Mervyn Maze

The Pharmacokinetics and Hemodynamic Effects of Intravenous and Intramuscular Dexmedetomidine Hydrochloride in Adult Human Volunteers

Background:Dexmedetomidine is an α2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties. Methods:The pharmacokinetics and hemodynamic changes that occurred in ten healthy male volunteers were determined after administration of dexmedetomidine 2 µg/kg by intravenous or intramuscular route in separate study sessions. Results:The intramuscular absorption profile of dexmedetomidine, as determined by deconvolution of the observed concentrations against the unit disposition function derived from the intravenous data, was biphasic. The percentage bioavailability of dexmedetomidine administered intramuscularly compared with the same dose administered intravenously was 73 ± 11% (mean ± SD). After Intramuscular administration, the mean time to peak concentration was 12 min (range 2-60 min) and the mean peak concentration was 0.81 ± 0.27 ng/ml. After intravenous administration of dexmedetomidine, there were biphasic changes in blood pressure. During the 5-min intravenous infusion of 2 μg/kg dexmedetomidine, the mean arterial pressure (MAP) increased by 22% and heart rate (HR) declined by 27% from baseline values. Over the 4 h after the infusion, MAP declined by 20% from baseline and HR rose to 5% below baseline values. The hemodynamic profile did not show acute alterations after intramuscular administration. During the 4 h after intramuscular administration, MAP declined by 20% and HR declined by 10% Conclusions:The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

Computer-controlled Infusion of Intravenous Dexmedetomidine Hydrochloride in Adult Human Volunteers

Background:This investigation extended the pharmacokinetic analysis of our previous study, of intravenous dexmedetomidine in 10 healthy male volunteers, and prospectively tested the resulting compartmental pharmacokinetics in an additional six subjects using a computer-controlled infusion pump (CCIP) to target four different plasma concentrations of dexmedetomidine for 30 min at each concentration. Methods:A three-compartment mamillary pharmacokinetic model best described the intravenous dexmedetomidine concentration versus time profile following the 5 min intravenous infusion of 2 µg/kg in our previous study. Nonlinear regression was performed using both two-stage and pooled data techniques to determine the population pharmacokinetics. The pooled technique allowed covariates, such as weight, age, and height of the subjects, to be incorporated into the nonlinear regression to test the hypothesis that these additional covariates would reduce the residual error between the measured concentrations and the predicted values. Results:The addition of age, weight, lean body mass, and body surface area as covariates of the pharmacokinetic parameters did not improve the predictive value of the model. However, the model was improved when subject height was a covariate of the volume in the central compartment. The residual error in the pharmacokinetic model was markedly lower with the pooled versus the two-stage approach. The following pharmacokinetic values were obtained from the pooled analysis of the zero-order dexmedetomidine infusion: V1=8.05, V2=12.4, V3=175 (L), Cl1=(0.0101·height [cm])−1.33, Cl2=2.05, and Cl3=2.0 (L/min). Prospective evaluation of the pooled pharmacokinetic parameters using a computer-controlled infusion in six healthy volunteers showed the precision (average [(absolute error)/measured concentration]) of the CCIP to be 31.5% and the bias (average [error/measured concentration]) to be -22.4%. A pooled regression of the combined CCIP and zero-order data confirmed that the covariate, height (cm), was related in linear fashion to Cl1. A striking nonlinearity of dexmedetomidine pharmacokinetics related to concentration was observed during the CCIP infusion. The final pharmacokinetic values for the entire data set were: V1=7.99, V2=13.8, V3=187 (L), Cl1=(0.00791·height [cm]) -0.927, Cl2=2.26, and Cl3=1.99 (L/min) Conclusions:Pharmacokinetics of dexmedetomidine are best described by a three-compartment model. Addition of age, weight, lean body mass, and body surface area do not improve the predictive value of the model. Additional improvement in CCIP accuracy for dexmedetomidine infusions would require magnification modification of the model based on the targeted concentration

