Patricia D. Kroboth

DHEA and DHEA‐S: A Review

Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA‐S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA‐S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA‐S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA‐S concentrations, as well as concentrations of DHEA and DHEA‐S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA‐S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.

Pharmacokinetics of the Newer Benzodiazepines

SummaryThe assay methods used to determine the concentrations of the newer benzodiazepines include electron-capture gas-liquid chromatography, high performace liquid chromatography with ultraviolet detection, gas chromatography-mass spectrometry, radioassay and radioreceptor assay. The method used frequently is the highly sensitive and specific electron-capture gas-liquid chromatography. Other methods are associated with limitations.The triazolo- and imidazolebenzodiazepines differ structurally from the ‘classical’ benzodiazepines such as diazepam, and offer distinct differences in pharmacological activity and in time-course of effect. Alprazolam and triazolam, both 1,4-triazolobenzodiazepines, have high affinities for the benzodiazepine receptor as do midazolam and loprazolam, which are 1,4-imidazolebenzodiazepines.Absorption is characteristically rapid, with peak alprazolam and triazolam concentrations occurring within 1 hour after oral administration. Sublingual administration results in peak alprazolam and triazolam concentrations that are higher and occur earlier than with the oral route.The volume of distribution of alprazolam and triazolam is approximately 1L. Alprazolam is 70% bound to plasma proteins and the extent of binding is independent of concentration. Similarly, triazolam is approximately 85% bound to plasma proteins, variability in binding being explained by variations in α1-acid glycoprotein concentration.The 1,4-triazolo ring prevents the oxidative metabolism of the classical benzodiazepines which results in formation of active metabolites with long elimination half-lives. Alprazolam is extensively metabolised: 29 metabolites have been identified in the urine, and its major metabolite, α-hydroxyalprazolam, has pharmacological activity. α-Hydroxyalprazolam and 4-hydroxyalprazolam are detectable in plasma in amounts which account for less than 10% of the administered dose. Mean alprazolam elimination half-life in healthy adult subjects ranges from 9.5 to 12 hours; liver disease prolongs alprazolam elimination, but renal insufficiency does not. Triazolam also undergoes oxidation and subsequent glucuronidation. α-Hydroxytriazolam is the major metabolite, in addition to which 4-hydroxyalprazolam and α-4-hydroxytriazolam have been identified in plasma and urine. The elimination half-life of triazolam ranges between 1.8 and 5.9 hours, while that of the conjugated metabolites is short, approximately 3.8 hours. Accumulation of triazolam or its metabolites after multiple doses does not occur. Liver disease prolongs triazolam elimination from the body, but renal disease does not.Factors such as age, gender, and obesity can influence the pharmacokinetics of alprazolam and triazolam. The reported drug-drug interactions with both agents are predominantly the result of inhibition of the microsomal enzyme system responsible for the hepatic metabolism and elimination of these benzodiazepines.Midazolam and loprazolam are basic compounds; the imidazole ring allows for the preparation of aqueous injectable solutions that are stable and well tolerated. Both drugs are rapidly absorbed after oral administration. Peak midazolam concentrations occur in 20 to 60 minutes, while peak loprazolam concentrations are reached in 0.5 to 2 hours. Bioavailability of oral midazolam ranges from 34 to 68%. It is also rapidly absorbed after intramuscular administration, and the bioavailability then ranges from 40 to 100%. The absolute bioavailability of loprazolam in man has not been reported; however, approximately 70 to 75% of the oral dose is absorbed in animals.The volume of distribution for both midazolam and loprazolam is large, 0.5 to 3 L/kg, with great intersubject variability. The plasma protein binding of midazolam is 95%, while loprazolam is 80% protein bound.Midazolam undergoes hydroxylation and subsequent glucuronidation. The elimination half-life of midazolam is approximately 2 hours; however, there have been reports of prolonged elimination (> 8 hours) in subpopulations of subjects. The elimination half-life of α-hydroxymidazolam, the major midazolam metabolite, is approximately 1 hour.Loprazolam is not as rapidly metabolised as midazolam. The major elimination pathway is N-oxidation of the piperazine ring. Depending on the assay method, the elimination half-life for loprazolam has ranged between 4 and 15 hours. The longer half-life may reflect the activity of metabolites, with the actual value being between 4 and 7 hours. The most common type of drug-drug interaction reported for midazolam also involves the inhibition of the microsomal mixed function oxidase system responsible for the metabolism of that drug. Loprazolam interactions have not been extensively studied.

