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Drug Prescriptions↗
Biomedical subjects
D G McDevitt
Publications and source records attributed to D G McDevitt.
Pharmacokinetics of propranolol during pregnancy.
Propranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postpartum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.
Administration, Oral↗
The clinical pharmacology of lidocaine congeners--review of encainide, flecainide, lorcainide and tocainide.
Among the newer antiarrhythmic drugs currently being evaluated are the four so-called lidocaine congeners, encainide, flecainide, lorcainide and tocainide. A knowledge of the pharmacokinetic properties of these agents may help to distinguish between them and may also be important for rational patient prescribing. Encainide and lorcainide both undergo predominantly hepatic elimination: both appear to form metabolites which have antiarrhythmic activity of their own and which have longer elimination half-lives than the parent compounds, resulting in accumulation with chronic administration. Flecainide and tocainide are cleared mainly by the kidneys, do not have active metabolites and have long elimination half-lives. All of the drugs have significant antiarrhythmic activity and this is proportionate to the plasma concentration of either the drug alone or combined with the active metabolites. Comparative effectiveness between the drugs has not been established. In general, all four drugs have only minor adverse effects, principally gastrointestinal or neurological, which may disappear with small dose reductions. However, cardiac effects can also occur and rarely pro-arrhythmic effects have been described, particularly with encainide and flecainide. All four drugs are suitable for long-term administration on a twice-daily basis.
Anilides↗
Pharmacokinetics of digoxin alone and in the presence of indomethacin therapy.
The effects of maintenance indomethacin therapy on single dose digoxin pharmacokinetics and dynamics were studied in six healthy volunteers with normal renal function. Indomethacin did not alter the elimination half-life, systemic clearance or distribution of digoxin. No pharmacodynamic interaction as assessed by changes in the systolic time intervals QA2 and LVET was found. This study does not lend support for a significant digoxin-indomethacin interaction in man.
Adult↗
Enhancement of physiological finger tremor by intravenous isoprenaline infusions in man: evaluation of its role in the assessment of beta-adrenoceptor antagonists.
Graded intravenous isoprenaline infusions produce dose-related increases in finger tremor. The dose-response curves constructed with intra-arterial or intravenous isoprenaline behave similarly in the presence of both atenolol 50 mg and propranolol 40 mg. In Five subjects, practolol 120 mg, atenolol 50 mg, propranolol 40 mg and sotalol 200 mg reduced exercise heart rate by 20.2 +/- 2.3, 21.4 +/- 1.8, 17.4 +/- 2.5, 23.9 +/- 3.6% respectively: the differences were not significant. The corresponding dose-ratios for reduction of an isoprenaline tachycardia were 2.8, 2.3, 19.1 and 16.9 respectively. At doses which had comparable effects on an exercise tachycardia, the non-selective beta-adrenoceptor antagonists, propranolol 40 mg and sotalol 200 mg, attenuated the finger response to isoprenaline (dose ratios 33.3 and greater than 25.0 respectively) more than the beta 1-selective adrenoceptor antagonists, practolol 120 mg and atenolol 50 mg (dose ratios 1.0 and 2.3 respectively). In two out of five subjects, dose-response curves could not be constructed with sotalol, either at a dose of 200 or 100 mg. The enhancement of physiological finger tremor by intravenous infusions of isoprenaline may be useful in the investigation of beta 2-adrenoceptors and their antagonists in man.
Adolescent↗
Vagal activity is increased during intravenous isoprenaline infusion in man.
Eight healthy normal subjects (19-23 years) received graded intravenous isoprenaline infusions PRE- and POST-atropine, 0.04 mg/kg i.v. The adequacy of atropinization was tested with bolus intravenous injections of phenylephrine. PRE-atropine, isoprenaline caused an increase in heart rate and systolic pressure, but a decrease in diastolic pressure with little change in mean pressure (+32.8 +/- 3.0 beats/min, +18.9 +/- 3.0 mm Hg, -13.5 +/- 1.9 mm Hg, -2.7 +/- 1.9 mg Hg respectively at isoprenaline 2 micrograms/min). POST-atropine, the increase in heart rate was enhanced, the rise in systolic pressure abolished and the falls in diastolic and mean pressures exaggerated (+47.0 +/- 2.8 beats/min, -8.9 +/- 2.9 mm Hg, -27.3 +/- 2.1 mm Hg, -21.1 +/- 1.9 mm Hg, respectively at isoprenaline 2 micrograms/min). During an isoprenaline infusion, when the heart rate and blood pressure changes are stable, there is an increase rather than a decrease in cardiac vagal tone.
