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1.  Comparison of two slow-release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients. 
We have compared the beta-adrenoceptor blocking and antihypertensive effects of chronic once daily treatment with conventional metoprolol 200 mg, two 'long-acting' formulations of metoprolol 200 mg and atenolol 100 mg in a cross-over study in 12 hypertensive patients concurrently receiving diuretic therapy. The peak effects of all compounds were similar, with significant reductions in exercise heart rate and blood pressure. Twenty-four hours after dosing only atenolol treatment was consistently associated with a reduction in both exercise heart rate (P less than 0.001) and blood pressure (P less than 0.02) when compared with placebo. Once daily treatment of hypertension with metoprolol, even in 'long-acting' formulations, cannot be recommended because of waning antihypertensive effect which would be missed at routine clinic attendance. Metoprolol should be prescribed twice daily in hypertension. So-called long-acting formulations do not always confer benefits over conventional dose forms.
PMCID: PMC1400893  PMID: 4074607
2.  Polymorphic metabolism of β-adrenoceptor antagonists 
British Journal of Clinical Pharmacology  1984;17(Suppl 1):11S-18S.
1 Most β-adrenoceptor blockers undergo extensive oxidative metabolism. The evidence for polymorphism of the debrisoquine type is reviewed.
2 The AUC and half-life of metoprolol were considerably greater in poor metabolisers (PM) of debrisoquine than in extensive metabolisers (EM). Metoprolol α-hydroxylation is impaired and O-dealkylation must also be affected. Polymorphism in the former route has been demonstrated in a population of 143 patients to be directly related to debrisoquine phenotype.
3 Bufuralol AUC and half-life are much higher in PM than EM subjects. Hydroxylation at the 1 and 4 positions are affected. Genetic polymorphism for 1-hydroxylation has been shown in family and population studies.
4 Propranolol 4-hydroxylation is defective in PM subjects of debrisoquine but propranolol AUC is not related to phenotype, presumably because other major pathways are unaffected.
5 Oxidation phenotype correlates well with intensity and duration of β-adrenoceptor blockade after metoprolol, PM subjects requiring only once-daily dosing. However, in EM subjects twice-daily dosing is required even if slow release preparations are used, since plasma metoprolol concentrations may remain negligible 24 h after dosing. The β-adrenoceptor blocking effects of propranolol and bufuralol are unlikely to be influenced by oxidation status. Anecdotal reports of toxicity arising in PM subjects taking metoprolol or propranolol need to be substantiated. However, vomiting after the administration of bufuralol often occurs in poor metabolisers.
6 Metabolic interactions with drugs sharing the same enzyme system are discussed. Debrisoquine and bufuralol competitively inhibit each other's metabolism in vitro. Furthermore, β-adrenoceptor blockers may be associated with inhibition of metabolism by affecting either hepatic blood flow or intrinsic clearance or both. It remains to be seen whether these potential interactions are of clinical importance.
PMCID: PMC1463263  PMID: 6146335
bufuralol; debrisoquine; metoprolol; polymorphism; propranolol
3.  Drug resistance, inappropriate dosing and non-compliance in hypertensive patients. 
1 From an understanding of the biological fate and hypotensive effect of debrisoquine (D) we have assessed the relative importance of true drug resistance, inappropriately low dosage and non-compliance as causes of apparent resistance to treatment with this drug. 2 Among 37 hypertensive patients prescribed D, eleven (30%) were non-compliant on the day of testing. 3 Non-compliance was found in 64% of patients with poor blood pressure control but only 15% of patients with intermediate and good blood pressure control (P less than 0.02). 4 Five patients received doses which were too low for pharmacological effect while in a further five an increase in dose may have improved blood pressure control. 5 Resistance to D was uncommon indicating that non-compliance and inadequate dosing are the major causes of apparent resistance to treatment with this compound.
