Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium.

Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population.

[Biochemical diagnostics of fatal opium intoxication].

Biochemical diagnostics of fatal opium intoxication remains a topical problem in forensic medical science and practice. We investigated materials obtained in the course of forensic medical expertise of the cases of fatal opium intoxication. The study revealed significant differences between myoglobin levels in blood, urine, myocardium, and skeletal muscles. The proposed approach to biochemical diagnostics of fatal opium intoxication enhances the accuracy and the level of evidence of expert conclusions.

Farmacología de los opioides / Pharmacology of opioid drugs

En los últimos años se ha avanzado en el conocimiento de la farmacología de los opioides. Los opioides endógenos y exógenos se unen a receptores específicos. Existen cuatro tipos de receptores opioides; mu, kappa, delta y nociceptina. Todos ellos pertenecen a la familia de receptores de membrana acoplados a proteína G. Los opioides se clasifican según su afinidad y eficacia en agonistas puros, agonistas-antagonistas, agonistas parciales y antagonistas. Los principales efectos farmacológicos tras la administración de un agonista son sedación, euforia, analgesia, náusea y vómito, miosis, supresión de la tos, depresión respiratoria, rigidez, estreñimiento, enrojecimiento facial y prurito, retención urinaria y la posibilidad de dependencia (tolerancia y abstinencia). La tolerancia y dependencia física parecen deberse a una regulación por incremento de la adenilciclasa y aumento del AMPc. Los opioides además producen efectos duraderos que parecen relacionados con un aumento de la concentración de factores de transcripción como el CREB y ΔFosB y que son relevantes para las recaídas. Se revisan la farmacocinética de los principales opioides, las interacciones farmacológicas y su utilización en terapéutica (AU)

Endogenous and exogenous opioid bind to specific receptors. There are four different types of opioid receptors: mu, kappa, delta and nociceptin. All of them are membrane receptors coupled to protein G. Opioid drugs are classified, taking into account its affinity and efficacy for receptors, in four classes: pure agonists, agonist-antagonists, partial agonists and antagonists. The main pharmacological effects induced by agonists are sedation, euphoria, analgesia, nausea and vomiting, miosis, cough suppression, respiratory depression, truncal rigidity, constipation, face flushing and pruritus, urinary retention, and dependence (tolerance, withdrawal). The upregulation of the AMPc pathway seem responsible for tolerance and withdrawal symptoms. Opioide agonist induce long-lasting neural adaptations that are related to the synthesis of some transcription factors as CREB and ΔFosB, that seem relevant in relapse. Pharmacokinetic, drug interactions and therapeutic indications are reviewed (AU)

Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.

BACKGROUND: Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED(95). METHODS: Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus does of 0.1 or 0.2 mg x kg-1 (2 or 4 times the ED(95), respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio > or = 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite. RESULTS: The clearances (5.28 +/- 1.23 vs. 4.66 +/- 0.67 ml x min(-1) x kg(-1) and terminal elimination half-lives (22.4 +/- 2.7 vs. 25.5 +/- 4.1 min) were not statistically different between patients receiving 0.1 mg x kg(-1) and 0.2 mg x kg(-1), respectively. Maximum concentration values for laudanosine averaged 38 +/- 21 and 103 +/- 34 ng x ml(-1) for patients receiving the 0.1 and 0.2 mg x kg(-1) doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101 +/- 27 and 253 +/- 51 ng x ml(-1), respectively. Monoquaternary acid was not quantified in any plasma sample. CONCLUSIONS: Cisatracurium undergoes Hofmann elimination to form laudanosine. The pharmacokinetics of cisatracurium are independent of dose after single intravenous doses of 0.1 and 0.2 mg x kg(-1).

Pharmacokinetics of 51W89: preliminary data.

The pharmacokinetics of the 1R cis-1'R cis-isomer of atracurium (51W89) and its metabolite, laudanosine, were studied in 11 healthy patients with normal renal function and in 12 patients with chronic renal failure undergoing regular dialysis. A bolus dose of 51W89 (0.1 mg/kg) was given, and the plasma concentration was measured at regular intervals for 480 min. The elimination half-life of 51W89 was significantly longer in renal failure patients than in healthy controls (38.9 min vs 30.6 min; P < 0.05). The plasma laudanosine levels were lower than those reported after an equipotent dose of atracurium besylate. 51W89 may have a prolonged effect in renal failure patients.

Pharmacokinetics of atracurium and laudanosine in the elderly.

The pharmacokinetics of a bolus dose of atracurium 0.6 mg kg-1 and its metabolite laudanosine were studied in 11 elderly (mean age 80.9 yr) and 10 young patients (mean age 23.8 yr) undergoing elective surgery. The elimination half-life (T1/2 beta) of atracurium was significantly longer in the elderly group (23.1 v. 20.1 min), but there was no significant difference between the two groups in clearance (Cl), the volume of distribution (V beta) or the mean residence time (MRT) of atracurium. Laudanosine T1/2 beta was also significantly longer (229.1 v. 173.1 min) and the clearance significantly slower (4.85 v. 7.29 ml min-1 kg-1) in the elderly. There was, however, no significant difference in V beta for laudanosine between the two groups. These data suggest that atracurium depends to a small extent on the liver or the kidney for its metabolism and excretion, and that, as these routes of excretion are less efficient in the elderly, T1/2 beta is prolonged in this age group. The deteriorating function of these organs with increasing age may also explain the altered pharmacokinetics of laudanosine.

[Remarks on some analgesics used in the pain clinic].

The mechanism of action of aspirin as an analgesic is an inhibition of biosynthesis of prostaglandins. Thus the site of action has been believed to be peripheral. However, when aspirin is injected intra- thecally, it produces an analgesic effect. Aspirin has a membrane-stabilizing effect and it is used locally for the treatment of post- herpetic neuralgia. Epidural opioids are frequently used for the management of post-operative pain or cancer pain. Pharmacokinetic studies have shown that delayed respiratory depression results from migration of morphine in the cerebrospinal fluid to the brain. Peak concentrations of morphine near the brain stem occur about 3 hours after lumbar epidural injection, whereas lipophilic opioids such as meperidine, peak concentration occur within 30 to 60 minutes. The clearance from cerebrospinal fluid of lipophilic opioids is more rapid than that of morphine. Besides opioids, alpha 2 receptor agonists such as clonidine also have analgesic action when administered into the epidural space. Somatostatin is one of many neuropeptides found in the spinal cord. It has dual action: a mediation of thermal nociception and a general antinociceptive action. When somatostatin is administered intrathecally or epidurally, it produces analgesic effect and its efficacy appears to be equal to that of morphine.