Anesthetic drugs requirements

Forms of local anesthesia. Local anesthetics are applied via different routes, including infiltration of the tissue (infiltration anesthesia] or injection next to the nerve branch carrying fibers from the region to be anesthetized (conduction anesthesia of the nerve, spinal anesthesia of segmental dorsal roots), or by application to the surface of the skin or mucosa (surface anesthesia]. In each case, the local anesthetic drug is required to diffuse to the nerves concerned from a depot placed in the tissue or on the skin. 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

In the caudal form of extradural anesthesia, the agent is introduced through the sacral hiatus above the coccyx. It is particularly applicable to perineal and rectal procedures. Anesthetization of higher anatomical levels is not easily obtained, because the required injection volume can be excessive. Although caudal anesthesia has been used extensively in obstetrics, lumbar epidural blockade is now more commonly used because of the lower dose of drug required in addition, the sacral segments are spared until their anesthesia is required for the delivery. 

Since local anesthetics are membrane-stabilizing drugs, both parenteral (eg, intravenous lidocaine) and oral (eg, mexiletine, tocainide) formulations of these drugs have been used to treat patients with neuropathic pain syndromes. Systemic local anesthetic drugs are commonly used as adjuvants to the combination of a tricyclic antidepressant (eg, amitriptyline) and an anticonvulsant (eg, carbamazepine) in patients who fail to respond to the standard tricyclic plus anticonvulsant combination. One to 3 weeks are required to observe a therapeutic effect after introduction of the local anesthetic in patients with neuropathic pain. 

Surgical patients who are premedicated with chlorpromazine respond poorly to pressor drugs, requiring larger-than-anticipated doses. The inotropic effects of epinephrine (increase in the strength of muscular contraction) are reduced by chlorpromazine. The chronotropic effects of epinephrine (increase in the rate of contraction) are increased as the result of chlorpromazine s anticholinergic properties. The local vasoconstrictor action of epinephrine (as used with a local anesthetic) is blocked by chlorpromazine, but its hyperglycemic effect is not. The lethal effect of toxic doses of epinephrine or norepinephrine can be reversed by chlorpromazine. 

These may enhance the effects of central nervous system depressants. Therefore, the doses of anesthetics drugs need to be titrated (usually reduced) to the effect required. 

Two studies report on the interaction of A -THC with anesthetics. The minimum alveolar anesthetic (MAC) requirements for cyclopropane in rats and halothane in dogs were significantly decreased by pretreatment with A -THC. Analgesia, sedation and prolonged barbiturate sleeping time after acute A -THC injection may reflect the potential additive anes-thetic-like action of the drug. Alternatively, drvigs that deplete norepinephrine in the CNS decrease halothane MAC . 

The low structural requirements for local anesthetic activity do not maintain in all classes of drugs. Structural requirements for biologic activity in fact follow a full continuum from those cases in which addition of a single carbon atom serves to abolish activity to the case of the local anesthetics that tolerate quite drastic alterations. 

Narcotic or antianxiety drug—to decrease anxiety and apprehension immediately before surgery. The patient who is calm and relaxed can be anesthetized more quickly, usually requires a smaller dose of an induction drug, may require less anesthesia during surgery, and may have a smoother anesthesia recovery period (awakening from anesthesia). 

It thus follows that the membrane concentration of typical P-gp substrates for halfmaximum activation of P-gp falls in the range of 1 to 10 mmole drug per mole lipid. This is a much narrower concentration range than that required for the same substances in the aqueous phase 10 8 to 10 3 M. A similar phenomenon has been observed in anesthesia. The membrane concentration of anesthetics required for anesthesia has been found to be 33 mM, independent of the anesthetic applied (Meyer-Overton rule). 

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