α2-Adrenoceptors inhibit a nociceptive response in neonatal rat spinal cord

Alpha 2-Adrenoceptors mediate analgesia in vivo. The present study explored the actions of the alpha 2-adrenoceptor agonists dexmedetomidine and clonidine on a nociceptive response in isolated neonatal rat spinal cord. Stimulation of a dorsal root generates a slow ventral root potential (slow VRP) at the corresponding ipsilateral ventral root. The slow VRP meets several criteria for a nociceptive response. Dexmedetomidine (10 nM) and clonidine (200 nM) depressed the slow VRP by approximately 80%. Dexmedetomidines action was approximately linear over the concentration range 0.5-500 nM, whereas clonidine (20 nM-5 microM) exerted biphasic effects. The profile of agonist and antagonist effectiveness characterized the receptor(s) as alpha 2-adrenoceptors; the subtype could not be identified as either alpha 2A or alpha 2B. Naloxone pretreatment partially blocked dexmedetomidines effect, suggesting a possible endogenous opiate involvement. Dexmedetomidine (0.5-2.0 nM) also depressed the VRP evoked by application of substance P to the cord, implicating postsynaptic as well as possible presynaptic actions. At high concentrations, dexmedetomidine (50-500 nM) depressed the monosynaptic reflex, probably through non-alpha 2-receptor(s). Results from the neonatal spinal cord correlate well with those from in vivo analgesia studies. They suggest an important direct spinal contribution to alpha 2-adrenoceptor-mediated analgesia.

Opiate receptors in the periaqueductal gray mediate analgesic effect of nitrous oxide in rats

The site of action and the pathways which are activated by nitrous oxide (N2O) to produce an analgesic effect are not well defined. Experiments were designed to determine whether N2O produces analgesia by activating opiate receptors or alpha2-adrenoceptors in periaqueductal gray. The analgesic effect of N2O was determined using the tail flick response to noxious radiant heat in lightly anesthetized rats. Different antagonists were bilaterally microinjected into ventrolateral periaqueductal gray to determine whether the analgesic effect produced by N2O was reversed. The increase in the tail flick latencies produced by N2O was reversed by bilateral microinjection into the ventrolateral part of periaqueductal gray with the opiate receptor antagonist naloxone 2.5 microg/0.5 microl, but not with the alpha2-adrenoceptors antagonist yohimbine 1.5 microg/0.5 microl. These results indicate that the N2O analgesic effect is mediated by activation of opiate receptors, but not alpha2-adrenoceptors, in the periaqueductal gray. Combined with the previous experiments that the N2O analgesic effect is reversed by intrathecal injection of an alpha2-adrenoceptor antagonist but not by an opiate receptor antagonist, it seems likely that N2O causes activation of the opiate receptors in the periaqueductal gray, which in turn activate the noradrenergic descending pathways to the spinal cord to produce the analgesic effect.

Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds.

Corticosteroids are probably an effective treatment for some types of neuropathic pain and complex regional pain syndromes. This study examined the effects of systemic methylprednisolone (MP) on acute nociception and on pain behavior and hyperalgesia in normal and neuropathic rats. There was no dose-response to intraperitoneal MP (up to 12 mg/kg) for nociceptive thresholds to heat (Peltier) or mechanical (analgesy-meter and von Frey fibers) stimuli in normal rats. Chronic high dose MP (3 mg/kg per day for 21 days) also had no effect on acute nociceptive thresholds in normal rats. After sciatic nerve section in rats a saphenous nerve mediated hyperalgesia to heat and mechanical stimuli gradually developed over 21 days. High dose MP (3 mg/kg per day for 21 days) had no effect on this adjacent neuropathic hyperalgesia. When systemic MP was started immediately after bilateral sciatic and saphenous nerve transection there was a dose-dependent reduction in autotomy behavior. Substance P has been proposed as a mediator of neuropathic pain and edema. Single dose MP (12 mg/kg) slightly reduced the substance P mediated extravasation induced with electrical stimulation of the saphenous nerve. Chronic MP (3.4 mg/kg per day for 28 days) severely reduced the neurogenic extravasation induced with saphenous nerve stimulation. Sciatic sectioned rats developed hindpaw edema between 7 and 14 days after surgery, and this neuropathic edema did not develop in rats chronically treated with MP (3.4 mg/kg per day). These results demonstrate that corticosteroids did not affect nociceptive thresholds in normal or neuropathic hyperalgesic rats. Chronic steroid treatment did prevent the development of autotomy and neuropathic edema, and completely blocked neurogenic extravasation, findings consistent with the hypothesis that primary afferent substance P release mediates autotomy pain behavior and neuropathic edema. This may be a relevant model for examining the effects of corticosteroids on neuropathic pain and complex regional pain syndromes.