Adult↗
Patient compliance with oral theophylline therapy.
Day-to-day variations in plasma theophylline concentrations at steady-state have been assessed in 29 hospital inpatients who required theophylline for obstructive airways disease. Plasma concentrations were measured at 09.00h and 14.00h for four consecutive days in the equilibrium state in 13 patients taking 350 mg/day and 16 patients taking 700 mg/day. Analysis of variance gave 95% confidence limits for day-to-day variation of +/- 2.9 micrograms/ml at 350 mg/day and +/- 4.8 micrograms/ml at 700 mg/day. In a separate study, compliance with sustained-release theophylline therapy has been assessed in a group of 63 patients receiving the drug in general practice but not attending hospital. Compliance was estimated by comparing plasma theophylline concentrations before and after a 7-day period of measured theophylline consumption and by tablet counting. Of the 63 patients, 16 had discontinued their theophylline prior to being contacted and two did so during the first week: these were considered non-compliant. Three patients had plasma concentrations which increased by more than the day-to-day variation for their dose level during monitored intake and one other took less than 80% of his tablets. These patients were also considered non-compliant. A further four patients in whom plasma theophylline levels were zero on at least one occasion during the study were also adjudged non-compliant. Thus non-compliance with prescribed theophylline dosage occurred in 26 (41.3%) of the patients studied. In the majority of these, treatment had been discontinued and the non-compliance was gross.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Central effects of single oral doses of propranolol in man.
The central effects of propranolol, a lipophilic beta-adrenoceptor antagonist, were investigated in six healthy male volunteers using two flash fusion threshold (2FFT), simple reaction time (SRT), digital copying test (DCT), symbol digit modalities test (SDMT), Gibson spiral maze test (GSMT) and mood rating scales for tension, alertness, depression, detachment and anxiety. Compared to placebo, 2FFT was prolonged by propranolol 40, 80 and 160 mg at one or more times tested but not by propranolol 320 mg: the largest effect was seen at 3 h after 40 mg, and the effects of 40, 80 and 160 mg were significantly greater than 320 mg at 2 h. SRTs were significantly prolonged by all doses of propranolol at 2 and 3 h and by 40 and 80 mg doses at 5 h. DCT was lowered by 40 and 80 mg at 2 and 3 h by 80 mg at 5 h, and by 320 mg at 2 h, but the 160 mg dose had no effect. Propranolol impaired the expected retest gain of the SDMT with all doses except 320 mg and at 2 h after 40, 80 and 160 mg, performance was actually worsened. Mood rating scales showed increased detachment with 40 mg and decreased alertness with 80 and 320 mg. The results show that propranolol has central effects in man: the effects appeared to be greater with lower doses, 40 and 80 mg, than with higher doses, 160 and 320 mg.
Adult↗
Pharmacodynamics and pharmacokinetics of digoxin in the presence of lithium.
Previous biochemical and clinical data suggest there may be an interaction between digoxin and lithium. The pharmacodynamics and pharmacokinetics of an intravenous infusion of digoxin were studied in six male subjects before and after 2 weeks treatment with lithium carbonate. The effects of lithium on sodium pump activity, intracellular electrolytes and extracellular electrolytes were studied. No significant interaction between digoxin and lithium was found. No significant effects of lithium on sodium pump activity or electrolyte concentrations were found.
Adolescent↗
Circadian variation in plasma theophylline concentrations during maintenance therapy with a sustained-release preparation in patients with obstructive airways disease.
Circadian variation in plasma theophylline concentrations was studied in eight patients with obstructive airways disease during regular 12-hourly dosing at 09.00 and 21.00 h with a sustained-release theophylline formulation. After regular dosing for a minimum period of 3 days, plasma concentration measurements were made at 09.00, 13.00, 21.00 and 01.00 h on 3 consecutive days and at more regular intervals during a complete 24 h period on day 4. On each day, theophylline concentrations for the first 4 h of the dosing interval were consistently higher during the day than at night. However, the differences were significant only at 13.00/01.00 h on day 2, and for each of the first 4 h on day 4. On day 4, following the dose at 21.00 h the mean peak plasma theophylline concentration occurred 6.9 +/- 0.8 h after dosing; in contrast, after the morning dose the mean peak concentration occurred at 4.5 +/- 0.8 h. However, the mean 'steady-state' concentrations during the two dose intervals were not significantly different. Thus circadian variations in plasma drug concentrations do occur in patients taking maintenance theophylline therapy: differing rates of absorption may account for the observed pattern.
