[Beta blockade after myocardial infarction?].
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Adrenergic beta-Antagonists↗
Biomedical subjects
O L Pedersen
Publications and source records attributed to O L Pedersen.
Afternoon plasma cortisol in depressed patients: a measure of diagnosis or severity?
Plasma cortisol concentration was measured at 20 min intervals from 3 p.m. (1500 hrs) to 6 p.m. (1800 hrs) in 26 hospitalized patients classified according to the Newcastle Index as endogenously depressed (n = 16) or non-endogenously depressed (n = 10). When examined in depressed state, before treatment, maximum, mean and range of plasma cortisol concentration in this time interval was significantly higher in the endogenously depressed patients than in the non-endogenously depressed patients (p less than 0.01-0.02). The diagnostic identification of endogenous depression on the basis of these cortisol concentration measurements was at least as good as that reported by others using post-dexamethasone cortisol levels. The plasma cortisol levels (maximum, mean) and fluctuations (range) correlated significantly with the degree of depression (Hamilton Depression Scale), and differences in severity of depression could explain most of the differences in cortisol levels between the two diagnostic groups. Nine patients were reexamined after 3-12 months in a non-depressed state, and all unipolar endogenously depressed patients (n = 6) then had clearly reduced cortisol levels and fluctuations.
Adult↗
Mianserin: cardiovascular effects in elderly patients.
Cardiovascular effects of the tetracyclic antidepressant drug mianserin were examined in a prospective study including ten elderly depressed patients (age 60-77 years). During 1 week on placebo and 5 weeks on mianserin, 60 mg per day, orthostatic blood pressure testing, recording of standard electrocardiogram, 24-h electrocardiographic recording and systolic time intervals were carried out along with frequent monitoring of plasma levels of mianserin (13-57 micrograms/l) and the primary metabolite desmethylmianserin (7-27 micrograms/l). Mianserin caused a significant increase in orthostatic systolic blood pressure drop, and this correlated well with the plasma mianserin levels (rs = 0.70). There were no significant changes in supine blood pressure or in orthostatic changes in heart rate. No cardiac conduction disturbances or arrhythmias were provoked, but mianserin caused changes in systolic time intervals indicating impairment of left ventricular contractility and performance. Like tricyclic antidepressants mianserin should thus be used with caution in patients with latent or overt cardiovascular disease.
Aged↗
Regional differences in the response of isolated human vessels to vasoactive substances.
1. Crural, mesenteric and pulmonary vessels obtained during surgery were studied. Isometric tension was recorded and contractions were induced by potassium 127 mM (K), noradrenaline 18 microM (NA), prostaglandin F2 alpha 2.9 microM (F2 alpha), ergotamine 3.8 microM (Erg) or digoxin 1.0 microM (Dig). 2. Spontaneous myogenic activity was only observed in pulmonary veins. F2 alpha induced spontaneous activity in mesenteric arteries. 3. In all types of vessels, except in mesenteric arteries, the response to K+ had a greater amplitude than contractions developed by NA. Erg induced a slowly developing contraction in mesenteric veins but no contraction in mesenteric arteries. Dig induced a long-lasting monophasic response in arteries and a biphasic response in the veins. 4. After immersion for 30 min in a Ca-free medium the amplitudes to both NA and K+ were significantly reduced. The veins were more susceptible to the effects of Ca-deprivation than the arteries.
Digoxin↗
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↗
Imipramine metabolites in blood of patients during therapy and after overdose.
Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.
Adult↗
Drinking water and drug dosage in rat studies.
Spontaneously hypertensive rats were treated with verapamil, hydralazine, indapamide or bepridil added to their drinking water. These substances had most different effects on the water consumption of the animals, displaying both positive and negative feed-back mechanisms. Furthermore there were considerable differences in stability of the drugs in solution. It is therefore concluded that continuous control of water intake and analysis of the stability of the drug is essential for the establishment of proper dose-response relationships.
Animals↗
Citalopram, a selective serotonin reuptake inhibitor: clinical antidepressive and long-term effect--a phase II study.
