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Biomedical subjects

G Johnsson

Publications and source records attributed to G Johnsson.

At least 37 records · Page 2Linked to original sources
PubMed1980

Metabolic and haemodynamic effects and pharmacokinetics of a new selective beta 1-adrenoceptor agonist, prenalterol, in man.

The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective beta 1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables--triglycerides, glucose, lactate pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.

Adrenergic beta-Agonists↗
PubMed1980

Plasma levels and pharmacological effects of metoprolol administered as controlled release (Durules) and ordinary tablets in healthy volunteers.

The bioavailability, plasma levels and pharmacological effect of a daily dose of 0.2 g of metoprolol in Durules and in regular 0.1 g tablets have been studied in eight healthy volunteers during steady state conditions. Durules and two 0.1 g metoprolol tablets were given once daily, and one 0.1 g metoprolol tablet was given every 12th hour. The maximum concentration of metoprolol in plasma after Durules was about half of that after two regular tablets. When one metoprolol 0.1 g tablet was administered every 12th hour, an average maximum concentration slightly higher than for the Durules was recorded about one hour after the administration. The minimum concentration of metoprolol during the day was about twice as high after Durules as after the same dose in regular tablets. The dose-corrected area under the plasma concentration vs time curve of Durules was 87 per cent of the b.i.d. regimen of metoprolol in regular tablets and about 75 per cent of two metoprolol 0.1 g tablets once daily. Metoprolol Durules maintained a more even effect on heart rate and systolic blood pressure during exercise during the day than the corresponding daily dose of metoprolol given as two metoprolol 0.1 g tablets once daily or as one metoprolol 0.1 g tablet every 12th hour. After maximum beta-blockade the effect declined by, on average, 0.60 per cent/hour for the Durules and 0.96 per cent for the regular tablet. The exercise heart rate before the morning dose was significantly lower during treatment with Durules and one metoprolol 0.1 g tablet b.i.d. than during the placebo period. The interaction of metoprolol with the effect of adrenaline (0.09 microgram x kg-1 x min-1, infused at 2, 3.5 and 5 hrs after metoprolol administration) on the diastolic blood pressure was more pronounced when two ordinary 0.1 g metoprolol tablets were administered once daily than for the corresponding dose in Durules, this probably reflecting a difference in degree of action of metoprolol on the vascular bed for Durules and regular metoprolol tablets in identical doses.

Administration, Oral↗
PubMed1979

Haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, and its interaction with metoprolol in man.

The haemodynamic effects of the selective beta1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selective beta1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/l) prenalterol had to be administered in doses that were twelve times higher than before the beta-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.

Adrenergic beta-Agonists↗
PubMed1979

Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide.

1. The plasma levels and the urinary excretion of hydrochlorothiazide (HCT) have been studied after administration of single doses of 12.5 and 25 mg of the drug in solution and in combination with 100 mg of the selective beta 1-adrenoreceptor antagonist metoprolol in a rapidly dissolving tablet. 2. Metoprolol did not significantly influence the bioavailability or the time-course of HCT. 3. HCT had no significant effect on the time-course or the plasma levels of metoprolol. The average half-life, 4.4 +/- 0.9 h, is about the same as previously observed for separate doses of this drug. 4. It seems unlikely that repeated doses of the combination product studied will lead to biopharmaceutic or pharmacokinetic interactions of clinical importance.

Biological Availability↗
PubMed1979

Interaction studies between three antidepressant drugs (chlorimipramine, imipramine and zimelidine) and noradrenaline, tyramine and vagal stimulation on the heart rate and blood pressure in dogs.

Anaesthetized Beagle dogs were given increasing intravenous doses of imipramine, chlorimipramine or zimelidine. At each dose interval the interference of the drug administered with the effects on blood pressure and heart rate of vagal stimulation, NA injection and tyramine injection was investigated. Also, the in vitro uptake of 5-HT into platelets after in vivo administration to unanaesthetized dogs of 5 mg chlorimipramine or 5 mg zimelidine was studied. Chlorimipramine and zimelidine were found to be about equipotent as regards 5 HT-uptake into platelets after in vivo administration. Imipramine and chlorimipramine potentiated the effects of NA after the 2 mg/kg dose. Imipramine but not chlorimipramine interfered with the effects of tyramine after the 4 mg/kg dose. Zimelidine did not interfere with either NA or tyramine at any dose level studied (maximal cumulative dose 62 mg/kg). The effect of vagal stimulation was significantly inhibited after 8 mg/kg (cumulative dose 14 mg/kg) of imipramine and 16 mg/kg (cumulative dose 30 mg/kg) of chlorimipramine and zimelidine, respectively. It is concluded that zimelidine in comparison with imipramine and chlorimipramine has no or at most a slight effect on peripheral adrenergic neurones. It has less pronounced anticholinergic properties than imipramine but is about equipotent to chlorimipramine in this respect.

Allylamine↗
PubMed1977

Mode of action of beta blockers in angina pectoris.

