[Drug-induced nausea and vomiting].
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Drug-Related Side Effects and Adverse Reactions↗
Biomedical subjects
F Andreasen
Publications and source records attributed to F Andreasen.
Increased thiopental sensitivity in cardiac patients.
The average dose of thiopental necessary for induction was 3.4 mg/kg body weight in seven patients on long-term therapy with digoxin and a diuretic and 4.7 mg/kg body weight in seven matched control patients (P less than 0.05). The initial volumes of distribution (V1) did not differ significantly. The amounts of thiopental redistributed (removed from V1) during the induction were calculated as V1 X k12 X ct and V1 X k13 X ct, where k12 and k13 are the rate constants describing the drug transfer from V1 to V2 and V3 and ct the computer-calculated average thiopental concentration in V1 during the initial 40 s of the induction period. There was no evidence of a lower amount being removed during the induction in the cardiac patients. The intravascular drug concentration at the time of sleep was expressed as the average of the arterial and the venous sleep concentrations. In the cardiac patients the average of that value was 20.1 micrograms/ml and in the control patients 30.2 micrograms/ml (P less than 0.05). It is concluded that the lower dose requirement in the cardiac patients was caused at least in part by a higher cerebral sensitivity to the drug.
Aged↗
The biological relevance of the protein binding of diazoxide.
The biological importance of the binding of diazoxide to serum protein was studied in vitro. Contractions in the rings of the rabbit pulmonary artery evoked by electrical field stimulation or exogenous noradrenaline (NA) were studied in the absence and presence of serum albumin (45 g/l) in Krebs-Henseleit (K-H) solutions. Diazoxide concentrations up to 128 micrograms/ml in the K-H solution and to 256 micrograms/ml in albumin K-H solutions diminished the contractions and albumin reduced this diminishing effect. Because of an apparent binding of exogenous noradrenaline to albumin only the experiments with electrical field stimulation were used to assess the biological importance of the protein binding of diazoxide. At 2 micrograms/ml of diazoxide the free drug fraction determined by ultrafiltration was 5% but determined by our biological method the free (active) fraction was 65%. In accordance with a previous clinical study we conclude that the binding of diazoxide to serum protein is important for the transportation of the drug to the arteriolar wall which apparently has a much higher affinity for the drug than serum albumin.
Animals↗
[Clinical experience with amiodarone in the treatment of supraventricular and ventricular tachyarrhythmia].
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Adult↗
Changes in blood chemistry in hypertensive patients during propranolol therapy.
Propranolol induced changes in blood plasma chemistry were followed in thirty hypertensive patients (WHO I-II) who were seen each week during 14-15 weeks. The initial 4 weeks were a drug free period and the next 2 weeks were a drug adjustment period. After that the patients were on an unchanged propranolol dose for 8 weeks (40, 80 or 160 mg four times daily). For all observed changes the correlation was studied to (1) dose, (2) free and total simultaneously determined plasma concentration and (3) free and total average plasma concentration of unchanged drug during the preceding 24 h period. Total protein and albumin did not change significantly. After 4 and 8 weeks on the final dose orosomucoid was increased significantly (by 10%) compared with the value from the end of the drug free period. Creatinine rose significantly during the initial 4-6 weeks therapy to remain at the same level during the last 4 weeks. Urate was increased at the two lowest dose levels. Total cholesterol fell significantly (5%) while triglycerides increased significantly (16%). T4 rose significantly, T3 fell and r-T3 rose significantly in a dose dependent way. Interindividually r-T3 was the only biochemical change showing a significant relationship to the propranolol plasma concentration. The relationship reached the highest level of significance to the average 24 h free concentration.
Adult↗
The influence of age on renal and extrarenal effects of frusemide.
