Epinephrine, auto-injectors, and anaphylaxis: Challenges of dose, depth, and device.

OBJECTIVE: This review was undertaken to review epinephrine dosing, site and route of administration, focusing on special populations (patients weighing less than 15 kg, and obese patients); and to discuss storage and delivery of epinephrine in prehospital and hospital settings. DATA SOURCES: Review of published literature. STUDY SELECTION: Relevance. RESULTS: The recommended 0.01-mg/kg (maximum 0.3-0.5 mg) epinephrine dose in anaphylaxis is based on limited pharmacokinetic data in healthy volunteers. No pharmacokinetic or pharmacodynamics studies involving patients in anaphylaxis have been published. When epinephrine auto-injectors (EAIs) are used in infants, the dose increasingly exceeds the recommended dose as weight decreases, although the clinical significance of this is unclear. Limited data indicate that the intramuscular route and lateral thigh site are superior. Ultrasound studies suggest that 0.15 EAI needles may be too long for many patients weighing less than 15 kg, and 0.3 mg EAI needles may be too short for obese patients weighing more than 30 kg. A newly available 0.1 mg EAI has a lower dose and shorter needle better suited to patients weighing 7.5 to 15 kg. In some medical settings, vials and syringes may provide a safe, efficient alternative with substantial cost savings over EAIs. CONCLUSION: EAIs should be available in the community with doses and needle depths that meet the needs of all patients. More research on epinephrine pharmacodynamics are needed in children and adults in anaphylaxis, to better delineate what optimal doses should be. Optimizing epinephrine dose and delivery has the potential to improve anaphylaxis outcomes and prevent adverse events.

Mirabegron: ß3-adrenergic receptor agonist for the treatment of overactive bladder.

OBJECTIVE: To review the place in therapy of mirabegron, a new oral ß3-adrenergic receptor agonist, for the treatment of overactive bladder (OAB). DATA SOURCES: A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-April 2013) was conducted using the key words mirabegron, receptor, adrenergic, beta-3; adrenergic beta-3 receptor; beta-3 receptor, and overactive bladder; urinary bladder; overactive. All published articles regarding mirabegron were included. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. STUDY SELECTION AND DATA EXTRACTION: Available English-language data from reviews, abstracts, presentations, and clinical trials of mirabegron in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: Mirabegron is the newest option for treatment of OAB with symptoms of urge incontinence. As a ß3-receptor agonist, it reduces bladder muscle contractions. In two 12-week, randomized, double-blind, placebo-controlled Phase 3 studies, mirabegron significantly reduced the number of incontinence episodes per 24 hours from baseline (-1.47, -1.63, and -1.13; p < 0.05; and -1.57, -1.46, and -1.17; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). Micturitions per 24 hours were also reduced from baseline (-1.66, -1.75, and -1.05; p < 0.05; and -1.93, -1.77, and -1.34; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). A 12-month trial found mirabegron to have a safety and efficacy profile similar to that of tolterodine. CONCLUSIONS: Treatment of OAB initially includes lifestyle and nonpharmacologic intervention; for patients with persistent symptoms despite these treatments, drug therapy represents a next-step approach for symptom control. Mirabegron alleviates symptoms of OAB while having a mechanism of action that provides an alternative for patients who are intolerant of or who have contraindications to anticholinergic agents. The place in therapy of mirabegron relative to anticholinergics in the treatment of urge incontinence has not yet been established.

Pharmacokinetics and pharmacodynamics of moist inhalation epinephrine using a mobile inhaler.

