Jh Silas

Oxidation Phenotype — A Major Determinant of Metoprolol Metabolism and Response

GENETIC polymorphism in the oxidative metabolism of debrisoquine1 is largely responsible for individual differences in its plasma concentration and antihypertensive effect.2 Poor hydroxylators have...

Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers

The hypothesis that variability in metoprolol metabolism stereoselectivity is related to debrisoquin oxidation phenotype was tested in six extensive (EM) and six poor (PM) debrisoquin metabolizers. In EM, plasma AUCs for (S)‐metoprolol were 35% higher than for (R)‐metoprolol, whereas in PM, AUCs for (S)‐metoprolol were lower than for (R)‐metoprolol. AUCs for total metoprolol correlated with the ratio of (S)‐ to (R)‐metoprolol AUC. The renal clearance of metoprolol was also stereoselective but to the same extent in both EM and PM. Findings suggest that the enzyme system responsible for polymorphic oxidation of the debrisoquin‐type is stereoselective. The relation between log total metoprolol plasma concentration and response (β‐blockade) was shifted to the right in PM relative to EM, which is compatible with a difference in pharmacologic activity of metoprolol enantiomers. Kinetic predictions based on total drug measurements will tend to overestimate dynamic differences between EM and PM, but the magnitude of the error is relatively small, and, in absolute terms, there is a large difference in pharmacologic activity between the phenotypes (β‐blockade at 24 hr: EM = 5.3 ± 5.6%; PM = 18.9 ± 3.8%).

Diuretic treatment of resistant hypertension.

In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of spironolactone, produced significant reductions in blood pressure and body weight. The response did not depend on the presence of overt fluid retention, renal impairment, or the use of antihypertensive drugs of high potency. Women had larger responses than men. Expansion of the plasma or extracellular fluid volume is an important cause of resistance to treatment even when a thiazide diuretic is used. An increase in diuretic treatment should be tried before using the postganglionic adrenergic blockers or minoxidil in resistant hypertension.

Hydralazine once daily in hypertension.

The effects of hydralazine formulation and dose interval were assessed in 20 patients with hypertension well controlled on conventional hydralazine tablets, 100 mg twice daily, in addition to atenolol and a diuretic. The double-blind study used four regimens crossed over in random order at five-week intervals; placebo; conventional hydralazine 100 mg twice daily; conventional hydralazine 200 mg once daily; and slow-release hydralazine 200 mg once daily. Blood pressure and pulse rate were assessed soon after (2.5 +/- 0.9 h) and immediately before taking hydralazine (previous dose: once daily, 26.5 +/- 0.9 h; twice daily, 13.6 +/- 2.0 h). Seventeen patients completed the study. All hydralazine regimens were associated with significant falls in blood pressure. Once-daily treatment with conventional hydralazine was unsatisfactory, as its hypotensive effect waned at 24 h; there was a significant difference between the peak and trough effects on blood pressure and pulse in rapid acetylators. Compared with placebo twice-daily conventional hydralazine and once-daily slow-release hydralazine gave satisfactory control for 24 hours in both rapid and slow acetylators, though the hypotensive effect was larger in the slow acetylators. It is concluded that there is no need to administer hydralazine more than twice daily.

Drug-related acute medical admissions.

1 A survey of urgent admissions to a general medical unit in Sheffield in 1978 showed that about 25% of admissions were caused by drug-related illness; 18% by self-poisoning, 3.1% by definite or probable adverse reactions, 3.1 % by possible adverse reactions, and 1.4 % by non-compliance with drug treatment. These patients accounted for 10.8% of the bed use by patients admitted urgently. 2 Drug-related admissions to the unit did not increase between 1974 and 1980. 3 The use of barbiturates for self-poisoning declined sharply, while that of paracetamol increased steadily. Self-poisoning with dextropropoxyphene appeared to peak in 1978, and then decline. 4 While drug-related illness caused the admission of 81 % of all patients under the age of 30 years, they rarely came to harm. Self-poisoning had a high mortality in older patients, and they were also the principal sufferers from adverse drug reactions.

A clinical and pharmacokinetic evaluation of tolmesoxide in hypertensive patients

SummaryThe pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and a diuretic. After a 50 mg oral dose mean (± SD) peak plasma concentration of T was 1.13±0.29 µg/ml−1 and occurred 0.79±0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37±0.09 µg/ml−1 at 1.92±1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78±0.77 h and 10.78±7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50–200 mg t. i. d. During in-patient administration of 600–900 mg T daily (n=6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n=4) was associated with a significant fall in mean systolic but not diastolic bp (lying −15/+1 mm Hg. standing −25/−8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean ± SD) significantly from 55±5/min to 66±8/min following 900–1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600–900 mg daily eventually necessitated drug withdrawal. In its present from T is not recommended for the treatment of hypertension.