General anesthetics toxicity

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 ... 

Hypotensive effect Narcotic analgesics may cause severe hypotension in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or coadministration of drugs such as phenothiazines or general anesthetics. Renal toxicity Avinza doses over 1,600 mg/day contain a quantity of fumaric acid that has not been demonstrated to be safe, which may result in serious renal 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. 

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. 

Based on their studies of animals, scientists believe that, in general, when toxic vapors circulate to the brain, they depress the central nervous system. The action is similar to that of alcohol, sedatives, and anesthetics. Thus, many of the immediate physical changes inhalant users experience are similar to those caused by alcohol or anesthetics, including relaxation, slurred speech, slowed reflexes, lack of coordination, sleepiness, dizziness, headache, nausea, and vomiting. Abusers might also sneeze, cough, and drool. 

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. 

Chlorinated Hydrocarbons Other Chlorinated Compounds. The substitution of chlorine atom for hydrogen in a compd greatly increases the anesthetic action of the derivative. In addn, the chlorine deriv is less specific than the parent hydrocarbon in its action, and may affect other tissues along with those of the central nervous system of this body. The chlorine deriv is generally quite toxic and may cause liver, heart Sc kidney damage. As a rule, unsaturated chlorine derivs are highly narcotic but less toxic than saturated derivs. Sax(Ref 4) has discussed in detail the toxicities Sc hazards of a number of chlorinated compds, including Chlorinated Diphenyls Chlorinated Hydrocarbons, Aromatic Aliphatic Chlorinated Naphthalenes Chlorinated Phenols Chlorinated Triphenyls others. 

The belladonna alkaloids are much more toxic than the indoles and phenethylamines. Furthermore, they are just plain dangerous, and the experiences they give are, at best, difficult to integrate with ordinary consciousness. Kava-kava seems to me more like alcohol than like the psychedelics, as does nitrous oxide, a general anesthetic with similar depressant qualities. PCP and ketamine are pharmacological curiosities, not related to other recreational drugs. Many users like the "dissociative" states they provide, but few find them truly psychedelic. Their toxicity and abuse potential are significant. 

SAFETY PROFILE A human poison by ingestion and possibly other routes. Poison experimentally by ingestion, intravenous, and rectal routes. Moderately toxic by subcutaneous, parenteral, and intraperitoneal routes. Experimental reproductive effects. Human systemic effects by ingestion general anesthetic, cardiac arrhythmias, blood pressure depression, eye effects, coma, pulse rate increase, arrhythmias. Human mutation data reported. 

SAFETY PROFILE Moderately toxic by inhalation. Human systemic effects by inhalation general anesthetic, decreased pulse rate without blood pressure fall, and body temperature decrease. An experimental teratogen. Experimental reproductive effects. Mutation data reported. An asphyxiant. Does not bum but is flammable by chemical reaction and supports combustion. Moderate explosion hazard it can form an explosive mixture with air. Violent reaction with Al, B, hydrazine, LiH, LiC6Hs, PH3, Na, tungsten carbide. Also self-explodes at high temperatures. 

SAFETY PROFILE Poison by ingestion, intraperitoneal, rectal, subcutaneous, and intravenous routes. Human systemic effects by intraarterial route acute arterial occlusion by rectal route respiratory depression, body temperature decrease, general anesthetic. An experimental teratogen. Experimental reproductive effects. An intravenous anesthetic. When heated to decomposition it emits toxic fumes of NOx and Na20. See also PENTOTHAL and BARBITURATES. 

Halothane is a volatile general anesthetic that was introduced into the practice of clinical anesthesia in 1956. Shortly after its introduction two forms of hepatic injury were noted to occur in patients who received halothane anesthesia. A subclinical increase in blood concentration of transaminase enzymes is observed in 20% of patients and has been attributed to lipid peroxidation caused by the free radical formed by reductive metabolism of halothane as shown in Figure 16.7 (39/ 40). The second form of toxicity is a potentially fatal hepatitis-like reaction that is characterized by severe hepatocellular necrosis and is thought to be initiated by the oxidative formation of trifluoroacetyl chloride (Figure 16.7). Fatal hepatic necrosis occurs in only 1 of 35/000 patients exposed to halothane/ but the risk of this adverse event is greater in females and is increased with repeat exposure/ obesity/ and advancing age (40). Because the onset of halothane hepatitis is delayed but is more frequent and occurs more rapidly following multiple exposures/ and because these patients usually are febrile and demonstrate eosinophilia/ this reaction is suspected... 