In a phase II study the antidepressive effect of citalopram, a selective and potent serotonin reuptake inhibitor, was examined in 20 endogenously and three non-endogenously depressed hospitalized patients. Four endogenously depressed patients dropped out due to deterioration early in the treatment period. The remaining 19 patients completed a 4-6 week treatment schedule. Of 16 endogenously depressed patients 11 responded, one was a partial responder and four did not respond. Of three patients with non-endogenous depressions, two responded and one did not respond. No correlation between plasma citalopram concentration and therapeutic outcome was found. Fourteen patients were given maintenance treatment for 8-113 weeks. One patient developed depression when the dose was reduced from 60 to 40 mg and one patient became manic. After discontinuation of treatment seven patients had a depressive relapse and six of these who again were treated with citalopram responded completely. Side effect rating scores of symptoms usually associated with depression or treatment with tricyclic antidepressants declined during treatment. Three patients complained of increased need of sleep for a period after several weeks of treatment. Apart from an unspecific, transient rise in liver enzymes in two patients, detailed biochemical laboratory tests were all normal. There were no effects on blood pressure, pulse rate, orthostatic reaction, or electrocardiogram. One patient took an overdose of citalopram resulting in plasma levels about six times higher than the average therapeutic level, but there were no signs of severe toxicity. In particular no change in consciousness, electrocardiogram or blood pressure occurred. Pharmacokinetic variables such as dose schedule, steady state kinetics, and metabolism are discussed.
Adult↗
Overdosage of antidepressants: clinical and pharmacokinetic aspects.
Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 micrograms/l, with concentrations above 500 micrograms/l in 11 cases. The serum amitriptyline concentration remained high for 3-4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 micrograms/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidepressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60-500 micrograms/l) but not high (greater than 500 micrograms/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
Adult↗
The individual variation in pharmacokinetics and pharmacodynamics of furosemide in young normal male subjects.
Following a 24 h control period in the ward 80 mg furosemide was injected intravenously to ten young healthy, male volunteers. The serum clearance of furosemide (Cls) was between 140 and 201 ml min-1 and on the average the renal clearance was 60% of Cls. During the initial 30 min period a maximum additional excretion rate of sodium of 3.3 mmol min-1 was reached at an excretion rate of 0.8 mg furosemide min-1. A marked initial drop in creatinine clearance (Clcr) was noted and Clcr(24 h) showed an average decrease of 12% after the drug administration. The serum concentration of potassium was decreased at 1 and 2 h after the injection and of sodium from 2 h and on. The concentration of albumin in serum increased by 3% (P less than 0.05) already after 5 min. After 2 h a maximum increase of 14% was reached. After 8 min diastolic blood pressure was increased by 13% (P less than 0.05), whereas systolic blood pressure reached a significant decrease gradually (7% after 3 h).
Adult↗
Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man.
Paroxetine kinetics and cardiovascular effects were studied in 4 healthy male subjects after single oral doses of 45 mg and after slow intravenous infusion of 23-28 mg. The plasma concentration/time curves could be described by a two-compartment open model, but the estimates of the model parameters were relatively inaccurate after the oral test. Plasma half-lives were longer after oral (19.8 hrs. S.D. 1.3 hrs) than after intravenous test (12.3 hrs. S.D. 3.8 hrs). Different methods of calculation of the systemic availability resulted in different values, most probably due to dose dependent kinetics. This is possibly related to saturated elimination kinetics during the first pass metabolism. Systolic time interval measurements showed that paroxetine causes a shortening of the electromechanical systole (QS2 corrected for heart rate) indicating a positive inotropic effect of the compound. Paroxetine also caused a reduction in heart rate and a moderate rise in systolic and diastolic blood pressure. After the intravenous dose some subjects experienced nausea and one subject a quite pronounced anxiety.
Administration, Oral↗
Comparison of the effects of a new vasodilator pinacidil and nifedipine on isolated blood vessels.
In isolated human crural veins studied in vitro pinacidil (0.038-380 microM) caused a concentration-related inhibition of noradrenaline, 18 microM (NA) and 127 mM K+-induced contractions. Pinacidil was more potent in inhibiting the NA-contraction than that induced by K+, whereas the reverse was seen for nifedipine. At the highest concentrations greater inhibitions of the NA-induced contractions could be obtained with pinacidil than with nifedipine. The inhibitory effect of pinacidil on the K+-induced contractions was eliminated during a 1 hr wash-out period. In contrast to this, the inhibitory effect of nifedipine could not be eliminated during 4 hrs repeated wash-out. Pinacidil was completely devoid of inhibitory effect on 45Ca net influx in rat aorta, whereas nifedipine caused a significant reduction of influx. The results indicate that both pinacidil and nifedipine are effective vasodilatators in human vessels. Pinacidil seems to be more effective in NA-induced contractions than does nifedipine. The mechanism of action of pinacidil cannot be attributed to an inhibitory effect on cellular calcium entry.
