Anesthetics, General

General anesthesia is a state of drug-induced reversible inhibition of central nervous function, during which surgical procedures can be carried out in the absence of consciousness, responsiveness to pain, defensive or involuntary movements, and significant autonomic reflex responses (A). 

In regional anesthesia (spinal anesthesia) with a local anesthetic (p. 202), nociceptive conduction is interrupted. Since consciousness is preserved, this procedure does not fall under the definition of anesthesia. 

According to their mode of application, general anesthetics in the narrow sense are divided into inhalational (gaseous, volatile) and injectable agents. 

Inhalational anesthetics are administered in and, for the most part, eliminated via respired air. They serve especially to maintain anesthesia (p. 216) 

Muscle relaxation Loss of consciousness Automatic stabilization 

General anesthetics are administered by intravenous, inhalation, or intramuscular routes. Adverse effects of general anesthetics are hypersensitivity, involuntary muscle movements, bronchospasm, cardiac arrhythmias, and respiratory 

Halothane Illicit use of halothane has been performed by either ingestion or injection. Occupational exposure of nitrous oxide can cause serious toxicity, such as bone marrow and neurologic impairment. Effective ventilation should be provided to control the nitrous oxide pollution in the area of its use. Nitrous oxide has been reported to affect the fertility of male and female workers.235-238 

In general, there are two broad mechanisms by which the decrease in synaptic transmission is achieved by general anesthetics, either increased inhibitory neurotransmission or decreased excitatory neurotransmission. Many general anesthetics, particularly inhalation anesthetics, appear to act at GABA-A receptors, increasing the sensitivity of the receptors to GABA. This is similar to the effects of the sedative-hypnotic agents, at least at a superficial level, and it results 

9 HIGHLY FLUORINATED COMPOUNDS WITH CLINICAL USES 8.9.1 General Anesthetics 

Agent bp ( C) Blood gas Partition Coefficient Muscular Coordination Recuperation Time (min) Metabohsm % 

Fluoroether anesthetic agents have few adverse cardiac effects. However, they are potent peripheral vasodilators and they often provoke shivers upon awakening. 

No difference has been observed in the interactions of the two enantiomers of isoflurane with hpid bilayers. But the (5)-enantiomer of isoflurane is two times more active than the (7 )-enantiomer toward a calcium channel receptor, that is sensitive to volatile anesthetic agents, while nodifference in activity has been observed toward an anesthetic nonsensitive receptor. The (5)-enantiomer of isoflurane is also more active than the (R)-enantiomer toward acetylcholine nicotinic receptor and GABA receptor. These data strongly suggest that fluoroethers interact not only with cerebral membranous lipids but also with receptor proteins. 

Cryofluorane (CIF2C-CF2CI) (Freon 114) is used as a local anesthetic agent for sport and dental uses. 

Identify the main inhalation anesthetic agents and describe their pharmacodynamic properties. Describe the relationship of the blood. gas partition coefficient of an inhalation anesthetic with its speed of onset of anesthesia and its recovery time. 

List the factors that influence inhalation anesthetic biodisposition. 

Describe the main pharmacokinetic and pharmacodynamic characteristics of the intravenous anesthetics. 

Balanced anesthesia Anesthesia produced by a mixture of drags, often including both inhaled and intravenous agents 

Inhalation anesthesia Anesthesia induced by inhalation of drag 

---

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Flurothyl [333-36-8] (bis-(2,2,2-trifluoroeth5i)ether) (9), an analeptic having strong convulsant properties, has been used for chemical shock therapy (13). The compound is unique in that it is a volatile fluorinated ether and its stmcture resembles those of many halogenated general anesthetics. Chemical shock therapy is rarely used. 

Other minor uses of ethyl chloride iaclude blowiag agents for thermoplastic foam (51) and styrene polymer foam (52), the manufacture of polymeric ketones used as lube oil detergents (53), the manufacture of acetaldehyde (qv) (54), as an aerosol propellent (55), as a refrigerant (R-160), ia the preparation of acid dyes (56), and as a local or general anesthetic (57,58). 

Inhalation is the most common means by which ethers enter the body. The effects of various ethers may include narcosis, irritation of the nose, throat, and mucous membranes, and chronic or acute poisoning. In general, ethers are central nervous system depressants, eg, ethyl ether and vinyl ether are used as general anesthetics. 

Diethyl ether [60-29-7] is one of the more important members of the ether family. It is a colorless, very volatile, highly flammable Hquid with a sweet, pungent odor and burning taste. As a commercial product it is available in several grades it is used in chemical manufacture, as a solvent, extractant, or reaction medium, and as a general anesthetic. 

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder that is triggered by exposure to inhalation of general anesthetics, such as halothane. In susceptible individuals, these drugs can induce tachycardia, a greatly increased body metabolism, muscle contracture and an elevated body temperature (above 40°C) with a rapid rate of increase. Many cases of MH are linked to a gene for type 1 ryanodine receptor (RyRl). 

Administration of the aminoglycosides with the cephalosporins may increase the risks of nephrotoxicity. When the aminoglycosides are administered with loop diuretics there is an increased risk of ototoxicity (irreversible hearing loss). There is an increased risk of neuromuscular blockage (paralysis of the respiratory muscles) if the aminoglycosides are given shortly after general anesthetics (neuromuscular junction blockers). 

Ketamine (Ketalar) is a rapid-acting general anesthetic. It produces an anesthetic state characterized by profound analgesia, cardiovascular and respiratory stimulation, normal or enhanced skeletal muscle tone, and occasionally mild respiratory depression. Ketamine is used for diagnostic and surgical procedures that do not require relaxation of skeletal muscles, for induction of anesthesia before the administration of other anesthetic drugp, and as a supplement to other anesthetic drags. 

There is a decreased effectiveness of ritodrine when the drug is administered with a -adrenergic blocking agent such as propranolol and an increased risk of pulmonary edema when administered with the corticosteroids. Co-administration of ritodrine with the sym-pathomimetics potentiates the effect of ritodrine. Cardiovascular effects (eg, arrhythmias or hypotension) of ritodrine may increase when the drug is administered with diazoxide, general anesthetics, magnesium sulfate, or meperidine... 

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. 

Inhalation of other general anesthetics susceptible to abuse, such as ether and chloroform, appears to be limited to health professionals who have easy access to these compounds and who tend to use these dtugs in isolation. Recreational and social use of these substances has been somewhat limited by their high flammability and by frequent and intense undesirable adverse effects at moderate doses. It has been suggested that the abuse of ether or chloroform alone is a rare phenomenon (Delteil et al. 1974 Deniker et al. 1972), occurring usually in the context of dependence on othet substances, particularly alcohol (Krenz et al. 2003). 

Intoxication delirium may occur with solvents, nitrous oxide (Sterman and Coyle 1983), ether, or other general anesthetics (Delteil et al. 1974). However, to our knowledge, there are no reports describing delirium associated with nitrite intoxication. The description of delirium presented here derives mainly from what has been observed during solvent intoxication. 

Price HE, Dripps RD General anesthetics, in The Pharmacological Basis of Therapeutics, 3th Edition. Edited by Goodman LS, Gilman A. New York, Macmillan, 1975, pp 88-96... 

HHMC can also be directly activated by agents injected intravenously for therapeutic (general anesthetics, protamine, etc.) or diagnostic purposes (radiocontrast media, etc.), which can cause non-IgE-mediated anaphylactic reactions in vitro [24,... 

---