Unaltered lymphocyte beta-adrenoceptor responsiveness in hyperthyroidism and hypothyroidism.

Beta adrenoceptor sensitivity may be altered in thyrotoxicosis and myxedema. We therefore studied beta-adrenoceptor responses of peripheral blood lymphocytes to stimulation with 10(-9) to 10(-6) M (-)-isoproterenol from patients before and after treatment of myxedema and thyrotoxicosis as well as in patients without thyroid disease. There were six patients in each group. Lymphocyte basal cyclic adenosine monophosphate (cAMP) concentrations were higher in untreated thyrotoxicosis (4.94 +/- 0.46 pmole/10(6) cells) than in controls (3.47 +/- 0.42 pmole/10(6) cells, p less than 0.05) and in untreated myxedema (3.11 +/- 0.50 pmole/10(6) cells, p less than 0.025). The full isoproterenol dose-response curves were similar in all groups. Calculated maximum velocity (Vmax) showed an approximate increase in cAMP of 14.5 pmole/10(6) cells. Isoproterenol concentrations at half-maximum velocity (EC50) were approximately 10(-8) M. It is concluded that lymphocyte beta 2-adrenoceptor responses are not altered in hypothyroidism and hyperthyroidism.

Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin.

We studied the pharmacokinetics and beta-blocking effects of a single, oral 20 mg dose of timolol in six poor metabolizers (PMs) and six extensive metabolizers (EMs) of debrisoquin. The plasma timolol concentration was significantly higher in PMs than in EMs. There was a fourfold difference in mean AUC (1590 +/- 1133 vs. 394 +/- 239 ng X hr/ml; P less than 0.01) and a twofold difference in mean t1/2 (7.5 +/- 3 vs. 3.7 +/- 1.7 hours; P less than 0.01), reflecting differences in oral clearance (13.1 +/- 7.8 vs. 48.5 +/- 23.2 L/hr; P less than 0.01). The degree of beta-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P less than 0.05) and at 24 hours (28.3% vs. 13.1%; P less than 0.05). In the group as a whole the metabolic ratio correlated positively with both kinetic data and beta-blockade, but some overlap was observed. Hence timolol metabolism appears to be subject to debrisoquin-type polymorphism, which results in interphenotypic variation in plasma concentration and beta-blocking effect.

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 (beta-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 (beta-blockade at 24 hr: EM = 5.3 +/- 5.6%; PM = 18.9 +/- 3.8%).

Professional attitudes to cardiopulmonary resuscitation in departments of geriatric and general medicine.

Cardiopulmonary resuscitation for the elderly has long been a contentious issue. We have established by means of a postal survey the attitudes of 300 consultant geriatricians, 300 consultant physicians and 249 registered nurses to cardiopulmonary resuscitation. We also audited 400 case notes to document current practice in departments of general medicine and medicine for the elderly. No formal resuscitation policies were in operation. Geriatricians were more likely than physicians to make a positive resuscitation decision (p < 0.001), and involve nursing staff in the decision-making (p < 0.001). All professional groups felt age was unimportant in deciding on resuscitation, while the patients' prognoses and their wishes were most important. Case note audit revealed that geriatricians were better at documenting resuscitation decisions. Inappropriate resuscitation of patients is unacceptable. Each department or hospital ought to have agreed guidelines for cardiopulmonary resuscitation.

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.

Permanent pacemaker insertion in a district general hospital: indications, patient characteristics, and complications.

UNLABELLED: This report reviews the experience of permanent pacemaker insertion in a district general hospital (catchment population of 350 000) and makes a comparison with the national database and other hospitals in the UK. METHODS: The records of all patients receiving a permanent pacemaker in the inclusive period January 1996 to December 1998 were reviewed. Data collected included number of patients paced each year, age, sex, indications, and complications. RESULTS: In the three years reviewed 200 patients received new permanent pacemakers, a rate of 190 per million population per year, which is similar to the national implantation rate of permanent pacemakers but lower than that of most European countries (see discussion). The majority of patients paced were elderly (75% were above the age of 70 years). Atrioventricular block (including complete heart block, 45%, and Mobitz type 2 block, 12.5%) was the commonest indication for permanent pacemaker insertion, followed by sick sinus syndrome (25%) and these findings are comparable to those reported previously. However, carotid sinus syndrome was responsible for 16% of the patients paced and this was higher than that reported in the national database (6.5%). Only 1% of the pacemaker modes used was inappropriate and the complication rate was low at 3%. CONCLUSIONS: This report confirms that permanent pacemaker insertion can be effectively and safely provided locally for the increasingly ageing population. The implantation rate both locally and nationally is still much lower than that of some countries in Europe.

Cardiac amyloidosis in the presence of Bence-Jones proteinuria and normal serum immunoglobulins.

We describe a case of cardiac amyloidosis, which is an uncommon cause of heart failure. This case is unusual, as the patient presented with symptoms of angina in the presence of normal coronary arteries and subsequently developed heart failure. Amyloidosis was secondary to myeloma with Bence-Jones proteinuria alone, which is rare.

