Pharmacokinetics and pharmacodynamics of propranolol stereoisomers in hyperthyroid patients

Tawara, Kazuji; Kawashima, Koichiro; Ishikawa, Hiromichi; Yamamoto, Kunihiro; Saito, Koshi; Ebihara, Akio; Yoshida, Shoma

doi:10.1007/bf00561949

Cited by 11 publications

(4 citation statements)

References 25 publications

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“…However, the effect of hyperthyroidism on the clearance of single oral doses of propranolol is less clear. As indicated above, the earlier studies of Bell et aL (1977) and Rubenfeld et aL (1978) did not detect any change, and indeed this has also been the conclusion of a number of other workers (Ishizaki et aL, 1980;Riddell et aL, 1980;Tawara et aL, 1981) who used the more appropriate within-subject comparison (table II). On the other hand, using a similar study design, both Aro et aL (1982) and Hallengren et aL (1982) reported a significant increase in clearance.…”

Section: Pharmacokinetics Of Propranolol In Hyperthyroidism After Orasupporting

confidence: 59%

“…However, few details were given and some of the levels reported are at the lower level of sensitivity of the propranolol assay. Japanese workers (lshizaki et aL, 1980;Tawara et aL, 1981) using single doses of 40 to 80mg detected no change. There was a small but insignificant increase in clearance following propranolol 100mg in the study by Riddell et aL (1980), while Hallengren et aL (1982) and Aro et aL (1982) using 80 and 160mg, respectively, reported a significant increase in clearance as did the studies using long term administration.…”

Section: Pharmacokinetics Of Propranolol In Hyperthyroidism After Oramentioning

confidence: 96%

“…Also, Tawara et al (1981) compared the disposition of propranolol stereoisomers following a single oral dose and found no difference in their clearance in the hyperthyroid state. When euthyroid, the clearance of dl-propranolol exceeds that of d-propranolol.…”

Section: Pharmacokinetics Of Propranolol In Hyperthyroidism After Oramentioning

confidence: 99%

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Clinical Pharmacokinetics of ??-Adrenoceptor Blocking Drugs in Thyroid Disease

Feely

1983

Clinical Pharmacokinetics

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3-Adrenoceptor blocking drugs (;3-blockers) have an established place in the management of patients with thyroid disease. Thyroid hormones, however, markedly alter hepatic, renal and cardiovascular function and thus may significantly influence drug disposition. In hyperthyroidism the clearance of propranolol following intravenous administration is increased by approximately 50%, an effect that may be attributed to the marked increase in liver blood flow that occurs in this condition. On the other hand, the increased clearance of propranolol during long term oral therapy is presumably due to increased hepatic drug metabolising enzyme activity. However, following single oral doses the clearance of propranolol has been reported both to be unchanged and increased in hyperthyroid patients. Both during single dose and long term therapy the elimination half-life of propranolol is unaltered, in part due to an increased apparent volume of distribution. The degree of plasma protein binding of propranolol appears to be slightly reduced in the hyperthyroid state.There is evidence to suggest that the clearance of metoprolol, which like propranolol undergoes extensive hepatic metabolism, is also increased in hyperthyroidism. In contrast, the oral clearance of renally excreted ;3-blockers such as sotalol and atenolol, and probably practolol also, is not altered in hyperthyroidism.In general, all ;3-blockers produce a similar degree of symptomatic response. Those with intrinsic sympathomimetic activity (e.g. oxprenolol) do not reduce heart rate to the same extent as propranolol. Recent studies have shown a significant relationship between plasma propranolol levels and the objective measures (reduction in exercise tachycardia, serum triiodothyronine concentration and weight change) but not the subjective measures of therapeutic response. Concentration-response relationships are also becoming apparent for other ;3-blockers such as metoprolol and nadolol. The 20-jold interindividual variation in propranolol plasma concentrations, which may be largely attributed to age and smoking habits, emphasises the need for individualisation of dosage. This may also explain the reported cases of thyroid crisis, particularly postoperatively in patients receiving a fixed dosage regimen. In the latter situation surgery may also markedly alter the handling of propranolol.The effect of hypothyroidism on the disposition of ;3-blockers has not been definitively studied. In hypothyroidism the elimina/ion half-life of propranolol following a single oral dose may be prolonged although clearance is not affected. During long term therapy, pre-