The effect of frusemide 80 mg i.v. was compared during 24 h in 10 young and eight elderly healthy male volunteers following a 24 h control period in the ward. During the 30 min following the injection the increments in excretion of urine, sodium, potassium and frusemide were significantly smaller in the elderly. The 24 h increase in sodium excretion was significantly larger in the 0 young and eight elderly healthy male volunteers following a 24 h control period in the ward. During the 30 min following the injection the increments in excretion of urine, sodium, potassium and frusemide were significantly smaller in the elderly. The 24 h increase in sodium excretion was significantly larger in the 0 young and eight elderly healthy male volunteers following a 24 h control period in the ward. During the 30 min following the injection the increments in excretion of urine, sodium, potassium and frusemide were significantly smaller in the elderly. The 24 h increase in sodium excretion was significantly larger in the elderly. The endogenous 24 h creatinine clearance was reduced by 12% (P less than 0.01) in both age groups. The frusemide induced changes in the 8 h serum concentration curves for albumin differed significantly between the two groups (analysis of variance, P less than 0.01). The drug induced increase in albumin concentration became significant in the young 5 min after the injection. In the elderly it took more than 15 min before the increase in serum albumin reached significance. The average maximal increase in albumin concentration was 14.3% in the young and 9.7% in the elderly (P less than 0.05). No difference was seen between the two age groups in the significant frusemide induced increases in the 24 h albumin excretion but in the elderly a significantly larger decrease in the 24 h excretion of beta 2-microglobulin was observed (P less than 0.05). No significant age difference was observed in the initial significant increases in diastolic blood pressure observed in both age groups or between the later changes in systolic blood pressure which was significantly reduced in the young only. The slower haemoconcentration response in the elderly seemed associated with the slower secretion rate of frusemide to the tubular lumen. We found no evidence of an age related difference in tubular cell response to frusemide. It is emphasized that a maximal initial frusemide response in the elderly, in contrast to what was found in the young, probably was not achieved by the 80 mg i.v.
Adult↗
Thiopentone-induced changes in the contraction pattern of vascular smooth muscle: the influence of albumin.
The influence of thiopentone on resting tension, contractions evoked by exogenous noradrenaline (NA) and contractions elicited by electrical field stimulation of rings of rabbit pulmonary artery was studied over a concentration range limited by the solubility of the drug. At thiopentone concentrations from 3 X 10(-5) to 1.4 X 10(-3)M in a protein-free electrolyte solution (K-H solution) a gradual increase in resting tension to 232% of the control value was observed. The concentration-effect curve was displaced to the left in the presence of albumin (45 gl-1) at drug concentrations below 1.6 X 10(-4)M. Above that concentration the curve was displaced to the right. The maximal contractile response to exogenous NA in K-H was reduced from 4.1 to 1.8 g by 5.6 X 10(-4)M thiopentone, but the effects of low concentrations of NA were potentiated by thiopentone. The concentration-effect curve for exogenous NA was displaced to the right by albumin itself. The contractions evoked by electrical field stimulation in K-H solution were increased by thiopentone up to 2.4 X 10(-4)M where a maximum of 141% of the control value was reached. Above that a gradual decrease was observed, the height of the contractions being reduced by 75% of the control value at 1.4 X 10(-3)M thiopentone. Thiopentone failed to potentiate electrically-induced contractions in the presence of albumin K-H, and the concentration-effect curve for the inhibitory effect of thiopentone was displaced to the right. 5 From relationships between observed responses and free and total drug concentrations, a procedure was suggested to determine a biologically relevant expression for the thiopentone binding to albumin. The biologically determined albumin binding was always less than the binding determined by equilibrium dialysis, indicating that the fraction of thiopentone bound to albumin could not necessarily be considered biologically inactive.
Albumins↗
The influence of intravenous furosemide on the renal excretion pattern of protein and protein degradation products.
To assist the attending physician who may have difficulties in deciding whether observed deviations from normal renal physiology are disease-induced or diuresis-induced we studied urinary excretion rate of proteins and protein degradation products in eight healthy male volunteers between 60 and 70 years. After a 24 hr control period in the ward the subjects received 80 mg furosemide intravenously. The 24 hr creatinine clearance was reduced from 95 +/- 9 to 83 +/- 6 ml/min. (P less than 0.05). The reduction in the 24 hr carbamide clearance from 35.8 +/- 9.4 to 33.1 +/- 6.2 ml/min. was not significant. The urinary pH was significantly increased during the first hour but after the pH showed a fall which was significant during 2-8 hours after the injection. Initially the urate excretion showed an apparent increase but from 1-8 hours after the injection significantly less urate was excreted. The 24 hr urate clearance was reduced by furosemide from 5.3 +/- 1.6 to 3.4 +/- 1.1 ml/min. (P less than 0.05) and the amount of urate excreted was reduced from 2.6 to 1.6 mmol per 24 hrs (p = 0.05). The excretion rate of beta 2-microglobulin was reduced (P less than 0.01) whereas the excretion rate of albumin was increased (P less than 0.05).
