Anesthetic agents

L(K al uncslhelic.s are blocking drugs thal, when administered locally in the correct conccmralion. block the nerves that carry nerve impulses in local areas of the body. TTiey do not block coarse touch or movement, and the action is reversible. Their methtxl of administration is governed by such properties as toxicity, stability, duration of action, water solubility, membrane permeability, and point of application, while their modes of action (see under heading. Mechanism of Action) depend on their lipid solubility. pK, . vasodilation, and pri tein binding characteristics. 

Although given locally, the drug may exert a systemic effect because of transport in the blood from the site of administration to other areas, sueh us the heart and central nervous system (CNS). These systemic effect.s. which depend on the concentration of the local anesthetic in the blood, are usually sedation and lighthcudedness. but restlessness, nausea, and anxiety may also occur. High plasma concentrations cun result in convulsions, chiropidy. and coma with rc.spiratory and cardiac depression. 

Local anesthetics an. u.scd to alleviate the pain caused by a wide variety of situations. They arc used in dentistry, in ophthalmology, in minor surgical operations including endoscopy. and in relieving pain in intractable medical conditions. such as tumors growing in the spine. Local anesthetics ore al.so used topically for the temporary relief of pain from insect bites, burns, and other types of surface wounds. They are particularly effective when they arc used on mucous membranes, such as the mouth, vagina, or rectum 

Einhorn. on realizing Mcriing s success with the benzoate 

Although the Orthoforms were relatively succc.ssful as topical anesthetics, their poor water solubility made them unsuitable fur other medicinal uses. Consequently, Einhorn attempted to improve their water solubility by introducing amine-containing aliphatic side chains. He reasoned that the formation of their amine hydrochlorides would improve water solubility without making the preparation too acidic. One of Einhom s compounds, Nirvanin, was introduced in 1898. Its activity was low. and it had to be used in high doses, which caused toxic effects. 

With very large concentrations of phenobarbital, regional differences disappear and glucose use becomes almost homogeneous at very low levels (Ingvar et aL, 1980). 

Region Thiopental Pentobarbitar hydrate s Urethane S (70% 30%/ Ketamine  

Auditory cortex Sensory cortex Medial geniculate body Ventral thalamic nucleus 

Globus pallidus Hypothalamus Superior olivary nucleus Hippocampus 

Pentobarbital (30 mg/kg, i.v.) administered 20 min before the measurement of glucose utilization (Nagai 

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Anxiolytics are compounds that act primarily to refleve the symptoms of anxiety although such agents can also be used as anticonvulsants, sedatives, hypnotics, and anesthetic agents (see Anesthetics). The principal class of anxiolytics, the BZs, shows dependence HabiUty (5) whereas newer agents such as buspkone [36505-84-7] and ritanserine [8705-43-2] produce antianxiety effects via central serotoninergic systems (6). 

The onset of action is fast (within 60 seconds) for the intravenous anesthetic agents and somewhat slower for inhalation and local anesthetics. The induction time for inhalation agents is a function of the equiUbrium estabUshed between the alveolar concentration relative to the inspired concentration of the gas. Onset of anesthesia can be enhanced by increasing the inspired concentration to approximately twice the desired alveolar concentration, then reducing the concentration once induction is achieved (3). The onset of local anesthetic action is influenced by the site, route, dosage (volume and concentration), and pH at the injection site. 

Opioids. Morphine [57-27-2] C yH NO, (8) the most prevalent and analgesicaHy potent of the naturally occurring opium alkaloids (qv), has been used as an anesthetic premedication for over one hundred years (93). It has also been used as an iv analgesic for the last four decades, and, since 1969, in high doses as an anesthetic agent (117). 

Table 4. In Vitro Conduction Blocking and Physiochemical Properties of Local Anesthetic Agents ...

The rate of removal of the local anesthetic from the site of injection also affects its profile. AH local anesthetic agents possess some vasodilatory activity at clinically useful concentrations. Agents which are more potent in this regard tend to be absorbed more rapidly by the vasculature. They are less potent anesthetics and have shorter durations than those having lower vasodilatory activity. A comparison of potency, onset, and duration as a function of physiochemical properties is presented in Table 4. 

Another clinical consideration is the abiUty of local anesthetic agents to effect differential blockade of sensory and motor fibers. In surgical procedures such as obstetrics or postoperative pain rehef, an agent which produces profound sensory block accompanied by minimal motor block is desirable. On the other hand some procedures such as limb surgery require both deep sensory and motor blockade. In clinical practice, bupivacaine ( 22,... 

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. 

Anesthetic Agents Under Development. Ropivacaine (AL-381) (22, R = similar in stmcture to mepivacaine and bupivacaine, has... 

The total U.S. market value for the anesthetic agents Hsted was 299.9 million ia 1990 (162). General inhalation agents, valued at 154.5 million, comprised over half (51.5%) of the 1990 market. General iv anesthetics were valued at 111.5 million (37.2%). Local iajectable agents, at 33.9 million, represented the smallest portion of the market (11.3%). U.S. sales for selected anesthesia pharmaceuticals are given ia Table 6. 

Untoward effects of both E and NE (usually to a lesser degree) are anxiety, headache, cerebral hemorrhage (from vasopressor effects), cardiac arrhythmias, especially in presence of digitaUs and certain anesthetic agents, and pulmonary edema as a result of pulmonary hypertension. The minimum subcutaneous lethal dose of E is about 4 mg, but recoveries have occurred after accidental overdosage with 16 mg subcutaneously and 30 mg intravenously, followed by immediate supportive treatment. 

Ethylene is slightly more potent as an anesthetic than nitrous oxide, and the smell of ethylene causes choking. Diffusion through the alveolar membrane is sufficiendy rapid for equilibrium to be estabUshed between the alveolar and the pulmonary capillary blood with a single exposure. Ethylene is held both ia cells and ia plasma ia simple physical solution. The Hpoid stroma of the red blood cells absorb ethylene, but it does not combine with hemoglobin. The concentration ia the blood is 1.4 mg/mL when ethylene is used by itself for anesthesia. However, ia the 1990s it is not used as an anesthetic agent. 

ANILINES, BENZYL AMINES, AND ANALOGUES An orally active local anesthetic agent that can be used as an (intiarrhythmic agent is meobenti ne (57). Its patented synthesis starts with -hydroxyphenyl nitrile and proceeds by dimethyl sulfate etherification and Raney nickel reduction to Alkylation of -methyl-dimethylthiourea with completes l.he synthesis of meobenti ne (57). ... 

Schatz M, Fung DL Anaphylactic and anaphylactoid reactions due to anesthetic agents. Clin Rev Allergy 1986 4 215-227. 

QUESTION Are the effects of amphetamine in the anesthetized preparation conformded by the anesthetic agent ... 

Phencyclidine (PCP), a dissociative anesthetic agent, which is subject to abuse, produces behavioral effects in man that frequently resemble schizophrenia (Luisada 1978). Manifestations of persistent psychopathology frequently remain after the acute effects of PCP have diminished. With PCP, subjects may display autistic and delusional thinking typical of schizophrenics (Luby et al. 1959). A more striking link between schizophrenia and PCP comes from observations of cases in which PCP was given to hospitalized schizophrenics (Luisada 1978). After receiving PCP, these patients showed extreme exacerbation of their psychoses the reaction persisted for up to 6 weeks. By contrast, LSD produced no more severe effects in schizophrenics than in normal subjects. 

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