European Journal of Clinical Pharmacology

Dollery, C.

doi: 10.1007/BF00618508pmid: 477706

Svendsen, T.; Hartling, O.; Trap-Jensen, J.

doi: 10.1007/BF00618509pmid: 38968

228 15 15 4 4 T. Lysbo Svendsen O. Hartling J. Trap-Jensen Department of Clinical Physiology Frederiksberg Hospital Copenhagen Denmark Summary Changes in cardiac output, heart rate and arterial blood pressure were determined in 31 healthy volunteers after i. v. administration of equipotent doses of five different adrenergic betareceptor blocking drugs. Propranolol was given to seven subjects, atenolol to five, practolol to seven, pindolol to five, and (a new drug) ICI 89,406 to seven. Each drug was given in six logarithmically spaced doses. Propranolol is non-cardioselective and lacks intrinsic sympathomimetic activity. Atenolol, practolol, and ICI 89,406 are cardioselective. Practolol, pindolol, and ICI 89,406 have intrinsic sympathomimetic activity. Cardiac output was determined by impedance cardiography at supine rest. The dose-response curves for cardiac output and heart rate were of three different types: one obtained after administration of drugs without intrinsic activity, represented by propranolol and atenolol, both of which caused a maximal decrease in cardiac output of about 27%, and in heart rate of about 21%. A second type, obtained after drugs with moderate intrinsic sympathomimetic activity, represented by practolol, showed small but significant decreases in cardiac output of 12%, and in heart rate of 11 per cent. A third type, after drugs with marked intrinsic sympathomimetic activity, was represented by pindolol and ICI 89,406, which did not significantly reduce cardiac output or heart rate. The blood pressure was essentially unchanged in all subjects, even after the largest dose of any of the drugs. It was concluded that the degree of intrinsic sympathomimetic activity possessed by an adrenergic betareceptor blocking agent is responsible for acute changes in heart rate and cardiac output, and cardioselectivity is of no importance in this respect.

Woods, K.; Linton, S.; Kendall, M.; Faragher, E.; Grieve, R.

doi: 10.1007/BF00618510pmid: 38969

228 15 15 4 4 K. L. Woods S. P. Linton M. J. Kendall E. B. Faragher R. J. Grieve Department of Therapeutics and Clinical Pharmacology University of Birmingham United Kingdom Selly Oak Hospital Birmingham United Kingdom Mathematical Analysis Section Geigy Pharmaceuticals Macclesfield United Kingdom Department of Medicine University of Birmingham United Kingdom Summary The effects of intravenous propranolol, metoprolol, acebutolol and placebo on exercise-induced changes in heart rate and peak flow rate (PFR) have been studied in a group of healthy subjects. The three β-blockers produced significant and comparable reductions in exercise-induced tachycardia and the magnitude of the reduction was related to the log plasma concentration of each drug. Significant cardiac β-blockade was detectable for three hours after giving propranolol and for four hours after metoprolol and acebutolol. The exercise-induced changes in PFR were small and variable and were not significantly affected by any of the drugs. We conclude that, contrary to published reports, exercise-induced changes in heart rate and PFR in healthy subjects do not provide a satisfactory test system for assessing the selectivity of β-blockers.

Pedersen, O.; Mikkelsen, E.; Christensen, N.; Kornerup, H.; Pedersen, E.

doi: 10.1007/BF00618511pmid: 477707

228 15 15 4 4 O. Lederballe Pedersen E. Mikkelsen N. J. Christensen H. J. Kornerup E. B. Pedersen Department of Clinical Pharmacology University of Aarhus Denmark Department of Internal Medicine I Aarhus Amtssygehus Denmark Department of Internal Medicine C and M Aarhus Kommunehospital Denmark Department of Internal Medicine and Endocrinology Herlev Hospital Denmark Summary Acute sublingual administration of nifedipine 10–20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r=0.92, p<0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r=0.80, p<0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30–60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p<0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r=0.74, p<0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.

Ng, C.; Gstöttner, M.; Gmeiner, R.

doi: 10.1007/BF00618512pmid: 477708

228 15 15 4 4 C. K. Ng M. Gstöttner R. Gmeiner Department of Internal Medicine University of Innsbruck Innsbruck Austria Summary The electrophysiological effects of lorcainide 1.25 or 2.5 mg/kg given iv over 2 or 4 min, were studied in 21 patients with normal and diseased impulse formation and conduction, by means of intracardiac recording and stimulation. Sinus rate and the effective atrial refractory period rose following both doses of lorcainide. The corrected sinus node recovery time rose only after lorcainide 2.5 mg/kg and then most markedly in patients with sinus node dysfunction. The P-A interval remained unchanged following the drug. The A-H interval during sinus rhythm, and the pooled A-H intervals during atrial pacing, increased slightly, and the functional and effective A-V nodal refractory period changed variably. Wenckebach periods above the bundle of His occurred at lower atrial pacing rates following both doses of lorcainide in 7 patients, at the same atrial pacing rate in 9 and at higher rates in 3. H-V intervals, pooled H-V intervals and QRS-width lengthened in all patients, most markedly in cases with a conduction delay below the His bundle, who had received lorcainide 2.5 mg/kg. Thus, lorcainide shares some electrophysiological properties with procainamide and aprindine. Higher doses should be used with caution in patients with pre-existing conduction delay below the bundle His.