PMCID: PMC1429983  PMID: 7378260
4.  Comparison of two long-acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing. 
1 Eight healthy men received two long-acting formulations of metoprolol 200 mg (SA Astra, SR Geigy), conventional metoprolol 200 mg and atenolol 100 mg once daily for 1 week each in balanced, crossover fashion. There was a washout period of at least a week between each phase. 2 On the last day of each phase, post-exercise heart rate was recorded at intervals and compared to pretreatment values. Plasma metoprolol concentrations were measured. 3 The mean AUC was similar after each of the three formulations of metoprolol (relative bioavailability of SA and SR v conventional was 97%) but with SA and SR metoprolol the time to peak was significantly delayed by about 2 h. 4 In comparison to conventional metoprolol only metoprolol SA was associated with significantly higher plasma metoprolol concentrations at the end of a dosing interval (mean values: conventional, 25 ng/ml, SR 37 ng/ml, SA 51 ng/ml). 5 Mean (+/- s.d.) reduction in exercise tachycardia at the end of a dosing interval was significantly greater with atenolol (14.8 +/- 4.5%) and metoprolol SA (13.7 +/- 10.3%) than with metoprolol SR (10 +/- 8.4%) and conventional metoprolol (8.2 +/- 7.1%). 6 The variability in beta-adrenoceptor blockade at 24 h was much greater with each of the three metoprolol formulations than that with atenolol. This was explained by the variability in metoprolol metabolism. 7 Oxidation phenotype testing with debrisoquine showed there were six extensive metabolisers and two poor metabolisers. The AUC, half-life and response to metoprolol at 24 h were much greater in poor metabolisers. Response to atenolol was not influenced by phenotype.
PMCID: PMC1427486  PMID: 7138751
5.  The Disposition of debrisoquine in hypertensive patients 
1 The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers.
2 Incremental doses and prolonged administration led to a proportionately greater urinary recovery and higher plasma concentration of D but the proportion recovered as HD fell while its plasma concentration remained unchanged. Dividing a dose or administering a single oral dose of D resulted in the formation of proportionately more HD and a lower urinary recovery of D. These findings suggest that the metabolism of D to HD may be partially saturated or inhibited by D itself or by HD.
3 Peak urinary excretion rates and plasma concentrations of both D and HD occurred 2 h after a single dose suggesting rapid absorption and presystemic metabolism.
4 HD was eliminated more rapidly than D. Mean (± s.d.) elimination half-life from the urine for HD was 9.6 ± 3.7 h and for D was 16.2 ± 5.7 h. Reasons for this are discussed.
5 Renal clearance of D and HD was not constant. A fall was observed with time after a single dose but on multiple dosing the clearance fell with increasing plasma concentrations. Mean (± s.d.) renal clearance values during multiple administration were D 282 ± 88 ml/min and HD 371 ± 178 ml/min. It is suggested that active saturable tubular secretion of D and HD may be responsible for their renal elimination.
6 The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively.
7 On early multiple dosing the hypotensive response was related to high plasma D concentrations.
PMCID: PMC1429235  PMID: 619932
6.  Defective metabolism of metoprolol in poor hydroxylators of debrisoquine. 
Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half-life and duration of beta-adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4-hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half-life and beta-adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.
PMCID: PMC1427748  PMID: 6125207
7.  Controlled trial of ketanserin in hypertension. 
We have completed a double-blind parallel group comparison of the 5-HT2 receptor antagonist ketanserin with placebo in 22 hypertensive patients. Ketanserin (20-40 mg twice daily) lowered sitting blood pressure more than placebo by 6.9 mm Hg systolic (NS), 13.1 mm Hg diastolic (P less than 0.05) and by 11.4 mm Hg mean arterial pressure (P less than 0.02). The fall in standing blood pressure was similar and we observed no first dose hypotensive effect. Ketanserin lowered the sitting heart rate by 11.1 beats/min (P less than 0.01). The drug was well tolerated.
PMCID: PMC1400636  PMID: 3161531
8.  Stereoselective metabolism of metoprolol in Caucasians and Nigerians--relationship to debrisoquine oxidation phenotype. 
The relationship between debrisoquine oxidation phenotype and the stereoselective metabolism of metoprolol was investigated in populations of British Caucasians (n = 139) and Nigerian subjects (n = 117). The 0-8 h urinary S/R-metoprolol (S/R-M) ratio was related to the ability to metabolise metoprolol and debrisoquine in both ethnic groups. The median S/R-M ratio was significantly higher in Caucasians (1.27) than in Nigerians (1.10). In the Caucasian population poor metabolisers of debrisoquine had significantly lower S/R-M ratio (median = 0.84) than extensive metabolisers (median = 1.28). Bimodality in the frequency distribution of the S/R-M ratio was not apparent in either ethnic group.
PMCID: PMC1379927  PMID: 2757883
9.  Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics and first dose effect of prazosin. 
The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of a single oral dose of prazosin has been studied in eight hypertensive patients (four extensive and four poor metabolisers). No significant differences between the two phenotypes were observed in either the area under the plasma prazosin concentration-time curve, the terminal half-life or the first-dose effect of prazosin.
