Como a dexmedetomidina e a clonidina devem ser prescritas no ambiente de terapia intensiva? / How should dexmedetomidine and clonidine be prescribed in the critical care setting?

RESUMO O manejo cardíaco, ventilatório e renal no ambiente de terapia intensiva tem melhorado nas últimas décadas. Cognição e sedação representam dois dos últimos desafios a vencer. Como a sedação convencional não é ideal, e a sedação evocada por agonistas adrenérgicos alfa-2 (sedação "cooperativa" com dexmedetomidina, clonidina ou guanfacina) representa uma alternativa valiosa, este artigo abrange três tópicos práticos para os quais há lacunas na medicina baseada em evidência. O primeiro deles é a mudança de sedação convencional para sedação cooperativa ("mudança"): a resposta curta consiste em retirada abrupta de sedação convencional, implantação imediata de infusão de um agonista alfa-2 e uso de "sedação de resgate" (bolos de midazolam) ou "sedação agressiva" (haloperidol em bolos) para estabilizar a sedação cooperativa. O segundo tópico é a mudança de sedação convencional para sedação cooperativa em pacientes instáveis (por exemplo: delirium tremens refratário, choque séptico, síndrome do desconforto respiratório agudo etc.), pois, para evitar a hipotensão e a bradicardia provocadas por desativadores simpáticos, a resposta curta é manter o volume sistólico por administração de volume, vasopressores e inotrópicos. Por fim, para evitar essas mudanças e dificuldades associadas, os agonistas alfa-2 podem ser sedativos de primeira linha. A resposta curta é administrar agonistas alfa-2 lentamente desde a admissão ou intubação endotraqueal, até estabilização da sedação cooperativa. Dessa forma, conclui-se que os agonistas alfa-2 são, ao mesmo tempo, agentes desativadores simpáticos e sedativos, bem como a desativação simpática implica na manutenção do volume sistólico e na avaliação persistente da volemia. A medicina baseada em evidência deve documentar esta proposta.

ABSTRACT Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.

Efeitos cardiovasculares da medetomidina e cetamina em Puma concolor e tempo de recuperação após aplicação de ioimbina ou atipamezole / [Cardiovascular effects of medetomidine and cetamine in Puma concolor and recovery time after application of ioimbin or atipamezole]

O objetivo deste estudo foi avaliar as alterações cardiorrespiratórias causadas pela medetomidina associada à cetamina, e o tempo de recuperação após aplicação intramuscular de atipamezole ou ioimbina em Puma concolor. Para isso, foi realizada a aplicação de medetomidina (100µg/kg) associada à cetamina (5mg/kg) em 11 onças-pardas, sendo os parâmetros cardiorrespiratórios registrados a cada 15 minutos, durante 90 minutos de avaliação. Em seguida, a anestesia foi revertida com aplicação intramuscular de ioimbina (0,4mg/kg; n=5) ou atipamezole (0,25mg/kg; n=6), sendo analisado o tempo até a recuperação. Dos parâmetros cardiorrespiratórios avaliados, houve diferença apenas na frequência respiratória (entre os momentos 60 e 90 minutos), estando esta, todavia, dentro do intervalo de referência para a espécie. Além disso, verificou-se tempo para decúbito esternal significativamente menor nos animais do grupo atipamezole (18±7 minutos), quando comparado ao grupo ioimbina (36±17 minutos), entretanto o tempo de recuperação completa foi estatisticamente igual entre os dois reversores analisados. Assim, a associação anestésica promoveu anestesia eficiente, segura e de rápida indução em onças-pardas, permitindo a imobilização dos animais durante os 90 minutos de avaliação, sem a ocorrência de complicações. Ao se comparar a reversão anestésica com atipamezole e ioimbina, observou-se equivalência dos fármacos no tempo de recuperação completa dos animais.(AU)

The aim of this study was to evaluate the cardiorespiratory changes caused by ketamine-associated medetomidine, and the recovery time after intramuscular application of atipamezole or yohimbine in Puma concolor. For this, the application of medetomidine (100µg/kg) associated with ketamine (5mg/kg) was performed in eleven brown ounces, and the cardiorespiratory parameters were recorded every 15 minutes during 90 minutes of evaluation. Afterwards, anesthesia was reversed with intramuscular application of yohimbine (0.4mg/kg; n=5) or atipamezole (0.25mg/kg; n=6), and time to recovery was analyzed. Of the cardiorespiratory parameters evaluated, there was a difference only in respiratory rate (between 60 and 90 minutes), however, within the reference range for the species. In addition, there was a significantly shorter time for sternal decubitus in the animals of the atipamezole group (18±7 minutes) when compared to the yohimbine group (36±17 minutes), however the complete recovery time was statistically equal between the two reversers analyzed. Thus, the anesthetic association promoted efficient, safe and fast induction anesthesia in puma, allowing the animals to be immobilized during the 90 minutes of evaluation without complications. Comparing anesthetic reversal with atipamezole and yohimbine, drug equivalence was observed in the complete recovery time of the animals.(AU)

Efecto del manejo farmacológico del sistema nervioso autónomo en la pancreatitis aguda inducida por el veneno de escorpión Tityus zulianus en un modelo ex vivo / Effect of the pharmacological management of the autonomic nervous system in the acute pancreatitis induced by the venom of Tityus zulianus scorpion in an ex vivo model