The therapeutic effect of beta adrenoceptor blockers in angina pectoris can be ascribed to an inhibition of beta1 receptor mediated stimulation of heart rate and myocardial contractility, resulting in an improved oxygen supply-demand balance in the myocardium. When given in equipotent beta1 blocking doses, the nonselective blocker propranolol and the beta1 selective blocker metoprolol differ markedly as regards inhibition of adrenaline induced beta2 mediated vasodilatation. Only propranolol will inhibit this effect. After propranolol, adrenaline therefore elicits a haemodynamic effect pattern characterized by high peripheral vascular resistance, high arterial blood pressure, low cardiac output and increased cardiac size. In view of these findings it is suggested that a beta1 selective blocker may be a more efficient antianginal agent than a nonselective blocker in those patients in which the anginal attack is associated with a significant release of adrenaline. The clinical relevance of this hypothesis has not been tested.

Adrenergic beta-Antagonists↗
PubMed1977

Bioavailability of quinidine in slow-release form. A comparison between two preparations containing quinidine bisulphate as the active constituent.

Two different slow-release preparations of quinidine bisulphate (A and B) have been tested. The in vitro dissolution rate of preparation B was substantially lower in intestinal than in gastric juice, whereas the release rate of quinidine from preparation A was virtually unaffected by the pH of the dissolution medium. After a single dose of two tablets of each of the preparations to 6 healthy volunteers, corresponding to 386 mg (B) and 320 mg of quinidine base (A), the maximum plasma concentration was attained after about 4.5 h. The peak concentration was 5.2 +/- 0.5 mumol/l for preparation A and 4.1 +/- 0.4 mumol/l for B. A similar difference was found in the area under the plasma concentration curve (AUC), which was 68 +/- 10 mumol-h/l and 54 +/- 5 mumol-h/l, respectively. Taking into consideration that preparation B contained 20.6% more active drug per tablet these values indicate that the extent of bioavailability is about 50% higher for tablet A than for tablet B.

Administration, Oral↗
PubMed1976

Effects of cedilanid-D in combination with metoprolol on exercise tolerance and systolic time intervals in angina pectoris.

The interaction between cedilanid-D and metoprolol, a selective beta receptor blocking agent, on exercise tolerance and systolic intervals was studied in 15 patients with angina pectoris. The patients had been treated with metoprolol for several months in a dose of 50 mg, three times daily (one patient received 25 mg three times daily). Each patient participated in two studies separated by at least 1 week. After arriving at the laboratory each received 50 mg of metoprolol orally; thereafter, either cedilanid-D or placebo was infused intravenously in a double-blind study performed in randomized order. When the effect of the drugs was maximal, the systolic intervals and the heart volume were recorded at rest, and the exercise tolerance was tested with a bicycle ergometer. The mean maximal value of plasma concentrations of metoprolol assessed during the study was about 50 ng/ml but the variation among subjects was great (20 to 187 ng/ml). After administration of cedilanid-D there was a shortening of the pre-ejection period and left ventricular ejection time compared with results after placebo; the reduction was similar to that found after administration of cedilanid-D without beta blocking drugs. The total heart volume decreased by an average of 55 ml, but the individual variation was great. The patients' average work capacity, expressed as total work, was not altered by cedilanid-D when compared with results after placebo. No relation was found between initial heart size and the effect of cedilanid-D on capacity for physical work. It therefore appears that there is no indication for the routine use of digitalis during beta blocking therapy in patients with angina pectoris who do not have cardiac failure.

Adrenergic beta-Antagonists↗
PubMed1976

Clinical pharmacokinetics of beta-adrenoreceptor blocking drugs.

All beta-adrenoreceptor blocking drugs seem to be fairly rapidly and completely absorbed from the gastro-intestinal tract. The rate of absorption, however, appears to be lower in elderly patients and possibly also in patients with renal failure than in younger patients. The extent of bioavailability varies considerably between different beta-blockers. Some of these drugs(e.g. alprenolol and propranolol) have a low extent of bioavailability due to a high first-pass elimination effect, while pindolol and practolol for example are in influenced very little by this effect. However, as some beta-blockers from active metabolites, the bioavailability calculated as the ratio between the area under the plasma concentration time curve of unchanged drug after oral and intravenous administration does not give an accurate estimation of the fraction of the biologically active dose reaching the systemic circulation. The beta-blockers so far studied are rapidly distributed in the body. The t1/2 of distribution ranges between 5 to 30 minutes. The apparent volume of distribution varies 3- to 4-fold between the compounds but in all cases the apparent volume of distribution exceeds the physiological body space. In patients with impaired liver function an increase of the volume of distrubution of propranolol has been found. The beta-blockers are relatively rapidly eliminated from the body and most of them have an elimination half-life between 2 to 4 hours. For atenolol, practolol and sotalol higher values have been reported. The most lipophilic beta-blockers are almost completely metabolised in the liver, wheras those of lower lipophilicity are mainly excreted via the kidneys. Impraired liver and kidney function have been found to significantly influence the rate of elimination of those beta-blockers eliminated via the insufficient organ of elimination. Numerous investigators have shown that the beta-blocking effect is linearly related to the logarithm of the plasma concentration. In spite of this relationship, it is difficult from mean data to predict the individual plasma concentration which is necessary for a certain degree of beta-blockade. This might be due to variations in the quantitative formation of active metablolites, individual differences in the plasma protein binding and rather flat plasma level-response curves. Also with respect to the therapeutic effect, the plasma levels vary considerably between individuals. This limits the value of determination of plasma concentrations in order to adjust the therapeutic dose. Our recommendation is that these facilities should be utilised in selected patient groups, eg. those who have a poor therapeutic response to a beta-blocker although the dose is high, and those patient with impaired renal or liver function. The duration of beta-blockade is dose-dependent since the pharmacological effect declines with a constant rate (zero-order kinetics) within relatively wide dosage intervals...