Aged↗
Antihypertensive effect of diazoxide given intravenously in small repeated doses.
Seven patients with acutely elevated diastolic blood pressure (DBP greater than or equal to 135 mmHg) were treated with repeated injections of diazoxide 1 mg/kg body weight i.v. at 10-min intervals. If the DBP was not reduced to 110 mmHg or less after 5 injections, a dose of 5 mg/kg was given. Serum diazoxide (total and unbound) was determined by high pressure liquid chromatography. In all the patients it was possible to reduce the blood pressure to a satisfactory level (i.e. DBP less than 110 mmHg). The individual plasma diazoxide concentrations necessary to achieve the desired response ranged from 20 to 85 micrograms/ml. A significant correlation was found between the initial venous concentration and the initial reduction in blood pressure (p less than 0.02). A high initial concentration in venous blood was associated with high protein binding ("transport function", p less than 0.05), and so were the elimination half-lives, which ranged from 14.7 to 61.3 h ("depot function", p less than 0.05). It is concluded that the previously recommended therapy of injection of 5 mg/kg as a bolus should be given only to patients who do not respond to small repeated doses.
Adult↗
Urine and plasma propranolol.
Eight hypertensive patients who had been followed in an outpatient clinic during long-term therapy with propranolol (40 to 160 mg twice daily) were studied during a 24-hr stay in the ward. The usual oral dose was given and the total and free plasma concentrations were determined during the 24 hr and the urinary excretion of unchanged drug was measured. Average free plasma concentration of propranolol (y free) was calculated from: y free = Excreted propranolol (ng/24 hr)/Creatinine clearance (ml/24 hr). There was a significant relationship between log y free and average free plasma concentration (means free) determined from the directly measured plasma concentration curve: log y free = 0.0743 means free - 0.0466 (r = 0.98, P less than 0.001). In another group of propranolol-treated hypertensive patients there was a significant positive relationship between orosomucoid concentration and reciprocal of the free propranolol fraction in plasma. From this relationship the average total drug concentration (y total) was calculated from y free; there was a significant correlation with directly measured total plasma level: log y total = 0.0038 . means total + 1.0895 (r = 0.91, P less than 0.001). It is suggested that individually determined values of y free below 30 ng/ml and y total below 400 ng/ml (the concentration range studied) can be used to calculate the average mean 24-hr free and total plasma concentrations.
Adult↗
Thiopentone sensitivity in young and elderly women.
Induction and maintenance doses of thiopentone were smaller in eight elderly women than in eight younger women. Mean venous anaesthetic concentrations were 34% less (P = 0.02) in the elderly. For each patient an "expected maintenance dose" was calculated from serum clearance and the area under the curve during the anaesthesia. In the elderly the average expected dose was equal to the dose given, but in the younger patients the dose given was greater than the expected (P less than 0.02). In younger women, but not in the elderly, a high cardiac output was accompanied by the need for a relatively high maintenance dose if a certain serum concentration was to be maintained. Cardiac output was equally reduced in both patient groups (30-40%). After induction the heart rate was reduced in the elderly during the entire period of anaesthesia and always more than in the younger. No correlation was found between serum concentration of thiopentone and haemodynamic effects.
Adult↗
Comparison of the anaesthetic and haemodynamic effects of chlormethiazole and thiopentone.