Bergman, U.; Dahlström, M.; Gunnarsson, C.; Westerholm, B.

doi: 10.1007/BF00618513pmid: 477709

228 15 15 4 4 U. Bergman M. Dahlström C. Gunnarsson B. Westerholm Department of Clinical Pharmacology at the Karolinska Institute Huddinge University Hospital Sweden National Corporation of Swedish Pharmacies, and District Health Centre of Örnsköldsvik Sweden Summary The prescription of psychotropic drugs at a multidoctor district health centre in northern Sweden in 1973, was analysed by means of problemoriented medical records. Of the 22,000 inhabitants of the district 10,700 consulted the health centre. Psychotropic drugs were prescribed for 11.3% of the patients, corresponding to 5% of the inhabitants of the area. Sixty per cent of the patients received one psychotropic prescription and 90% not more than three. Two-thirds of prescriptions were for women. Hypnotics, sedatives and minor tranquillisers constituted 64% of all prescriptions, major tranquillisers 24% and antidepressants 12%. One fifth of the patients obtained drugs belonging to more than one of the major psychotropic groups during the year. Insomnia, psychoneurosis and depression made up two-thirds of the indications for psychotropic drug therapy. More than thirty different psychotropic drugs were prescribed for the two major indications. There was considerable variation in how the different doctors prescribed drugs for the same indication. Fifty-nine different drug products were prescribed, of which the commonest five constituted more than half of the total number. Individual doctors used from 22 to 38 different psychotropic drugs.

Redolfi, A.; Borgogelli, E.; Lodola, E.

doi: 10.1007/BF00618514pmid: 477710

228 15 15 4 4 A. Redolfi E. Borgogelli E. Lodola Division of Geriatric Medicine Ospedale di Circolo Varese Italy Zambon Research Laboratories Bresso-Milan Italy Summary The blood level versus time curve for unchanged cimetidine after a 200 mg oral dose has been determined in 20 apparently healthy subjects, ranging from 22 to 84 years of age. A significant relationship between the area under the curve (AUC) and age was found (r=0.81; P<0.001). The peak concentrations of cimetidine were significantly inversely related to body weight (r=−0.71; P<0.001). The age-related increase in bioavailability of oral cimetidine, as measured by AUC, was probably due to decreased total clearance of the drug, which resulted from the opposed changes (by themselves not significant) of distribution volume towards a decrease and of half-life towards an increase with age. Reduction in the standard oral dose of cimetidine by one third to one half should be feasible in the elderly without loss of efficacy, and it may be advisable in order to obviate extreme individual responses that may occur in this population.

Neuvonen, P.; Lehtovaara, R.; Bardy, A.; Elomaa, E.

doi: 10.1007/BF00618515pmid: 314381

228 15 15 4 4 P. J. Neuvonen R. Lehtovaara A. Bardy E. Elomaa Department of Clinical Pharmacology University of Helsinki Helsinki Finland The Pitäjänmäki Epilepsy Research Centre Helsinki Finland Summary The effect of administration for three days of acetylsalicylic acid (1500 mg/day), phenylbutazone (300 mg/day), paracetamol (1500 mg/day) and tolfenamic acid (300 mg/day) on serum concentrations of phenytoin and carbamazepine were studied in a group of patients on continuous antiepileptic therapy. When measured 10 h after the last dose of the analgesics, the only significant effect was a decrease in total serum phenytoin after three days of phenylbutazone. When six patients on continuous phenytoin therapy took phenylbutazone for two weeks there was at two days an initial decrease, followed by a significant increase in total serum phenytoin and a concomitant increase in free phenytoin in serum. Even phenylbutazone was well tolerated by most of the patients. However, its use had to be discontinued in one patients due to obvious signs of phenytoin intoxication, with concomitant increases in the serum free and total phenytoin concentrations.

Melander, A.; Brante, G.; Johansson, Ö.; Lindberg, T.; Wåhlin-Boll, E.

doi: 10.1007/BF00618516pmid: 477711

228 15 15 4 4 A. Melander G. Brante Ö. Johansson T. Lindberg E. Wåhlin-Boll Departments of Clinical Pharmacology and Pediatrics Malmö General Hospital Sweden Clinical Chemistry, St. Lars Hospital University of Lund Sweden Department of Community Care Sciences Dalby Sweden Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.

Friis, M.; Grøn, Ulla; Larsen, N.; Pakkenberg, H.; Hvidberg, E.

doi: 10.1007/BF00618517pmid: 477712

228 15 15 4 4 M. L. Friis Ulla Grøn N. -E. Larsen H. Pakkenberg E. F. Hvidberg Department of Neurology Hvidovre Hospital Copenhagen Denmark Department of Clinical Chemistry, Division of Clinical Pharmacology Glostrup Hospital Copenhagen Denmark Department of Clinical Pharmacology, Rigshospitalet Copenhagen Denmark Summary The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (C min ) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the C min . First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.