BACKGROUND: Intramuscular (L-)epinephrine is used as self-medication for serious hypersensitivity reactions. Inhalative administration has the theoretical advantage of a more rapid absorption and better controllability. OBJECTIVES: The current trial was conducted to explore pharmacokinetics and pharmacodynamics of two nebulized inhalative epinephrine doses (4 mg and 8 mg in aqueous solution) using a mobile pocket inhaler relative to intramuscular administration (0.3 mg) and placebo. METHODS: This randomized, open-label, change-over pilot study involved eight young healthy men and women. Noncompartmental pharmacokinetic and pharmacodynamic parameters were calculated from epinephrine plasma concentrations and hemodynamic parameters. RESULTS: Mean exposure to epinephrine decreased from the 8 mg dose to the 4 mg inhalative dose, and further with the 0.3 mg intramuscular dose, with active treatments showing significantly higher concentrations than placebo (geometric mean area under the curve AUC0-t(last) values: 282, 236, 204 and 81.6 hr*ng/L). Maximal concentrations were reached within approximately 15 min for all active treatments. Epinephrine effects for inhalative administrations on heart rates were significantly higher than those for the intramuscular or placebo administration, while no excessive effects occurred. Pronounced overall variability prohibited a definite assessment of relative bioavailability between treatments. However, results indicated that epinephrine concentrations obtained following the 8 mg inhalative dose were not inferior to those after 0.3 mg i.m. CONCLUSIONS: A relevant fraction of moist inhalation epinephrine doses is absorbed and mediates systemic effects. This suggests that administration of epinephrine via a suitable pocket inhaler device may be beneficial in ambulatory emergency treatment of systemic hypersensitivity reactions. EudraCT number: 2010-021493-11.

Drug infusion system manifold dead-volume impacts the delivery response time to changes in infused medication doses in vitro and also in vivo in anesthetized swine.

BACKGROUND: IV infusion systems can be configured with manifolds connecting multiple drug infusion lines to transcutaneous catheters. Prior in vitro studies suggest that there may be significant lag times for drug delivery to reflect changes in infusion rates set at the pump, especially with low drug and carrier flows and larger infusion system dead-volumes. Drug manifolds allow multiple infusions to connect to a single catheter port but add dead-volume. We hypothesized that the time course of physiological responses to drug infusion in vivo reflects the impact of dead-volume on drug delivery. METHODS: The kinetic response to starting and stopping epinephrine infusion ([3 mL/h] with constant carrier flow [10 mL/h]) was compared for high- and low-dead-volume manifolds in vitro and in vivo. A manifold consisting of 4 sequential stopcocks with drug entering at the most upstream port was contrasted with a novel design comprising a tube with separate coaxial channels meeting at the downstream connector to the catheter, which virtually eliminates the manifold contribution to the dead-volume. The time to 50% (T50) and 90% (T90) increase or decrease in drug delivery in vitro or contractile response in a swine model in vivo were calculated for initiation and cessation of drug infusion. RESULTS: The time to steady state after initiation and cessation of drug infusion both in vitro and in vivo was much less with the coaxial low-dead-volume manifold than with the high-volume design. Drug delivery after initiation in vitro reached 50% and 90% of steady state in 1.4 ± 0.12 and 2.2 ± 0.42 minutes with the low-dead-volume manifold and in 7.1 ± 0.58 and 9.8 ± 1.6 minutes with the high-dead-volume manifold, respectively. The contractility in vivo reached 50% and 90% of the full response after drug initiation in 4.3 ± 1.3 and 9.9 ± 3.9 minutes with the low-dead-volume manifold and 11 ± 1.2 and 17 ± 2.6 minutes with the high-dead-volume manifold, respectively. Drug delivery in vitro decreased by 50% and 90% after drug cessation in 1.9 ± 0.17 and 3.5 ± 0.61 minutes with the low-dead-volume manifold and 10.0 ± 1.0 and 17.0 ± 2.8 minutes with the high-dead-volume manifold, respectively. The contractility in vivo decreased by 50% and 90% with drug cessation in 4.1 ± 1.1 and 14 ± 5.2 with the low-dead-volume manifold and 12 ± 2.7 and 23 ± 5.6 minutes with the high-dead-volume manifold, respectively. CONCLUSIONS: The architecture of the manifold impacts the in vivo biologic response, and the drug delivery rate, to changes in drug infusion rate set at the pump.

Sex differences in the systemic response to adrenoreceptor antagonists during sympathetic activation.