Two groups of eight women (60-85 yr) undergoing gynaecological operations of 50 to 130 min duration were compared. Anaesthesia was induced with either thiopentone (mean 4.5 mg kg-1) or chlormethiazole (mean 6.0 mg kg-1) and maintained with nitrous oxide and pethidine in combination with the drug used for the induction. The hourly maintenance dose and the plasma concentration determined at equilibrium were greater for chlormethiazole (means 4.7 mg kg-1 h-1 and 27 mumol litre-1) compared with 1.3 mg kg-1 h-1 (P less than 0.01) and 16 mumol litre-1 respectively for thiopentone (P less than 0.02). Impedance cardiography showed that cardiac output was decreased by 30-40% in the thiopentone group (P less than 0.01), whereas no significant change was observed in the chlormethiazole group. Chlormethiazole anaesthesia was followed by a significant increase (P less than 0.02) in stroke volume. No correlations were found between the plasma concentrations and changes in the haemodynamic indices for either of the drugs.
Aged↗
The pharmacokinetics of frusemide are influenced by age.
After a 24 h control period 80 mg frusemide was given intravenously over 2 min to a group of young and a group of elderly healthy male volunteers. The serum concentration of frusemide and the excretion in urine of the drug and a glucuronidated metabolite were followed for 24 h. The elimination of the drug from serum was described by an open two compartment model. The serum clearance (CLs) was 170 +/- 19 ml min-1 in the young and 129 +/- 11 ml min-1 in the elderly (P less than 0.01) and the average renal clearance (CLr) was 67% of CLs in the young and 58% of CLs in the elderly (NS). The average amount of unchanged frusemide in the urine during the first 30 min was 30 +/- 6 mg in the young but only 20 +/- 4 mg in the elderly (P less than 0.01). The albumin concentration in serum was 15% lower in the elderly but on the average the protein bound fraction of frusemide was 98.6% in both groups. The Vd ss did not differ between the two age groups (0.130 1 kg-1) but the elimination half-life was 70 +/- 20 min in the young and 102 +/- 33 min in the elderly (P less than 0.05). In the young 11.4 +/- 5.0 mg frusemide was excreted as a glucuronidated compound whereas this figure was only 5.4 +/- 2.9 mg in the elderly (P less than 0.01). It is concluded that the age-related changes in the fate of unchanged frusemide in the organism mainly can be explained by a reduction in the tubular secretion of the drug which in turn may be caused by a reduction in renal plasma flow.
Adult↗
Pharmacokinetics and pharmacodynamics of thiopental in patients undergoing renal transplantation.
The effects and pharmacokinetics of thiopental were studied in eight patients undergoing renal transplantation. The results were compared with findings in a group of patients with normal renal function. No differences were observed in induction doses or between arterial or venous sleep concentrations. The average V3 in the renal failure group was 1441 or 2.5 times the value of the control group (P less than 0.01). The apparent differences indicating longer elimination half-lives and higher serum clearances in the renal patients were not significant. The average binding of thiopental to serum protein shortly after the induction was 83.9% (78.2-88.1) in the renal patients and 89.0% (85.2-91.6) in the control patients (P less than 0.05). The difference in V3 could be explained by the differences in protein binding and when the serum clearance was calculated by using the unbound fraction, this "intrinsic clearance" was significantly lower in the renal failure group (P less than 0.05). Haemodynamic parameters were determined during the initial 5 min. No significant difference was observed between the thiopental-induced changes in stroke volume. Cardiac output was unchanged in both patient groups.
Adult↗
The binding of thiopental to human serum albumin at variable pH and temperature.
The binding of thiopental was studied in vitro by equilibrium dialysis over the concentration range 0.8-80 micrograms/ml in solutions with 45 g albumin (HSA) per litre. The binding at 37 degrees was from 79% to 67.6% at pH 6 while it was 94.5% to 93.0% at pH 9. At intermediate values of pH the observed values for binding were compatible with the assumption of a gradual transition of an N-form of HSA present exclusively at pH 6 to a B-form present exclusively at pH 9. The variation in binding could not be explained by changes in the balance between ionised and nonionized drug (pKa = 7.6). An increase in r (number of thiopental molecules bound per HSA molecule) was demonstrated when the temperature was lowered to 2 degrees. Graphs showing the relation between drug concentrations and percentual binding all showed a very modest slope and it was concluded that a traditional binding model with calculation of the number of binding sites and association constants was of little use in the evaluation of our binding studies of thiopental. The binding between thiopental and albumin may be characterized best by the solubility of thiopental in hydrophobic areas in the albumin solutions.
