Biomedical subjects
Publications and source records attributed to C F George.
The elderly are at risk from stroke and cardiac complications of hypertension. There is strong circumstantial evidence to indicate that these risks may be reduced by hypotensive therapy. However, the decision to treat must be taken after careful appraisal of the patient and, because the risks of therapy are higher in this age group, the choice of drugs should be restricted.
1. Plasma propranolol concentrations were measured in healthy old and young subjects following single oral doses of 40 mg, single i.v. infusions of 0.15 mg kg-1 and after nine 40 mg oral doses given four times daily. 2. In each of the three studies, the elderly had higher plasma propranolol concentrations than the young despite having similar apparent volumes of distribution. 3. The terminal half-life of propranolol was similar in the two groups after oral propranolol but significantly shorter in the young after intravenous dosing (P less than 0.05). 4. The bioavailability assessed from the concentration-time curves after i.v. and oral dosing was greater in the elderly (P less than 0.05). 5. The differences between peak concentrations observed in old and young subjects after single oral doses were maintained during chronic therapy and there was a correlation between the individual values obtained on multiple therapy with that after a single dose (P less than 0.05). 6. Ageing appears to affect the pharmacokinetics of propranolol in two ways. Firstly, distribution to the tissues appears to be slowed. Secondly, the increased bioavailability following oral administration suggests diminished intrinsic clearance by metabolism.
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The hangover effects of 768 mg chlormethiazole, an hypnotic with a half-life of approximately 4 hr, were compared with those of placebo in a double-blind cross-over study in 8 young subjects. Ten hours after dosing there were no differences between the preparations in the subjects' psychomotor performance, EEG sleep scores, or visual analogue ratings. Thus, an hypnotic which is rapidly removed from the body may confer considerable advantages. However, all 8 subjects had unpleasant nasal symptoms following chlormethiazole, and it is therefore not an ideal hypnotic for this age group.
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1 No correlation was found between the rate of gastric emptying and peak plasma propranolol concentrations in six hypertensive patients after single oral doses of 80 mg. 2 In four normal subjects given oral propranolol the peak plasma concentration was highest when a simultaneous injection of metoclopramide and lowest when propantheline was given. The mean time to peak was 1.5 h after metoclopramide, 2.8 h after normal saline and 4.5 h after propantheline. 3 Gastric emptying has some influence on the time of peak plasma propranolol concentrations but individual variation in its bioavailability is determined mainly by first-pass metabolism in the liver.
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Response to oral and intramuscular emepronium bromide was assessed cystometrically in nine patients with urinary incontinence caused by an uninhibited bladder. Oral therapy had no effect, whereas intramuscular administration increased bladder capacity and significantly delayed the onset of bladder spasm and the desire to void. Plasma-propranolol response was delayed and concentrations were reduced after an oral 40 mg dose of propranolol in 3 patients who had received oral emepronium bromide. These results indicate that although oral emepronium bromide had some anticholinergic effect--i.e., in reducing gastrointestinal motility--absorption of an oral dose was not sufficient for the bladder to be affected.
The effects of a single 10 mg oral dose of nitrazepam were compared with those of a placebo in healthy young and old people. Both the young and the elderly slept better on three successive nights after nitrazepam but they felt less awake at 12 and 36 hours (P less than 0-01). Elderly people made significantly more mistakes in a psychomotor test than did the young, despite similar plasma concentrations of nitrazepam and half lives in the two groups. This difference in response to psychomotor testing is probably explained by an increased sensitivity of the ageing brain to the action of nitrazepam.
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The hypertensive action of atenolol has been studied in a randomized double-blind crossover comparison. Twelve patients showed a highly significant reduction in average supine systolic and diastolic blood pressures from pre-treatment values of 196.3/115.9 to 159.1/89.2 mmHg (26.1/15.4 kPa to 22.2/11.9 kPa) after 2 weeks on once daily atenolol. No dose-related reduction in blood pressure was seen and the single 100 mg daily dose was as effective as 100 mg twice daily or 50 mg twice daily. Blood pressures recorded after 2 weeks' atenolol were lower than those obtained at 7 days irrespective of dose.
In a double-blind study in six subjects propranolol significantly reduced the respiratory sensitivity to carbon dioxide rebreathing. This effect seems to have been due to beta-adrenergic blockade, since it was not seen with D-propranolol. In two subjects increasing doses of propranolol caused progressive reductions in respiratory sensitivity to values below normal and similar to those of patients with ventilatory failure. These changes are probably due to a central action of propranolol.
Thirteen hypertensive patients entered a double-blind crossover trial of guanethidine and oxprenolol in combination. In nine patients who completed the trial there was an additive effect on blood pressure, but the combination had a smaller effect on heart rate than was expected from the individual effects, and side effects were not increased. During treatment with oxprenolol the plasma potassium concentration rose from 3.6 mmol (mEq)/1 to 3.9 mmol (mEq)/1. No correlation was found between the plasma oxprenolol concentration and changes in blood pressure or response to injected isoprenaline, but measurements of plasma oxprenolol concentrations were of value in determining compliance with the protocol.
1. The effects of propranolol and RO3-4787, a new beta-adrenoceptor antagonist with a partial agonist activity, have been studied in a blind, cross-over comparison with placebo. 2. In ten patients who completed the study, the two drugs produced a similar reduction in blood pressure; the reduction in heart rate with propranolol was significantly (P less than 0.001) greater than that produced by RO3-4787. 3. Plasma renin activity averaged 4.13 +/- 1.37 ng h-1 ml-1 on placebo, fell to 3.64 +/- 1.47 ng h-1 ml-1 on propranolol and to 2.50 +/- 1.39 ng h-1 ml-1 on RO3-4787. 4. No correlation was demonstrable between the log plasma concentration of either propranolol or RO3-4787 and change in blood pressure.
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