La pancreatitis es una de las consecuencias principales del envenenamiento escorpiónico producido por el género Tityus. El manejo farmacológico mediante el uso de agonistas y antagonistas α adrenérgicos en modelos experimentales in vivo e in vitro, permiten establecer una aproximación del papel del Sistema Nervioso Simpático (SNS) en el desarrollo de la pancreatitis. Objetivo: determinar el papel del SNS en el desarrollo de la pancreatitis aguda inducida por el veneno de escorpión Tityus zulianus (TzV), por medio del uso de simpaticolíticos como la clonidina y el prazosin. Métodos: La Extravasación de Proteínas Plasmáticas (EPP) en el páncreas se evaluó mediante el método de Azul de Evans (AE), modificado de Saria y Lundberg (1983) a 620 nm; n=3 ratones NIH en cada grupo experimental. Las comparaciones se hicieron por ANOVA de una vía y las pruebas post HOC por Tukey-Kramer. Resultados: Ambos fármacos (1mg/Kg), disminuyeron significativamente p< 0,01 (**) la EPP en el páncreas inducida por el TzV, en comparación con los animales inoculados solo con TzV. No hubo diferencias significativas entre los animales del grupo control y los grupos tratados con los fármacos más el TzV. Conclusiones: El efecto pancreatotóxico del TzV en ratones podría tener un componente autonómico dado que drogas simpaticolíticas al disminuir la actividad noradrenérgica reducen la magnitud del edema. Esto sugiere que ambos fármacos pueden usarse como estrategia terapéutica en estos casos(AU)

Pancreatitis is one of the main consequences of scorpionic poisoning produced by the genus Tityus. The pharmacological management through the use of agonists and α adrenergic antagonists in experimental models in vivo and in vitro, allow us to establish an approximation of the role of the Sympathetic Nervous System (SNS) in the development of pancreatitis. Objective: to determine the role of SNS in the development of acute pancreatitis induced by the scorpion venom Tityus zulianus (TzV), through the use of sympatholytics such as clonidine and prazosin. Methods: Plasma Protein Extravasation (PPE) in the pancreas was evaluated by the method of Evans Blue (EA), modified by Saria and Lundberg (1983) at 620 nm; n = 3 NIH mice in each experimental group. Comparisons were made by one-way ANOVA and post-HOC tests by Tukey-Kramer. Results: Both drugs (1mg / Kg) significantly decreased p <0.01 (**) the EPP in the pancreas induced by TzV, compared to animals inoculated only with TzV. There were no significant differences between the animals in the control group and the groups treated with drugs plus TzV. Conclusions: The pancreatotoxic effect of TzV in mice could have an autonomic component since sympatholytic drugs by decreasing noradrenergic activity reduce the magnitude of edema. This suggests that both drugs can be used as a therapeutic strategy in these cases(AU)

Avaliação cardiorrespiratória e de sedação da associação de dexmedetomidina-butorfanol-midazolam ou detomidina-butorfanol-midazolam em catetos (Pecari tajacu) / Cardiorespiratory and sedation evaluation of the combination of dexmedetomidine-butorphanol-midazolam or detomidine butorphanol-midazolam in collared peccaries (Pecari tajacu)

A presente pesquisa comparou os efeitos cardiorrespiratórios, hemogasométricos e sedativos da associação midazolam (0,41mg/kg) e butorfanol (0,31mg/kg) acrescida de detomidina (157µg/kg) (DTMB) ou dexmedetomidina (36µg/kg) (DXMB) em catetos. Catetos adultos (n=20) foram distribuídos em dois grupos, DTMB ou DXMB. As variáveis (FC, f, PAM, SpO2, EtCO2 e TR) foram avaliadas após aplicação dos fármacos. A sedação foi avaliada por meio de escala analógica visual, relaxamento muscular, postura e resposta auditiva. Foi realizada ANOVA, seguida de teste t pareado (paramétricos) e teste de Mann-Whitney rank-sum test (não paramétricos), com P<0,05. Não foi observada diferença estatística entre os grupos para o período de latência. Observou-se diferença significativa entre grupos para as variáveis f, PAM e SpO2, com maiores valores para DTMB, e EtCO2, com maiores valores para DXMB. Os dois grupos apresentaram redução da FC e da concentração de lactato, bem como aumento da concentração de bicarbonato. A SpO2 permaneceu abaixo de 90%, durante todo o período experimental, nos dois grupos estudados. Os animais dos dois grupos apresentaram sedação profunda e relaxamento muscular máximo. Conclui-se que os dois protocolos testados proporcionaram adequada sedação, podendo ser indicados para contenção química de catetos adultos.(AU)

The study compared the cardiorespiratory, hemogasometric and sedative effects of the combination of midazolam (0.41mg/kg) and butorphanol (0.31mg/kg) plus detomidine (157µg/kg) (DTMB) or dexmedetomidine (36µg/kg) (DXMB) in collared peccaries. Collared peccaries (n= 20) were divided into two groups, either DTMB or DXMB. The variables (FC, f, PAM, SpO2, EtCO2 and TR) were evaluated after application of the drugs. Sedation was assessed by visual analogue scale, muscle relaxation, posture and auditory response. ANOVA followed by paired t-test (parametric) and Mann Whitney Rank Sum Test (non-parametric) with P< 0.05 were performed. No statistical difference was observed for the latency period. A significant increase was observed between groups for the variables f, PAM and SpO2 with higher values for DTMB and EtCO2 with higher values for DXMB. The two groups presented a reduction in HR and lactate concentration, and an increase in bicarbonate concentration. SpO2 remained below 90% throughout the experiment in both groups. The animals of the two groups presented deep sedation and maximum muscle relaxation. It is concluded that the two protocols tested provided adequate sedation and could be indicated for chemical containment of collared peccaries.(AU)