Dexmedetomidine Decreases Cerebral Blood Flow Velocity in Humans

This study was designed to determine the effects of dexmedetomidine on CBF velocity as measured by transcranial Doppler sonography in human volunteers. Dexmedetomidine, a potent α-2 adrenergic agonist, was administered by computer-driven infusion pump to six male volunteers. Serial measurements of middle cerebral artery blood flow velocity at four steady-state plasma concentrations of dexmedetomidine were made with a 2-MHz transcranial Doppler transducer via the temporal window. The targeted plasma concentrations were 0.49, 0.65, 0.81, and 0.97 ng/ml. These represent 60, 80, 100, and 120%, respectively, of the mean peak concentration following the intramuscular administration of 2 μg/kg of dexmedetomidine. Subjects experienced a significant degree of sedation at the highest infusion rates. Mean CBF velocity decreased with each increase in plasma concentration of dexmedetomidine and then began to return to basal levels after termination of the infusion. A trend toward an increase in the pulsatility index at the higher levels of dexmedetomidine suggests that the observed decrement in CBF velocity was due to an increase in cerebral vascular resistance. Upon initiation of the drug infusion, mean arterial pressure decreased from ∼95 mm Hg to 78 mm Hg. There were no further decreases in arterial pressure with subsequent increases in plasma concentrations of dexmedetomidine. Arterial carbon dioxide tension increased to a maximum of 45 mm Hg during the drug infusion, but this increase from baseline was not statistically significant. These studies are in agreement with previous animal studies which demonstrate a decrease in CBF after administration of dexmedetomidine.

The α2A adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice

&NA; We have addressed the role of the sympathetic nervous system in the development and maintenance of neuropathic pain. Using a new neuropathic mouse model, we examined the development of hyperalgesia in transgenic mice lacking functional &agr;2A adrenoceptors and in sympathectomized wild‐type mice, to determine if sympathetic–sensory coupling generates hyperalgesia. The development of neuropathic heat hyperalgesia required the presence of both the &agr;2A adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the development of mechanical hyperalgesia did not require either the &agr;2A adrenoceptor or the SPGN, indicating different mechanisms of sensitization. These results suggest that the development of neuropathic heat hyperalgesia, but not mechanical hyperalgesia, requires sympathetic–sensory coupling in the peripheral nervous system. Nerve injury enhanced the analgesic efficacy of the &agr;2 adrenoceptor agonist dexmedetomidine, and paradoxically also induced an analgesic response to &agr;2 adrenoceptor antagonists. The &agr;2 agonist‐evoked analgesia to mechanical stimuli was mediated by activating central &agr;2A adrenoceptors, possibly at the spinal level. The peripherally restricted &agr;2 antagonist L659,066 evoked analgesia for heat, but not for mechanical stimuli, findings which support the hypothesis that the peripheral &agr;2 adrenoceptor plays a role in both the development and the maintenance of neuropathic heat hyperalgesia. The &agr;2 antagonist‐evoked analgesia for heat stimuli was mediated by blocking peripheral and probably central &agr;2 adrenoceptors, while the analgesia for mechanical stimuli was mediated by blocking central &agr;2A adrenoceptors. Intradermal injections with an &agr;2 agonist or antagonist had no effect on nociceptive thresholds, indicating that sympathetic–sensory coupling at the level of the cutaneous nociceptor did not contribute to the maintenance of neuropathic hyperalgesia.