Adrenergic beta-Antagonists↗
PubMed1976

Clinical pharmacokinetics of beta-adrenoreceptors blockers.

beta-blockers are completely and rapidly absorbed from the gastro-intestinal tract. In their first passage through the liver they are metabolised to a varying extent - the so-called first-pass effect. For propranolol and alprenolol this degradation is partly compensated for by the formation of active metabolites, the 4-OH derivatives. The beta-blocking effect is linearly correlated with the log plasma concentration of the drugs. Although there is also a relationship between the antihypertensive effect of the drugs and their log plasma concentration, it seems to be of limited value to determine the plasma levels of the drugs in order to adjust the therapeutic dose. This is due to the great inter-individual differences of the plasma concentration-antihypertensive effect relationship. It is essential to investigate whether pharmacologically active metabolites are formed. These may not only influence the relationship between plasma concentration and therapeutic effect but may also modify the pharmacological profile of the drug. The plasma levels, and thereby the effects of the drugs, can be modified by other drugs and diseases. Thus practolol, which is mainly eliminated via the kidneys, has a longer plasma half-life in patients with renal failure. The plasma of propranolol, which is eliminated from the body by bio-transformation in the liver, is not prolonged in patients with renal failure, but its metabolites are excreted at a lower rate in such patients. Although most beta-blockers have a relatively short plasma half-life (2 to 5 hours), the drugs can be administered twice daily in clinical practice. This due to the fact that the effect declines according to zero-order kinetics while the elimination of the drug follows first-order kinetics. It is desirable that all these factors are clarified before a drug is used in clinical practice as they all will have an influence on its dose regimen. The responsibility for this must be on the drug company, which must be able to inform physicians not only about the standard dosage of the drug but also how other drugs and diseases can change the individual responses to the drug.

Adrenergic beta-Antagonists↗
PubMed1976

Use of beta-adrenoreceptor blockers in combination with beta-stimulators in patients with obstructive lung disease.

Lung function can be reduced not only by a non-selective beta-blocker but also by a selective beta1-receptor blocker. If both types of drug are without intrinsic sympathomimetic activity, the effect of the non-selective drug is more pronounced than that of a beta1-receptor selective drug under basal conditions. The effect of a beta2-receptor stimulating drug on the bronchi is inhibited by a non-selective drug, but much less by a selective beta1-receptor blocker. A selective beta1-receptor blocker can be used in asthmatics when it is combined with optimal anti-asthmatic therapy, while a non-selective drug is contra-indicated in patients with broncho-obstructive diseases. It is necessary to induce bronchodilatation (e.g. with a beta2-stimulator) in order to test whether or not a beta-blocker can be used in broncho-obstructive disease.

Adrenergic beta-Agonists↗
PubMed1976

Studies with a new cardioselective beta-blocker, metoprolol.

These studies indicate that the cardioselective beta-adrenergic blocking drug metoprolol might be expected to be at least as effective for the treatment of arterial hypertension as propranolol. The difference in effect on the peripheral vascular bed may be of importance when acute increase of the blood adrenaline level occur, as in severe anxiety states. Experience in long-term studies in all kinds of patients with raised arterial pressure has confirmed that metoprolol is an active antihypertensive agent of similar potency to other beta-blocking agents.

Adult↗
PubMed1976

Hemodynamic effects of thiothixene and chlorpromazine in schizophrenic patients at rest and during exercise.

The hemodynamic effects and plasma levels of noradrenaline were studied in schizophrenic patients at rest and during exercise after long-term treatment with chlorpromazine (150-600 mg daily) and thiothixene (60-80 mg daily). The results are compared with those from previous studies in untreated patients and patients receiving very large doses of chlorpromazine. The effects of thiothixene on the different hemodynamic variables were very moderate, and the observed differences between this group and the control group may be due to the different patient materials. In the two groups of patients receiving chlorpromazine, the heart rate at rest and durng exercise tended to be higher than in the control group. There was also a tendency towards a lower stroke volume after this drug and thiothixene during exercise. The noradrenaline levels in plasma were highest after the high dose of chlorpromazine both at rest and during exercise, while they were lower after the moderate chlorpromazine dose. After thiothixene, the values were between those of the group on the low chlorpromazine dose and those of the control group.

Adult↗