily dose of 240 mg for 2 weeks.'30' In agreement with other studies, serum T4 and rT3 increased and T3 decreased, MCRs decreased (greatest for rT3), and T, PR decreased. The mass transfer rate of T4 from plasma into rapidly or into the slowly equilibrating pools, however, did not change. The fractional transfer rates from plasma of T3 and rT3 overall did not change either. Therefore, the effect of propranolol could not be ex¬ plained from inhibition of thyroid hormone transport. Consequently, propranolol or one of its metabolites appears to inhibit 5'-deiodination directly. Therapeutic plasma concentra¬ tions of propranolol in humans seldom exceed 0.5 µ . This is three orders of magnitude lower than the K¡ value of 500 µ (the D,L-propranolol concentration that causes a 50% inhibition of rat liver 5'-deiodinase).
Propranolol and Thyroid Hormone Metabolism W.M. WIERSINGA
ABSTRACT
Propranolol decreases plasma T3 and increases plasma rT3 in a dose-dependent manner due to a decreased production rate of T3 and a decreased metabolic clearance rate of rT3, respectively, caused by inhibition of the conversion of T4 into T3 and of rT3 into 3,3'-T2. This inhibition of 5'-deiodination is not secondary to inhibition of thyroid hormone transport across the plasma membrane. Propranolol and its major metabolite, 4-hydroxypropranolol, are not directly responsible for these effects, but an unidentified metabolite of propranolol might be involved, ß-blockers ameliorate clinical symptoms and signs of thyrotoxicosis indepen¬ dent of the decrease of plasma 13, that is confined to ß-blockers with membrane-stabilizing activity, such as propranolol and alprenolol. The decrease of plasma T3, however, appears responsible for some of the metabolic responses to ß-blockers.
INTRODUCTION
not change, al¬ of TSH is observed in increase minor though on hypothyroid patients thyroxine, presumably caused by a diminished bioavailability of oral thyroxine due to decreased intestinal absorption.'21" Propranolol does not interfere di¬ rectly with pituitary TSH secretion, nor does it affect thyroidal radioiodine uptake or iodine release."2~14)
volume.'5'9·I0) Plasma TSH in general does in
Propranolol rT3. Although ago,"·2'
T3 and increases plasma this effect was described more than 10 years the mechanism by which propranolol inhibits iodothyronine 5'-deiodination is still unknown. We review the effect of ß-blockers on thyroid hormone metabolism, indicate areas for future research, and discuss the clinical relevance of these decreases plasma
findings.
some
studies
a
EFFECT ON IODOTHYRONINE KINETICS
EFFECT ON PLASMA THYROID HORMONES In hyperthyroid patients, the mean decrease of plasma T3 is 20% after 1 week of treatment with a daily oral dose of 80 mg propranolol and 30% after 1 week of 160 mg propranolol daily.'2' There is a good dose-response relationship between plasma propranolol concentrations and the reciprocal changes in plasma T3 and rT3.'3·4' The magnitude of the response is similar in hypothyroid patients on thyroxine medication, suggesting ah effect on peripheral thyroid hormone metabolism.'2' Changes of plasma T3 and rT3 in euthyroid subjects are qualitatively similar but quantitatively much smaller.'5' Plasma T4 either does not change or increases slightly/5 8) Free thyroid hormone concen¬ trations vary in accordance with total thyroid hormone levels (Table 1 ). These effects cannot be explained by the propranololinduced decrease of plasma TBG nor by changes in plasma