BACKGROUND: Sex differences in sensitivity to adrenergic agonists have been described in forearm plethysmography studies. The attenuation in noradrenaline-mediated vasoconstriction is because of enhanced ß(2)-adrenergic stimulation in women. The systemic relevance of these observations is unknown. The aim of this study was to determine sex inequalities in the systemic haemodynamic response to sympathetic activation by isometric forearm contraction in the presence of adrenoreceptor blockade. MATERIALS AND METHODS: Isometric forearm contraction was performed in the presence of isotonic saline, esmolol and phentolamine, respectively, in six men and six premenopausal women. RESULTS: Isometric forearm contraction increased heart rate by 9·5% ± 4·8 CI(95%), P = 0·00001 in both sexes. Mean arterial pressure was also increased in both sexes 13·9% ± 3·2 CI(95%), P = 0·002. Esmolol attenuated the rise in mean arterial pressure in men (5·9% ± 3·6 CI(95%), P = 0·6) but not in women (14·3% ± 3·2 CI(95%), P = 0·007). CONCLUSIONS: This study supports previous findings of sex differences in adrenergic responsiveness and suggests that its consequences are systemically relevant.

Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.

Neuroprotective effects of alpha2-adrenergic receptor agonists.

Alpha2-adrenergic receptor agonists exert potent analgesic and sedative/hypnotic effects. In addition, they have been shown to be neuroprotective in various experimental models, but the molecular pathways leading to these actions are still poorly defined. This review summarizes the available literature and discusses potential mechanisms of alpha2-adrenergic receptor agonist mediated neuroprotection.

Recent developments in the design of orally bioavailable beta3-adrenergic receptor agonists.

The beta3-adrenergic receptor (beta3-AR) has been shown to mediate various pharmacological and physiological effects such as lipolysis, thermogenesis, and relaxation of the urinary bladder. Activation of the beta3-AR is thought to be a possible approach for the treatment of obesity, type 2 diabetes mellitus, and frequent urination. Therefore, the beta3-AR is recognized as an attractive target for drug discovery. On the other hand, activation of the beta1- or beta2-AR can cause undesirable side effects such as increased heart rate or muscle tremors. Consequently, a number of recent efforts in this field have been directed toward the design of selective agonists for the beta3-AR. This review summarizes recent advances in beta3-AR agonists with an emphasis on recent attempts to create potent, selective and orally bioavailable small-molecule agonists.

Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler.

Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown.

Indomethacin and epinephrine effects on outflow facility and cyclic adenosine monophosphate formation in monkeys.

PURPOSE: To investigate the effect of indomethacin inhibition of prostanoid production on the epinephrine-stimulated increase in outflow facility and cyclic adenosine monophosphate (cAMP) production in the anterior segment of the monkey eye. METHODS: Topical indomethacin was given 1 hour before the intracameral administration of epinephrine to living cynomolgus monkeys. Outflow facility was measured for 45 to 60 minutes, beginning 3 hours after epinephrine administration, by two-level constant pressure perfusion of the anterior chamber. Cyclic adenosine monophosphate formation was measured in cell membranes isolated from rhesus monkey ciliary muscle, ciliary processes, trabecular meshwork, and iris in the presence of forskolin, indomethacin, epinephrine, or indomethacin and epinephrine combined. RESULTS: Three hours after the intracameral administration of 5.5 micrograms epinephrine, facility increased by approximately 40%, a putatively maximal response, at which time the intracameral epinephrine concentration was approximately 15 microM. Pretreatment with topical indomethacin produced a dose-dependent inhibition of epinephrine's facility-increasing effect; the maximum inhibition of 50% to 70% occurred at an indomethacin dose of 50 to 125 micrograms. Doubling the indomethacin dose (250 micrograms) produced no further inhibition, whereas a fivefold larger epinephrine dose (27.5 micrograms) did not overcome the inhibition. Forskolin and epinephrine both stimulated cAMP production in vitro, whereas [indomethacin] > or = 10(-4) M partially inhibited both basal and epinephrine-stimulated cAMP production in all four tissues. CONCLUSIONS: Approximately half of the epinephrine-induced facility increase is inhibited by indomethacin, but it is unclear whether the indomethacin-inhibitable fraction is mediated by epinephrine-stimulated prostanoid production or release.

[Pharmacology in critical illness]. / Farmacologie bij kritieke ziektetoestanden.