Correlates and Prevalence of Benzodiazepine Use in Community-Dwelling Elderly

OBJECTIVE: To describe the prevalence of benzodiazepine use, sociodemographic and physical health factors associated with use, dosages taken, and directions for use among individuals aged 65 years and older.DESIGN: Cross-sectional analysis of baseline data from the community-based, prospective observational Cardiovascular Health Study.PATIENTS/PARTICIPANTS: Medicare eligibility lists from four U.S. communities were used to recruit a representative sample of 5,201 community-dwelling elderly, of which 5,181 participants met all study criteria.MEASUREMENTS AND MAIN RESULTS: Among participants, 511 (9.9%) were taking at least one benzodiazepine, primarily anxiolytics (73%). Benzodiazepines were often prescribed to be taken pro re nata (PRN “as needed”), and 36.5% of prescriptions with instructions to be taken regularly were taken at a dose lower than prescribed. Reported over-the-counter (OTC) sleep aid medication use was 39.2% in benzodiazepine users and 3.3% in nonusers. In a multivariate logistic model, the significant independent correlates of benzodiazepine use were being white (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.0, 3.4), female (OR 1.7; CI 1.4, 2.2), and living in Forsyth County, North Carolina, or Washington County, Maryland, compared with living in Sacramento County, California, or Allegheny County, Pennsylvania (OR 2.3; CI 1.4, 2.2); having coronary heart disease (OR 1.6; CI 1.2, 2.1), health status reported as poor or fair (OR 1.8; CI 1.4, 2.3), self-reported diagnosis of nervous or emotional disorder (OR 6.7; CI 5.1, 8.7), and reporting use of an OTC sleep aid medication (OR 18.7; CI 14.1, 24.7).CONCLUSIONS: One in 10 participants reported taking a benzodiazepine, most frequently an anxiolytic, often at a lower dose than prescribed and usually PRN. The high prevalence of OTC sleep aid medication and benzodiazepine use may place the patient at increased risk of psychomotor impairment. Physicians should assess OTC sleep aid medication use when prescribing benzodiazepines.

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration.

Six fasting male subjects (20–32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam wre as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.

Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic interaction study with lorazepam.

This study was conducted to determine the potential for an interaction between nefazodone (NEF), a new antidepressant, and lorazepam (LOR) after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in healthy male volunteers. A total of 12 subjects per group received either placebo (PLA) twice daily, 2 mg of LOR twice daily, 200 mg of NEF twice daily, or the combination of 2 mg of LOR and 200 mg of NEF (LOR+NEF) twice daily for 7 days. Plasma samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of LOR, NEF, and NEF metabolites hydroxy (HO)-NEF, m-chlorophenylpiperazine (mCPP), and dione by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for LOR, NEF, HO-NEF, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that there was no effect of LOR on the single dose or steady-state pharmacokinetics of NEF, HO-NEF, or dione after coadministration. The steady-state mCPP Cmax values decreased 36% for the LOR+NEF group in comparison to that when NEF was given alone. There was no effect of NEF on the pharmacokinetics of LOR after coadministration. The absence of an interaction appears to be attributable to LORs metabolic clearance being dependant on conjugation rather than hydroxylation. Overall, no change in LOR or NEF dosage is necessary when the two drugs are coadministered.

Endogenous concentrations of DHEA and DHEA-S decrease with remission of depression in older adults.

