Single-dose kinetics predict steady-state concentrations on imipramine and desipramine.

Single-dose prediction of ultimate steady-state concentrations of tricyclic antidepressants at the outset of treatment can be a valuable therapeutic tool that has had only limited application. We demonstrate accurate steady-state predictions following both the tertiary amine, imipramine hydrochloride, and the secondary amine, desipramine hydrochloride, in a carefully monitored long-term treatment patient population. Results show that long-term treatment does not alter metabolism of either imipramine or desipramine. The relative merits of single-dose predictions using total and "abbreviated" areas under the curve and concentration at 24 hours are compared. These findings demonstrate that single-dose prediction can be used as a practical therapeutic, as well as, research tool.

Influence of vagotomy on changes in feline plasma catecholamine levels induced by occlusion of either the left or right coronary vessel.

The purpose of this study was two-fold: (1) to determine the effect of occlusion of the left anterior descending branch (LAD) of the left coronary artery or the right coronary (RC) artery on plasma catecholamine levels, and (2) to determine whether bilateral vagotomy has an effect on changes in plasma catecholamine levels evoked by coronary occlusion. Chloralose anaesthetised cats subjected to LAD occlusion exhibited increases in plasma noradrenaline and adrenaline at 3 min post-occlusion. The increases in noradrenaline and adrenaline were unrelated to the hypotension that occurred at this time. Bilateral vagotomy did not appear to alter the effect of LAD occlusion on catecholamine release into the circulation but did unmask a significant correlation between the degree of hypotension and the magnitude of increase in plasma catecholamines. Right coronary occlusion in animals with intact and sectioned vagus nerves evoked noradrenaline and adrenaline release that was significantly correlated with a fall in arterial pressure. Bilateral vagotomy per se caused an increase in baseline plasma catecholamine levels. Pretreatment with atropine mimicked the increase in baseline catecholamine levels seen with vagotomy. These results indicate that occlusion of the LAD and RC arteries increase the release of catecholamines into the circulation. The role of the vagus nerves in this response was observed only with LAD occlusion and consisted of altering the relationship between the degree of hypotension and the magnitude of increase in plasma catecholamines. That is, after vagotomy, the decrease in blood pressure following LAD occlusion was effective in causing release of catecholamines, presumably because of the hypotension causing a decrease in baroreceptor stimulation. Finally, it appeared that vagotomy increases the release of noradrenaline into the circulation by removing efferent vagal tone that inhibits noradrenaline release. This inhibitory action is mediated by activation of muscarinic receptors.

Circadian rhythm of serum cortisol in Cushing's disease.

Two women with typical clinical and biochemical features of pituitary-dependent Cushing's disease each underwent hourly blood sampling for 24 h on two separate occasions for measurement of serum cortisol. The 24-h mean serum cortisol concentrations (17.7 and 15.4 micrograms/dl in patient 1; 19.0 and 15.8 micrograms/dl in patient 2) were elevated (normal level, less than 12.5 micrograms/dl), as expected. Cosinor analysis of the patients' serum cortisol patterns revealed statistically significant circadian rhythms on all four profiles. The amplitude of the rhythm on both occasions in patient 1 (5.8 and 6.6 micrograms/dl) and on one of two occasions in patient 2 (7.2 and 10.5 micrograms/dl) fell in the range for the amplitude of the cortisol circadian rhythm in normal subjects (2.2-8.6 micrograms/dl). In contrast to commonly held belief, some patients with Cushing's disease may exhibit circadian variation of serum cortisol.

Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity.

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.

Effects of chronic desipramine on plasma norepinephrine concentrations and cardiovascular parameters in elderly depressed women: a preliminary report.

The effect of chronic administration of desipramine, a relatively specific inhibitor of the reuptake of norepinephrine (NE), on heart rate, blood pressure, and concentrations of NE in plasma was examined in elderly depressed women. Plasma NE concentrations rose significantly following administration of desipramine, while there was no significant change in either heart rate or blood pressure. Implications of these findings are discussed with relationship to the selection of appropriate types and doses of antidepressants in the elderly.

Effect of imipramine on norepinephrine and blood pressure in enuretic boys.

The effect of imipramine, desmethylimipramine, and methscopolamine on blood pressure (BP) and plasma norepinephrine (NE) was measured in enuretic boys in a double-blind, placebo-controlled study. Measurements were obtained on the thirteenth day of medication (75 mg at bedtime). The tricyclic drugs induced a rise in diastolic BP as well as an increase in plasma NE but there was no significant relationshhip between the increments in plasma NE and BP. The plasma concentration of drug correlated with the drug-induced BP rise. This is the fifth study to demonstrate a hypertensive effect of tricyclic drugs in children in contrast to the systolic hypotension usually seen in adult patients. It is not clear from our data whether children have different cardiovascular compensatory reflexes or whether they experience a greater stimulant effect from the drug.

Altered hydroxydesipramine concentrations in elderly depressed patients.

