Comparison of two slow‐release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients.

Silas, J H; Freestone, S.; Lennard, M. S.; Ramsay, LE

doi:10.1111/j.1365-2125.1985.tb05082.x

Cited by 21 publications

(10 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There was some overlap in these data, however, which could be explained, in part, by the higher plasma concentrations of (S)-metoprolol, the pharmacologically active enantiomer, observed in EMs . Nevertheless, all PMs but only two EMs had a clinically significant degree of ,-adrenoceptor blockade (10% or more) at the end of 24 h. In addition Silas et al (1984) have reported that the hypotensive effect of metoprolol is not maintained in EMs for 24 h after a single dose. Adequate control of angina pectoris and blood pressure might therefore be achieved with once daily dosing of metoprolol in PMs, whereas most EMs will require more frequent dosing.…”

mentioning

confidence: 90%

Metoprolol metabolism and debrisoquine oxidation polymorphism‐ population and family studies.

McGourty¹,

Silas²,

Lennard³

et al. 1985

Brit J Clinical Pharma

Self Cite

150

112

View full text Add to dashboard Cite

1 The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. 2 The loglo metoprolol to a-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P < 0.001).3 The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. 4 The major urinary metabolite of metoprolol metabolism was H117-04, the endproduct of O-dealkylation. The distribution of the log1o metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P < 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. 5 These results indicate that both the a-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. 6 Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 7 In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

show abstract

mentioning

confidence: 90%

Metoprolol metabolism and debrisoquine oxidation polymorphism‐ population and family studies.

McGourty¹,

Silas²,

Lennard³

et al. 1985

Brit J Clinical Pharma

Self Cite

150

112

View full text Add to dashboard Cite

show abstract

“…However, in a study of 12 hypertensive patients, all of whom were extensive metabolisers, the 24-hour blood pressure lowering effect of metopro-101 did not reach statistical significance following once-daily treatment for 1 month with 200mg drug given as conventional tablets or in 2 slow release forms (Silas et al 1985). …”

Section: Pharmacodynamicsmentioning

confidence: 95%

“…However, in view of a lack of a significant hypotensive effect of metoprolol in extensive metabolisers at 24 hours after dosing (Silas et al 1985), once-daily dosing with metoprolol and its slow release preparations may Table II. Possible clinical consequences of polymorphic oxidation of fj-adrenoceptor antagonists (fj-blockers)…”

Section: Hypertensionmentioning

confidence: 99%

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Lennard

Tucker

Woods

1986

Clinical Pharmacokinetics

View full text Add to dashboard Cite

Wide variability in response to some drugs such as debrisoquine can be attributed largely to genetic polymorphism of their oxidative metabolism. Most beta-blockers undergo extensive oxidation. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers (PMs) of debrisoquine have claimed that the oxidation of these drugs is under polymorphic control. Subsequently, controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol, timolol and bopindolol. The poor metaboliser phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta-blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, viz. alpha-hydroxylation and O-demethylation of metoprolol and 1'- and possibly 4- and 6-hydroxylation of bufuralol. In contrast, the overall pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lower in poor metabolisers. As anticipated, the disposition of atenolol which is eliminated predominantly unchanged by the kidney and in the faeces, is unrelated to debrisoquine phenotype. The clinical significance of impaired elimination of beta-blockers is not clear. If standard doses of beta-blockers are used in poor metabolisers, these subjects may be susceptible to concentration-related adverse reactions and they may also require less frequent dosing for control of angina pectoris.

show abstract

“…8 However, Freestone's group also reported that atenolol's reduction of the pulse during exercise was less at 24 h than at 3 [1/2] h after dosing. 9 The INVEST study dosed atenolol twice a day if more than 50 mg per day was needed. 10 Dr. Wallace coauthored the Multicenter Study of Perioperative Ischemia trial, which is the largest placebo-controlled trial of atenolol for perioperative ß-blockade.…”

Section: To the Editormentioning

confidence: 99%