Patients suffering from critical illnesses like cardiac arrest with resuscitation and hypovolemic shock often are in need of medication. Under these conditions pharmacokinetics and pharmacodynamics can be markedly altered. In this paper the results of our experimental work in animals on the pharmacology during resuscitation and hypovolemia is discussed. The data show that during cardiopulmonary resuscitation in the dog the kinetics of epinephrine are changed. The administration of the calcium antagonist nimodipine does not result in a cerebroprotective action in a cardiopulmonary arrest model in the rat. The pharmacokinetics and pharmacodynamics of the anesthetics etomidate and propofol were studied in a model of hemorrhagic hypovolemia in the rat. Changes in plasma concentrations as well as in brain sensitivity occur. It is concluded that animal experiments highlight changes in the action of drugs during critical conditions. Such information can be helpful in view of the practical and ethical problems related to the study of the action of drugs in critically ill patients.

The effects of aging on anesthetic pharmacology.

Aging alters both the pharmacokinetic and the pharmacodynamic aspects of anesthetic requirement. Studies of the relationship between drug concentration and effect in older adults clearly demonstrate a decline in median effective dose requirement for agents that act within the central nervous system, but there appears to be little change in the dose required for peripheral effects such as neuromuscular blockade. Most drugs also undergo somewhat slower biotransformation and demonstrate prolonged clinical effects if they require hepatic or renal degradation, although many newer agents such as remifentanil and cisatracurium have organ-independent pathways that are not affected by age. In some cases, however, the appearance of increased sensitivity to a given dose of anesthetic or opiate may actually reflect higher-than expected plasma concentrations of drug following a rapid intravenous injection. Therefore, it is impossible to completely separate the interactions between pharmacodynamic and pharmacokinetic factors associated with aging. The use of pharmacological sympathectomy with intrathecal agents and with sympatholytic adrenergic agonists may further improve outcome in a patient population at high risk because of reduced functional reserve, increased incidence of polypharmacy, and the consequences of age-related disease.

[Dopexamine: a new dopaminergic agonist]. / La dopexamine: un nouvel agoniste dopaminergique.

Dopexamine hydrochloride is a new synthetic catecholamine for intravenous use in low cardiac output states with co-existing raised systemic or pulmonary vascular resistance. Dopamine has been commonly used since several years in these situations. The drawbacks of dopamine include a vasoconstrictive effect with high infusion rates, and a marked tendency for ventricular ectopy due to the potent beta-1 adrenergic stimulation. Dopexamine hydrochloride has interesting vasodilator properties, with marked intrinsic agonist activity at beta-2 adrenoreceptors and a lesser agonist activity at dopaminergic receptors (DA1 and DA2). Its mild inotropic activity arises primarily from baroreceptor reflex stimulation with a possible contribution from direct stimulation of myocardial beta 2-adrenoreceptors. Dopexamine hydrochloride is responsible for an inhibition of neuronal re-uptake of catecholamines (uptake-1), producing an indirect stimulation of cardiac beta 1-receptors. This catecholamine has no effect at alpha 1 and alpha 2-adrenoreceptors, and only very weak and clinically insignificant beta 1-adrenoreceptor agonist activity. Dopexamine hydrochloride improves cardiac performance by a marked vasodilation and a mild inotropic activity. The specific activity at dopaminergic receptors increases cerebral, myocardial, splanchnic and renal blood flows. These haemodynamic effects are associated with an increase in diuresis and natriuresis. These benefits are achieved without side effects such as an increased myocardial oxygen consumption, although induced tachycardia may be responsible for chest pain/anginae pain in patients with ischaemic heart disease. In clinical practice, dopexamine hydrochloride is easy to use; the short plasma half-life (6 minutes in healthy volunteers and 11 minutes in patients with low cardiac output) allows a rapid return to pretreatment status at discontinuation of the infusion. Preliminary studies have shown that dopexamine hydrochloride can produce beneficial effects in patients with acute heart failure or with compromised left ventricular function following cardiac surgery. The drug has also been assessed in patients with septic shock, most often in association with dopamine or norepinephrine. In these patients, dopexamine produces a dose-related increase in cardiac index, stroke volume, heart rate and a decrease in systemic vascular resistance. Its use in this indication must be cautious, particularly in patients with hypotension or decreased venous return. Comparative therapeutic trials are clearly required to establish the efficiency and tolerance of dopexamine hydrochloride in comparison with dopamine and dobutamine, before its place in therapy can fully be defined.