Recent reports demonstrate that hydroxy metabolites of desipramine (DMI) have pharmacologic activity and do not just produce side effects. In patients treated with DMI, we determined the ratio of 2-hydroxydesipramine (2-OH-DMI) to drug at steady state. The ratios in the elderly patients were higher than in younger patients, and whereas plasma levels of 2-OH-DMI increased with age, urinary clearances decreased. The known decrease in glomerular filtration with age may explain the selective increase of 2-OH-DMI concentration in the elderly.

Effects of desmethylimipramine on plasma norepinephrine, pulse, and blood pressure.

We followed the effects of a tricyclic antidepressant selective for norepinephrine (NE) uptake inhibition, desmethylimipramine (DMI), on blood pressure, heart rate, and plasma NE level in healthy subjects. After a single oral dose of 100 mg DMI, supine systolic and diastolic blood pressure and supine and upright heart rate rose, and there was an increment in heart rate with standing. After long-term low doses of the drug (mean daily dosage 67.5 mg), the upright level and increment with standing in plasma NE also rose. Supine NE levels also rose after the long-term higher dose (mean daily dosage 125 mg). No differences in any measures were detected between the short- and the two long-term dose levels of DMI. Our findings suggest that NE uptake inhibition induces physiologic elevation of NE concentration in the sympathetic neuroeffector region. A similar effect at synapses in the CNS might be involved in the mechanism of antidepressant action.

Active metabolites of imipramine and desipramine in man.

Active hydroxy metabolites of imipramine (IMI) and desipramine (DMI) have been quantified in plasma and cerebrospinal fluid (CSF) from patients at steady-state. In plasma of prepubescent boys and adults the concentration of unconjugated 2-hydroxyimipramine is only 15% to 25% that of IMI; 2-hydroxydesipramine (OH-DMI) concentration, however, is usually 50% that of DMI and in some cases OH-DMI is the predominant compound. In CSF from adult patients the ratio of concentrations of OH-DMI/DMI is higher than in plasma. Judging from the CSF/plasma ratio 12% of DMI exists in the free form at steady state, whereas 16% of OH-DMI is free (P less than 0.02). There is no evidence for saturation of hydroxylation within the therapeutic dose and concentration ranges investigated. On the basis of a steady-state OH-DMI/DMI ratio of less than 1/30 in plasma 5% of the population studied could be classified as deficient DMI hydroxylators. This in the same as the incidence of deficient debrisoquine hydroxylators reported in other populations.

Concentrations of desipramine in elderly women.

Seven elderly depressed women were given desipramine, and plasma concentrations of the drug were measured from blood samples drawn after a single dose and during long-term use. The concentrations were no different from those found in younger patients. Aging does not seem to alter the plasma concentration of desipramine, and the authors conclude that the increased incidence and severity of the drug's side effects are probably not due to high drug concentrations.

Differential effects of d- and l-propranolol on dopamine turnover stimulated by oxotremorine in striatal and mesolimbic areas of rat brain.

The effects of l-propranolol, d-propranolol and clonidine on homovanillic acid (HVA) concentrations in the corpus striatum and nucleus accumbens of rats were studied under normal conditions and after treatment with oxotremorine or haloperidol. Thile propranolol and clonidine given alone had no significant effect on HVA levels in either area, l-propranolol (1--10 mg/kg) and clonidine (0.1 mg/kg), both significantly inhibited the elevation of striatal HVA, found 60 min after oxotremorine administration. Both l- and d-propranolol (2.5 mg/kg), reduced the effect of oxotremorine in the nucleus accumbens. Neither l-propranolol no clonidine affected the rise in HVA in either brain area seen after haloperidol. Our results suggest that propranolol may reduce cholinergic activation of dopaminergic pathways by two different mechanisms. One is stereospecific for the l-isomer and operates in the striatum and another, which is shared by both isomers, occurs in the nucleus accumbens.

Evidence that noradrenaline modulates the increase in striatal dopamine metabolism induced by muscarinic receptor stimulation.

The effect of oxotremorine was studied on the concentration of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethylglycol (MHPG) in the corpus striatum of rats. At a dose of 1 mg/kg oxotremorine increased HVA levels by 68% and MHPG, by 51%. MHPG was also increased in the nucl. accumbens (58%) and neocortex (42%). Pretreatment with clonidine, 0.1 mg/kg abolished the increase in MHPG in the striatum and significantly inhibited the rise in HVA. 1-Propranolol 2.5 mg/kg, but not d-propranolol, had an effect similar to that of clonidine. A lower dose of oxotremorine (0.5 mg/kg) increased striatal HVA by 36% but did not alter MHPG levels. This increase in HVA was not reduced by 1-propranolol. Eight days after bilateral lesions of the locus coeruleus, there was a reduction in the basal concentrations of noradrenaline (41%) and MHPG (57%) in the striatum. The data suggest that at higher doses of oxotremorine (1 mg/kg), but not a lower dose (0.5 mg/kg), a noradrenergic pathway is stimulated to increase the rate of metabolism of noradrenaline in the striatum. Oxotremorine also appears to increase dopamine metabolism in the striatum by at least two separate mechanisms, one of which involves the mediation of noradrenaline.

