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PubMed1991

Age affects the pharmacokinetics of inhaled anesthetics in humans.

To define the effect of aging on the pharmacokinetics of volatile anesthetics, we determined the end-tidal and mixed expired anesthetic concentrations of isoflurane, enflurane, halothane, and methoxyflurane during 30 min of simultaneous administration and for 5-12 days of elimination in seven healthy young patients (31 +/- 1.8 yr [mean +/- SEM]) and in 11 healthy aged patients (73.2 +/- 3.1 yr [mean +/- SEM]). A five-compartment mammillary function was fit to the end-tidal and mixed expired anesthetic elimination data simultaneously using ordinary least-squares analysis. We assumed the compartments to represent the following tissue groups: lungs and pulmonary capillary blood (V1), vessel-rich tissues (i.e., liver, heart, kidneys, and brain) muscle, an unidentified fourth compartment, perhaps fat adjacent to well-perfused tissues, and fat tissues. The tissue volumes and perfusions estimated for these compartments approximated values from the literature. In general, the volume of the fourth and fifth compartments increased with age, and perfusion to the second and fifth compartments decreased with age. Aging delayed anesthetic elimination and increased the apparent volume of distribution at steady state. These observations are compatible with decreased tissue perfusion and an increase in the ratio of fat/lean body weight in the elderly. Our mammillary analysis described the behavior of less soluble anesthetics such as isoflurane well, but that of highly soluble anesthetics such as methoxyflurane less well.

Adipose Tissue↗

PubMed1993

Inhibitory effects of four inhaled anesthetics on canine tracheal smooth muscle contraction and intracellular Ca2+ concentration.

To clarify the mechanisms by which inhaled anesthetics directly inhibit tracheal smooth muscle contraction, we investigated the effects of these anesthetics on muscle tension and intracellular Ca2+ concentration ([Ca2+]i). Tension was measured using an isometric transducer, and [Ca2+]i was measured using Fura-2, an indicator of [Ca2+]i. Addition of 1 microM carbachol increased muscle tension and [Ca2+]i. All inhaled anesthetics significantly decreased both muscle tension and [Ca2+]i in the following order of inhibitory potency: halothane >> isoflurane > enflurane >> sevoflurane. In the presence of 10 microM verapamil, carbachol moderately increased muscle tension, but induced a transient increase of [Ca2+]i followed by a substantial reduction. Inhaled anesthetics in the presence of both carbachol and verapamil significantly decreased muscle tension without decreasing [Ca2+]i. Potency for suppression of tension under these conditions, which appeared to be independent of [Ca2+]i, was in the order: halothane >> enflurane > or = isoflurane >> sevoflurane. The best correlation we found with a measured reduction of muscle tension independent of [Ca2+]i was with oil/gas partition coefficients (r = -0.88, P < 0.001). In conclusion, inhaled anesthetics inhibit tracheal smooth muscle contraction by at least two mechanisms: 1) reduction of [Ca2+]i and 2) suppression of contractility, independent of [Ca2+]i. The close correlation between the muscle inhibition independent of [Ca2+]i and the oil/gas partition coefficients suggests that one of the major sites of action of inhaled anesthetics is membrane phospholipids.

Anesthetics↗

PubMed2003

Small risk of serious neurologic complications related to lumbar epidural catheter placement in anesthetized patients.

