Handbook of experimental pharmacology
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The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. ⋯ In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
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The heart has a strong endogenous cardioprotection mechanism that can be triggered by short periods of ischaemia (like during angina) and protects the myocardium during a subsequent ischaemic event (like during a myocardial infarction). This important mechanism, called ischaemic pre-conditioning, has been extensively investigated, but the practical relevance of an intervention by inducing ischaemia is mainly limited to experimental situations. Research that is more recent has shown that many volatile anaesthetics can induce a similar cardioprotection mechanism, which would be clinically more relevant than inducing cardioprotection by ischaemia. ⋯ Since ischaemia-reperfusion of the heart routinely occurs in a variety of clinical situations such as during transplant surgery, coronary artery bypass grafting, valve repair or vascular surgery, anaesthetic-induced cardioprotection might be a promising option to protect the myocardium in clinical situations. Initial studies now confirm an effect on surrogate outcome parameters such as length of ICU or in-hospital stay or post-ischaemic troponin release. In this chapter, we will summarize our current understanding of the three mechanisms of anaesthetic cardioprotection exerted by inhalational anaesthetics.
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There are two optical isomers of the 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone ketamine: S(+) ketamine and R(-) ketamine. Effects of this drug are mediated by N-methyl-d-aspartate (NMDA), opioid, muscarinic and different voltage-gated receptors. Clinically, the anaesthetic potency of the S(+)-isomer is approximately three to four times that of the R(-)-isomer, which is attributable to the higher affinity of the S(+)-isomer to the phencyclidine binding sites on the NMDA receptors. ⋯ The combination of ketamine with midazolam or propofol can be extremely useful and safe for sedation and pain relief in intensive care patients, especially during sepsis and cardiovascular instability. In the treatment of chronic pain ketamine is effective as a potent analgesic or substitute together with other potent analgesics, whereby it can be added by different methods. There are some important patient side-effects, however, that limit its use, whereby psycho-mimetic side-effects are most common.
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Most opioids used in anaesthesia are of the anilidopiperidine family, including fentanyl, alfentanil, sufentanil and remifentanil. While all share similar pharmacological properties, remifentanil, the newest one, is probably the most original, which is the reason this review focusses especially on this drug. ⋯ Consequently, it offers a unique titratability when its effects need to be quickly achieved or suppressed, but it requires specific drug delivery schemes such as continuous infusion, target-controlled infusion and anticipated postoperative pain treatment. Kinetic differences between opioids used in anaesthesia and some clinical uses of remifentanil are reviewed in this chapter.
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In this chapter, drawn largely from the synthesis of material that we first presented in the sixth edition of Miller's Anesthesia, Chap 31 (Stanski and Shafer 2005; used by permission of the publisher), we have defined anesthetic depth as the probability of non-response to stimulation, calibrated against the strength of the stimulus, the difficulty of suppressing the response, and the drug-induced probability of non-responsiveness at defined effect site concentrations. This definition requires measurement of multiple different stimuli and responses at well-defined drug concentrations. There is no one stimulus and response measurement that will capture depth of anesthesia in a clinically or scientifically meaningful manner. ⋯ We demonstrate the scientific evidence that profound degrees of hypnosis in the absence of analgesia will not prevent the hemodynamic responses to profoundly noxious stimuli. Also, profound degrees of analgesia do not guarantee unconsciousness. However, the combination of hypnosis and analgesia suppresses hemodynamic response to noxious stimuli and guarantees unconsciousness.