The effect of desmethylimipramine on the metabolism of norepinephrine.

Eleven normal volunteers were given an acute and two chronic doses of desipramine (DMI). The plasma norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and dihydroxyphenylglycol (DHPG) concentrations were measured before and during drug administration. DMI reduced plasma concentrations of MHPG by 13% and DHPG by 17%. After two weeks of drug administration, the MHPG/NE ratio was reduced, and there was a significant negative correlation with the concurrent drug concentration. These results suggest that DMI: (1) reduces the turnover of NE; and (2) diminishes the oxidative deamination of NE. In addition, the drug concentration response relationship indicates that the effects of uptake inhibition may not be maximal until concentrations in the apparent therapeutic range are achieved.

Comparative pharmacokinetics of zimelidine and desipramine in man following acute and chronic administration.

Single dose and steady-state pharmacokinetics of zimelidine and desipramine were compared in eight depressed patients who were subjects in a double-blind crossover study. Within the same patient, there was no relationship between the pharmacokinetics of desipramine (pharmacokinetically similar to all other tricyclic antidepressants) and those of zimelidin, a bicyclic antidepressant. The weight-corrected dose of zimelidine gives a reasonable index of the concentration of its active metabolite norzimelidine, which predominates over zimelidine by a ratio of approximately 3 to 1. The variation in steady-state concentration of norzimelidine for a given dose of zimelidine in adults is about twofold and can be reduced by correcting for weight.

Hormonal responses to zimelidine and desipramine in depressed patients.

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.

Diphenylbarbituric acid: its effects on neuromuscular and spinal cord function in the cat.

In studies of neuromuscular function in the cat soleus muscle, diphenylbarbituric acid (DPB; 10-80 mg/kg i.v.) depressed both the degree and the duration of posttetanic potentiation (PTP) in a dose-dependent manner. At doses of greater than 20 mg/kg, twitch strength was increased in both indirectly stimulated and directly stimulated chronically denervated preparations, indicating a direct effect of DPB on muscle. In the spinal cord, DPB (10-60 mg/kg) depressed both monosynaptic (2N) and polysynaptic discharges, with flexor and extensor reflexes being similarly affected. In addition, DPB was not selective for isolated 2N as compared with posttetanically potentiated monosynaptic responses. Thus, in its actions on neuromuscular function DPB resembles phenytoin; in the spinal cord the drug resembles phenobarbital. The data suggest that the capacity of a drug to curb high-frequency repetitive discharges is more important than curbing recruitment as exhibited by PTP of the 2N reflex.

Peripheral catecholamines mediate certain responses to central cholinergic receptor stimulation by oxotremorine.

The role of peripheral catecholamines in mediating the pressor and tremorigenic effects of oxotremorine were investigated in conscious rats. At time of peak tremor intensity induced by oxotremorine, plasma adrenaline and noradrenaline were increased 3--4-fold. Tremor intensity was substantially reduced by either adrenal medullectomy, chemical sympathectomy with 6-hydroxydopamine, or injection of 2.5 mg/kg L-propranolol. The pressor response to oxotremorine was not reduced by adrenal denervation, which however prevented the usual rise in plasma adrenaline but not that of noradrenaline. It is concluded that central cholinergic receptor stimulation activates the sympatho-adrenal system. While both adrenaline and intact sympathetic nerves are necessary for the mediation of the full tremorigenic effect, the pressor response to oxotremorine is mainly due to the effect of noradrenaline on vascular alpha-receptors.

The role of peripheral catecholamines in oxotremorine tremor in the rat and its antagonism by beta adrenoceptor blocking agents.

Oxotremorine, 0.25 mg/kg, produces marked tremor in the rat, which is abolished by scopolamine, 0.5 mg/kg, and is substantially reduced in intensity and duration both by adrenalmedullectomy and by chemical sympathectomy with 6-hydroxydopamine. Oxotremorine increases plasma norepinephrine from 0.62 +/- 0.07 to 3.01 +/- 0.47 ng/ml and plasma epinephrine, from 0.82 +/- 0.14 to 3.42 +/- 0.48 ng/ml, in conscious unrestrained rats. l-Propranolol (0.5-2.5 mg/kg) reduces tremor, and at 2.5 mg/kg is more effective than either chemical sympathectomy or adrenal demedullation. d-Propranolol and sotalol are also active at 4 and 10 times the dose of l-propranolol, respectively. l-Propranolol does not prevent the rise in catecholamines induced by oxotremorine. It is suggested that stimulation of central muscarinic receptors causes tremor by a combination of two effects. There is an increase in cholinergic influence to motor efferents accompanied by an activation of the sympathoadrenal system to release catecholamines which augment tremor by stimulation of beta2 adrenoceptors.