UNLABELLED: Previous studies have identified pain during needle/catheter placement or during the injection of local anesthetic as a risk factor for the development of persistent paresthesias after regional anesthetic techniques. The performance of regional blockade on anesthetized patients theoretically increases the risk of postoperative neurologic complications, because these patients are unable to respond to painful stimuli. In this study, we evaluated the frequency of neurologic complications in 4298 thoracic surgical patients undergoing lumbar epidural catheter placement while under general anesthesia. Catheters were placed immediately after the induction and tracheal intubation or on completion of the surgical procedure, before emergence. Most epidural catheters (4220, or 98.2%) were used solely for postoperative analgesia; only 78 (1.8%) epidural catheters were used for intraoperative anesthesia. In 4239 (98.6%) patients, an opioid alone was administered. The remaining 56 (1.3%) patients received a local anesthetic or local anesthetic/opioid mixture epidurally. Analgesia was graded as excellent or good in 92.2% of patients. Side effects included sedation in 455 (10.6%), nausea or emesis in 328 (7.6%), pruritus in 116 (2.7%), and respiratory depression (pH or=50 mm Hg) in 308 (7.2%) patients. The mean duration of epidural analgesia was 2.4 +/- 0.8 days (range, 0-10.7 days). There were no neurologic complications, including spinal hematoma, epidural abscess or catheter site infections, radicular symptoms, or persistent paresthesias (95% confidence interval, 0%-0.08%). In one patient, the epidural catheter broke during removal, and a portion was retained. The patient was notified; no long-term sequelae were noted. Six patients developed new neurologic symptoms or postoperative worsening of a previous neurologic condition unrelated to epidural catheterization. We conclude that the risk of neurologic complications associated with lumbar epidural catheter placement in anesthetized patients is small. However, the relative risk of this practice, compared with epidural catheter placement in awake patients, is unknown. IMPLICATIONS: We report no neurologic complications in 4298 patients undergoing epidural catheter placement while under general anesthesia. Although the risk of neurologic complications associated with lumbar epidural catheter placement in anesthetized patients is small, the relative risk compared with epidural catheterization in awake patients is unknown.

Adolescent↗

PubMed2003

Choice of electrocardiography lead does not affect the usefulness of the T-wave criterion for detecting intravascular injection of an epinephrine test dose in anesthetized children.

UNLABELLED: Accidental intravascular injection of an epinephrine-containing test dose increases T-wave amplitude of lead II electrocardiogram (EKG) in anesthetized children. We designed this study to test whether the choice of EKG lead would affect the usefulness of simulated intravascular test dose. We studied 32 ASA physical status I infants and children (aged 6-49 mo) undergoing elective surgeries during 1.0 minimum alveolar anesthetic concentration sevoflurane and 67% nitrous oxide in oxygen. When hemodynamic stability was obtained, all subjects received IV saline 0.1 mL/kg, followed 4 min later by an IV test dose (0.1 mL/kg) consisting of 1% lidocaine with 1:200,000 epinephrine (epinephrine 0.5 microg/kg) via a peripheral vein to simulate the intravascular injection of the test dose. Heart rate and systolic blood pressure were recorded every 20 and 60 s, respectively, and leads II (n = 32), V(5) (n = 32) and either lead I (n = 15) or III (n = 17), choosing the one with greater preinjection T-wave amplitude, were continuously recorded for 4 min after the saline and the test dose injections. An IV test dose produced significant increases in heart rate, systolic blood pressure, and T-wave amplitude of all EKG leads studied in all subjects, whereas IV saline elicited no changes in these variables. Maximal increases in T-wave amplitude of leads II, I, III, and V(5) were 158% +/- 69%, 175% +/- 78%, 147% +/- 89%, and 170% +/- 72%, respectively (mean +/- SD, P > 0.05). There was no significant difference in temporal changes in T-wave amplitude among the 4 leads, and sensitivity and specificity were 100% on the basis of the T-wave criterion irrespective of the lead examined. Our results indicate that leads II, I, III, and V(5) of EKG are equally effective for detecting intravascular injection of the epinephrine-containing test dose in sevoflurane-anesthetized children. IMPLICATIONS: To determine whether an epidurally administered local anesthetic has been accidentally injected into a blood vessel, a small dose of epinephrine is often added to a local anesthetic. We found that increases in T-wave amplitude in leads I, II, III, and V(5) of the electrocardiogram are equally sensitive and specific for detecting intravascular injection of the epinephrine-containing test dose in sevoflurane-anesthetized infants and children.

Anesthesia, Epidural↗

PubMed2004

Inhibition of spinal protein kinase C-epsilon or -gamma isozymes does not affect halothane minimum alveolar anesthetic concentration in rats.