PMCID: PMC1386486  PMID: 3358891
10.  Sample size for short-term trials of antihypertensive drugs. 
1 Controlled trials of antihypertensive drugs published in the British Journal of Clinical Pharmacology during 1979 and 1980 were examined. Studies comparing two or more active drugs or dosage regimens nearly always failed to separate and treatments significantly. The sample size (mean 19 patients) and power of these studies were too low. 2 When planning such studies the aims should be a power of at least 0.8; significance 0.05 or less; and to detect a difference between treatments of 10/5 mmHg, or 6.7 mmHg mean arterial pressure (MAP). The sample size needed can be derived readily from a nomogram if the standard deviation of differences (SDD) between BP measurements under trial conditions is known. 3 In five studies the SDDs were fairly constant despite different observers, patient groups and measuring devices, at approximately 14 mmHg systolic, 9 mmHg diastolic, and 9 mmHg MAP. Use of three BP measurements at each visit reduced the SDD by about 1 mmHg, and would reduce the sample size required by about 20%. Replicate BP measurements at separate visits would be expected to have a larger effect on the power of the study. 4 Published studies with negative results should give an estimate of the power of the study.
PMCID: PMC1427750  PMID: 7104177
11.  Accumulation of debrisoquine by platelets in vivo 
1 The possibility that in vivo uptake of D by human platelets might reflect its accumulation in the post-ganglionic adrenergic neurone, and hence be a useful predictor of hypotensive response, was investigated.
2 During chronic oral dosage of D in three hypertensive patients average concentrations of the drug in blood fractions relative to plasma were: platelet rich plasma, 2.93; whole blood, 2.23; red cells plus granulocytes, 0.75. These findings indicate extensive uptake of D by platelets but not by other cells.
3 After single oral doses of 30 mg debrisoquine to four healthy volunteers platelets continued to accumulate the drug over at least 24 h. Although platelet D concentrations varied between subjects their platelet/plasma drug concentration ratios were similar.
4 Amitriptyline (75 mg p.o.) given 2 h before a single 30 mg oral dose of D inhibited platelet uptake of the latter by 40 ± 14 s.d.% over a 24 h period.
5 Platelets accumulated D but not its inactive 4-hydroxy metabolite. During chronic dosage of D in 10 patients the mean pre-dose platelet/plasma D concentration ratio was 8.52 ± 429 s.d. Within a 12 h dosing interval the concentration of D was constant in platelets but varied two-fold in plasma.
6 Uptake of D by platelets approached saturation with increasing plasma D concentrations.
7 After chronic D therapy in patients the fall in standing diastolic bp was more closely correlated with plasma D concentration (r = -0.88; P < 0.001) than with platelet D concentration (r = -0.65; P < 0.05).
8 In relation to the therapeutic response to D, observations 3-5 but not 7 are consistent with a view of the platelet as a useful model of the peripheral adrenergic neurone.
PMCID: PMC1429981  PMID: 7378259
12.  Tolerability of combined treatment with verapamil and beta-blockers in angina resistant to monotherapy. 
Postgraduate Medical Journal  1985;61(713):229-232.
We have used a combination of a beta-blocker and verapamil to treat 42 consecutive patients with angina resistant to either agent alone. Patients with heart failure, heart block or uncontrolled hypertension were excluded. The mean duration of follow-up was 6.5 months. Thirty-six patients (81%) reported an improvement and the number of angina attacks was reduced from 17/week to 5/week. Side effects necessitated withdrawal of one or both drugs in 6 patients, 2 of whom developed bradyarrhythmias not solely related to drug treatment. The most common complication was mild left ventricular failure (6) treated by reducing or stopping the beta-blocker. The data suggest that the combination of verapamil and a beta-blocker may be used in a relatively unselected group of patients with difficult angina. However, as dosage adjustment and close observation may be necessary to minimise side effects, the use of this combination should be limited to hospital practice.
PMCID: PMC2418202  PMID: 2858847
13.  Why hypertensive patients vary in their response to oral debrisoquine. 
British Medical Journal  1977;1(6058):422-425.
