Study General Anesthetics

Despite the paucity of systematic studies in humans, the available evidence suggests that, like drugs such as alcohol, sedatives, and stimulants, inhalant drugs (i.e., solvents, general anesthetics, and nitrites) exert reinforcing effects and increase motor activity. Furthermore, with continuous use, these drugs appear to induce both tolerance and symptoms of withdrawal. 

FIG. 1 Molecular structures of the drugs examined in the delivery study the general anesthetics, alkanols (I), halothane (II), enflurane (III), isoflurane (IV), halogenated cyclobutane (V) the local anesthetics, dibucaine hydrochloride (VI), procaine hydrochloride (VII), tetracaine hydrochloride (VIII), lidocaine hydrochloride (IX), benzyl alcohol (X) the endocrine disruptor, bisphenol A (XI), and alkylbenzenes, benzene (XII), toluene (XIII), ethylbenzene (XIV), and propylbenzene (XV). 

Doring HJ. 1975. Reversible and irreversible forms of contractile failure caused by disturbances by general anesthetics in myocardial ATP utilization. In Fleckenstein A, DhallaNS, eds. Recent Advances in Studies on Cardiac Structure and Metabolism, vol. 5 Basic functions of cations in myocardial activity. Baltimore, MD University Park Press, 395-403. 

GHB was hrst synthesized in the laboratory by the French biochemist Henri Lahorit (1914-1995) in 1961. In the succeeding four decades, extensive research has been conducted on the pharmacological uses and effects of GHB. In general, those studies appear to suggest that GHB has some valuable applications in the medical sciences. It functions well as an anesthetic with apparently few or no serious side effects. Based on this research, the drug has been adopted in many parts of the world for use as a general anesthetic, a treatment for narcolepsy and insomnia, a treatment for alcoholism, and an aid in childbirth. 

Mild burning of the eyes after acute exposure to either trow-1,2-dichloroethylene vapor or aerosol was reported by two subjects in a 1936 self-experimentation study. However, dichloroethylene has been used in combination with ether as a general anesthetic in at least 2000 cases with no evidence of ocular toxicity ... 

General anesthetic drugs have the ability to reduce the level of consciousness in a dose dependent fashion. The study of the neurobiological mechanisms of action of these drugs may provide insight into the systems that are necessary for the existence of consciousness. It clearly cannot be assumed however, that the systems that underlie the action of these substances are in themselves sufficient for consciousness. Indeed, within a complex neural network, any number of small alterations can disturb the whole. This chapter focuses on what is known about the molecular mechanism of action of drugs that are used clinically for general anesthesia. 

Table 1. The modulatory elFect of general anesthetic drugs on ligand-gated ion channels. The effect of chnicaUy relevant concentrations of general anesthetic drugs. -I- indicates potentiation, 0 indicates no signihcant effect in the majority of studies and -indicates inhibition of activation. indicates insufficient data is available.

Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose-dependent fashion. Of the general anesthetics that have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following order isoflurane (most) sevoflurane, desflurane, enflurane, and halothane and nitrous oxide (least) (Figure 27-9). The most important factors involved in this interaction are the following (1) nervous system depression at sites proximal to the neuromuscular junction (ie, central nervous system) (2) increased muscle blood flow (ie, due to peripheral vasodilation produced by volatile anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction and (3) decreased sensitivity of the postjunctional membrane to depolarization. 

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

Hence, it is believed that general anesthetics exert most, if not all, of their effects by binding to one or more neuronal receptors in the CNS. This idea is a departure from the general perturbation theory described earlier that is, that the inhaled anesthetics affected the lipid bilayer rather than a specific protein. Continued research will continue to clarify the mechanism of these drugs, and future studies may lead to more agents that produce selective anesthetic effects by acting at specific receptor sites in the brain and spinal cord. 

In 1958 the Parke-Davis pharmaceutical company synthesized and patented PCP and tested it further on animals. Studies revealed that moderate doses had a stimulant effect and higher doses had depressant effect. After some further testing on humans, Parke-Davis began selling the drug as a general anesthetic called Sernyl. 

The toxicities of alkyl halides vary a great deal with the compound. Although some of these compounds have been considered to be almost completely safe in the past, there is a marked tendency to regard each with more caution as additional health and animal toxicity study data become available. Perhaps the most universal toxic effect of alkyl halides is depression of the central nervous system. Chloroform, CHC13, was the first widely used general anesthetic, although many surgical patients were accidentally killed by it. 

There is a long history of controversy in the literature regarding the mode of action of general anesthetics. Experimental results derived from model systems of lipids alone or lipid-cholesterol are somewhat controversial. To mention just a few, using Raman spectroscopy it was found that, at clinical concentrations, halothane had no influence on the hydrocarbon chain conformations, and it was concluded that the interaction between halothane and the lipid bilayer occurs in the head group region [57]. This idea was also supported by 19F-NMR studies. The chemical shifts of halothane in a lipid suspension were similar to those in water and differed from those in hydrocarbons. In contrast, from 2H-NMR experiments, it was concluded that halothane is situated in the hydrocarbon region of the membrane (see also chapter 3.3). 

The effects of intravenous and caudal epidural clonidine on the incidence and severity of postoperative agitation have been assessed in a randomized, double-blind study in 80 children, all of whom received sevoflurane as the sole general anesthetic for induction and maintenance... 

General anesthetics are soluble in lipids. Only a few are soluble in water. Furthermore, there is a well known correlation between anesthetic potency and lipid solubility. It is the Meyer-Overton rule that has been known for 80 years to researchers in anesthesia.. This relationship was thoroughly studied and reexamined in recent years (See ). In its most modem form the lipid solubility or oil/water partition coefTicient is plotted against the so-called righting reflex taken for a measure of anesthetic potency. It is log 1/p where p is the effective anesthetic pressure in atmospheres required to suppress the righting reflex of mice in half of the experimental animals On this relationship arc based the unitary hypothesis and the hydrophobic site theory which state that all general anesthetics act by the same mechanism at the same molecular or sub-cellular sites of the membrane and that the sites are hydrophobic. 

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