Aged↗
Pharmacokinetics of sotalol during pregnancy.
Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32-36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4 +/- 0.3 ml/min/kg) than in the post-natal phase (1.5 +/- 0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6 +/- 0.6 h ante-natally and 9.3 +/- 0.7 h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10 h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.
Administration, Oral↗
Erythrocyte cation transport and age: effects of digoxin and furosemide.
The uptake of rubidium 86 (86Rb) by human erythrocytes was measured at various ages. Effects of digoxin and furosemide on this process were examined and, in the case of digoxin, related to its numbers of specific cellular binding sites. There were no significant effects of age on absolute cellular Rb uptake, digoxin-sensitive Rb uptake, or numbers of cellular binding sites for digoxin, but the ability of digoxin to inhibit digoxin-sensitive 86Rb uptake increased with age. The ability of furosemide to inhibit digoxin-insensitive 86Rb uptake did not change with age. Results suggest a dynamic contribution to altered sensitivity to digoxin in elderly persons.
Adolescent↗
Central effects of beta-adrenoceptor antagonists.
The central effects of atenolol, a cardioselective beta-adrenoceptor antagonist, were investigated in six healthy men. Two flash-fusion threshold (2FFT), simple reaction time (SRT), digital copying (DCT), symbol-digit modalities (SDMT), and Gibson's spiral maze tests (GSMT) and mood rating scales for tension, alertness, depression, detachment, and anxiety were used. Each subject took 50, 100, 200, and 400 mg atenolol and identical placebo orally in a randomized, double-blind, crossover study and the psychomotor tests were performed at 0, 2, 3, 5, and 8 hr. 2FFT was prolonged at 3 hr after all doses and at 2 and 5 hr with 100, 200, and 400 mg. The maximum effect was achieved with 200 mg and mean 2FFT correlated with mean plasma atenolol concentration. SRTs were prolonged after all doses at between 2 and 5 hr. The DCT and the retest gain of the SDMT were both lower than after placebo at 2 hr with 100, 200, and 400 mg. The time taken to perform the GSMT was not altered by active drug, but the number of errors was lower at 2 hr with 100 and 200 mg. The self-rating mood scales showed a subjective decrease in tension 2 hr after 400 mg. The results show that atenolol exerts central effects in man.
Adult↗
Changes in heart rate and forearm blood flow following intravenous boluses of isoprenaline in the presence of practolol and propranolol.
1 Increases in heart rate and forearm blood flow following graded intravenous bolus injections of isoprenaline sulphate, were measured in a double-blind randomised study of six subjects who received either placebo, practolol 50 mg, practolol 200 mg, propranolol 10 mg or propranolol 40 mg. 2 Dose related increases in forearm blood flow were produced by the graded boluses of isoprenaline sulphate. 3 Practolol 50 mg attenuated the heart rate response to isoprenaline but did not significantly affect the changes in forearm blood flow. Practolol 200 mg further attenuated the heart rate responses but also decreased the forearm blood flow responses. 4 Propranolol 10 mg and propranolol 40 mg significantly attenuated both the heart rate and forearm blood flow responses. The effect on forearm blood flow tended to be greater than the effect on heart rate. 5 Practolol 200 mg had the same effect on heart rate responses as propranolol 10 mg but a significantly smaller effect on the forearm blood flow responses. 6 The measurement of forearm blood flow following intravenous bolus injections of isoprenaline provides useful information about the beta 2-adrenoceptor antagonism of propranolol and practolol. However, application of the technique may be limited by the magnitude of the heart rate response and by the short-lived nature of the increase in forearm blood flow.
Adult↗
The effect of digoxin on 86rubidium uptake by erythrocytes from mothers and babies.
1 The uptake of 86rubidium by erythrocytes from mothers and babies has been used as a model system to investigate possible differences in sensitivity to digoxin in the very young. 2 While total 86rubidium uptake was not significantly different between mothers and babies, the digoxin-sensitive proportion was higher in neonatal erythrocytes. Neonatal cells were less sensitive to digoxin, demonstrated by the requirement for a larger amount of digoxin to inhibit 86rubidium uptake and this was accompanied by an increase in numbers of specific erythrocyte binding sites for digoxin. 3 These results provide further evidence in support of the hypothesis of decreased sensitivity to digoxin in the very young.
