A comprehensive review of MDMA and GHB: two common club drugs.

"Club drugs" have become alarmingly popular. The use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and gamma-hydroxybutyrate (GHB), in particular, has increased dramatically from 1997-1999. The pharmacokinetics of MDMA and GHB appear to be nonlinear, making it difficult to estimate a dose-response relationship. The drug MDMA is an amphetamine analog with sympathomimetic properties, whereas GHB is a gamma-aminobutyric acid analog with sedative properties. Symptoms of an MDMA toxic reaction include tachycardia, sweating, and hyperthermia. Occasional severe sequelae include disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Treatment includes lowering the body temperature and maintaining adequate hydration. Symptoms of GHB intoxication include coma, respiratory depression, unusual movements, confusion, amnesia, and vomiting. Treatment includes cardiac and respiratory support. Because of the popularity of these agents and their potentially dangerous effects, health care professionals must be familiar with these substances and the treatment options for patients who present with symptoms of a toxic reaction.

Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokers.

Eleven healthy tobacco smoking adult male volunteers of mixed race were tobacco abstinent overnight for this study. In each subject, positron emission tomographic images of regional cerebral metabolism of glucose with [18F]fluorodeoxyglucose were obtained in two conditions in the morning on different days: about 3min after approximately 1-2mg of nasal nicotine spray and after an equivalent volume of an active placebo spray of oleoresin of pepper in a random counterbalanced design. A Siemens/CTI 931/08-12 scanner with the capability of 15 horizontal brain slices was used. The images were further converted into a standard uniform brain format in which the mean data of all 11 subjects were obtained. Images were analysed in stereotactic coordinates using pixel-wise t statistics and a smoothed Gaussian model. Peak plasma nicotine levels varied three-fold and the areas under the curve(0-30min) varied seven-fold among the individual subjects. Nicotine caused a small overall reduction in global cerebral metabolism of glucose but, when the data were normalized, several brain regions showed relative increases in activity. Cerebral structures specifically activated by nicotine (nicotine minus pepper, Z score >4.0) included: left inferior frontal gyrus, left posterior cingulate gyrus and right thalamus. The visual cortex, including the right and left cuneus and left lateral occipito-temporal gyrus fusiformis, also showed an increase in regional cerebral metabolism of glucose with Z scores >3. 6. Structures with a decrease in regional cerebral metabolism of glucose (pepper minus nicotine) were the left insula and right inferior occipital gyrus, with Z scores >3.5. Especially important is the fact that the thalamus is activated by nicotine. This is consistent with the high density of nicotinic cholinoceptors in that brain region. However, not all brain regions affected by nicotine are known to have many nicotinic cholinoceptors. The results are discussed in relation to the cognitive effects of nicotine.

Comparison of central and peripheral pharmacologic effects of biperiden and trihexyphenidyl in human volunteers.

In this double-blind, randomized study, indices of central (memory, sedation) and peripheral (salivation, ratio of R-R interval on electrocardiogram) muscarinic function were evaluated in 14 healthy volunteers who received trihexyphenidyl, biperiden, and placebo. Additionally, serum drug levels were obtained 2 hours after oral administration. All subjects participated in three study sessions. During each session, subjects received two doses of biperiden (4 mg), trihexyphenidyl (5 mg), or placebo, and four series of tests were administered. The tests included the determination of cardiac response to standing (R-R ratio), mouth salivation, finger-tapping speed, digit span (forward and backward), a selective reminding task, and visual analog scales (VAS). On the VAS, subjects rated biperiden as significantly more sedating than either trihexyphenidyl or placebo, and both biperiden and trihexyphenidyl were associated with more dizziness than was placebo. Saliva production was significantly reduced by both trihexyphenidyl and biperiden compared with placebo. Digit span performance was significantly decreased in only the backward direction. The selective reminding task revealed highly significant decrements in the number of words recalled and consistent long-term retrieval after both biperiden and trihexyphenidyl. Delayed recall was significantly decreased by both active drugs. Both trihexyphenidyl and biperiden caused a significant increase in the R-R ratio comparison with placebo. With the exception of the VAS measurement of sedation, the effects caused by biperiden and trihexyphenidyl did not differ. The results of this study do not support the hypothesis that the side effect profile of biperiden is significantly different from that of trihexyphenidyl.

