Atsuko Kobayashi

Clinical Pharmacokinetics and Pharmacodynamics of Glyceryl Trinitrate and its Metabolites

This review discusses the pharmacokinetics and pharmacodynamics of glyceryl trinitrate (nitroglycerin; GTN) pertinent to clinical medicine. The pharmacokinetics of GTN associated with various dose regimens are characterised by prominent intra- and inter-individual variability. It is, nevertheless, important to clearly understand the pharmacokinetics and characteristics of GTN to optimise its use in clinical practice and, in particular, to obviate the development of tolerance.Measurements of plasma concentrations of GTN and of 1,2-glyceryl dinitrate (1,2-GDN), 1,3-glyceryl dinitrate (1,3-GDN), 1-glyceryl mononitrate (1-GMN), and 2-glyceryl mononitrate (2-GMN), its four main metabolites, remain difficult and require meticulous techniques to obtain reliable results. Since GDNs have an effect on haemodynamic function, pharmacokinetic analyses that include the parent drug as well as the metabolites are important.Although the precise mechanisms of GTN metabolism have not been elucidated, two main pathways have been proposed for its biotransformation. The first is a mechanism-based biotransformation pathway that produces nitric oxide (NO) and contributes directly to vasodilation. The second is a clearance-based biotransformation or detoxification pathway that produces inorganic nitrite anions (NO2-). NO2- has no apparent cardiovascular effect and is not converted to NO in pharmacologically relevant concentrations in vivo.In addition, several non-enzymatic and enzymatic systems are capable of metabolising GTN.This complex metabolism complicates considerably the evaluation of the pharmacokinetics and pharmacodynamics of GTN. Regardless of the route of administration, concentrations of the metabolites exceed those of the parent compound by several orders of magnitude. During continuous steady-state delivery of GTN, for instance by a patch, concentrations of 1,2-GDN are consistently 2–7 times higher than those of 1,3-GDN, and concentrations of 2-GMN are 4–8 times higher than those of 1-GMN. Concentrations of GDNs are approximately 10 times higher, and of GMNs approximately 100 times higher, than those of GTN during sustained administration.The development of tolerance is closely related to the metabolism of GTN, and can be broadly categorised as haemodynamic tolerance versus vascular tolerance. Efforts are warranted to circumvent the development of tolerance and facilitate the use of GTN in clinical practice. Although this remains to be accomplished, it is likely that, in the near future, regimens will be developed based on a full understanding of the pharmacokinetics and pharmacodynamics of GTN and its metabolites.

Elevated expression of inducible nitric oxide synthase and inflammatory cytokines in the alveolar macrophages after esophagectomy.

Objective To evaluate the role of inducible nitric oxide (NO) synthase (iNOS) and inflammatory cytokines in alveolar macrophages (AMs) after esophagectomy in the pathogenesis of acute lung injury. Design Prospective, exploratory, open-labeled clinical study. Setting Intensive care unit and operating room in a university hospital. Patients Thirteen patients receiving esophagectomy with carcinoma of the esophagus (postesophagectomy group), ten patients just before the surgery (preoperation group), and seven patients receiving surgery less invasive than esophagectomy (other surgery group) were selected. Interventions Bronchoalveolar lavage fluid (BALF) and blood samples were obtained from study groups. Measurements and Main Results The AMs in the BALF collected from each group were stained immunohistochemically with antibodies against iNOS, interleukin (IL)-6, and IL-8. The intensities of these expressions were determined by semiquantitative cytofluorometric system. NOx (NO2−+NO3−), IL-6, and IL-8 levels in the BALF and plasma were measured concurrently. The expressional intensities of iNOS, IL-6, and IL-8 in AMs obtained from the postesophagectomy group were maximal 24 hrs after the skin incision and significantly more evident than those from other groups. The IL-6, IL-8, and NOx levels in BALF and IL-6 and IL-8 levels in plasma in the postesophagectomy patients were also elevated. The intensities of iNOS and inflammatory cytokines expressions in AMs were closely related to postoperative respiratory failure. Conclusions The activation of topical alveolar macrophages may be involved in the pathogenesis of pulmonary complications in the postoperative period after esophagectomy.