Custo-efetividade de mirabegrona no tratamento de primeira escolha da síndrome da bexiga hiperativa: uma análise sob a perspectiva do sistema de saúde brasileiro / Cost-effectiveness of mirabegron as first-choice treatment for overactive bladder syndrome: an analysis from the Brazilian health system perspective

Objetivo: Avaliar a relação de custo-efetividade de mirabegrona como tratamento de primeira escolha de pacientes adultos com síndrome da bexiga hiperativa (SBH) comparada a antimuscarínicos orais comumente prescritos no manejo dessa condição. Métodos: O modelo de Markov foi utilizado, com ciclos mensais e horizonte temporal de um ano, para analisar a relação de custo-efetividade de mirabegrona em comparação a tolterodina, oxibutinina, darifenacina e solifenacina. Os pacientes iniciaram o modelo em tratamento com mirabegrona ou um dos comparadores, sendo distribuídos em cinco níveis de gravidade da doença, de acordo com a frequência miccional e número de episódios de incontinência, e a cada ciclo mensal poderiam melhorar, piorar ou permanecer no mesmo nível de severidade do ciclo anterior. Os resultados foram apresentados por meio de uma razão de custo-efetividade incremental. Resultados: Considerando a perspectiva do sistema de saúde suplementar, o custo total do tratamento com mirabegrona foi de R$ 2.455,26 e os parâmetros de efetividade em 0,491 e 0,498 (melhora na gravidade da incontinência e frequência miccional, respectivamente), sendo mais efetivo que os comparadores. Com relação à perspectiva pública, foi estimado um custo com o tratamento de R$ 1.396,01, com características similares de efetividade. De maneira geral, o tratamento com mirabegrona foi dominante quando comparado à tolterodina e custo-efetivo na comparação com os demais antimuscarínicos, em ambas as perspectivas analisadas. Conclusão: Mirabegrona demonstrou ser a melhor opção para tratamento de primeira escolha da SBH com potencial de redução de custos ao longo do tempo, tanto para o sistema público quanto para o sistema de saúde suplementar brasileiro.

Objective: To assess the cost-effectiveness of mirabegron as first-choice treatment in adult patients with of overactive bladder (OAB) compared to oral antimuscarinics, usually prescribed for this condition. Methods: A Markov model has been adopted, with monthly cycles and a one-year time horizon, to analyze the cost-effectiveness of mirabegron compared to antimuscarinic agents: tolterodine; oxybutynin; darifenacin; and solifenacin. The model started with patients receiving treatment with mirabegron or one of the comparators and then, they were assigned to five disease severity levels according to micturition frequency and number of incontinence episodes, and within each monthly cycle they could improve, worsen or remain at the same symptom severity level. Results were presented using an incremental cost-effectiveness ratio. Results: Considering the Brazilian private perspective, treatment with mirabegron resulted in a total cost of R$ 2,455.26 and effectiveness parameters at 0.491 and 0.498 (improvement in incontinence severity and micturition, respectively), being more effective than the comparators. Regarding the Brazilian public perspective, treatment with mirabegron resulted in a total cost of R$ 1,396.01 with similar effectiveness estimation. In general, a dominance was observed when mirabegron was compared to tolterodine and a cost-effectiveness profile against the other muscarinic antagonists, considering both health perspectives. Conclusion: Mirabegron has proven to be the best option for OAB first-line treatment with potential cost savings over time for both the public and private health care systems in Brazil.

​Comparison of Block Characteristics and Hemodynamic Effects of Low Doses of Clonidine and Dexmedetomidine as an Adjuvant to Hyperbaric Bupivacaine for Spinal Anesthesia in Patients Undergoing Lower-limb Surgeries

Background: Various adjuvants are being used with local anesthetics for prolongation of intraoperative and post-operativeanalgesia. Among them, clonidine and dexmedetomidine are two α2-agonists which can be used as neuraxial adjuvants.Dexmedetomidine, a highly selective α2- adrenergic agonist, is a newer neuraxial adjuvant gaining popularity.Objectives: The objective of the study was to compare sensory and motor block characteristics, hemodynamic effects and sideeffects of low doses of clonidine or dexmedetomidine as an adjuvant to 12.5 mg hyperbaric bupivacaine in spinal anesthesiain lower-limb surgeries.Materials and Methods: A total of 90 patients of American Society of Anesthesiology I and II posted for lower-limbsurgeries were randomly allocated into three groups of 30 each. Group B received plain 12.5 mg of hyperbaric bupivacainediluted to 3 ml with normal saline. Group C received 30 mcg clonidine added to 12.5 mg hyperbaric bupivacaine anddiluted to 3 ml. Group D received 3 mcg dexmedetomidine added to 12.5 mg hyperbaric bupivacaine and diluted to 3 mlwith normal saline.Results: Patients in Group D and Group C had a significantly shorter onset time of sensory and motor block and significantlylonger duration of sensory and motor block compared to bupivacaine group. The mean time for sensory regression to S1 segmentwas 301.90 ± 31.96 min in Group D, 283.23 ± 13.59 min in Group C, and 181.70 ± 18.55 min in Group B (B vs. D and B vs. C,P < 0.001). There was a statistically significant difference in the two segment regression of sensory block in Group D (140.32± 17.6 min) when compared to Group C (124.5 ± 16.10 min) and Group B (92.13 ± 11.45 min). The regression of motor blockto Bromage 0 was 262 ± 24.40 min in Group D, 261 ± 24.19 min in Group C, and 164.40 ± 15.26 min in Group B (B vs. D andB vs. C, P < 0.0001). The onset and regression times were comparable between Groups D and C. Time for the first request ofrescue analgesia was nearly equal in Groups D and C and prolonged compared to Group B. Patients were hemodynamicallystable in all the groups.Conclusion: Dexmedetomidine and clonidine have a similar onset of sensory and motor block, prolonged duration of analgesia.Dexmedetomidine provides better analgesia than clonidine