Arterial/venous plasma nicotine concentrations following nicotine nasal spray.

BACKGROUND AND OBJECTIVES: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. SUBJECTS AND METHODS: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1-2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. RESULTS AND CONCLUSIONS: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r = 0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations.

Depression in primary care: review of AHCPR guidelines.

OBJECTIVE: To present an overview and evaluation of the Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines for the treatment of depression. INTRODUCTION: One responsibility of the AHCPR is the development and periodic review and update of clinical practice guidelines. This process is undertaken by an independent panel composed of groups of clinicians and other experts from the private sector. Their findings are published in a four-volume, softcover set of booklets. DATA SOURCE AND EVALUATION: Volume 2 in the four-volume set includes a comprehensive complication, synthesis, and critical evaluation of the studies of different treatments for depression. Studies included for evaluation were randomized, prospective clinical trials that were pertinent to all topics concerning the treatment of depression. In some areas, the opinions of the panel were included due to a paucity of data from well-controlled clinical trials. Each AHCPR guideline was followed by a code that indicated whether the strength of evidence supporting that guideline was based on good or fair research-based evidence, or whether it was based primarily on panel members' opinions. CONCLUSIONS: With regard to drug treatment, the guidelines are good. However, since these guidelines were published in 1993 they might be considered somewhat dated because more antidepressants have become available in the interim. Overall, the AHCPR guidelines reflect an extensive review of the literature provided by the panel, as well as input from a highly respected group of reviewers. The panel included physicians, a nurse, a social worker, a psychologist, and a consumer representative. Unfortunately, a pharmacist was not included on the panel. Input from pharmacy practitioners would have been valuable.

The effect of paroxetine on thiothixene pharmacokinetics.

OBJECTIVE: In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. METHOD: Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 +/- 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre-treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 ml blood samples were collected over the next 72 h. RESULTS: None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. DISCUSSION: It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thiothixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance.

Clinical issues associated with urine testing of substances of abuse.

Several factors may affect the validity and outcome of urine testing for abused drugs such as amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, opiates, and phencyclidine. Urine is used for large-scale testing because acquisition of the sample is noninvasive and because most abused drugs can be detected in urine for a reasonable duration after ingestion. Urine testing for drugs of abuse is a two-step process. In the first step, screening assays are used to identify presumably positive specimens. Common screening tests are radioimmunoassays, enzyme immunoassays, fluorescence polarization immunoassay, and thin layer chromatography. Since they may be subject to cross-reactivity, once a possible positive sample has been identified by a preliminary test, a second more specific methodology, gas chromatography with mass spectrometry, is done to confirm the results. Knowledge of the pharmacology and pharmacokinetics of abused drugs affects selection and interpretation of test results.

Interactions of ethanol and quinidine on contractility and myocyte action potential in the rat ventricle.

The combined effects of ethanol and quinidine on cardiac electromechanical coupling are unknown, but both drugs affect cardiac conduction and can cause myocardial depression. Isolated left ventricular papillary and ventricular myocytes were used to assess the combined effects of quinidine and ethanol on the electrophysiologic and mechanical properties of rat myocardium. The combination of quinidine (1-300 microM) and ethanol (120-240 mg/dL) depressed active papillary muscle tension within the clinically useful concentration range. In electrophysiologic studies of isolated ventricular myocytes, quinidine prolonged the action potential duration at 50% (APD50) and 90% (APD90) repolarization, the absolute refractory period, and the relative refractory period, but decreased the maximum rate of change of depolarization in phase 0 (Vmax). When cells were exposed to ethanol (240 mg/dL) and quinidine (1.5 microM) together, a significant decrease in the quinidine-induced prolongation of the absolute refractory and relative refractory periods was seen. Additional changes in action potential parameters from the quinidine values included slight reductions in Vmax and in APD50 and APD90, but these reductions were not consistently displayed, nor were they statistically significant.

Antipsychotic drug use in older adults.