Anesthetic effects on receptor or ion channel phosphorylation by enzymes such as protein kinase C (PKC) have been postulated to underlie some aspects of anesthesia. In vitro studies show that anesthetic effects on several receptors are mediated by PKC. To test the importance of PKC for the immobility produced by inhaled anesthetics, we measured the effect of intrathecal injections of PKC-epsilon and -gamma inhibitors on halothane minimum alveolar anesthetic concentration (MAC) in 7-day-old and 21-day-old Sprague-Dawley rats. The inhibitors were made as solutions of 100 pmol/5 microL and were given in a volume of 5 microL (7-day-old [P7] rats) or 10 microL (21-day-old [P21] rats). Controls were saline injections or injections of the peptide carrier at the same concentration and volumes; there were six animals in each group. In P7 rats, MAC values (in percentage of an atmosphere) were 1.63 +/- 0.0727 (mean +/- SEM) in saline controls, 1.55 +/- 0.141 in carrier controls, 1.54 +/- 0.0800 in rats given PKC-epsilon, and 1.69 +/- 0.0554 in rats given PKC-gamma. In P21 animals, the values were 1.20 +/- 0.0490, 1.31 +/- 0.0124, 1.27 +/- 0.0367, and 1.15 +/- 0.0483, respectively. Injection of the inhibitors did not change MAC in either age group. These results do not support an anesthetic effect on phosphorylation as a mechanism underlying the capacity of inhaled anesthetics to prevent movement in response to noxious stimulation, and they indirectly support a direct action on receptors or ion channels.

Aging↗

PubMed2005

Species-specific differences in response to anesthetics and other modulators by the K2P channel TRESK.

UNLABELLED: TRESK (TWIK-related spinal cord K+ channel) is the most recently characterized member of the tandem-pore domain potassium channel (K2P) family. Human TRESK is potently activated by halothane, isoflurane, sevoflurane, and desflurane, making it the most sensitive volatile anesthetic-activated K2P channel yet described. Herein, we compare the anesthetic sensitivity and pharmacologic modulation of rodent versions of TRESK to their human orthologue. Currents passed by mouse and rat TRESK were enhanced by isoflurane at clinical concentrations but with significantly lower efficacy than human TRESK. Unlike human TRESK, the rodent TRESKs are strongly inhibited by acidic extracellular pH in the physiologic range. Zinc inhibited currents passed by both rodent TRESK in the low micromolar range but was without effect on human TRESK. Enantiomers of isoflurane that have stereoselective anesthetic potency in vivo produced stereospecific enhancement of the rodent TRESKs in vitro. Amide local anesthetics inhibited the rodent TRESKs at almost 10-fold smaller concentrations than that which inhibit human TRESK. These results identified interspecies differences and similarities in the pharmacology of TRESK. Further characterization of TRESK expression patterns is needed to understand their role in anesthetic mechanisms. IMPLICATIONS: Mouse and rat TRESK (TWIK-related spinal cord K+ channel) have different pharmacologic responses compared with human TRESK. In particular, we found stereospecific differences in response to isoflurane by the rodent TRESKs but not by human TRESK. TRESK may be a target site for the mechanism of action of volatile anesthetics.

Anesthetics↗

PubMed2006

Do N-methyl-D-aspartate receptors mediate the capacity of inhaled anesthetics to suppress the temporal summation that contributes to minimum alveolar concentration?

Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of inhaled anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by inhaled anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.

Anesthetics, Inhalation↗

PubMed1982

Effects of local anesthetics on monoamine oxidase, and their membrane effects.