Autonomic hyperreflexia during labour

We present two cases of automatic hyperreflexia (AH) during labour in women with spinal cord damage, in whom AH developed before and after delivery. The AH was successfully controlled using epidural anaesthesia in Case #1, but failed in Case #2. The blood pressure was controlled with nicardipine. However, overdose of nicardipine produces vasodilatation and its side effects include headache, flushing and palpitation similar to AH1. Considering these effects, we recommend epidural anaesthesia to control AH, because epidural anaesthesia does not only reduce BP, but also blocks the noxious stimuli and relieves the symptoms of AH. Our experience suggests that the epidural catheter can be placed two to three weeks before the date of predicted childbirth, because the onset of labour in a patient with spinal cord damage is difficult to predict and can proceed very rapidly. Also, the epidural catheter is available after the delivery. We recommended the epidural catheter is maintained for 24–48 hr postpartum.RésuméLes auteurs présentent deux cas d’hyperréflexie autonome (HA) survenue pendant le travail de parturientes souffrant de lésion de la moelle épinière. Dans un cas, l’HA est apparue avant l’accouchement, et dans l’autre, après l’accouchement. Dans le premier cas, l’HA a été contrôlée efficacement avec une anesthésie épidurale. Dans le deuxième, on a réussi à contrôler la pression artérielle (PA) avec de la nicardipine. Cependant, une surdose de nicardipine a produit, comme il survient au cours de l’HA, une vasodilatation et des effets secondaires dont de la céphalée, des rougeurs et des palpitations. A cause des effets secondaires de la nicardipine, les auteurs recommandent l’anesthésie épidurale pour le contrôle de l’HA, parce que l’anesthésie épidurale ne contrôle pas seulement la PA, mais bloque aussi les stimuli nocifs et atténue les symptômes de l’HA. Les auteurs suggèrent d’insérer le cathéter épidural deux ou trois semaines avant la date prédite de l’accouchement, parce que le début du travail est difficile à prédire chez les patientes qui souffrent d’une lésion de la moelle épinière et parce qu’il peut se dérouler très rapidement. De plus le cathéter épidural reste disponible après l’accouchement. Les auteurs recommandent le maintien du cathéter pendant les 24 à 48 heures du postpartum.

Severe Legionella pneumophila pneumonia associated with the public bath on a cruise ship in Japan

SpO2 was 80% (ambient air) on admission, he was transferred to the intensive care unit (ICU). Because of his progressive respiratory failure, tracheal intubation and mechanical ventilation was needed, with continuous intravenous administration of propofol. Arterial gas analysis with ventilatory support (FIO2 1.0; PEEP, 5cmH2O; SIMV 18min 1) showed pH 7.48, PaO2 66mmHg, and PaCO2 55mmHg. A chest radiograph revealed bilateral diffuse pneumonia with existing emphysema. A computed tomogram (CT) of the chest revealed multiple areas of infiltration. Laboratory examination showed a leukocyte count of 16500/mm3; C-reactive protein (CRP) level was 36.4mg/dl and total bilirubin level was 2.6 mg/dl. The administration of panapenem (1g/day i.v.) was started. On hospital day 1, we obtained a specimen for determination of the causative microorganism by bronchoendscopy, but culture of the aspirated fluid showed no significant growth of organisms. Based on this finding, with the characteristics of the chest radiograph, we suspected interstitial pneumonia, and methylrednislone (1g/day) was given for 3 days. In spite of the treatment, the infiltrative shadow grew, and the patient’s oxygenation remained unimproved. His condition continued to deteriorate, with ongoing multiple organ failure (MOF) and refractory hypotension. On hospital day 4, Legionella pneumophila was isolated from culture of the sputum on buffered charcoal yeast extract with alpha-ketoglutarate (BCYE-α) agar plates. Culture of bronchial lavage was positive for L. pneumophila serogroup 5. After confirmation of these colonies, the antibiotic administration was switched to erythromycin (2000mg/day i.v.), ciprofloxacin (400mg/day i.v.), and rifampicin (450mg/day p.o.) in combination. Specific urinary antigen detection of L. pneumophila was later reported to be positive (Binax, Portland, ME, USA). His condition was ameliorated dramatically after the changing of antibiotics. Arterial gas analysis with ventilatory support (FIO2, 0.4; CPAP

Effects of prostaglandin E1 on renal hemodynamics

The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and the ratio of mean arterial pressure (MAP) to RBF (MAP/RBF), reflecting renal vascular resistance (RVR) were determined to investigate the effects of intravenously administered prostaglandin E1 (PGE1) on renal hemodynamics in humans. PGE1 produced no significant changes in GFR, but did cause significant increases in RPF and RBF and significant decreases in FF and MAP/RBF. The relationships between MAP and GFR, MAP and RBF, and MAP and MAP/RBF were investigated. PGE1 suppressed the increase of MAP/RBF along with the increase of MAP, increased the RBF along with the increase of MAP, and kept the GFR constant, regardless of MAP. Also, the effects of PGE1 on renal pericapillary vessels were simulated. According to this simulation, PGE1 had a vasodilator action on both preglomerular and postglomerular capillaries.

Recurrence of asthma after removal of adrenaline secreting pheochromocytoma.

Only four cases of asthma attack after adrenalectomy in pheochromocytoma have been reported l 4 • The combination of pheochromocytoma and asthma troubles anesthesiologists, since therapy for either disease can have a detrimental effect on the other. We report our experience of an asthmatic patient with adrenaline secreting pheochoromocytoma and discuss the choice of drug in such cases.

Pulmonary edema induced by laryngospasm

A 63-year-old female, weight 62 kg and height 143 em, was scheduled for a radical operation to correct an umbilical hernia. No respiratory or circulatory abnormalities were noted. The preoperative chest X-ray was clear and the electrocardiogram was normal. Serum protein was 5.9 g-dl~l and serum albumin 3.2 g-dl1 • Other laboratory findings were normal. The patient was premedicated with atropine 0.5 mg, hydroxyzine 50 mg, and ranitidine 50 mg given intramuscularly 1 hour before the operation. Anesthe-