The pharmacology, pharmacokinetics, drug interactions, adverse effects, indications for use, efficacy, dosage, and pattern of use of antipsychotics in adults older than 65 years are reviewed. Most available antipsychotic agents block dopamine type 2 postsynaptic receptors. Antipsychotics also bind to cholinergic, alpha-adrenergic, histamine type 1, and serotonin receptors. The affinities of a given agent for receptors determine its adverse effects and probably its efficacy. There are many obstacles to therapeutic drug monitoring. Many antipsychotics are metabolized into multiple active compounds. Drug clearance from brain tissue may be slower than from plasma. Therapeutic steady-state concentrations are difficult to define. Age-related physiological changes alter the pharmacokinetic and pharmacodynamic characteristics of antipsychotics, placing the elderly adult at heightened risk for adverse effects. Agents that may interact with the antipsychotics include carbamazepine, phenytoin, phenobarbital, tricyclic antidepressants, and lithium. Adverse effects frequently observed in the elderly are orthostatic hypotension, anticholinergic effects, pseudoparkinsonism, and tardive dyskinesia. Neuroleptic malignant syndrome is a rare but potentially fatal reaction. The antipsychotics carry approved labeling for use in treating psychotic disorders; many antipsychotics are approved for use in treating other conditions as well, such as behavioral problems. The Omnibus Budget Reconciliation Act of 1987 established dosage and documentation guidelines for antipsychotic drug use in residents of nursing homes. The guidelines specify that antipsychotics should not be used in this population if the only indication is a problem behavior like wandering. Although antipsychotics are often prescribed for behavioral control in older adults, most studies show only modest efficacy, while some show worsening of symptoms. As-needed orders for antipsychotics are controversial. Antipsychotics can relieve symptoms in the older adult, but lower dosages and more frequent assessments are necessary than for younger adults.

Treatment of acute neuroleptic-induced movement disorders.

Acute extrapyramidal syndromes (EPS), including dystonia, parkinsonism, and akathisia, are associated with the use of virtually all neuroleptic agents. They may be alleviated by reducing the neuroleptic dosage, switching to a lower-potency drug, or administering an adjunctive agent such as an anticholinergic, amantadine, benzodiazepine, or beta-blocker. Akathisia may be only partly dispelled by anticholinergics; alternatives are beta-blockers, benzodiazepines, and clonidine. In patients receiving long-term neuroleptic therapy, both the prophylactic use and the duration of treatment with concomitant anti-EPS drugs are controversial. Administration of prophylactic anti-EPS drugs should be based on the likelihood that the patient will develop EPS, as well as the risk of adverse reactions resulting from extended use of the agents in a specific patient. The decision to continue anti-EPS therapy should be reevaluated frequently, especially in elderly patients.

Noradrenergic response to intravenous yohimbine in patients with depression and comorbidity of depression and panic.

Adrenergic response following infusions of yohimbine or normal saline was evaluated in 9 control subjects, 8 patients suffering from a major depressive episode (MDE), and 12 patients suffering from concurrent MDE and panic disorder (MDE + P). Blood was drawn at -20, 0, 5, 10, 20, 45, and 90 min following the infusions, and assayed for norepinephrine (NE) and 3-methoxy-4-hydroxy-phenyl glycol (MHPG). Although the patient groups exhibited higher baseline NE concentrations, and a greater NE area under the plasma concentration versus time curve (AUC0-90) during the yohimbine infusion, the differences were not statistically significant. Baseline NE was significantly correlated with the NE AUC0-90 in all three groups, suggesting that, although the NE system may be dysregulated in the MDE and MDE + P patients, the NE system still appears to respond somewhat predictably following a challenge, even though the actual magnitude of response may vary.

Differences between smokers and never-smokers in sensitivity to nicotine: a preliminary report.

Sensitivity to nicotine was explored using test doses administered via intra-nasal aerosol in 10 smokers and 10 never-smokers. Smokers received 1.50 mg nicotine (in 2 sprays, < 5 seconds apart, one spray per nostril); never-smokers received either 0.50 mg (n = 3) or 0.25 mg (n = 7) nicotine. Accumulation of nicotine in plasma, per unit dose administered, was nearly four times greater in never-smokers than in smokers, indicating differences in pharmacokinetic tolerance. To examine sensitivity to nicotine without this confound, peak physiological reactivity (heart rate and blood pressure changes) was divided by peak plasma nicotine increment and the ratio was expressed as a function of cotinine level prior to dosing, thereby relating sensitivity to nicotine to history of exposure. In smokers, functional sensitivity to nicotine was inversely related to customary nicotine intake, replicating previous findings for light and heavy smokers. The observation that never-smokers were not much more sensitive to nicotine than light smokers is notable given the disparity in previous history of exposure.