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Section: Pharmacokinetics Of Propranolol In Hyperthyroidism After Orasupporting

confidence: 59%

Section: Pharmacokinetics Of Propranolol In Hyperthyroidism After Oramentioning

confidence: 96%

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Clinical Pharmacokinetics of ??-Adrenoceptor Blocking Drugs in Thyroid Disease

Feely

1983

Clinical Pharmacokinetics

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“…In order to evaluate the relative contribution of the different actions to the overall pharmacological effect, many authors have studied the enantiomers separately, both in experimental (Anlezark et al, 1979;Jaillon et al, 1980) and clinical situations (Tyrer & Lader, 1974;Stensrud & Sjaastad, 1976). Concomitantly the pharmacokinetics (George et al, 1972;Kawashima & Ishikawa, 1980;Tawara et al, 1981;Jackman et al, 1981;Silber et al, 1982) and the metabolism (von Bahr et al, 1982) of the two enantiomers have been studied.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective binding of propranolol enantiomers to human alpha 1‐ acid glycoprotein and human plasma.

Albani¹,

Riva²,

Contin³

et al. 1984

Brit J Clinical Pharma

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The binding of propranolol enantiomers to human albumin (ALB), al-acid glycoprotein (aI-AGP) and plasma was studied. (-) propranolol is more bound than (+) propranolol to a1-AGP (P < 0.001) and to plasma (P < 0.05). In solutions containing ALB at a constant concentration (580 ,umol/l) and a1-AGP at increasing concentrations, the binding of both isomers increases but the stereo selectivity is evident throughout the a1-AGP concentration range examined (25-100 ,umol/l).

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Synthesis and effects on peripheral thyroid hormone conversion of (R)‐4‐hydroxypropranolol, a main metabolite of (R)‐propranolol

et al. 1991

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The inhibiting effect of (R,S)-propranolol on peripheral T4E3 conversion can be related to the (R)-isomer. The intention of this study is to clarify if (R)-4-hydroxypropranolol, a main metabolite of (R)-propranolol, develops the same or even a stronger effect on peripheral thyroxine metabolism as the parent drug. (R)-4-hydroxypropranolol was synthesized via (R)-4-methoxypropranolol and their optical purity was checked chromatographically. Twenty patients suffering from hyperthyroidism were divided into five groups and treated with (Rb4-h~-droxypropranolol HC1 in dosages from 12 to 75 mg per day in a placebo controlled study over a period of 5 days. The serum hormone levels and resting pulse rate were measured. No significant changes of thyroid parameter could be observed but a significant decrease of resting pulse rate under treatment with 75 mg (R)-4-hydroxypropranolol occurred. It could be concluded that (R)-4-hydroxypropran-0101 possesses negative chronotropic effects but develops no changes in thyroid hormone metabolism in hyperthyroid patients.KEY WORDS: hyperthyroidism, (R)-4-hydroxypropranolol, peripheral conversion, metabolites of propranolol, negative chronotropic effect

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Pharmacokinetics and pharmacodynamics of propranolol stereoisomers in hyperthyroid patients

Cited by 11 publications

References 25 publications

Clinical Pharmacokinetics of ??-Adrenoceptor Blocking Drugs in Thyroid Disease

Clinical Pharmacokinetics of ??-Adrenoceptor Blocking Drugs in Thyroid Disease

Stereoselective binding of propranolol enantiomers to human alpha 1‐ acid glycoprotein and human plasma.

Synthesis and effects on peripheral thyroid hormone conversion of (R)‐4‐hydroxypropranolol, a main metabolite of (R)‐propranolol

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