A weak solution of hdocaine has sometimes been injected into excess fat before liposuction, so that the procedure can be carried out without general anesthesia. The technique is generally regarded as safe (51). However, deaths are increasingly reported, associated with local anesthetic toxicity or drug interactions (49). 

Anesthetic agents are a diverse class of chemicals which are extremely important in modern medicine. They are generally used to produce a loss of sensation to all stimuli, either in a specific anatomical area, or a total loss of consciousness. Anesthetics differ from analgesics in that analgesics such as aspirin, acetaminophen, ibuprofen, or morphine act to decrease pain, but not other sensations. Anesthetics can be broadly categorized into two general classes, local anesthetics and general anesthetics. These classes are independent as far as indication, chemical class, routes of administration, and toxicity, and thus will be considered separately. It will be noted when one compound within a class differs from the others. 

Propofol Propofol has been relatively free of acute side effects other than those associated with its mechanism of action. Continuous infusions lasting greater than 10 days in ICUs have demonstrated no significant apparent toxicities. Propofol is not recommended for obstetrics, including cesarean section deliveries. It crosses the placenta, and as with other general anesthetic agents, may be associated with neonatal depression. Propofol is not recommended for use in nursing mothers because it is excreted in human milk, and the effects of oral absorption of small amounts of propofol in newborn and infants are not known. 

The precise mechanism of toxicity of cyclohexane has not been identified, but is likely similar to other central nervous system (CNS) depressants and general anesthetics. These compounds are believed to exert their effects through a general interaction with the CNS, and interference with neuronal membrane functions has been postulated as a mechanism of action. Disruption of membrane enzymes and the corresponding alterations in cell functions may account for the behavioral and anesthetic effects observed following exposure to various solvents. 

Meprobamate s chief toxicity is through central nervous system depression. Its precise mechanism of action is unknown. It appears to inhibit or affect neurotransmission in the thalamus, hypothalamus, limbic system, and spinal cord. In high doses, meprobamate can act as a general anesthetic with respiratory depression and cardiovascular collapse thought to be from a combination of vascular muscle and direct cardiac effects. 

This is a broad category of toxic action in which exaggeration of the therapeutic effects of many drugs in overdose can lead to poisoning. For example, general anesthetics are also respiratory depressants, and too high concentrations can cause fatalities. Many antihypertensives cause potentially fatal vascular collapse and shock when taken in overdose. Overdoses of certain antiarrhythmic drugs can themselves cause fatal arrhythmias, actions that are related to their action on ion channels. 

Methoxyflurane (Fig. 18.6) is seldom used beoause of its propensity to cause renal toxicity. It is the most potent of the agents discussed here, and it has the highest solubility in blood. Induotion and recovery would be expected to be slow. Chemically, it is rather unstable, and as much as 50% of an administered dose can be metabolized. Toxic metabolites significantly limit its utility as a general anesthetic (Fig. 18.7). 

Propionaldehyde is a mild irritant to human skin and eyes. The irritation effect from 40 mg was severe in rabbits eyes. The toxicity of this compound observed in test animals was low. Subcutaneous administration in rats exhibited the symptoms of general anesthetic effect, convulsion, and seizure. Inhalation toxicity was determined to be low. A concentration of 8000 ppm (19,000 mg/m ) in air was lethal to rats. 

Toxicity of n-butyraldehyde is very low. The effect is primarily narcotic. No toxic effect, however, was observed in mice from 2-hour exposure at a concentration of 44.6 g/m. At a higher concentration, 174 g/m for 30 minutes, it exhibited a general anesthetic effect on rats. Subcutaneous administration of a high dose, >3 g/kg, produced the same effect, affecting the kidney and bladder. 

PGME is a mild toxicant. The toxicity is lower than that of the methyl, ethyl, and butyl ethers of ethylene glycol. The toxic symptoms from inhaling high concentrations are nausea, vomiting, and general anesthetic effects. In humans, toxic effects may be felt at exposure to a level of 3000-4000 ppm. 

The toxicity of 1,3-butadiene has been found to be very low in humans and animals. It is an asphyxiant. In humans, low toxic effects may be observed at exposure to 2000 ppm for 7 hours. The symptoms may be hallucinations, distorted perception, and irritation of eyes, nose, and throat. Higher concentrations may result in drowsiness, lightheadedness, and narcosis. High dosages of 1,3-butadiene was toxic to animals by inhalation and skin contact. General anesthetic effects and respiratory depression were noted. Concentrations of 25-30% may be lethal to rats and rabbits. Contact with the liquefied gas can cause bum and frostbite. 

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