Influencia adrenérgica y colinérgica sobre la producción de especies reactivas de oxígeno en neutrófilos humanos* / Adrenergic and cholinergic influence on the production of reactive oxygen species in human neutrophils*

RESUMEN Objetivos. Determinar y comparar el efecto de fármacos agonistas adrenérgicos y colinérgicos sobre la producción de especies reactivas de oxígeno (ROS) en neutrófilos de individuos sanos. Materiales y métodos. Se tomaron muestras de sangre total de cinco participantes para purificar los neutrófilos mediante el método de gelatina. Se midió la producción de ROS por quimioluminiscencia (QLM) usando un contador de centelleo y forbol-12-miristato-13-acetato (PMA) como estímulo. También se realizaron pruebas sin PMA para medir la producción espontánea. Posteriormente, con el mismo método se midió la formación de ROS en presencia de nicotina (agonista colinérgico), salbutamol y clonidina (agonistas adrenérgicos), cada uno en concentraciones de 10-2 M, 10-3 M, 10-4 M y 10-5 M. Se calculó el área integrada bajo las curvas de QLM y se halló el porcentaje de inhibición o de estimulación según sea el caso. Se comparó el efecto provocado por las drogas con sus controles correspondientes y se realizó el análisis estadístico. Resultados. Se obtuvo una disminución de la producción de ROS como efecto de las sustancias estudiadas con una diferencia significativa entre los controles y el efecto producido a 10-2 M, 10-3 M y 10-4 M. Este efecto aumentó de intensidad conforme la concentración de las drogas se incrementó. Los mayores porcentajes de inhibición se mostraron a 10-2 M y 10-3 M. Salbutamol presentó los máximos valores con todas las concentraciones con diferencia significativa entre su inhibición y la generada por las demás drogas. Conclusiones. Los estímulos adrenérgico y colinérgico tienen un efecto inhibitorio de la producción de ROS en neutrófilos de individuos sanos.

ABSTRACT Objectives. To determine and compare the effect of adrenergic and cholinergic agonist drugs on the production of reactive oxygen species (ROS) in neutrophils of healthy individuals. Materials and Methods. Whole blood samples were taken from five participants to purify neutrophils using the gelatin method. The production of chemiluminescent (QLM) ROS was measured using a scintillation counter and phorbol-12-myristat-13-acetate (PMA) as a stimulus. Non-PLA tests were also conducted to measure spontaneous production. Subsequently, with the same method, ROS formation was measured in the presence of nicotine (cholinergic agonist), salbutamol, and clonidine (adrenergic agonists), each in concentrations of 10-2 M, 10-3 M, 10-4 M, and 10-5 M. The area integrated under the QLM curves was calculated and the percentage of inhibition or stimulation was found as the case may be. The effect of the drugs was compared with their corresponding controls and statistical analysis was carried out. Results. A decrease in the production of ROS was obtained as an effect of the substances studied with a significant difference between the controls and the effect produced at 10-2 M, 10-3 M, and 10-4 M . This effect increased in intensity as drug concentration increased. The highest percentages of inhibition were shown at 10-2 M and 10-3 M. Salbutamol presented the maximum values with all the concentrations with a significant difference between its inhibition and that generated by the other drugs. Conclusions. Adrenergic and cholinergic stimuli have an inhibitory effect on the production of ROS in neutrophils of healthy individuals.

Avaliação da dexmedetomidina e do tramadol, associados ao midazolam, em gatas anestesiadas com isoflurano e submetidas à ovário-histerectomia / Evaluation of dexmedetomidine and tramadol, associated with midazolam, in cats anesthetized with isoflurane, undergoing ovariohysterectomy

Objetivou-se comparar as alterações cardiorrespiratórias e a analgesia pós-operatória promovidas pela dexmedetomidina e pelo tramadol, quando associados ao midazolam, em felinas. Para tal, foram selecionadas 18 gatas hígidas, divididas em dois grupos randomizados: GDM, tratadas com dexmedetomidina (10µg/kg) e GTM, tratadas com tramadol (2mg/kg), ambos associados a midazolam (0,2mg/kg,) IM. Após 15 minutos, procedeu-se à indução anestésica com propofol (1,46±0,79mL), mantendo-se a anestesia com isoflurano. As felinas foram submetidas à ovário-histerectomia, registrando-se as variáveis cardiorrespiratórias 15 minutos após a MPA (M0), 15 minutos após a indução (M15) e sequencialmente a cada cinco minutos, até o término do procedimento cirúrgico (M20, M25, M30, M35 e M40). A avaliação da dor iniciou-se 30 minutos após o término do procedimento cirúrgico (MP30) e sequencialmente em intervalos de 30 minutos (MP60, MP90, MP120). A partir do MP120, as avaliações foram registradas a cada hora (MP180, MP240 e MP360). A associação dexmedetomidina-midazolam infere diminuição inicial de frequência cardíaca (FC) sem significado clínico e está relacionada à sedação mais pronunciada, à analgesia menor e menos duradoura e a episódios de êmese, quando comparada à associação tramadol-midazolam. Ambos os protocolos denotaram estabilidade cardiorrespiratória e podem ser considerados seguros em felinas submetidas à ovário-histectomia.(AU)