BACKGROUND Clinical studies of endogenous concentrations of dehydroepiandrosterone (DHEA) and its sulfated conjugate DHEA-S in depression are limited. This study was designed to evaluate the influence of successful pharmacological treatment of late-life depression on concentrations of DHEA, DHEA-S and cortisol. METHODS We determined endogenous concentrations of DHEA, DHEA-S and cortisol in elderly control subjects (n = 16) and in elderly depressed patients who remitted (n = 44) or failed to remit (n = 16) with pharmacological treatment. Depressed patients were treated for 12 weeks with either nortriptyline or paroxetine. RESULTS In remitters, DHEA and DHEA-S concentrations were lower at week 12 than at week 0 (p =.002 and p =.0001, respectively). In the nonremitters and control subjects, neither DHEA nor DHEA-S concentrations changed. Decreases in hormone concentrations were associated with improvement in mood and functioning in depressed patients. Although cortisol concentrations decreased in remitters and nonremitters, the change was not significant. CONCLUSIONS Our data suggest that the decrease in DHEA and DHEA-S in remitters is related to remission of depression rather than to a direct drug effect on steroids, as nonremitters had no change in hormone concentrations.

Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping

Determination of hepatic and intestinal cytochrome P450 (CYP) 3A activity is important, because CYP3A substrates show substantial variability in plasma concentrations as a result of variations in both hepatic and intestinal metabolism. The goals of this study were (1) to determine whether the hepatic and intestinal extraction ratios (ERH and ERG, respectively) of the CYP3A probe drug midazolam are different when determined after semisimultaneous administration, as compared with administration on separate occasions (traditional method), and (2) to evaluate the hepatic and intestinal metabolism of midazolam in the presence and absence of ketoconazole by the semisimultaneous method.

Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics

The effects of low‐dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the A UC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low‐dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects

The relationships between alprazolam and metabolite concentrations and CNS effects were determined in a double-blind placebo controlled four-way crossover trial in 16 normal male volunteers. Active drug treatments consisted of 4-day regimens of 4 mg alprazolam PO daily as 2 mg bid., 1 mg qid, and 0.25 mg each hour. On days 1 and 4, the kinetics, sedative and psychomotor effects were evaluated. Plasma concentrations of the 4- and α-hydroxy metabolites of alprazolam were less than 10% of unchanged alprazolam levels on both days. Accumulation of these metabolites and alprazolam was dependent on alprazolam half-life (11.6 h). Acute and chronic tolerance to the sedative and psychomotor effects was observed with all active drug treatments. All alprazolam treatments resulted in significantly greater sedation than placebo on days 1 and 4. However, on day 4, sedation was 16–36% less than observed on day 1, despite plasma concentrations 1.4–2.76 times the day 1 concentrations. Sedation from alprazolam was reduced in each successive study phase, suggesting a tolerance which was sustained during the 10-day washout between phases. By day 4, psychomotor performance was not different from placebo, indicating more complete development of tolerance than occurred for the sedative effect. Sedation and psychomotor impairment on day 1 were greatest with 2 mg alprazolam bid. During the initiation of therapy, the patient will likely experience less sedation and psychomotor impairment with smaller, more frequent doses. Since tolerance develops to these effects, the advantage of more frequent dosing regimen dissipates by the 4th day.

Severe theophylline toxicity: Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion

The presenting symptoms, course, and treatment of 10 patients with severe theophylline toxicity (heart rate above 120, multifocal atrial tachycardia or premature ventricular contractions, hypotension, seizures) are described. Theophylline levels at presentation averaged 66 micrograms/ml (range 30 to 180 micrograms/ml). All patients had marked tachycardia; 80 percent had gastrointestinal symptoms, 50 percent were hypotensive, and 20 percent had seizures. A known history of poor compliance or other risk factors to overdosage was present in 60 percent. Of the five patients in whom drug clearances were determined, two had uniform first-order drug elimination. Three had biphasic elimination with an initial period of delayed elimination due to either zero-order kinetics or continued drug absorption. During the first-order elimination period, mean plasma theophylline clearance was 28.0 +/- 4.3 ml per minute with a half-life of 8.2 hours. In the patients with initially delayed elimination, the mean clearance during the slow phase was 9.6 +/- 3.3 ml per minute with an apparent half-life of 31 hours. One patient was treated with charcoal hemoperfusion but the others received conservative management alone; all recovered without permanent sequelae. Propranolol and verapamil were useful in controlling supraventricular tachycardia. It appears that most patients with severe theophylline toxicity can be managed without hemoperfusion, which should be considered only when drug clearance is reduced, and hypotension, tachycardia, ventricular ectopy, or seizures are refractory to conservative measures.