Toxic agents anesthetics

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

This consists in the injection of the local anesthetic into or around the nerve trunk or in the area of its distribution, so as to block off sensory impulses from the operative field. Because fatal effects may arise from the absorption of the anesthetic, the smallest amount of the least-toxic agent that is effective should be employed, under conditions that minimize absorption. Procaine with the addition of epinephrine (1 100,000) is generally preferred. A well-planned technique is important. It is not necessary to flood the entire field of operation, as in the earliest methods, nor even to infiltrate the whole line of incision, as in infiltration anesthesia. It is now aimed at confining the anesthetic mainly to the nerves, by placing it where the nerves chiefly run or injecting it into the nerves themselves. 

Toxic agents cause injuries in different ways and have been categorized into seven types (see Figure 5-1) asphyxiates, irritants, systemic poisons, anesthetics, neurotics, corrosives, and carcinogens. 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Specific Local Anesthetic Agents. Clinically used local anesthetics and the methods of appHcation are summarized in Table 5. Procaine hydrochloride [51-05-8] (Novocain), introduced in 1905, is a relatively weak anesthetic having along onset and short duration of action. Its primary use is in infiltration anesthesia and differential spinal blocks. The low potency and low systemic toxicity result from rapid hydrolysis. The 4-arninobenzoic acid... 

Lidocaine hydrochloride [73-78-9] (Xylocaine), is the most versatile local anesthetic agent because of its moderate potency and duration of action, rapid onset, topical activity, and low toxicity. Its main indications are for infiltration, peripheral nerve blocks, extradural anesthesia, and in spinal anesthesia where a duration of 30 to 60 min is desirable. Because of its vasodilator activity, addition of the vasoconstrictor, epinephrine, increases the duration of action of Hdocaine markedly. It is also available in ointment or aerosol preparations for a variety of topical appHcations. 

The reader is advised to exercise caution in the extrapolation of toxicity data from animals to humans. Species-related differences in sensitivity must be accounted for. Some studies utilized to derive MRLs or otherwise extrapolate data, is dated however, they do represent the body of knowledge regarding chloroform toxicity. In addition, many of the human studies quoted involved clinical case reports in which chloroform was utilized either as an anesthetic or as an agent of suicide. Such doses are clearly excessive and would not be encountered by the general population. These and other issues are addressed in Section 2.10. 

An effective anesthetic agent must be easy to use, quickly render the patient unconscious, and not produce any toxicity. Dr. William T. G. Morton first publicly demonstrated the use of ether as an effective anesthetic agent at the Massachusetts General Hospital on 16 October 1846 before a crowd of skeptical physicians. Raymundus Lullius, a Spanish chemist, discovered ether (CH3CH2)20 in 1275. Its hypnotic effects were soon appreciated (and enjoyed by some), but for many decades ether was only used to treat the occasional medical ailment. Even with ether, the success of surgical procedures did not improve until the introduction of antiseptic procedures and infection control some 20 years later. Ether was replaced by cyclopropane in 1929, which was replace by halothane in 1956. While anesthetic agents are desirable for the patient, exposure of hospital staff is highly undesirable and an important occupational consideration. 

Usually various anesthetic agents are combined to increase efficacy and at the same time decrease toxicity and shorten the time to recovery. For example induction of anesthesia is obtained with an intravenous agent with a rapid onset of action like thiopentone and then anesthesia is maintained with a nitrous oxide/oxygen mixture in combination with halothane or a comparable volatile anesthetic. 

Halogenated hydrocarbon inhalation anesthetics may increase intracranial and CSF pressure. Cardiovascular effects include decreased myocardial contractility and stroke volume leading to lower arterial blood pressure. Malignant hyperthermia may occur with all inhalation anesthetics except nitrous oxide but has most commonly been seen with halothane. Especially halothane but probably also the other halogenated hydrocarbons have the potential for acute or chronic hepatic toxicity. Halothane has been almost completely replaced in modern anesthesia practice by newer agents. 

