What makes a general anesthetic a general anesthetic? We shall review first what general anesthesia is all about and which drugs are being used as anesthetics. There is neither a unique definition of ...general anesthesia nor any consensus on how to measure it. Diverse drugs and combinations of drugs generate general anesthetic states of sometimes very different clinical quality. Yet the principal drugs are still considered to belong to the same class of 'general anesthetics'. Effective concentrations of inhalation anesthetics are in the high micromolar range and above, and even for intravenous anesthetics they do not go below the micromolar range. At these concentrations, many molecular and higher level targets are affected by inhalation anesthetics, fewer probably by intravenous anesthetics. The only physicochemical characteristic shared by anesthetics is the correlation of their anesthetic potencies with hydrophobicity. These correlations depend on the group of general anesthetics considered. In this review, anesthetic potencies for many different targets are plotted against octanol/water partition coefficients as measure of hydrophobicity. Qualitatively, similar correlations result, suggesting several but weak interactions with proteins as being characteristic of anesthetic actions. The polar interactions involved are weak, being roughly equal in magnitude to hydrophobic interactions. Generally, intravenous anesthetics are noticeably more potent than inhalation anesthetics. They differ considerably more between each other in their interactions with various targets than inhalation anesthetics do, making it difficult to come to a decision which of these should be used in future studies as representative 'prototypical general anesthetics'.
The development of resistance to pharmacological treatment is common to many human diseases. In chronic epilepsy, many patients develop resistance to anticonvulsant drug treatment during the course ...of their disease, with the underlying mechanisms remaining unclear. We have studied cellular mechanisms underlying drug resistance in resected hippocampal tissue from patients with temporal lobe epilepsy by comparing two groups of patients, the first displaying a clinical response to the anticonvulsant carbamazepine and a second group with therapy‐resistant seizures. Using patch‐clamp recordings, we show that the mechanism of action of carbamazepine, use‐dependent block of voltage‐dependent Na+ channels, is completely lost in carbamazepine‐resistant patients. Likewise, seizure activity elicited in human hippocampal slices is insensitive to carbamazepine. In marked contrast, carbamazepine‐induced use‐dependent block of Na+ channels and blocked seizure activity in vitro in patients clinically responsive to this drug. Consistent with these results in human patients, we also show that use‐dependent block of Na+ channels by carbamazepine is absent in chronic experimental epilepsy. Taken together, these data suggest that a loss of Na+ channel drug sensitivity may constitute a novel mechanism underlying the development of drug‐resistant epilepsy. Ann Neurol 2003
The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5‐HT
3A
receptors and 5‐HT reuptake carriers, stably expressed in HEK‐293 cells, were ...studied with patch‐clamp‐ and (
3
H5‐HT)‐uptake techniques.
At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5‐HT
3A
receptors concentration‐dependently (IC
50
=0.064 and 0.076
μ
M
, respectively) when it was applied in equilibrium (60 s before and during 5‐HT (30
μ
M
) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200‐fold (IC
50
=19.0
μ
M
, peak current suppression).
Metoclopramide (0.10
μ
M
) did not alter the EC
50
of 5‐HT‐induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5‐HT in this functional assay, metoclopramide inhibited specific
3
HGR65630 binding to human h5‐HT
3A
receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5‐HT‐induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200 n
M
metoclopramide).
At low concentrations (1–10 n
M
), ergotamine had no effect on 5‐HT (30
μ
M
)‐induced peak currents. Above clinical concentrations, ergotamine (>3
μ
M
) inhibited them.
When both drugs were applied together (0.10
μ
M
metoclopramide+0.001 to 0.01
μ
M
ergotamine), an inhibition of both, peak and integrated current responses was observed.
Neither metoclopramide (30
μ
M
) nor ergotamine (30
μ
M
) had an effect on the 5‐HT reuptake carrier as they did not alter the citalopram‐sensitive
3
H5‐HT uptake.
British Journal of Pharmacology
(2005)
146
, 543–552. doi:
10.1038/sj.bjp.0706351
Voltage‐gated Na+ channels are a main target of many first‐line anticonvulsant drugs and their mechanism of action has been extensively investigated in cell lines and native neurons. Nevertheless, it ...is unknown whether the efficacy of these drugs might be altered following chronic epileptogenesis. We have, therefore, analysed the effects of phenytoin (100 µm), lamotrigine (100 µm) and valproate (600 µm) on Na+ currents in dissociated rat hippocampal granule neurons in the pilocarpine model of chronic epilepsy. In control animals, all three substances exhibited modest tonic blocking effects on Na+ channels in their resting state. These effects of phenytoin and lamotrigine were reduced (by 77 and 64%) in epileptic compared with control animals. Phenytoin and valproate caused a shift in the voltage dependence of fast inactivation in a hyperpolarizing direction, while all three substances shifted the voltage dependence of activation in a depolarizing direction. The anticonvulsant effects on Na+ channel voltage dependence proved to be similar in control and epileptic animals. The time course of fast recovery from inactivation was potently slowed by lamotrigine and phenytoin in control animals, while valproate had no effect. Interestingly, the effects of phenytoin on fast recovery from inactivation were significantly reduced in chronic epilepsy. Taken together, these results reveal that different anticonvulsant drugs may exert a distinct pattern of effects on native Na+ channels. Furthermore, the reduction of phenytoin and, to a less pronounced extent, lamotrigine effects in chronic epilepsy raises the possibility that reduced pharmacosensitivity of Na+ channels may contribute to the development of drug resistance.
