Purpura and bleeding due to calcium-channel blockers: an underestimated problem? Case reports and a pilot study.

BACKGROUND: Surgical bleeding and occasionally purpura due to calcium-channel blockers have been described. AIM: To present cases in whom purpura or internal bleeding due to calcium-channel blockers was a presenting feature, including one subject with drug-induced haematuria and haematospermia due to amlodipine and one with the Rumpel-Leede sign. Further support for a true association was sought in a pilot study using Hess testing to provoke purpuric skin lesions. METHODS: Four representative cases presenting due to purpura or bleeding are described, all of whom had an abnormal Hess test. A further 19 patients taking calcium-channel blockers and 13 control subjects were also tested. RESULTS: Of 19 patients on calcium-channel blockers, 16 had either abnormal Hess results (n = 13) or marked acral purpura (n = 3) after a Hess test procedure. A similar abnormal response, of milder degree, occurred in only 2 of 13 control subjects. CONCLUSIONS: The high frequency of purpura shown in this study, whether spontaneous or provoked, suggests that this is a pharmacological class effect rather than idiosyncratic. Purpura in patients taking these drugs may be a clue to diagnosis of internal or postsurgical bleeding. We conclude that purpura related to calcium-channel antagonists is probably underestimated, but further studies are needed to identify the mechanism by which this occurs.

Hydropneumopericardium and oesophagitis: a non-fatal case.

Hydropneumopericardium is a very rare and usually fatal complication of peptic oesophageal ulceration. The patient reported here survived and the report resembles one previously made about a child. In both patients failure to show the fistula radiologically or on endoscopy suggests that rapid spontaneous healing had occurred, and that this was responsible for survival.

Recurrent migraine after propranolol.

A 70-year-old woman with angina pectoris developed a migrainous headache 3 days after starting oral propranolol. She had not complained of headaches since her second and third decade when she had suffered occasional attacks of migraine. It is likely that propranolol was the cause of her headache, since it recurred when she was rechallenged with the drug.

A pharmacokinetic study of doxapram in patients and volunteers.

1. Following intravenous bolus injections or brief infusions in healthy volunteers, plasma concentrations of doxapram declined in a multi-exponential fashion. The mean half-life from 4-12 h was 3.4 h (range 2.4-4.1h), the mean apparent volume of distribution was 1.5 1 kg-1 and the whole body clearance was 370 ml min-1. 2. Enteric-coated capsules of doxapram base were absorbed rapidly after an initial delay, and the systemic availability was about 60%. 3. Doxapram is extensively metabolized and less than 5% of an i.v. dose was excreted unchanged in the urine in 24 h. A metabolite (AHR 5955) was present in plasma in amounts comparable to the parent compound and had a similar half-life. 4. The disposition of doxapram appears to be similar in healthy volunteers and patients with respiratory failure. 5. The previously held belief that plasma concentrations fall rapidly when an infusion is stopped is only true following short duration infusions. The pharmacokinetic properties of doxapram are such that steady-state plasma concentrations will not be achieved for many hours with the recommended constant rate infusion régime.

Autonomic blockade and coronary catecholamines and cyclic AMP in exercising man.

To assess in man the effects of autonomic blockade on the response of catecholamines in the coronary circulation to dynamic exercise, arterial and coronary sinus catecholamine concentrations were measured in six patients during supine cycling exercise, following atropine 1.8 mg and oxprenolol 0.2 mg/kg iv. Although arterial concentrations did not increase significantly, coronary sinus catecholamine concentrations increased from 2.54 +/- 0.59 nmol/1 at rest 4.44 +/- 1.3 nmol/1 during exercise (P less than 0.05; one-tailed test) and were associated with a small increase in heart rate and coronary sinus cyclic AMP concentrations from 9.4 +/- 0.7 nmol/1 (rest) to 11.6 +/- 1.1 nmol/1 (exercise) (0.05 greater than P greater than 0.01). Although autonomic blockade may have increased catecholamine release, this was not reflected in an increased efflux of catecholamines from the heart, because similar increases in coronary sinus catecholamine concentrations occurred in the absence of autonomic blockade.

Smoking and catecholamine and c-AMP concentrations in the coronary circulation of man and the effect of oxprenolol.

Changes in catecholamine, c-AMP and lactate concentrations in the coronary circulation of man, during smoking, were studied in 12 patients. The heart rate increase from 63 +/- 2 beats/min (control) to 74 +/- 3 (smoking)(P less than 0.01), falling to 70 +/- 2 (10 min after smoking) (0.05 greater than P greater than 0.01), whilst coronary sinus c-AMP concentrations rose from 11 +/- 0.7 nmol/l (smoking) to 11.9 +/- 0.8 nmol/l (after smoking) (0.05 greater than P greater than 0.01; one tailed 't' test). There was no significant change in blood pressure, catecholamine or lactate concentrations. The study was repeated in eight of the patients following intravenous oxprenolol. Coronary sinus catecholamine concentrations increased from 4.1 +/- 0.7 nmol/l (control) to 5.5 +/- 1.1 nmol/l (after smoking) (0.05 greater than P greater than 0.01; one tailed 't' test), but heart rate and c-AMP concentrations remained unchanged, confirming that smoking-induced tachycardia is a result of a beta-adrenergic mechanism, at least part of which is due to a release of cardiac catecholamines. Arterial lactate concentrations increased only following oxprenolol from 0.74 +/- 0.07 mmol/l (control) to 0.83 +/- 0.09 mmol/l (smoking).

Effect of isometric exercise on catecholamines in the coronary circulation.