Procainamide (Pwnestyl, Procan SR) is a derivative of the local anesthetic agent procaine. Procainamide has a longer half-life, does not cause CNS toxicity at therapeutic plasma concentrations, and is effective orally. Procainamide is a particularly useful antiarrhythmic drug, effective in the treatment of supraventricular, ventricular, and digitalis-induced arrhythmias. 

Combining agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine, 1 200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. 

Several first-generation Hi antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to conventional local anesthetic drugs. A small number of these agents also block potassium channels this action is discussed below (see Toxicity). 

The development of newer agents continues because it is relatively easy to synthesize chemicals with local anesthetic properties. Unfortunately, it is difficult to reduce the toxicity of these compounds because the common side effects of local anesthetics represent extensions of their therapeutic effects. New research into the mechanisms of local anesthetic-induced cardiac and spinal toxicity and identification of alternative drug targets for spinal analgesia (eg, opioid receptors, [Pg.560]

The anesthetic effect of the agents with short and intermediate durations of action can be prolonged by increasing the dose or adding a vasoconstrictor agent (eg, epinephrine or phenylephrine). The vasoconstrictor slows the removal of the local anesthetic from the injection site. In addition, it decreases the blood level and the probability of cardiovascular and CNS toxicity. 

Datura alba Nees. D. fastuosa L. var. alba Clark D. innoxia Mill. D. metel L. D. stramonium L. D. talula L. Man Tu Luo (Jimsonweed) (leaf, seed, flower) Scopolamine, hyoscyamine, daturodiol, daturolone, hyoscine.33-144 450 This herb is toxic. Spasmolytic, analgesic, antiasthmatic, antirheumatic agent. A general anesthetic for major operations. 

Inhaled anesthetics currently in use include halo-genated volatile liquids such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, and sevoflurane (Table 11-1). These volatile liquids are all chemically similar, but newer agents such as desflurane and sevoflurane are often used preferentially because they permit a more rapid onset, a faster recovery, and better control during anesthesia compared to older agents such as halothane.915 These volatile liquids likewise represent the primary form of inhaled anesthetics. The only gaseous anesthetic currently in widespread use is nitrous oxide, which is usually reserved for relatively short-term procedures (e.g., tooth extractions). Earlier inhaled anesthetics, such as ether, chloroform, and cyclopropane, are not currently used because they are explosive in nature or produce toxic effects that do not occur with the more modern anesthetic agents. 

Local anesthetics block the sodium channels, are cardiac depressants, and bring about a ventricular conduction defect and block that may progress to cardiac and ventilatory arrest if toxic doses are given. In addition, these agents produce arteriolar dilation. Circulatory failure may be treated with vasopressors such as ephedrine, metaraminol (Aramine), or mephentermine (Wyamine). Artificial respiration and cardiac massage may also become necessary. Among the local anesthetics, only cocaine blocks the uptake of norepinephrine, causes vasoconstriction, and may precipitate cardiac arrhythmias. 

Many substances of widely different chemical structure abolish the excitability of nerve fibers on local application in concentrations that do not cause permanent injury and that may not affect other tissues. Sensory nerve fibers are most susceptible, so that these agents produce a selective sensory paralysis, which is utilized especially to suppress the pain of surgical operation. This property was first discovered in cocaine, but because of its toxicity and addiction liability, it has been largely displaced by synthetic chemicals. The oldest of these, procaine (novocaine), is still the most widely used. Its relatively low toxicity renders it especially useful for injections, but it is not readily absorbed from intact mucous membranes and is therefore not very effective for them. Many of its chemical derivatives are also used. They differ in penetration, toxicity, irritation, and local injury as well as in duration of action and potency. Absolute potency is not so important for practical use as is its balance with the other qualities. If cocaine is absorbed in sufficient quantity, it produces complex systemic actions, involving stimulation and paralysis of various parts of the CNS. These are mainly of toxicological and scientific interest. Its continued use leads to the formation of a habit, resembling morphinism. This is not the case with the other local anesthetics. 

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