The aim of this study was to compare cardiorespiratory changes and post-operative analgesia provided by dexmedetomidine or tramadol, associated with midazolam, in female cats. For that purpose, 18 healthy cats were assigned to two randomized groups: GDM, which received dexmedetomidine (10 µg/kg) and GTM, which received tramadol (2 mg/kg), both associated with midazolam (0.2 mg/kg) IM. After 15 minutes, anesthesia was induced with propofol (1.46±0.79 mL) and maintained with isofluorane. Ovariohysterectomy was performed and cardiorespiratory variables were registered 15 minutes after pre-anesthetic medication (M0), 15 minutes after anesthetic induction (M15), and every five minutes until the end of the surgical procedure (M20, M25, M30, M35 e M40). Pain evaluation started 30 minutes after the surgery (MP30) and sequentially at thirty-minute intervals (MP60, MP90, MP120). After MP120, each evaluation was registered at every hour (MP180, MP240 e MP360). Dexmedetomidine-midazolam association results in decreases on initial heart rate (HR) without clinical relevance and it is related to pronounced sedation, poor and less durable antinociception and vomiting events, when compared to tramadol-midazolam association. Both protocols indicate cardiorespiratoy stability and safety in cats undergoing ovariohysterectomy.(AU)

Overactive bladder - 18 years - Part II

ABSTRACT Traditionally, the treatment of overactive bladder syndrome has been based on the use of oral medications with the purpose of reestablishing the detrusor stability. The recent better understanding of the urothelial physiology fostered conceptual changes, and the oral anticholinergics – pillars of the overactive bladder pharmacotherapy – started to be not only recognized for their properties of inhibiting the detrusor contractile activity, but also their action on the bladder afference, and therefore, on the reduction of the symptoms that constitute the syndrome. Beta-adrenergic agonists, which were recently added to the list of drugs for the treatment of overactive bladder, still wait for a definitive positioning – as either a second-line therapy or an adjuvant to oral anticholinergics. Conservative treatment failure, whether due to unsatisfactory results or the presence of adverse side effects, define it as refractory overactive bladder. In this context, the intravesical injection of botulinum toxin type A emerged as an effective option for the existing gap between the primary measures and more complex procedures such as bladder augmentation. Sacral neuromodulation, described three decades ago, had its indication reinforced in this overactive bladder era. Likewise, the electric stimulation of the tibial nerve is now a minimally invasive alternative to treat those with refractory overactive bladder. The results of the systematic literature review on the oral pharmacological treatment and the treatment of refractory overactive bladder gave rise to this second part of the review article Overactive Bladder – 18 years, prepared during the 1st Latin-American Consultation on Overactive Bladder.

Overactive bladder - 18 years - Part I

ABSTRACT Abstract: Overactive bladder syndrome is one of the lower urinary tract dysfunctions with the highest number of scientific publications over the past two decades. This shows the growing interest in better understanding this syndrome, which gathers symptoms of urinary urgency and increased daytime and nighttime voiding frequency, with or without urinary incontinence and results in a negative impact on the quality of life of approximately one out of six individuals – including both genders and almost all age groups. The possibility of establishing the diagnosis just from clinical data made patients' access to specialized care easier. Physiotherapy resources have been incorporated into the urological daily practice. A number of more selective antimuscarinic drugs with consequent lower adverse event rates were released. Recently, a new class of oral drugs, beta-adrenergic agonists has become part of the armamentarium for Overactive Bladder. Botulinum toxin injections in the bladder and sacral neuromodulation are routine modalities of treatment for refractory cases. During the 1st Latin-American Consultation on Overactive Bladder, a comprehensive review of the literature related to the evolution of the concept, epidemiology, diagnosis, and management was conducted. This text corresponds to the first part of the review Overactive Bladder 18-years.

Farmacovigilancia intensiva de agonistas adrenérgicos empleados en la atención al paciente grave / Intensive pharmacovigilance of adrenergic agonists used in the severe patient care

La farmacovigilancia es una rama de la Farmacología de reciente evolución. Surge por acontecimientos desencadenados con la explosión farmacológica después de la II Guerra Mundial, que permitieron grandes avances en el tratamiento de enfermedades que antes conducían rápida e inexorablemente a la muerte o a una grave incapacidad. Objetivo: monitorear los tratamientos administrados con agonistas adrenérgicos empleados en el paciente grave. Método: se realizó un estudio de tipo observacional prospectivo en pacientes que recibieron tratamiento con agonistas adrenérgicos en la unidad de cuidados intermedios del Hospital Municipal Manuel Piti Fajardo de Florida, Camagüey; desde enero a julio de 2010. La muestra quedó constituida por 71 pacientes. Para el estudio se tuvieron en cuenta variables sociodemográficas, epidemiológicas, tipo y grado de severidad, causalidad, mecanismos de producción de las reacciones adversas medicamentosas, así como el desenlace final de las mismas. Resultados: se obtuvo más de un cincuenta por ciento de pacientes con sospechas de reacción adversa medicamentosa a predominio de aquellos en que se detectaron manifestaciones como taquicardia, palidez e hipertensión arterial entre los signos y síntomas, según el agonista adrenérgico administrado se observóefectos de (tipo A) en aquellos que adquirieron un grado de severidad moderado, clasificadas como probadas, donde el mayor por ciento de la muestra necesitó tratamiento para la resolución de los síntomas

