Protriptyline kinetics.

The kinetics of protriptyline were examined in 8 subjects after a single oral dose of 30 mg protriptyline hydrochloride. Peak protriptyline levels ranged from 10.4 to 22.3 ng/ml and were reached 6 to 12 hr after the oral dose. The mean protriptyline half-life (t1/2) was 74.3 hr and ranged from 53.6 to 91.7 hr in individual subjects, confirming the long t1/2 of protriptyline reported by Moody and associates. The estimated first-pass metabolism of protriptyline was relatively small, ranging from 10% to 25% of the oral dose, assuming complete absorption. The mean volume of distribution was 22.5 L/kg and ranged from 15.0 to 31.2 L/kg. No relationship was found between the kinetics of protriptyline and those of doxepin studied previously in 7 of the 8 subjects.

Protriptyline plasma levels and antidepressant response.

Twenty-one depressed outpatients were treated for 4 wk with 20 mg/day of protriptyline. Protriptyline plasma in individuals after 4 wk ranged from 22 ng/ml to 167 ng/ml. There was a negative correlation (-0.50, less than 0.05) between the severity of depression measured by the Hamilton Rating Scale (HRS) and the wk 4 protriptyline concentration. Patients with plasma levels above 70 ng/ml (wk 4) had better outcomes measured by the HRS (p less than 0.05) and the Zung Self-Rating Depression Scale (p less than 0.05) and had greater percent decreases on both scales (p less than 0.05) during treatment than those with lower plasma levels. An upper limit to the therapeutic plasma level range beyond which response to treatment was less satisfactory was not demonstrated in this study.

Steady-state protriptyline levels in an outpatient population.

The authors measured steady-state protriptylive levels in 12 outpatients undergoing treatment for depression. The steady-state level of protriptyline was surprisingly high compared with levels obtained when other tricyclic antidepressants were prescribed. This finding probably accounts for the effectiveness of protriptyline at low doses and its frequent side effects.

The clinical application of tricyclic antidepressant pharmacokinetics and plasma levels.

The authors present a clinical approach for predicting and using plasma concentrations of tricyclic antidepressants in the treatment of depressed patients. They review the pharmacokinetics of this group of drugs and their side effects and toxicity. There is a suggested therapeutic range for plasma concentrations of imipramine, amitriptyline, and nortriptyline; more definitive studies are needed to determine the necessary plasma levels for achieving clinical response with the other tricyclic antidepressants (desmethylimipramine, protriptyline, doxepin, clomipramine, impiramine N-oxide, and butriptyline). A more thorough knowledge of the clinical pharmacokinetics of tricyclic antidepressants should lead to more rational use of these drugs, with a higher response rate and fewer adverse reactions.

Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat.

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 mug/ml for desipramine and from 0.04 to 1.2 mug/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40 degrees rotation were 1.35 mug/ml (desipramine) and 1.75 mug/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 mug/ml for desipramine and 3.6 mug/ml for protriptyline.5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.

Tricyclic antidepressants and delirium.

Some patients who take tricyclic antidepressants (TCAs) develop delirium. Charts were reviewed of 125 inpatients whose TCA plasma levels had been assayed. Delirium was documented in 10 cases. The occurrence of delirium was statistically related to age, race, and loge plasma TCA levels.

Plasma levels of tricyclic antidepressants and clinical efficacy: review of the literature -- part II.