Humans↗
Amiodarone induced cornea verticillata.
Among 30 patients (17 men, 46-76 years and 13 women, 15-70 years), treated with the antiarrhythmic drug amiodarone, 21 patients (11 men and 10 women) developed bilateral cornea verticillata. Total doses up to 494 g had been given and the duration of therapy was up to 113 weeks. In 14 patients samples of 50 microliters tear fluid were analyzed for aminodarone. No amiodarone was present in the tears at low serum concentrations but a rapid increase in tear concentrations was seen at serum values above 1.2 micrograms/ml (P less than 0.001). The grade of cornea verticillata was significantly correlated to total dose as well as to duration of treatment (P less than or equal to 0.001). On the day of examination at the eye clinic there was no significant correlation between se-amiodarone, tear-amiodarone concentration and the grade of cornea verticillata. One patient complained of coloured haloes. None had decreased visual acuity, fundus changes, cataract, exophthalmus, increased intraocular pressure, abnormal colour vision, or abnormal central corneal thickness, which could be attributed to the treatment of amiodarone.
Adolescent↗
Binding of aprindine and moxaprindine to human serum, alpha 1-acid glycoprotein and serum of healthy and diseased humans.
A comparison was made between the binding of the anti-arrhythmic agents aprindine and moxaprindine to human serum, to human serum albumin (HSA), to alpha 1-acid glycoprotein (alpha 1-AGP) and to a mixture of HSA and alpha 1-AGP. In serum from healthy volunteers (n = 4) the binding of aprindine-HCl 5 micrograms/ml (13.8 microM) was 93.8% (SD +/- 1.0), and that of moxaprindine-HCl 5 micrograms/ml (12.8 microM) was 94.15 (SD +/- 1.1). Their binding to the mixture of alpha 1-AGP and albumin approximated their binding to serum. For alpha 1-AGP, the binding was similar for both compounds, whereas for HSA the binding of aprindine was more pronounced than that of moxaprindine: for both products the affinity coefficient for binding to alpha 1-AGP was about 100 times greater than that for binding to albumin. In serum from rheumatoid patients and from patients with renal failure a small but significant increase in binding of aprindine and moxaprindine was observed, approximately 1%. Increased and decreased binding was seen in serum from cirrhotic patients; for example, for aprindine the range in cirrhosis was 96.7%-79.8%, and the range in controls was 95.0%-92.4%. Free drug fraction and alpha 1-AGP concentration were inversely correlated. The results show that alpha 1-AGP plays an important role in the binding of aprindine and moxaprindine, and that alteration in the binding of the two compounds in disease states to a large extent can be explained by changes in serum alpha 1-AGP concentration.
Aprindine↗
The influence of PO2, pH, and albumin on the in vitro contraction of vascular smooth muscle.
A method by which gases can be added to a tissue bath containing proteins in solution is described and utilized in a study of the importance of O2, CO2 and albumin for the contraction of rings of rabbit pulmonary artery. In electrolyte solutions without protein, reduction of the oxygen tension from 700 to 150 mm Hg caused a shortening of the period during which contractions could be elicited by nerve specific electrical field stimulation before a significant decrease in the contractile response occurred. The addition of albumin (45 g/l) to the bath caused a significant increase in contractile response during the first hour and furthermore a prolongation of the period during which the following gradual decrease remained at an insignificant level. A reduction in oxygen tension in the albumin solution from 700 to 150 mm Hg caused a more abrupt and pronounced reduction in contractile response than the one seen in the protein free solution. The response increased when the pH in the saline solution was raised early during an experiment but not if the pH was raised later. Decreased responses were seen when the pH was reduced regardless of the length of the period prior to the pH change. It is emphasized that the method improves the possibilities for in vitro studies of the activity of protein bound drugs in the presence of dissolved proteins.
Albumins↗