Clonidine and other alpha2 adrenergic agonists: Strategies for the rational use of these novel anesthetic agents

Clonidine and other clinically available alpha-2 adrenergic agonists reduce inhalational and narcotic anesthetic requirements while providing hemodynamic stability during stressful periods of surgery. Like the opiates, the alpha-2 adrenergic agonists are potent analgesics when given systemically, epidurally, or intrathecally. Their effects are reversed by alpha2 adrenergic antagonists. Newer and more selective alpha2 adrenergic agonists are more potent in their anesthetic action than the clinically available opiates. The important difference is that these agents do not appear to be respiratory depressants and do not have an addiction liability of the opioid type. They have anxiolytic properties and therefore can be potentially useful in the preanesthetic period. This drug class has the potential to provide many of the component effects required for perioperative care. For these reasons, the alpha2 adrenergic class of drugs should be important in the future of anesthesia.

Analysis of Anesthetic Action on the Potassium Channels of the Shaker Mutant of Drosophila

Recent evidence suggest that exposure to volatile anesthetic agents causes a change in conductance through an undelineated potassium channel. With recently developed genetic and molecular techniques the Drosophila melanogaster (D.m.) genome can be manipulated to study the role that potassium ion channel function plays in anesthetic action. The IA potassium channel is encoded by the Shaker (Sh) locus on the X chromosome of D.m. Because this channel may be one of those involved in volatile anesthetic action, we tested the sensitivity to isoflurane in three Shaker strains with different degrees of dysfunctional IA conductance (Shnull greater than ShKS133 greater than Sh5). Anesthetic sensitivity was also examined in mutant strains of D.m. which express abnormalities either in other potassium channel conductances (eag, slo) or other ion conductances (para). The normally conducting wild type served as the control. Two-day-old adult D.m. were stimulated with a heat source during exposure to the volatile anesthetic isoflurane, and the number moving in response to the noxious stimulus was noted. After testing the Shaker and control strains at no fewer than 13 concentrations, the IC50S (isoflurane concentration in percent vol/vol at which 50% of the flies did not respond to the heat stimulus) were derived. The IC50 values for Sh 5 (0.89), Sh133 (1.29), and Shnull (1.37) were significantly different from the wild type (0.56). The rank order of insensitivity of these Shaker mutants corresponded to the extent of the alteration in IA conductance as established by previous studies in these mutants. Neither eag (0.66), para (0.48), nor slo (0.63) differed significantly from the wild type. These data suggest that the IA potassium channel plays a role in volatile anesthetic action.

Pertussis toxin-mediated ribosylation of G proteins blocks the hypnotic response to an α2-agonist in the locus coeruleus of the rat

Biologic responses mediated by adrenoceptors are transduced by a receptor-effector mechanism that involves a guanine nucleotide binding protein (G protein). Recently, we determined that the transduction mechanism for the hypnotic response to dexmedetomidine, a highly selective alpha 2-agonist, is located in the locus coeruleus (LC) of the rat. In this study, we examined the role of pertussis toxin-sensitive (PTX) G proteins in the LC for the hypnotic response to dexmedetomidine. The LC of rats were stereotactically cannulated and treated with PTX, 0.34 micrograms, or vehicle. Five days later, the hypnotic response to dexmedetomidine, 7 micrograms into the LC or 50 micrograms.kg-1 IP, was tested. On the following day, the LC was harvested and assayed to determine whether the G proteins had been ribosylated by pretreatment with PTX in vivo. Quantitative immunoblotting of G0 alpha, Gi alpha 1,2, and Gi alpha 3, the alpha-subunit of three PTX-sensitive proteins, was also performed. In vivo treatment with PTX into the LC blocked the hypnotic response to LC-administered dexmedetomidine and, to a lesser extent, IP-administered dexmedetomidine. The in vivo PTX treatment effectively ribosylated the G proteins. No alteration in the amount of the different species of PTX-sensitive alpha-subunit was produced by in vivo PTX treatment. These data suggest a pivotal role for PTX-sensitive G proteins in the LC in the hypnotic response to alpha 2-agonists in the rat.