The relation between dose, systemic availability, and response to oral debrisoquine was studied in 13 hypertensive patients receiving no other treatment. In 11 who received the same daily dose (40 mg) the fall in mean standing systolic blood pressure varied between 0-3 and 44-4 mm Hg. There was a ninefold difference in the daily urinary excretion and pre-dose plasma concentration of unchanged drug but an inverse correlation between daily urinary excretion of debrisoquine and its 4-hydroxy metabolite (r= -0-86), suggesting that a low recovery of debrisoquine occurs because of extensive metabolism. There was a significant correlation between the fall in standing systolic blood pressure and the mean daily urinary excretion (r= +0-82) and pre-dose plasma concentration (r= +0-82) of unchanged debrisoquine. In contrast, there was a significant inverse correlation between the urinary recovery of the metabolite and the fall in blood pressure (r= -0-82). The availability of debrisoquine is the major determinant of response to this drug. In the absence of side effects a poor response may be an indication to increase the daily dose rather than add another hypotensive agent.
PMCID: PMC1604845  PMID: 837136
14.  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.
PMCID: PMC1498542  PMID: 6805621
16.  Clinical evaluation of Dinamap 845 automated blood pressure recorder. 
British Heart Journal  1980;43(2):202-205.
The Dinamap 845 blood pressure recorder has been evaluated over a wide range of blood pressure by comparison with the Hawksley random zero sphygmomanometer in 32 subjects, six of whom had a cardiac arrhythmia. Group mean radings for systolic and phase 5 diastolic pressure were almost identical but Dinamap diastolic values were on average significantly lower (mean difference 3.4 mmHg) than phase 4 diastolic readings obtained with the Hawksley machine. Correlations between readings with the two instruments were high but the slopes and intercepts of the regression for systolic but not diastolic pressure were significantly different from unity and zero, respectively. The Dinamap is easy to use, portable, and capable of rejecting some motion artefact. Its major disadvantage is that the systolic blood pressure measurement is limited to a maximum of 210 mmHg, a point not made clear in the manufacturer's literature. Nevertheless, the Dinamap 845 is acceptable for blood pressure determinations in subjects who are normotensive or who have mild hypertension.
PMCID: PMC482263  PMID: 7362713
17.  The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris. 
1. The pharmacokinetics and pharmacodynamics of oral verapamil and propranolol were studied in patients with stable angina pectoris during chronic mono- and dual therapy. 2. The peak plasma concentrations (Cmax) and areas under the plasma concentration-time curves (AUC) of verapamil were similar during combined treatment with propranolol (mean +/- s.d.: Cmax = 491 +/- 397 ng ml-1; AUC = 2075 +/- 1524 ng ml-1 h) or atenolol (mean +/- s.d.: Cmax = 372 +/- 320 ng ml-1; AUC = 1985 +/- 1660 ng ml-1 h). 3. No differences in Cmax and AUC were observed during verapamil monotherapy (mean +/- s.d.: Cmax = 287 +/- 105 ng ml-1; AUC = 1375 +/- 455 ng ml-1 h) vs combined treatment with propranolol (mean +/- s.d.: Cmax = 312 +/- 55 ng ml-1; AUC = 1566 +/- 486 ng ml-1 h). 4. Treatment with verapamil increased the Cmax (mean +/- s.d.: 227 +/- 117 vs 116 +/- 62 ng ml-1, P less than 0.05) and AUC (1389 +/- 617 vs 837 +/- 316 ng ml-1 h, P = 0.0625) of propranolol in all subjects. 5. Transient atrioventricular dissociation occurred in two patients 2 h after dosing with verapamil and propranolol or atenolol. 6. Close observation of patients is essential when beta-adrenoceptor antagonists and verapamil are used together.
PMCID: PMC1386359  PMID: 3358897
19.  Successful pregnancy soon after oral contraceptive-associated malignant hypertension 
Postgraduate Medical Journal  1980;56(661):790-791.
A woman who developed malignant hypertension while taking a very low oestrogen oral contraceptive underwent an uncomplicated pregnancy conceived 3 months later. Her BP was well controlled with propranolol alone.
PMCID: PMC2426073  PMID: 7267484
22.  Metoprolol metabolism and debrisoquine oxidation polymorphism--population and family studies. 
The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P less than 0.001). The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. The major urinary metabolite of metoprolol metabolism was H117-04, the end-product of O-dealkylation. The distribution of the log10 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 less than 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. These results indicate that both the alpha-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 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.
PMCID: PMC1400824  PMID: 2868742
23.  Diuretic treatment of resistant hypertension. 
British Medical Journal  1980;281(6248):1101-1103.
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.
PMCID: PMC1714545  PMID: 7427599

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