The authors have critically reviewed the literature regarding the relationship between plasma levels of tricyclic antidepressant and their clinical efficacy. When available, drug-drug interactions, pharmacokinetics, and other factors influencing plasma levels of tricyclic antidepressants are discussed. Although many studies are confounded by significant methodological and statistical problems, it appears to these reviews that the available evidence suggests a curvilinear relationship between nortriptyline plasma levels and antidepressant efficacy in tricyclic responsive endogenously depressed inpatients, with maximal therapeutic efficacy achieved with notriptyline plasma levels between 50-175 ng/ml. The evidence for imipramine supports a linear relationship between plasma levels of imipramine plus desmethylimipramine and clinical response in nondelusional endogenously depressed tricyclic responsive inpatients. For amitriptyline, the picture is less clear. However, with the exception of one well-controlled study, the available evidence suppprts some significant relationship between amitriptyline plus nortriptyline plasma levels and antidepressant efficacy in tricyclic respoonsive endogenously depressed patients, but it is not clear as to whether this is a linear relationship or a curvilinear one. For the other antidepressants: protriptyline, desmethylimipramine, doxepin, clomipramine, maprotiline, and butriptyline, a significant relationship (if any) awaits further elucidation. It is important to point out that these plasma level relationships probably do no generalize to other types of depressions (e.g. neurotic, characterological, delusional, acute situationa, etc.) and clearly do not apply to every endogenous tricyclic responsive patient. /owever, it appears that, in general, a clinician will obtain therapeutic efficacy for endogenously depressed patients if these guidelines are followed. The actual therapeutic levels will depend on the assay's sensitivity and specificity and may vary from center to center, illustrates the importance of each center defining its own therapeutic limits, or conversely all centers adoptina a universal reproducible assay methodology for each compound measured. Despite these limitations, these reviewers feel that routine monitoring of plasma levels of the tricyclic antidepressants is a useful method to maximize therapeutic efficacy and prvent undue side effects, as well as to insure good medication compliance.

Effects of protriptyline on snoring characteristics.

We evaluated the effects of protriptyline on snoring characteristics in 14 nonapneic snorers (age range, 23 to 54 years; body mass index, 27.4 +/- 0.9 kg/m2, mean +/- SEM). The study design was a double-blind placebo-controlled crossover trial. Patients were evaluated during a polysomnographic study after each 2 weeks of treatment. Breathing sounds were recorded with two microphones symmetrically placed on each side of the bed, the signal being preamplified, equalized, and analyzed by using a real time analyzer. A snoring event was defined as a breathing sound with a sound pressure level (SPL) greater than 60 dB SPL. The snoring index (number/sleep hour) and the sound intensity of each event were automatically determined. Mild side effects were observed in ten subjects, but no subject interrupted the study because of them. The REM sleep time decreased with protriptyline with a parallel increase in stages 1 to 2. There was no difference in body position during sleep between the placebo and protriptyline trials. The snoring index decreased from 335 +/- 40 with placebo to 238 +/- 41 with protriptyline (p < 0.05) with important individual differences. Among the different sleep stages, the highest values of the snoring index were observed in slow-wave sleep with placebo. The snoring index decreased in each sleep stage with protriptyline, the highest decrease occurring in slow-wave sleep. The percentage of total sleep time (TST) spent above 60 dB SPL was significantly lower with protriptyline (6.1 +/- 1.2 percent TST) than with placebo (8.6 +/- 1.2 percent TST). Changes in snoring characteristics were not correlated with snoring severity, the drug blood level, the body mass index, or the drug-induced modifications in sleep architecture. We conclude that protriptyline can improve both snoring frequency and loudness in some nonapneic snorers, and that this improvement occurs mostly in the sleep stages where snoring is worst.

Liquid-chromatographic analysis for common tricyclic antidepressant drugs and their metabolites in serum or plasma with the technicon "FAST-LC" system.

We describe a single procedure for assay of seven tricyclic antidepressant drugs and metabolites in serum or plasma: protriptyline, nortriptyline, amitriptyline, desmethyldoxepin, doxepin, desipramine, and imipramine. With the Technicon "FAST-LC" system, samples are aspirated directly into the unit and pretreated via double extraction; the concentration of each drug is then determined by "high-performance" liquid chromatography. Final chromatograms are monitored at 205 nm, at analysis rates of 7.5 samples/h. Concentration and absorbance are linearly related for each drug from 0 to 1400 micrograms/L. Day-to-day CVs averaged 5 to 6% for each drug, and there is good correlation of FAST-LC values with those obtained by gas-chromatographic methods. Total sample volume is 750 microliters.