The effects of various local anesthetics on rat brain and liver monoamine oxidase (MAO) and their antihemolytic and local anesthetic effects were studied. All local anesthetics tested at 1 x 10(-7) M to 1 x 10(-3) M inhibited MAO activity in rat liver mitochondria with 5-hydroxytryptamine (5-HT) as substrate. The order of potency was tetracaine>procaine>dibucaine>lidocaine>prilocaine. Tetracaine and procaine inhibited 5-HT oxidation much more than beta-phenylethylamine (PEA) oxidation. Dibucaine inhibited PEA oxidation as much as 5-HT oxidation. Inhibition of MAO by local anesthetics other than dibucaine was reversible. Tetracaine and procaine inhibited 5-HT oxidation competitively, whereas dibucaine inhibited it non-competitively. Antihemolytic effects were observed with dibucaine and tetracaine at concentrations of 6 x 10(-5) M and 1 x 10(-4), respectively. The order of surface anesthetic potencies was dibucaine>tetracaine>prilocaine>lidocaine>procaine. These results suggest that the inhibition of MAO activities by local anesthetics depends on both electrostatic and hydrophobic interactions between these drugs and enzyme-associated phospholipids or the hydrophobic regions of proteins.

Anesthetics, Local↗

PubMed2004

Concentration effects of volatile anesthetics on the properties of model membranes: a coarse-grain approach.

To gain insights into the molecular level mechanism of drug action at the membrane site, we have carried out extensive molecular dynamics simulations of a model membrane in the presence of a volatile anesthetic using a coarse-grain model. Six different anesthetic (halothane)/lipid (dimyristoylphosphatidylcholine) ratios have been investigated, going beyond the low doses typical of medical applications. The volatile anesthetics were introduced into a preassembled fully hydrated 512-molecule lipid bilayer and each of the molecular dynamics simulations were carried out at ambient conditions, using the NPT ensemble. The area per lipid increases monotonically with the halothane concentration and the lamellar spacing decreases, whereas the lipid bilayer thickness shows no appreciable differences and only a slight increase upon addition of halothane. The density profiles of the anesthetic molecules display a bimodal distribution along the membrane normal with maxima located close to the lipid-water interface region. We have studied how halothane molecules fluctuate between the two maxima of the bimodal distribution and we observed a different mechanism at low and high anesthetic concentrations. Through the investigation of the reorientational motions of the lipid tails, we found that the anesthetic molecules increase the segmental order of the lipids close to the membrane surface.

Anesthetics, Inhalation↗

PubMed2004

A model membrane protein for binding volatile anesthetics.

Earlier work demonstrated that a water-soluble four-helix bundle protein designed with a cavity in its nonpolar core is capable of binding the volatile anesthetic halothane with near-physiological affinity (0.7 mM Kd). To create a more relevant, model membrane protein receptor for studying the physicochemical specificity of anesthetic binding, we have synthesized a new protein that builds on the anesthetic-binding, hydrophilic four-helix bundle and incorporates a hydrophobic domain capable of ion-channel activity, resulting in an amphiphilic four-helix bundle that forms stable monolayers at the air/water interface. The affinity of the cavity within the core of the bundle for volatile anesthetic binding is decreased by a factor of 4-3.1 mM Kd as compared to its water-soluble counterpart. Nevertheless, the absence of the cavity within the otherwise identical amphiphilic peptide significantly decreases its affinity for halothane similar to its water-soluble counterpart. Specular x-ray reflectivity shows that the amphiphilic protein orients vectorially in Langmuir monolayers at higher surface pressure with its long axis perpendicular to the interface, and that it possesses a length consistent with its design. This provides a successful starting template for probing the nature of the anesthetic-peptide interaction, as well as a potential model system in structure/function correlation for understanding the anesthetic binding mechanism.

Amino Acid Sequence↗

PubMed1998

Anesthetic effects on the glycerol model of rhabdomyolysis-induced acute renal failure in rats.