Pharmacovigilance is a branch of Pharmacology of recent development. It arises by events triggered with the pharmacological explosion after the Second World War, which allowed great advances in the treatment of diseases which before lead to a rapid and inexorably death or a severe disability.Objective: to observe treatments administered with adrenergic agonists used in the severe patient. Methods: a prospective observational study was performed on patients who were treated with adrenergic agonists in the intermediate care unit at the Municipal Hospital Manuel "Piti" Fajardo, Florida, Camagüey; from January to July 2010. The sample was constituted by 71 patients. The study took into account sociodemographic and epidemiological variables, type and degree of severity, causation, mechanisms of production of drug adverse reactions, as well as their final outcome. Results: more than fifty percent of patients with suspicion of adverse drug reaction was obtained to predominance of those in which were detected manifestations such as tachycardia, pallor and hypertension between signs and symptoms,according to adrenergic agonist was observed (type A) effects in those who acquired a moderate degree of severity, classified as proven, where the greatest percent of the sample needed treatment to the resolutionof symptoms

Effects of insulin and β-adrenergic agonist on adiponectin secretion and expression in rats / 中华内分泌代谢杂志

Objective To explore the potential mechanisms of regulating adiponectin secretion and expression in vivo in rats.Methods To observe the regulation of adiponectin by fasing-refeeding and β-adrenergic agonists, male Wistar rats were fasted for 18 h and allowed to refeed or a β3-adrenergic receptor agonist was infused into refeeding rats.The effects of insulin clamp on adiponectin secretion and expression, including euglycemichyperinsulinemic clamp and hyperglycemic-hyperinsulinemic clamp, were also investigated.Plasma adiponectin level was determined by radioimmunoassay.Adiponectin mRNA expression in adipose tissue of rats was detected by realtime PCR.Results (1) Refeeding 18 h fasted rats increased plasma adiponectin concentration (about 2-fold) and adipose tissue adiponectin expression (about 3-fold), which were completely blocked by administration of β-adrenergic agonist.(2) Hyperinsulinemic clamp increased plasma adiponectin concentration and adiponectin gene expression in adipose tissue.Conclusions Adiponectin secretion and expression are acutely regulated in vivo by nutritional status.Insulin and β-adrenergic agonists regulate adiponectin secretion and expression in adipose tissue.

Effects of cholinergic receptor antagonists, adrenergic drugs and pethidine on the function of sphincter of Oddi isolated from rabbits / 中华消化杂志

Objective To investigate the contractive effect of atropine, noradrenaline,adrenaline and pethidine on sphincter of Oddi (SO) isolated from rabbits. Methods The rings of SO isolated from 60 rabbits were treated with Krebs solution and then were exposed to gradient atropine,anisodamin, noradrenalin, adrenaline or pethidine with 10 each. The rest 10 rings of SO treated with Krebs solution only were served as controls. The amplitude and frequency of contraction of SO were recorded. Results Compared with control group, all of the 5 medicines were able to significantly decrease the contractive amplitude, but not frequency, of SO at the concentrations ranged from 10-6 mol/L to 10-2 mol/L (P＜0.05). The inhibition order was as follows: noradrenaline ＞ adrenaline ＞atropine ＞ anisodamin ≈ pethidine. Conclusions Beside atropine and anisodamin, noradrenaline,adrenaline and pethidine also showed the direct relaxation of SO by decreasing contractive amplitude of SO. Adrenaline or noradrenaline displayed stronger effect in decreasing contractive amplitude of SO when compared with atropine or anisodamin.

Síndrome do balonamento apical secundário ao uso abusivo de descongestionante nasal / Apical ballooning syndrome secondary to nasal decongestant abuse / Síndrome del abombamiento apical secundario al uso abusivo de descongestionante nasal

Descrevemos um caso típico de síndrome do balonamento apical em uma paciente octogenária com alteração eletrocardiográfica, de contratilidade do ventrículo esquerdo, e que apresentou recuperação da função ventricular. A paciente é portadora de rinite alérgica e fez uso excessivo de descongestionante nasal horas antes do episódio da dor.

We describe a typical case of apical ballooning syndrome in an octogenarian female patient with left ventricular wall motion abnormality on electrocardiography, whose ventricular function returned to normal. The patient has allergic rhinitis and had used nasal decongestant excessively a few hours prior to the episode of pain.

Describimos un caso típico de síndrome de abombamiento apical en una paciente octogenaria con alteración electrocardiográfica, de contractilidad del ventrículo izquierdo, y que presentó recuperación de la función ventricular. La paciente es portadora de rinitis alérgica y hace uso excesivo de descongestionante nasal horas antes del episodio del dolor.

Priapismo na doença falciforme / Sickle cell priapism

Priapismo é a complicação relativamente freqüente na doença falciforme. Consiste de ereção peniana prolongada e dolorosa, não acompanhada de desejo ou estímulo sexual, usualmente persistente por mais de quatro horas. A disfunção erétil é seqüela comum no tratamento inadequado. A forma típica de priapismo nestes pacientes é a de baixo fluxo, ocorrendo, ainda, a forma de priapismo recorrente ou stuttering. O tratamento inicial para esta complicação ainda não está bem estabelecido. São propostas várias opções medicamentosas, tais como agonistas adrenérgicos, hormônios análogos à gonadotrofina, dietil-estilbestrol, hidroxiuréia entre outras. Nos casos de falha com as medidas conservadoras e medicamentosas, a intervenção cirúrgica, com confecção de shunt cavernoso, é necessária. Este estudo revisa a incidência, patogênese e opções terapêuticas desta complicação na doença falciforme.