Liquid chromatographic separation of antidepressant drugs: I. Tricyclics.

A simple normal-phase (silica), high-performance liquid chromatographic (HPLC) assay of amitriptyline (AMI), doxepin (DOX), imipramine (IMI), nortriptyline (NORT), desmethyldoxepin (DESDOX), desipramine (DESIP), and protriptyline (PRO) in serum with no coelution is described here. Trimipramine and promazine were used as internal standards. Extraction of the 1.0-ml serum samples (collected in plastic) was done with Bond-Elut C18 columns. The compounds of interest were eluted with 10 mM methanolic ammonium acetate. The eluates were evaporated at 56-58 degrees C and reconstituted with 200 microliters of the mobile phase. The mobile phase was absolute ethanol-acetonitrile-tert-butylamine (98:2:0.05, vol/vol/vol). Detection of eluted drugs was at 254 nm at 0.01 absorbance units full scale (AUFS), except for PRO, which was detected at 229 nm at 0.02 AUFS. Absolute recoveries were 87-97%. A 5-micron silica (4.6 X 250 mm) HPLC column was used; results with a 10-micron silica column (3.9 X 300 mm) are also presented. Peak height ratios with trimipramine were linear for each analyte between 25 and 1200 ng/ml. Peak height ratios with promazine as the internal standard were linear for each analyte between 25 and 600 ng/ml. Detection limits under the conditions described were 2 ng/ml for AMI, DOX, and IMI, 4 ng/ml for NORT, DESDOX, and DESIP, and 10 ng/ml for PRO. Coefficients of within-day and day-to-day variation at three concentration levels were less than 9.8% and less than 11.2%, respectively. The hydroxylated metabolites of IMI, DES, NORT, and the cis isomer of DOX are discussed. Steady-state daily dosages and corresponding serum levels are presented for 69 patients. The total assay time was less than 10 min for DESIP and 12 min for PRO. This assay can be used in correlating serum levels with clinical effects, compliancy, and pharmacokinetic studies.

Pharmacokinetic aspects of protriptyline plasma levels.

Plasma levels of protriptyline have been determined in 30 patients undergoing antidepressant therapy. After 3 1/2 weeks treatment at dosage levels of 40 mg/day, protriptyline plasma levels ranged from 430 to 1430 nmol/l. During this period only two-thirds of the subjects had definitely achieved asymptotic concentrations. Single dose studies in 5 volunteers suggest that the volume of distribution of protriptyline shows little intersubject variation. The half life of the drug, however, may vary appreciably from subject to subject, ranging from 54 to 198 h. The effects of two sedatives on mean protriptyline plasma levels have been determined. Mean plasma levels for nitrazepam recipients are indistinguishable from those for patients receiving no night sedation. The mean plasma levels for a group of patients receiving sodium amylobarbitone were significantly reduced. The problems of choice and early adjustment of dosages in order to achieve satisfactory plasma levels is discussed. For practical purposes it is suggested that early values may be of predictive significance in allowing early dosage adjustments to be made.

Plasma concentrations of protriptyline and clinical effects in depressed women.

We studied the relationship between side effects, clinical outcome and the drug plasma levels in 28 female depressed patients treated with protriptyline. After 3 1/2 weeks treatment, patients with plasma levels within a median range (630 to 900 nmol/l) showed better responses to the drug than patients with plasma levels outside this range. There were no statistically signficant correlations between plasma levels and side effect scores or 'corrected' side effect scores (scores after subtracting pretreatment values) for the group at any time after starting the treatment. But we found positive correlations between plasma levels and 'corrected' side effect scores for the neurotic subgroup after 14 and 21 days of treatment. Other correlations between plasma levels and side effect scores were non-significant.