Isoflurane, the most widely used inhalational anesthetic, releases inorganic fluoride during its metabolism by the cytochrome P450 system. Recent experimental data indicate that when cultured proximal tubular cells are exposed to inorganic fluoride, they become relatively resistant to myoglobin- and ATP depletion-mediated attack. The present study was undertaken to assess whether isoflurane anesthesia might confer in vivo cytoprotection, possibly by causing renal tubular inorganic fluoride exposure, thereby mitigating a combined myoglobin/ATP depletion model of acute renal failure (glycerol-induced ARF). Rats were injected with hypertonic glycerol (50%; 9 ml/kg, intramuscularly) while undergoing 4 h of isoflurane anesthesia. Glycerol-injected rats anesthetized with a virtually nondefluorinated inhalational anesthetic (desflurane) or with a nonfluorinated anesthetic (pentobarbital) served as controls. The severity of ARF was assessed 24 h later (blood urea nitrogen, plasma creatinine [Cr], and renal histology). Anesthetic effects on extrarenal injury (plasma creatine phosphokinase, lactate dehydrogenase, and hematocrit levels), acute intrarenal heme loading (cast formation), and BP during the initiation phase of renal injury (0 to 4 h after glycerol injection) were also assessed. Glycerol induced severe ARF under pentobarbital anesthesia (Cr, 2.8 +/- 0.3 mg/dl; severe tubular necrosis). Somewhat worse azotemia, but comparable tubular necrosis, resulted with desflurane use. Conversely, glycerol plus isoflurane anesthesia induced only mild renal damage (Cr, 0.9 +/- 0.1, minimal tubular necrosis; P < 0.01). This reduction apparently was not due to differences in degrees of muscle necrosis, hemolysis, acute renal heme loading, or BP during the initiation phase of ARF, suggesting that a direct renal mechanism was operative. These results: (1) underscore that differing anesthetics can profoundly alter the expression of experimental renal injury; (2) raise the intriguing possibility that isoflurane could potentially protect surgical/trauma patients from rhabdomyolysis-induced ARF; and (3) further support the concept that renal fluoride exposure may confer proximal tubular cytoprotective effects.

Acute Kidney Injury↗

PubMed2004

Patient evaluation of a novel non-injectable anesthetic gel: a multicenter crossover study comparing the gel to infiltration anesthesia during scaling and root planing.

BACKGROUND: Periodontal scaling procedures commonly require some kind of anesthesia. From the patient's perspective, the choice of anesthetic method is a trade-off between the degree of anesthesia and accepting the side effects. The present study evaluates the preferences for a novel non-injection anesthetic product (a gel, containing lidocaine 25 mg/g plus prilocaine 25 mg/g and thermosetting agents) versus injection anesthesia (lidocaine 2% adrenaline) in conjunction with scaling and/or root planing (SRP). METHODS: In a multicenter, crossover, randomized, open study patients were asked, after they had experienced both products, if they preferred anesthetic gel or injection anesthesia. In addition, the adequacy of anesthesia and occurrence of post-procedure problems were assessed. The patients were also asked about their willingness to return if they were offered anesthetic gel at their next visit and their maximum willingness to pay (WTP) for this option. RESULTS: One-hundred seventy (170) patients at eight centers in Belgium were included in the study. There were 157 per protocol (PP) patients. A vast majority of the PP patients (70%) preferred the anesthetic gel to injection anesthesia (22%). The most common reason was less post-procedure numbness. Eighty percent (80%) of the patients expressed satisfactory anesthesia with the gel and 96% with injection anesthesia (P <0.001). Post-procedure problems were significantly less with the gel than with injection (P <0.001): numbness 15% versus 66%, unpleasant sensations such as soreness and pain 44% versus 63%, and problems connected with daily activities 19% versus 69%. The majority of patients (60%) who preferred gel were also willing to pay for it. A conservative estimate of the median WTP was $10.00. Furthermore, anesthetic gel would make almost every second patient (45%) more or much more willing to return for the next treatment. CONCLUSIONS: The data suggest that a somewhat less profound anesthesia with gel is clearly preferred by the patients because of the low incidence of post-procedure problems as compared to conventional injection anesthesia. The median WTP is likely in excess of the acquisition cost of the product, which indicates a favorable cost-benefit ratio for the individual patient.

Administration, Topical↗

PubMed2000

Tandem pore domain K channels: an important site of volatile anesthetic action?