Priapism is a common complication of sickle cell disease. It is defined as a painful and persistent penil erection not accompanied by sexual desire or stimulation, usually lasting for more than 4 hours. The typical forms of priapism in sickle cell disease are low-flow and recurrent priapism (stuttering). The first-line treatment for this complication is not totally clear. Several treatments have been proposed such as adrenergic agents, gonadotropin-releasing hormone analogues, diethylstilbestrol, hydroxyurea. If conservative treatments fail, surgical intervention is required with cavernous shunts. This study reviewed the incidence, pathogenesis and management of sickle cell priapism.

Glycogenolysis response to adrenergic agonists in the liver of rats treated with monosodium glutamate (MSG)

Administração de glutamato monossódico (MSG) em ratos neonatos causa lesão no núcleo arqueado (NA), seguido por uma síndrome de disfunção neuroendócrina caracterizada por obesidade e reduzida atividade simpática. O objetivo da presente investigação foi examinar a resposta da glicogenólise hepática a agonistas adrenérgico em ratos tratados com MSG. Ratos Wistar machos receberam injeções subcutâneas de MSG (4 mg g-1 de peso corporal) ou salina equimolar (controles) durante cinco dias após o nascimento. Noventa dias após o tratamento, os fígados de ratos-MSG ou controles foram perfundidos in situ com epinefrina e agonistas alfa- e beta-adrenérgico. Isoproterenol, fenilefrina e epinefrina aumentaram a glicogenólise em ratos-MSG, comparados aos controles (50 ± 2,8 Vs 17 ± 0,89 µmol min-1 g-1 de fígado, p < 0,0001; 64 ± 0,15 Vs 37 ± 0,39, p < 0,0001; 35 ± 2,48 Vs 27 ± 0,98, p < 0,05, respectivamente). Concluiu-se que a lesão do NA aumentou o catabolismo do glicogênio aos agonistas adrenérgicos, possivelmente devido à reduzida atividade do eixo simpático - medula adrenal.

Administration of MSG to neonate rats causes lesions in the arcuate nucleus (AN), followed by a syndrome of neuroendocrine dysfunction characterized by obesity and decreased sympathetic activity. The aim of the present investigation was to examine the responses of hepatic glycogenolysis to alpha and beta-adrenergic agonists in rats? treatment with MSG. Male Wistar rats received subcutaneous injections of MSG (4 mg g-1 body weight) or hyperosmotic saline (controls) during five days after birth. Ninety days after treatment, the livers of the MSG or controls rats were perfused in situ with epinephryne and alpha- and beta-adrenergic agonists. Epinephryne, Isoproterenol and phenylephrine increased glycogenolysis in the MSG-treated rats, compared to the controls (50 ± 2.8 Vs 17 ± 0.89 µmol min-1 g-1 of liver, p < 0.0001; 64 ± 0.15 Vs 37 ± 0.39, p < 0.0001; 35 ± 2.48 Vs 27 ± 0.98, p < 0.05, respectively). Results indicated that the lesion in the AN increased glycogen catabolism to adrenergic agonists, possibly, due to the reduced activity of the sympathetic-adrenal axis.

La testosterona inhibe las respuestas contráctiles del agonista adrenérgico alpha1, fenilefrina, asociadas con la liberación de calcio intracelular en la aorta de rata / Testosterone inhibits the contractile responses to phenylephrine associated with the release of intracellular calcium in rat aorta

Utilizando segmentos de aorta de rata sin endotelio inmersos en solución sin Ca2+, evaluamos la capacidad de la testosterona para modificar el efecto contráctil del agonista adrenérgico fenilefrina, así como el incremento en el tono de reposo (ITR) asociado con la entrada capacitativa de calcio por el sarcoplasma. La testosterona [10-5–10- 4 M] inhibió significativamente la contracción activada por la fenilefrina [10-6 M] y el ITR. Estos efectos no fueron modificados con cicloheximida [10-5 M] (inhibidor de la síntesis protéica), flutamida [10-5 M] (antagonista de receptores androgénicos), o aminoglutetimida [10-5 M] (inhibidor de la citocromo P450 aromatasa). La testosterona también inhibió las respuestas contráctiles de la serotonina [10-5 M], pero no de la cafeína [10-2 M]. Además, la testosterona inhibió las contracciones del ácido ciclopiazónico [10-6 M] y de la ryanodina [10- 5 M] asociadas con el ingreso capacitativo de Ca2+ mediante canales de Ca2+ tipo no L. Estos datos sugieren que la testosterona interfiere con la vía de transducción de los receptores acoplados a proteínas Gq- 11, e inhibe la entrada capacitativa de Ca2+ a través de canales de Ca2+ tipo L y tipo no L; los efectos son no genómicos, independientes de receptores androgénicos, y de la conversión testosterona en estrógenos.

Using endothelium-denuded rat aortic rings incubated in Ca2+ -free solution, we assessed the ability of testosterone to influence the contractile effect of phenylephrine, and the increase in resting tone (IRT) associated with Ca2+ ability to cross the plasma membrane. The addition of testosterone [10(-5)-10(-4) 5 min before phenylephrine [10(-6) M], inhibited both phenylephrine-induced contraction and IRT. These changes were not affected by cycloheximide (10(-5) M; a protein synthesis inhibitor of), flutamide (10(-5) M; an androgenic receptor antagonist), or by adding aminoglutethimide (10(-5) M; an aromatase inhibitor). Testosterone also blocked the contractile response to serotonin [10(-5) M] but not to caffeine [10(-2) M]. On the other hand, testosterone inhibited the contractile responses to cyclopiazonic acid (10(-6) M; a selective Ca2+ -ATPase inhibitor) or ryanodine (10(-5 M; an activator of sarcoplasmic reticulum Ca2+ -release channels) associated with capacitative Ca2+ influx through non-L-type Ca2+ channels. These data suggest that by acting on the cellular membrane, testosterone interferes with the signal transduction pathway of G(q-11) protein-coupled receptors, and inhibits capacitative Ca2+ influx through both L-type and non-L-type Ca2+ channels. These effects are non-genomic, non-mediated by the intracellular androgen receptor, and not due to the conversion of testosterone to estrogens.