Uso de asenapina en la práctica clínica: recomendaciones de un panel de expertos / Management of asenapine treatment in clinical practice: Recommendations from a panel of experts

Introducción: La selección del antipsicótico adecuado para el tratamiento de pacientes con trastorno bipolar (TB) debe basarse en los síntomas presentes, así como en las necesidades terapéuticas de cada paciente y en los posibles efectos adversos asociados al tratamiento. Asenapina es un antipsicótico de segunda generación indicado para el tratamiento de pacientes con TB de tipoI, cuyo perfil farmacocinético y farmacodinámico presenta características diferenciales con respecto al resto de antipsicóticos. Material y métodos: Este documento de recomendaciones ha sido elaborado por un panel de expertos con experiencia en el uso de asenapina en los ámbitos de la atención psiquiátrica de urgencias, hospitalaria y ambulatoria. Las recomendaciones se debatieron en una única reunión y fueron elaboradas a partir de la práctica clínica de los expertos y la evidencia proporcionada por la literatura científica. Resultados: Se describe el perfil de pacientes que mejor se ajusta a las características farmacodinámicas de asenapina, así como las ventajas y limitaciones del perfil farmacocinético asociado a la administración sublingual. Se abordan también las principales características de seguridad de asenapina, así como las posibles medidas a tomar para mitigar los efectos adversos más frecuentes. Finalmente, el documento proporciona una orientación acerca de la dosificación y el manejo general del fármaco, incluyendo las combinaciones con otros fármacos y el cambio de otros antipsicóticos a asenapina. Conclusiones: Este artículo proporciona una orientación para el uso adecuado de asenapina, así como para la identificación de los pacientes en los que este antipsicótico puede resultar más adecuado

Introduction: The choice of an antipsychotic should be based on bipolar disorder (BD) symptoms and the particular needs of each patient, as well as the adverse events potentially associated with treatment. Asenapine is an atypical antipsychotic indicated for the management of type-I BD, with distinct pharmacokinetic and receptor affinity profiles. Material and methods: Recommendations document developed by a panel of experts with extensive experience in the use of asenapine in psychiatric care, including emergency department, hospital, and outpatient care. Recommendations were discussed in a single meeting and were based on both the clinical experience of the panel of experts and the empirical evidence provided in the scientific literature. Results: The present document describes the patient profile that best suits the pharmacodynamic characteristics of asenapine, as well as the advantages and limitations of the pharmacokinetics associated with the sublingual route. The document also addresses the main safety issues of asenapine and suggests interventions aimed at mitigating the most frequent adverse reactions associated with asenapine treatment. Finally, the article provides advice on dosing and overall management of asenapine treatment, including the combination with other treatments and the switch from other antipsychotics to asenapine. Conclusions: In this recommendations document, we provide clinicians with guidance on the use of asenapine in real-life practice, including the identification of patients who best suit the characteristics of this antipsychotic

Pharmacokinetics of mirabegron, a ß3-adrenoceptor agonist for treatment of overactive bladder, in healthy Japanese male subjects: results from single- and multiple-dose studies.