Despite over 150 years of clinical use, the mechanism and molecular elements by which volatile anesthetics produce unconsciousness are not established. Although enhanced activity of inhibitory neurotransmitter systems (GABAA) and depression of excitatory neurotransmitter systems (NMDA) probably contribute to the anesthetic state, the role of other ion channels families have also been studied. Potassium channels represent the largest group of mammalian ion channels and their activity to reduce neuronal excitability makes them viable candidates as sites of anesthetic action. Several studies from the 1970's and 80's identified volatile anesthetic enhancement of neuronal potassium currents. More recently, a new family of K channels with a unique structure (tandem pore domains) that may be responsible for baseline or background K currents have been isolated and some members of this family can be activated by volatile anesthetics. These emerging findings suggest a new molecular mechanism by which volatile anesthetics may mediate central nervous system depression.

Action Potentials↗

PubMed2003

Mechanism of action of volatile anesthetics: involvement of intracellular calcium signaling.

There have been extensive efforts to characterize the mechanism of action of volatile anesthetics, but their molecular and cellular actions are still a matter of debate. Volatile anesthetics act primarily on synaptic transmission in the central nervous system but proof of this as the predominant mechanism of action remains elusive. Changes in neurotransmitter release may relate to direct interaction of the anesthetic molecule with an ion channel protein or synaptic protein, but can also be a consequence of alterations in intracellular signaling. Calcium is one of the most important messengers in cells and its intracellular concentration may be modified by several agents including volatile anesthetics. Neuronal excitability is in part determined by calcium availability that is controlled by several mechanisms. Because voltage-gated calcium channels (VGCC) play a key role in controlling Ca2+ entry and in initiating cellular responses to stimulation through an elevation of intracellular calcium concentration ([Ca2+](i)), they are thought to be one of the targets for volatile anesthetics. However, [Ca2+](i) can also be altered without the participation of VGCC through receptor-mediated pathways. Indeed, calcium homeostasis is also controlled by plasma membrane Ca2+ -adenosine triphosphatase, sarcoplasmic-endoplasmic reticular Ca2+ -ATPase, the Na+ -Ca2+ exchanger, and mitochondrial Ca2+ sequestration. Alteration of any of those mechanisms that control [Ca2+](i) may lead to a change in presynaptic transmission or postsynaptic excitability. Here we will review some of the recent progress in identifying putative actions of volatile anesthetics, specifically the effect on intracellular calcium homeostasis in neurons.

Anesthetics, Inhalation↗

PubMed2004

Preconditioning of the myocardium by volatile anesthetics.

Cardiovascular disease continues to be a major health problem. Tremendous efforts have been invested in clinical and laboratory research in the hopes of decreasing the risk of patients with cardiovascular disease undergoing cardiac and non-cardiac surgeries. A powerful endogenous mechanism of cardioprotection, termed ischemic preconditioning, was reported in a laboratory setting whereby the myocardium can be preconditioned by a brief ischemic episode and protected against a subsequent prolonged ischemic attack. Since this initial observation, several pharmacological agents have been demonstrated to mimic ischemic preconditioning. These include opioids, potassium channel openers such as pinacidil and diazoxide, and adenosine agonists. Recently, volatile anesthetics were found to be powerful cardiac preconditioning agents. Infarct size reduction as the result of anesthetic-induced preconditioning paralleled that of ischemic preconditioning. The use of volatile anesthetics as preconditioning agents in high-risk patients undergoing cardiac and non-cardiac surgeries can potentially result in the reduction of morbidity and disability in this class of patients. However, to fully realize the potential use of this novel property of volatile anesthetics, the underlying mechanism of anesthetic-induced preconditioning would need to be elucidated. This review highlights the major recent findings on the cardioprotective effects of volatile anesthetics.

Anesthetics, Inhalation↗

PubMed2001

The cardiotoxicity of local anesthetics: the place of ropivacaine.