5-Hydroxytryptamine type 3 (5-HT3) receptors are excitatory ligand-gated ion channels which are involved in postoperative nausea and vomiting. They are depressed by the anesthetic propofol, which, in ...contrast, enhances the activity of inhibitory ligand-gated ion channels such as gamma-aminobutyric acid type A receptors and glycine receptors. To investigate the molecular mechanisms responsible for these contrasting actions, we examined the kinetics of the action of propofol and its lesser hydrophobic derivatives 2-isopropylphenol and phenol on human 5-HT3A receptors.
Human embryonic kidney 293 cells containing stably transfected cDNA of the human 5-HT3A receptor subunit were patch clamped (excised outside-out patches). Drugs were applied with a fast solution exchange system (within 2 ms) and their concentrations were determined by high performance liquid chromatography.
When applied in equilibrium (60 s before and during the 5-HT pulse), propofol inhibited human 5-HT3A receptors (IC50 = 18 +/- 1.0 microM). In equilibrium, the less hydrophobic 2-isopropylphenol was surprisingly a similarly potent inhibitor of human 5-HT3A receptors (IC50 = 17 +/- 3.2 microM), whereas phenol was considerably less potent (IC50 = 1.6 +/- 0.2 mM). Varying the duration of drug application before currents were elicited, and then applying 5-HT still in the presence of the drug revealed that fast and slow processes contributed to the (equilibrium) effects of propofol (tau(IN-1) = 35 ms and tau(IN-2) = 4.8 s), 2-isopropylphenol (tau(IN-1) = 64 ms and tau(IN-2) = 6.6 s), and phenol (tau(IN-1) < 10 ms, tau(IN-2) = 20.4 s). When applied transiently together with 5-HT (open channel application), propofol depressed currents and accelerated the 5-HT-induced desensitization significantly, whereas, in contrast, 2-isopropylphenol and phenol increased currents and slowed desensitization. Slowed desensitization was also observed for 5-hydroxyindole (1 mM), a 5-HT derivative, but not for benzene. The fast effects of phenol, 2-isopropylphenol, and propofol were more pronounced when the 5-HT concentration was decreased from 30 to 3 microM, whereas the slow effects were not sensitive to 5-HT.
At least two separate inhibitory actions on 5-HT3A receptors could be identified for propofol, whereas the enhancing action seen for the two related smaller phenol derivatives could no longer be detected. 5-HT-dependent and 5-HT-independent interactions could be distinguished for all three drugs. Propofol was less potent than expected from its hydrophobic properties. Underlying mechanisms appear to involve the phenolic hydroxyl group, hydrophobic interactions, and steric restrictions.
The spinal H-reflex has been shown to correlate with surgical immobility, i.e., the absence of motor responses to noxious stimulation, during isoflurane anesthesia. Here, the authors established ...individual concentration-response functions for H-reflex amplitude and tested the predictive power of the H-reflex for movement responses during sevoflurane anesthesia in comparison to electroencephalographic parameters. In addition, they investigated the effect of noxious stimulation on the H-reflex itself.
The authors studied 12 female patients during sevoflurane anesthesia before surgery. The sevoflurane concentration was increased, a laryngeal mask was inserted, and then the sevoflurane concentration was decreased until H-reflex amplitude (recorded over the soleus muscle) recovered. Thereafter, the end-tidal sevoflurane concentration was kept at a constant value close to the minimum alveolar concentration for suppression of movement responses after tetanic stimulation (MACtetanus), determined by the Dixon up-down method. Pharmacodynamic modeling of H-reflex amplitude and of the Bispectral Index was performed, and predictive values for motor responses to noxious electrical stimulation (50 Hz, 60 mA tetanus, volar forearm) were compared using the prediction probability.
Concentration-dependent depression of H-reflex amplitude by sevoflurane was well modeled (median r2 = 0.97) by a sigmoid function with a median EC50 of 1.5 vol% and a median slope parameter of 3.7, much steeper than the slope for the Bispectral Index. MACtetanus calculated by logistic regression was 1.6 vol%. H-reflex amplitude predicted motor responses to noxious stimulation with a prediction probability of 0.76, whereas the prediction probability for Bispectral Index and spectral edge frequency (SEF95) were not different from chance alone. Noxious stimulation was followed by a substantial increase of H-reflex amplitude for several minutes, whereas the Bispectral Index and SEF95 exhibited no significant changes.
Suppression of movement to noxious stimulation and suppression of H-reflex amplitude by sevoflurane follow similar concentration-response functions. Although this does not imply a causal relation, it explains the high predictive value of H-reflex amplitude for motor responses to noxious stimuli, even in a narrow concentration range around the MACtetanus.
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