The effect of propranolol on extrathyroidal kinetics of iodothyronines has been evaluated by Lumholtz et al. in T4-treated hypothyroid patients who were studied before and after propra¬ nolol administration in a daily dose of 80 mg for 1 week."5-17' Analysis was by noncompartmental kinetics. The metabolic clearance rates (MCR) of iodothyronines decrease, that of rT3 to a much greater extent than of T4. The production rate (PR) of T3 decreases, and that of rT3 remains unchanged. The conversion rate of T4 into T3 decreases. Conversion of T4 into rT3 and of rT3 into 3',5'-T2 is not affected. Distribution volumes of iodothy¬ ronines remain unchanged. The overall picture is that propra¬ nolol does not interfere with 5-deiodination but inhibits 5'-deiodination (Fig. 1). Inhibition of 5'-deiodination results in a decreased MCR of the substrates of T4, rT3, and3',5'-T2and, consequently, in a rise of their serum levels. On the other hand, inhibition of 5'-deiodination results in a decreased PR of the
Department of Endocrinology, Academisch Medisch Centrum, Amsterdam, The Netherlands. 273
WIERSINGA
274 Table 1. Effect of Propranolol on Plasma Iodothyronines
Hyperthyroidism Plasma T3 Plasma rT3 Plasma T4 Plasma TSH no
Propranolol inhibits the in vitro 5'-deiodination of T4 into T3 in whole cell preparations, such as isolated rat hepatocytes"8' or renal tubules,"91 by acting as a weak noncompetitive inhibitor with a K¡ value of 400-700 µ .'2"' However, the effect of propranolol is absent or only observed with large doses of the drug (2s 1 mM) in studies using rat kidney homogenates."9-2" This suggests that membranes are an important site of action for propranolol. Propranolol is usually administered as the racemic 1:1 mixture of D- and L-propranolol. whereas D-propranolol is devoid of ß-blocking activity but has membrane-stabilizing activity (MSA). Heyma et al."9' demonstrated in vitro inhibi¬ tion of T4 5'-deiodination by D-propranolol and the unrelated drug quinidine (well known for its MSA) but not by ß-blockers without MSA, such as sotalol and atenolol (Table 2). D-Propranolol administered to human subjects decreases plasma T3 and increases plasma rT,,'22'2·" whereas ß-blockers without MSA do not.'24"27' A reduced hepatic blood flow, which by itself might inhibit the conversion of T4 into T3,128' cannot be the causal machanism, since it is induced specifically by ß-blockade
serum*
PR!
Ig
3.
PRl (NS)
FIG. 1.
Effect of
Euthyroidism 1 t
Kt)
change; ( ), minor change.
MECHANISM OF INHIBITION OF 5-DEIODINATION
(NS)
T4
=(t) =(D
=0)
products T3, 3,3'-T2, and, to a lesser extent, 3'-T, and. consequently, in a fall of their serum levels.
PR
on
t
1, decrease; 1, increase; =,
serum
Hypothyroidism
and not by D-propranolol. Thus, the inhibition of 5'-deiodina¬ tion by ß-blockers is dependent on their MSA and not related to the ß-blockade itself. Another membrane effect of propranolol was described by Krenning et al.,(29) who demonstrated inhibition of the active transport of T4 and T3 into rat hepatocytes in primary culture at a rather low dose (50% inhibition by 1 µ of d- or lpropranolol). They hypothesized that inhibition of 5'-deiodination by propranolol could be secondary to an inhibition of thyroid hormone transport across me plasma membrane, result¬ ing in a decreased intracellular substrate concentration available for deiodination. This was tested by kinetic experiments using a three-compartment model in euthyroid volunteers on thyroxine, who were studied before and after D-propranolol administered in a daily dose of 240 mg for 2 weeks.'30' In agreement with other studies, serum T4 and rT3 increased and T3 decreased, MCRs decreased (greatest for rT3), and T, PR decreased. The mass transfer rate of T4 from plasma into rapidly or into the slowly equilibrating pools, however, did not change. The fractional transfer rates from plasma of T3 and rT3 overall did not change either. Therefore, the effect of propranolol could not be ex¬ plained from inhibition of thyroid hormone transport. Consequently, propranolol or one of its metabolites appears to inhibit 5'-deiodination directly. Therapeutic plasma concentra¬ tions of propranolol in humans seldom exceed 0.5 µ . This is three orders of magnitude lower than the K¡ value of 500 µ (the D,L-propranolol concentration that causes a 50% inhibition of rat liver 5'-deiodinase).