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.

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.

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.

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.

Open access echocardiography: a prospective audit of referral patterns from primary care.

Following recently published recommendations and guidelines, a prospective audit of 222 consecutive patients referred for open access echocardiography was conducted over a period of three months in a large district general hospital in the UK. Our study demonstrated the waiting time for an open access echocardiogram to be shorter than the waiting time for the outpatient clinic, which allowed identification of clinically significant cardiac disease sooner, leading to early advice on patient management. Specialist referral was avoided by the inclusion of management comments by a cardiologist in the technical echocardiogram report. We showed that open access echocardiography for detection of left ventricular systolic function, should be performed only if the ECG is abnormal, confirming previous reports. ECG interpretation in primary care is unreliable. In view of limited resources, hospitals should vigorously screen referrals for open access echocardiography.

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.

Tolerability of combined treatment with verapamil and beta-blockers in angina resistant to monotherapy.

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.

Comparison of once daily endralazine with placebo in the treatment of hypertension uncontrolled by a beta-blocker and diuretic.

We report the first placebo controlled parallel group study of once daily endralazine (5-20 mg) in hypertension uncontrolled by a beta-blocker plus a diuretic. Following a 4-week run-in period 22 patients with a sitting mean arterial pressure (MAP) greater than 110 mm Hg were entered into the study and received either endralazine 5 mg or placebo. Blood pressure was measured 2 h and 24 h after dosing and the drug dose doubled at 2 and 4 weeks if the 24-h MAP remained greater than 110 mg Hg. The final blood pressure assessment was made after 6 weeks treatment in the 19 patients who completed the study. Three patients withdrew from the study because of side effects. The hypotensive effect (sitting) was in excess of placebo at 2 h by 15.8 mm Hg systolic (NS), 15.4 mm Hg diastolic (p less than 0.01), 15.5 mm Hg MAP (p less than 0.02) and at 24 hours by 7.7 mm Hg systolic (NS), 8.9 mm Hg diastolic (p less than 0.02) and 11.1 mm Hg MAP (p less than 0.02). This study suggests that endralazine should be prescribed twice daily.

Could the increased antihypertensive efficacy of ketanserin in the elderly be due to altered pharmacokinetics?

Ketanserin is a serotonin S2-receptor antagonist that is an effective antihypertensive agent with a greater blood pressure reduction in older patients. We have reviewed the data from two studies of ketanserin pharmacokinetics in elderly patients, one in general practice (GP) and one in hospital patients. We compared these data with the results from two of our previous studies in young volunteers. The purpose was to determine whether the enhanced efficacy of ketanserin in elderly hypertensive patients could be due to altered pharmacokinetics. After a single dose of ketanserin, elderly hypertensives showed about a 60% increase in bioavailability compared with young volunteers. This increase is likely to be explained by a reduced metabolism of ketanserin on first pass through the liver. The elimination half-life of ketanserin was found to be longer in elderly hospital outpatients, but not in our elderly subjects in general practice. This prolongation of the elimination half-life of ketanserin appears to be unrelated to age, since the hospital outpatient elderly and elderly subjects in general practice were of similar ages. The elimination half-life of ketanserinol was longer in the hospital elderly subjects. This probably reflects a slight diminution of renal function in the elderly hospital outpatients, resulting in reduced clearance of ketanserinol. The peak and trough ketanserin concentrations were similar in young and elderly subjects during chronic treatment, and it is therefore unlikely that the increased efficacy of ketanserin in elderly patients is due to altered pharmacokinetics.

Clinical evaluation of Dinamap 845 automated blood pressure recorder.

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.

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.

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.

Role of carotid sinus syndrome and neurocardiogenic syncope in recurrent syncope and falls in patients referred to an outpatient clinic in a district general hospital.

Carotid sinus syndrome (CSS) and neurocardiogenic syncope (NCS) are recognised as important causes of recurrent syncope and falls in the elderly. In this study the role of CSS (diagnosed with carotid sinus massage) and NCS (diagnosed with prolonged head-up tilt) in a district general hospital were investigated. Over 27 consecutive months carotid sinus massage was performed in 139 patients. Of these 29 (20.8%) patients (mean (SD) age of 78 (9) years) showed a positive response. Of these 18 (62%) patients showed a positive response only when carotid sinus massage was performed with 70( degrees ) head-up tilt. Thirteen (8.7%) of the 149 patients who had prolonged head-up tilt testing were found to have NCS. The mean (SD) age for patients with NCS was 59 (26) years and the mean (SD) time required to produce a positive response during prolonged head-up tilt was 12 (5) minutes. It is concluded that carotid sinus massage and head-up tilt testing are useful in patients presenting with unexplained syncope and falls in a district general hospital setting. Carotid sinus massage should be repeated upon head-up tilt if a negative response is obtained in the supine position.