Farmacovigilancia de los Agonistas Adrenérgicos en pacientes de la unidad de cuidados intensivos del hospital "Dr. Miguel Pérez Carreño"

Se realizó un estudio de tipo prospectivo descriptivo en 84 pacientes en quienes se determinaron las reacciones adversas (RAM´s) tras la administración IV de alguno de los siguientes agonistas adrenérgicos: noradrenalina (0,5 my/kg/min.), adrenalina (0,1my/kg/min), dopamina (3my/kg/min.) y dobutamina (5my/kg/min.). Se utilizó como instrumento de registro de las RAM´s la Hoja Amarilla de CEVIFARE. Se procedió a la identificación de las RAM´s por su tipo, severidad y causalidad. El 83,33% de los pacientes presentaron RAM´s, siendo las más frecuentes: taquicardia (47,61%), palidez (23,80%), hipertensión (11,90%) y arritmias (7,14%). Todas las RAM´s fueron del tipo A, el 50% leves, 40% moderadas y 10% graves. El 100% de las RAM´s analizadas fueron probadas. Aunque los agonistas adrenérgicos estudiados resultaron ser seguros, la adrenalina tiene el riesgo de producir necrosis tisular distal, por lo cual el papel de la Enfermera(o) que practica la farmacovigilancia es prevenir o disminuir la posibilidad de aparición de RAM´s en los pacientes a su cuidado.

A descriptive study was made in 84 patients to determined adverse drugs reactions (DAR) during the IV treatment with some of the following adrenergic agonists: norepinephrine (0,5mu/kg/min), epinephrine (0.1mu/kg/min), dopamine (3mu/kg/min.) and dobutamine (5mu/kg/min). The Yellow Card of CEVIFARE was used as the instrument for registry of the DAR. DAR were analyzed by its type, severity and causality. 83.33% of the patients had DAR, being most frequent: tachycardia (47,61%), pallor (23,80%), hypertension (11,90%) and arrhythmias (7,14%). All the DAR were type A, mild 50%, moderate 40% and serious 10%. 100% of DAR analyzed were proved. Although the adrenergic agonists turned out to be safe, the epinephrine has the risk of producing distal necrosis, thus the Nursing role in practicing pharmacovigilance is to prevent or to diminish the possibility of appearance of DAR in the patients under her care.

Acute Pulmonary Edema Occurred During the Cesarean Section in a Patient with Ritodrine Pretreatment: A case report / 대한마취과학회지

The mechanism of development of pulmonary edema associated with -sympathomimetic agent is still not fully understood. 2-sympathomimetic drugs such as ritodrine, terbutaline, and fenoterol are widely used for the treatment of premature uterine contraction. We describe a case of pulmonary edema that occurred suddenly during Cesarean section in a previously healthy parturient, associated with ritodrine pretreatment for 5 days in an attempt to arrest preterm labor. Pulmonary edema was completely treated with mechanical ventilation and diuretic therapy.

Effects of Phenylephrine Induced Hypertension on the Cerebral Hemodynamics in Dogs / 대한마취과학회지

BACKGROUND: Induced hypertension has long been considered a potential adjunct to the management of focal cerebral ischemia. Whether induced hypertension causes an increase in cerebral blood flow(CBF), dependent on cerebral perfusion and/or an intracerebral redistribution of CBF by a vasoconstrictive effect of vasoconstrictor is controversial. In this study, effect of phenylephrine induced hypertension on the cerebral hemodynamics and mechanism of reduced ischemic area were studied. METHODS: Six mongrel dogs weighing between 13 and 18 kg were anesthetized with halothane 0.5 vo1%-N2O 1 L/min-O2 1 L/min. Ventilation was controlled to maintain PaCO2 within 35~40 mmHg. Cerebral blood flow was measured and calculated by the posterior sagittal sinus outflow method. Cerebral metabolic rate for oxygen(CMRO2) was calculated. Intracranial pressure(ICP) was also measured. Phenylephrine was infused to increase mean arterial blood pressure(MAP) to a level 30% above baseline value and MAP was held constant for 20 minutes before CBF, ICP, CMRO2 determination. These parameters were measured at 10, 20 minutes after induced hypertension. RESULTS: Induced hypertension resulted in increased MAP and decreased heart rate. There were no differences between baseline, hypertension 10 min, and hypertension 20 min in terms of PaCO2, PaO2, hematocrit and temperature. CBF was not changed after induced hypertension(39.1+/-9.7 vs 40+/-10 vs 40.2+/-10.1 ml 100g(-1) min(-1) (meanv+/-SD) at baseline, hypertension 10 min, hypertension 20 min, respectively). Cerebral metabolic rate was not changed also after induced hypertension. ICP increased after induced hypertension significantly(20.5+/-12.5 vs 26+/-15.3 vs 29.8+/-17 mmHg at baseline, hypertension 10 min, 20 min, respectively). CONCLUSIONS: Phenylephrine is a cerebral vasoconstrictor and that causes redistribution of cerebral blood flow to ischemic brain area.