Central and regional block procedures have a well-defined role as safe and effective methods in modern anesthesia and analgesia with long-acting local anesthetics. Recent studies have shown that the incidence of intoxication by these drugs is a rare but catastrophic event. As classic neuronal sodium channel inhibitors, local anesthetics block peripheral fast voltage-gated sodium channels on neuronal axons, and these drugs have a particularly high level of activity in the CNS and the cardiovascular system. CNS-toxicity follows a two-stage process, whereby at lower concentrations inhibitory neurons are blocked first resulting in generalized convulsions, and at higher concentrations a global CNS depression can be seen. Although seizures are an impressive clinical syndrome, they can often be treated safely without permanent damage. More important is the cardiotoxicity of these drugs, which can be divided into indirect cerebrally mediated and a direct myocardial component. Like CNS-toxicity in general, indirect cardiotoxicity demonstrates an initial stimulating effect, followed by a depressive component at higher concentrations. Direct myocardial actions are comprised of negative chronotropic, dromotropic and inotropic effects. For dromotropy, stereoselectivity was found. The S-(-)-isomers of the longacting local anesthetics were less delayed compared to racemic mixtures and the R-(+)-enantiomers. For inotropy, no stereospecific depression of this parameter was noted between isomers of ropivacaine or bupivacaine, but bupivacaine produced a significantly greater depression of LV pressure than ropivacaine, mepivacaine, or lidocaine. Pharmacokinetic differences in lipophilicity of local anesthetics correlate well with the depression mitochondrial ATP-synthesis in fast metabolizing cells. Intracellular ATP-level may be involved in contractility and resuscitation of cardiomyocytes, as be proven by in-vitro and in-vivo data. Therefore the use of pure optical S-(-)-isomers of local anesthetics may help to reduce these rare but catastrophic events. Presently, ropivacaine appears to be the safest long-acting local anesthetic.

Action Potentials↗

PubMed2006

Pharmacokinetics of inhaled anesthetics in green iguanas (Iguana iguana).

OBJECTIVE: To test the hypothesis that differences in anesthetic uptake and elimination in iguanas would counter the pharmacokinetic effects of blood:gas solubility and thus serve to minimize kinetic differences among inhaled agents. ANIMALS: 6 green iguanas (Iguana iguana). PROCEDURES: Iguanas were anesthetized with isoflurane, sevoflurane, or desflurane in a Latin-square design. Intervals from initial administration of an anesthetic agent to specific induction events and from cessation of administration of an anesthetic agent to specific recovery events were recorded. End-expired gas concentrations were measured during anesthetic washout. RESULTS: Significant differences were not detected for any induction or recovery events for any inhalation agent in iguanas. Washout curves best fit a 2-compartment model, but slopes for both compartments did not differ significantly among the 3 anesthetics. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in blood:gas solubility for isoflurane, sevoflurane, and desflurane did not significantly influence differences in pharmacokinetics for the inhalation agents in iguanas.

Anesthesia, Inhalation↗

PubMed2001

Cooperative binding of inhaled anesthetics and ATP to firefly luciferase.

Firefly luciferase is considered a reasonable model of in vivo anesthetic targets despite being destabilized by anesthetics, as reflected by differential scanning calorimetry (DSC). We examined the interaction between two inhaled anesthetics, ATP, luciferase, and temperature, using amide hydrogen exchange, tryptophan fluorescence, and photolabeling in an attempt to examine this apparent discrepancy. In the absence of ATP/Mg2+, halothane and bromoform cause destabilization, as measured by hydrogen exchange, suggesting nonspecific interactions. In the presence of ATP/Mg2+ and at room temperature, the anesthetics produce considerable stabilization with a negative DeltaH, indicating population of a conformer with a specific anesthetic binding site. Stabilizing interactions are lost, however, at unfolding temperatures. We suggest that preferential binding to aggregated forms of luciferase explain the higher temperature destabilization detected with DSC. Our results demonstrate a cooperative binding equilibrium between native ligands and anesthetics, suggesting that similar interactions could underlie actions at biologically relevant targets.

Adenosine Triphosphate↗