Arterial and coronary sinus blood levels of catecholamines, adenosine 3', 5'-cyclic monophosphate (c-AMP) and lactate were measured during isometric exercise in fourteen patients. In no patient did lactate production occur. Mean resting total catecholamine levels both arterial (0.53 +/- 0.07 ng/ml; 2.94 +/- 0.38 nmol/l) and coronary sinus (0.4 +/- 0.08 ng/ml; 2.22 +/- 0.44 nmol/l), did not change significantly on exercise. Coronary sinus c-AMP levels fell on exercise from 11.5 +/- 0.8 nmol/l (resting) to 9.9 +/- 0.8 nmol/l (exercise) (P less than 0.01) with an arterial-coronary sinus difference of 1.2 nmol/l (P less than 0.01) on exercise. Our findings suggest that isometric exercise does not normally result in excessive cardiac symphathetic activity.

Obsolete but dangerous antacid preparations.

One case of acute hypercalcaemia and two of recurrent nephrolithiasis are reported in patients who had regularly consumed large amounts of calcium carbon-ate-sodium bicarbonate powders for more than 20 years. The powders had been obtained from pharmacists unknown to the patients' medical practitioners. It is suggested that these preparations were responsible for the patient's problems, and that such powders should no longer be freely obtainable.

Effect of submaximal isometric exercise on catecholamine, cAMP and lactate concentrations in the coronary circulation of man, following atropine and oxprenolol.

The effects of atropine and oxprenolol on changes occurring in total catecholamine, cyclic AMP (cAMP) and lactate concentrations in arterial and coronary sinus blood, during submaximal isometric exercise, were studied in 10 patients. Static one-third-maximal handgrip exercise, sustained for 5 minutes, did not produce an increase in either arterial or coronary sinus plasma catecholamine concentrations (measured at rest and during the last minute of exercise) and was not influenced by atropine and oxprenolol. Myocardial lactate production did not occur. Coronary sinus cAMP concentrations fell during isometric exercise from 11.53 +- 0.93 to 9.42 +/- 0.81 nmol/l (+/ SEM), and following autonomic blockade from 12.46 +/- 1.12 TO 9.6 +/- 0.87 nmol/l but rose on subsequent isometric exercise to 11.27 +/- 0.8 nmol/l (p less than 0.05). Although this latter increase could still be due to beta-adrenergic stimulation, the absence of any change in catecholamine concentrations in the presence of beta-blockade suggests that other factors may have been responsible.

Arterial and coronary sinus catecholamines and cyclic-AMP during dynamic supine exercise in patients with chest pain.

Arterial and coronary sinus catecholamine concentrations were measured during dynamic exercise in patients to assess the sympathetic response. Arterial concentrations increased from 1.77 nmol/1 (SEM = 0.53, n = 7) (control) to 2.95 nmol/1 (SEM = 0.65, n = 7) during exercise (0.05 greater than P greater than 0.01) and coronary sinus concentrations from 2.78 nmol/1 (SEM = 0.53, n = 7) (control) to 4.43 nmol/1 (SEM = 0.71, n = 7) (0.05 greater than P greater than 0.01). Resting, and exercise, arterial-coronary sinus differences in catecholamine concentrations were not statistically significant. In some patients, higher catecholamine concentrations occurred post-exercise than during exercise. The coronary sinus-arterial difference in catecholamine concentration during exercise was greatest in the one patient who developed angina pectoris. Cyclic-AMP concentrations were also measured, but these did not change significantly, consistent with the predominantly noradrenaline response to exercise.

Evaluation of rapid atrial pacing in diagnosis of coronary artery disease. Evaluation of atrial pacing test.

Seventeen patients presenting with anginal-type pain were studied by bicycle exercise testing, rapid atrial pacing, and coronary angiography. Ten patients with angina and abnormal pacing tests at rates less than 180/minute were found to have significant coronary artery disease as demonstrated by coronary angiography. Seven patients with pacing-induced chest pain only at rates of 180 and above had normal coronary angiogram. This suggests that patients requiring rates of 180 or more to produce a positive atrial pacing test, following our protocol, do not usually have significant coronary artery disease though confirmation requires a larger study.

The disposition of intravenous doxapram in man.

The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg . kg-1) and by intravenous infusion (6.5 mg . kg-1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances 5.9 and 5.6 ml . min-1 . kg-1) following i.v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 microgram . ml-1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 microgram . ml-1 from 15--25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.

The ventilatory effects of doxapram in normal man.

1. To determine the mode of action of doxapram in man we have measured ventilation, oxygen uptake, CO2 production, hypoxic and hypercapnic ventilatory responses in six healthy men before and during intravenous infusion to maintain a constant plasma level. 2. Doxapram changed neither resting oxygen uptake nor CO2 production but produced a substantial increase in resting ventilation at both levels of end-tidal CO2 studied. 3. Doxapram increased the ventilatory response to isocapnic hypoxia from -0.8 +/- 0.4 litre min-1 (%SaO2)-1 to -1.63 +/- 0.9 litres min-1 (%SaO2)-1. This was similar to the increase in hypoxic sensitivity which resulted from raising the end-tidal CO2 by 0.5 kPa without adding doxapram. 4. The slope of the ventilatory response to rebreathing CO2 rose from 11.6 +/- 5.3 litres min-1 kPa-1 to 20.4 +/- 9.8 litres min-1 kPa-1 during doxapram infusion. 5. The marked increase in the ventilatory response to CO2 implies that doxapram has a central action, but the potentiation of the hypoxic drive also suggests that the drug acts on peripheral chemoreceptors, or upon their central connections, at therapeutic concentrations in normal unanaesthetized subjects.