A longitudinal evaluation of dexamethasone pharmacokinetics in depressed patients and normal controls.

Ten depressed patients and eight control subjects received 1 mg of dexamethasone intravenously at two different time points. Depressed patients were studied when they were depressed and following an improvement in their depression. In control subjects the first and second studies were performed approximately 1 month apart. Dexamethasone and cortisol were determined at 0, 5, 15, and 30 minutes, then at 1, 1.2, 2, 3, 4, 5, 6, 7, 9, 12, 17, and 24 hours following dexamethasone administration. Data from each patient was fit using a computer to a two compartment pharmacokinetic model and area under the time versus plasma concentration curve, elimination half-life, and clearance were also determined. Depressed patients exhibited a slower dexamethasone clearance and a larger area under the curve than control subjects at the first time point, but not at the second time point. The groups did not differ significantly in any of the other pharmacokinetic parameters (including distribution half-life, elimination half-life, or volume of distribution) at either time point. The possible causes and implications of these findings are discussed.

Sertraline: a new specific serotonin reuptake blocker.

Sertraline hydrochloride is a new naphthylamino compound that specifically blocks neuronal reuptake of serotonin. It is currently available in the United Kingdom and under review in the US. Sertraline follows first-order kinetics, with a plasma elimination half-life of 24-26 hours. It is highly bound to plasma proteins and has a large volume of distribution. Multicenter studies conducted by the manufacturer have shown sertraline to be efficacious in the treatment of depression and obsessive-compulsive disorder. The daily dose will range from 50 to 200 mg/d for the treatment of depression. The adverse-effect profile differs greatly from the tricyclic antidepressants, but is similar to that of fluoxetine. The most prominent adverse effects are gastrointestinal (nausea, diarrhea/loose stools, dyspepsia).

A longitudinal evaluation of dexamethasone and cortisol plasma concentrations in the dexamethasone suppression test before and during treatment with antidepressant drugs.

Thirty depressed in- and outpatients received serial dexamethasone suppression tests (DSTs). Plasma dexamethasone and cortisol concentrations were drawn at 1600 on the day following a 1-mg oral dose of dexamethasone. The first DST was performed after patients were drug-free for a period of 1 week; the second, third, and fourth DSTs while patients received antidepressant medication. Dexamethasone and cortisol concentrations drawn in the drug-free period correlated significantly. The cortisol to dexamethasone ratio changed significantly with time in DST nonsuppressors, suggesting that nonsuppression is associated with an altered pharmacodynamic response of the hypothalamopituitary-adrenal axis to dexamethasone during depression. When dexamethasone concentrations from the drug-free period were compared with those drawn during antidepressant treatment, no significant differences were noted.

Pharmacologic interventions for the treatment of opioid dependence and withdrawal.

This article discusses current pharmacologic methods in the treatment of heroin dependence and withdrawal. Methadone hydrochloride, the most commonly used opiate agonist, is used for both withdrawal and maintenance therapy. However, it produces dependence and withdrawal results upon abrupt discontinuation. Other opiate agonists including L-alpha acetyl methadyl (LAAM) and propoxyphene napsylate have been used for both withdrawal and maintenance therapy. LAAM is currently available only as an investigational agent and propoxyphene is easily accessible but has been associated with hallucinations and dysphoria at high doses. Alpha 2-adrenergic agonists decrease opiate withdrawal symptoms by decreasing the central adrenergic hyperarousal that is associated with withdrawal. Clonidine effectively attenuates but does not totally eliminate withdrawal symptoms. Other alpha 2-adrenergic agonists (e.g., lofexidine hydrochloride, guanfacine hydrochloride, and guanabenz) have undergone only preliminary investigations. Although alpha 2 agonists effectively decrease most withdrawal symptoms they often cause hypotension. Buprenorphine hydrochloride is a partial opiate agonist that shows some promise in the treatment of the heroin-dependent population. It attenuates opiate craving and causes only minimal withdrawal upon abrupt discontinuation. Because it is well accepted by the heroin-dependent population, however, it may ultimately become an abused substance. Naltrexone is a potent, orally acting opiate antagonist that blocks all opiate-agonist effects and causes no euphoria. Unfortunately, it has not been well accepted by the heroin-dependent population. Scant research has been conducted concerning the use of adjunctive medications during opioid withdrawal.