Digoxin↗
Standardised isoprenaline sensitivity tests--a comparison of existent methods.
1 Six healthy subjects (four male, two female, aged 19-24 years) received intravenous boluses of isoprenaline sulphate by two standardised methods of injection (Cleaveland et al., 1972; George et al., 1972). Heart rate changes were analysed by three different methods. 2 The I25 (dose of isoprenaline required to increase the heart rate by 25 beats/min) was not significantly altered by either the method of injection or the method of heart rate measurement. 3 The slope of the heart rate dose response curve was significantly steeper when isoprenaline was injected in a fixed 2 ml volume through a three-way tap, and when the heart rate was measured from the shortest three R-R intervals. 4 However the differences in method of injection and heart rate measurement between the two techniques do not appear to produce major alterations in the results obtained, particularly the I25.
Adult↗
Contribution of the vagus to the haemodynamic responses following intravenous boluses of isoprenaline.
1 Eight healthy subjects (six male, two female, aged 18-21 years) received graded intravenous bolus injections of isoprenaline sulphate. Heart rate and intra-arterial blood pressure were continuously monitored PRE- and POST-atropine (0.04 mg/kg). 2 PRE-atropine, an increase in heart rate of 25 beats/min was produced by 2.15 +/- 0.53 micrograms of isoprenaline and was associated with a fall in mean, systolic and diastolic pressures (18.9 +/- 2.8, 17.7 +/- 3.4 and 20.4 +/- 2.3 mm Hg respectively). 3 POST-atropine, the heart rate dose response curve was shifted to the right so that the dose of isoprenaline which increased heart rate 25 beats/min PRE-atropine, produced a significantly smaller heart rate rise of 20.3 +/- 1.7 beats/min (P less than 0.001). This was associated with a shift of the blood pressure dose-response curves to the left, and larger falls in mean, systolic and diastolic pressures (30.9 +/- 2.8, 31.8 +/- 3.3, 30.1 +/- 3.3 mm Hg respectively; P less than 0.01). 4 It is concluded that there is a significant contribution from a reflex withdrawal of cardiac vagal tone, to the tachycardia produced by a bolus of isoprenaline.
Adolescent↗
Prediction of optimum oral theophylline dose in patients with obstructive airways disease.
The hypothesis that a logarithmic correlation exists between the plasma theophylline concentrations 6 h after a test dose C(6) and the maintenance dose calculated to achieve a desired drug concentration during chronic oral administration (DM,CALC) was tested. A nomogram based on this relationship was evaluated as a means of predicting the optimum dose of theophylline in 14 patients with obstructive airways disease (DM,PRED). Each patient was given 5 mg/kg theophylline intravenously (i.v.) and plasma theophylline concentrations were measured for 12 h thereafter including one exactly 6 h after commencing the i.v. infusion C(6). Pharmacokinetic parameters derived from the plasma concentration-time curve were used to establish DM,CALC for a concentration of 10 micrograms/ml. DM,PRED was obtained from the nomogram using both the optimum and the actual values for C(6). Subsequently oral sustained-release theophylline was administered and the dose adjusted to establish a trough concentration of approximately 10 micrograms/ml. This dose was then corrected arithmetically, assuming a linear relationship between dose and plasma level, to represent that required to achieve a plasma concentration of exactly 10 micrograms/ml (DM,ACT). The correlation between C(6) and log DM,CALC was confirmed (r = 0.97 P less than 0.001), validating the hypothesis. DM,ACT was found to correlate significantly with DM,PRED (r = 0.90, P less than 0.01) substantiating the value of the nomogram. In nine of the 14 patients, DM,ACT corresponded satisfactorily to DM,PRED. In the remaining five, for whom DM,ACT lay outside the 95% confidence limits for the predicted dose, DM,PRED in general underestimated DM,ACT, an advantage in a drug with a low therapeutic index. The predictive error for DM,PRED was lower than that for DM,CALC, and the bias using either method was not significant. The results suggest that a single plasma theophylline assay following a test dose, and the nomogram may be useful in simplifying optimal theophylline administration.
Adult↗