BACKGROUND: Mirabegron is a human ß3-adrenoceptor agonist for the treatment of overactive bladder. The pharmacokinetic profile of mirabegron has been extensively characterized in healthy Caucasian subjects. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron following single and multiple oral doses in healthy Japanese male subjects. The results were compared with those reported in non-Japanese (primarily Caucasian) subjects. METHODS: Two studies were conducted. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study (Study 1), mirabegron oral controlled absorption system (OCAS) tablets were administered at single doses of 50, 100, 200, 300, and 400 mg, with eight subjects (six active, two placebo) per dose group (Part I), and once daily for 7 days at 100 and 200 mg with 12 subjects (eight active, four placebo) per group (Part II). In an open-label, three-period, single-ascending dose study (Study 2), mirabegron OCAS was administered to 12 subjects at 25, 50, and 100 mg in an intra-subject dose-escalation design. Plasma and/or urine samples were collected up to 72 h after the first and last dose and analyzed for mirabegron. Pharmacokinetic parameters were determined using non-compartmental methods. Tolerability assessments included physical examinations, vital signs, 12-lead electrocardiogram, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event (AE) monitoring. RESULTS: Forty and 24 young male subjects completed Part I and II, respectively, of Study 1. Twelve young males completed Study 2. After single oral doses (25-400 mg), maximum plasma concentrations (C max) were reached at approximately 2.8-4.0 h postdose. Plasma exposure (C max and area under the plasma concentration-time curve) of mirabegron increased more than dose proportionally at single doses of 25-100 mg and approximately dose proportionally at high doses of 300 and 400 mg. A more than dose proportional increase in plasma exposure was noted in the body of the same individual. Mirabegron accumulated twofold upon once-daily dosing relative to single-dose data. Steady state was reached within 7 days. Mirabegron was generally well-tolerated at single doses up to 400 mg and multiple doses up to 200 mg. The AE with the highest incidence was increased pulse rate at 400 mg in Study 1. CONCLUSIONS: Mirabegron OCAS exhibits similar single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects compared with those observed in non-Japanese (primarily Caucasian) subjects in previous studies.

Tryptamine-based human beta3-adrenergic receptor agonists. Part 3: improved oral bioavailability via modification of the sulfonamide moiety.

The continued SAR investigation of tryptamine-based human beta(3)-adrenergic receptor (AR) agonists is reported. Prior efforts resulted in the identification of 2 as a potent beta(3)-AR agonist. Further modification of the left side arylsulfonamide portion in 2 provided compounds with good cell permeability, which have potent agonistic activity for beta(3)-AR. Cinnamylamine analog 16i exhibited an excellent agonistic profile in vitro and good oral bioavailability in rats.

Thresholds for the physiologic effects of adrenergic agents: a methodologic appraisal.

For hemodynamic responses to adrenergic agents, classical pharmacodynamic theory describes differences between agents in receptor specificity, potency and pharmacologic profile from derived parameters such as the ED50 or half-maximal concentration. However, pharmacodynamic parameters are derived exclusively from in vitro studies. We describe a method of analysis which permits derivation of the 'threshold' or minimum plasma drug concentration associated with discernible effects. The threshold is derived by graphic analysis of in vivo dose response data. We provide examples of both animal and human data which demonstrate agreement of experimental results with predicted responses. This approach permits more direct comparison of studies from different investigators, from different patient or diagnostic categories or at different developmental ages.

Absorption and hemodynamic effects of airway administration of adrenaline in patients with severe cardiac disease.

BACKGROUND: If intravenous access cannot be attained during resuscitation of adult patients, endotracheal application of at least 2 mg of adrenaline is recommended. However, the effects of this intervention have not yet been demonstrated in adults. OBJECTIVE: To demonstrate the effects of adrenaline administered through the airways. DESIGN: Prospective clinical trial. SETTING: Operating theater at university hospital. PATIENTS: 34 patients receiving implantable cardioverter defibrillators under general anesthesia. INTERVENTION: When mean arterial pressure decreased below 80 mm Hg, 100 times the effective central intravenous dose of adrenaline (mean +/- SD, 1.3+/-0.6 mg [range, 0.7 to 3 mg]) was administered over 5 seconds into the endotracheal tube or through a bronchial catheter. Ten forced ventilations followed. MEASUREMENTS: Hemodynamic variables were recorded with a polygraph recorder. Adrenaline levels were measured in 13 patients. RESULTS: Plasma levels and arterial pressure increased in all patients (P < 0.002). Higher plasma levels (P < 0.039) and greater arterial pressure (P < 0.001) were achieved with this method than with intravenous injection. The effects of adrenaline did not differ between the two airway routes. Sustained ventricular arrhythmia did not occur. CONCLUSION: These substantial effects support the standard recommendation to consider the airways as an alternate route for at least 2 mg of adrenaline during resuscitation.