Adult↗
Drug level monitoring in psychopharmacology: usefulness and clinical problems, with special reference to tricyclic antidepressants.
The gradual onset of action and pronounced pharmacokinetic variability provide a solid rationale for drug plasma level monitoring in psychopharmacology. For tricyclic antidepressants a well-established drug level therapeutic effect relationship is available for a few compounds (imipramine, nortiptyline, amitriptyline); and for these, plasma level monitoring can ensure more efficient and safe treatment. The relationship has been demonstrated only in endogenously depressed patients. Various pharmacokinetic problems such as dose-dependent kinetics (imipramine in elderly patients), autoinduction (chlorpromazine), drug interaction (inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants), and changes in protein binding may be better controlled by monitoring the drug levels. In amitriptyline intoxications, a possible change in the elimination kinetics results in a very slow decline in plasma levels for several days; and plasma level measurements might help to identify those patients at prolonged risk of adverse reactions. Some side effects--in particular, orthostatic hypotension--occur at subtherapeutic drug levels and therefore cannot be prevented by drug level monitoring, and monitoring of other (physiological) variables is more important. Drug level monitoring of tricyclic antidepressants thus can be considered a valuable addition to the treatment program, but it cannot replace proper clinical practice in terms of diagnostic evaluation and control of patients.
Antidepressive Agents, Tricyclic↗
[Disopyramide (Dirytmin, Durbis, Norpace)].
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Disopyramide↗
Dose-dependent kinetics of imipramine in elderly patients.
In a group of elderly depressed patients treated with imipramine (50-200 mg/day), six patients had the dose changed after 1-3 weeks of treatment. In all cases an increased dose resulted in a considerably disproportional rise in the plasma level of the active metabolite desipramine. In a group of elderly depressed patients treated with nortriptyline (40-100 mg/day) the dose/plasma level ratio could be examined in 6 patients, and there was no tendency towards a disproportional rise in plasma level, when the dose was raised. Dose changes, thus, may result in unpredictable changes in plasma levels during imipramine treatment and therapy control by plasma level monitoring may be difficult in these patients. Additional treatment with perphenazine (8-16 mg/day) to patients on imipramine (N = 3) or nortriptyline (N = 2) caused a marked rise in drug levels for imipramine in particular affecting the desipramine levels.
Aged↗
Correlation between propranolol in plasma and urine, renin-aldosterone system and blood pressure in essential hypertension.
Thirty patients with mild or moderate essential hypertension, and a fixed elevation of diastolic blood pressure, were randomly allocated to three groups and treated with propranolol 40 mg x 4 (Group 1), 80 mg x 4 (group 2) and 160 mg x 4 (Group 3). Blood pressure (BP), pulse rate (PR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), total plasma propranolol (tPP), free plasma propranolol (fPP), and 24 h urinary propranolol excretion (UP) were determined at the end of four consecutive periods: (A) after four weeks without any treatment; (B) after two to three weeks during which the propranolol dose was gradually increased to the intended level; (C) after four weeks, and (D) after eight weeks of unchanged treatment. The maximum reduction in diastolic BP occurred after period B, and in systolic BP after Period C, for Groups 2 and 3, and for all groups together; for Group 1, however, the maximum diastolic BP reduction was first seen after period C. PR was reduced to the same level in all groups after period B. After period B, PRA an PAC fell in all groups, and remained reduced during C and D Group 1. After periods C and D, PRA and PAC in Groups 2 and 3 did not differ significantly from the levels after period A; tPP, fPP and UP were significantly correlated with the propranolol dose, and were lowest in Group 1 and highest in Group 3; UP was negatively correlated with systolic but not diastolic BP in Periods B, C and D. In contrast neither fPP nor tPP were correlated with systolic or diastolic BP. There was no significant correlation between PRA, PAC and changes in PRA or PAC on the one hand and tPP, fPP, UP, BP or changes in BP on the other. It was concluded that propranolol effectively reduced BP, but diastolic BP reduction was most rapidly obtained at 320 and 640 mg daily, that the activity of the renin -aldosterone system was initially suppressed in all group, but for unknown reasons it increased towards the control level after seven to eleven weeks of therapy with 320 and 640 mg/day, and that the reduction in systolic BP increased with higher doses of propranolol and with increasing urinary propranolol excretion.
Adult↗