Anesthetics mechanisms of action

B. G. Coviao and H. G. VasaHo, Local Anesthetics Mechanism of Action and Clinical Use, Grune and Stratton, New York, 1976. 

Covino, B. G. and H. G. Vasallo Inca Anesthetics Mechanism of Action and Clinica Use. On me and Stratton. New York, NY, 1976 Evers, A. S, and M. Maze Anesthetic Pharmacology Physiologic Principles and Clinical Practice, Elsevier Science, New York, NY, 2003. 

The mechanism of action of these anesthetics involves the blockade of sodium channels in the membrane of the second-order sensory neuron. The binding site for these anesthetics is on a subunit of the sodium channel located near the internal surface of the cell membrane. Therefore, the agent must enter the neuron in order to block the sodium channel effectively. Without the influx of sodium, neurons cannot depolarize and generate an action potential, so the second-order sensory neuron cannot be stimulated by impulses elicited by pain receptors associated with the first-order sensory neuron. In other words, the pain signal is effectively interrupted at the level of the spinal cord and does not travel any higher in the CNS. In this way, the brain does not perceive pain. 

Inhalation of certain hydrocarbons, including some anesthetics, can make the mammalian heart abnormally sensitive to epinephrine, resulting in ventricular arrhythmias, which in some cases can lead to sudden death (Reinhardt et al. 1971). The mechanism of action of cardiac sensitization is not completely understood but appears to involve a disturbance in the normal conduction of the electrical impulse through the heart, probably by producing a local disturbance in the electrical potential across cell membranes. The hydrocarbons themselves do not produce arrhythmia the arrhythmia is the result of the potentiation of endogenous epinephrine (adrenalin) by the hydrocarbon. 

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). 

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic Liillmann, Color Atlas of Pharmacology... 

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. 

The mechanisms of action of the effects of alcohol on the nervous system remain unclear. For some time, researchers thought that the depressant effects of alcohol, like other anesthetic agents, were caused by dissolving into the cell lipid membranes and disrupting the function of various proteins. More recently, researchers have focused on specific receptors such as glutamate (excitatory) and GABA (inhibitory). Despite intensive research, the mechanism of effect of alcohol on the fetus is unknown. 

General anesthetic drugs have the ability to reduce the level of consciousness in a dose dependent fashion. The study of the neurobiological mechanisms of action of these drugs may provide insight into the systems that are necessary for the existence of consciousness. It clearly cannot be assumed however, that the systems that underlie the action of these substances are in themselves sufficient for consciousness. Indeed, within a complex neural network, any number of small alterations can disturb the whole. This chapter focuses on what is known about the molecular mechanism of action of drugs that are used clinically for general anesthesia. 

Local anesthetics, when applied at effective concentrations locally to nerve tissue, reversibly block nerve impulse conduction and block somatic sensory, somatic motor and autonomic nerve transmission. Their mechanism of action is based on both... 

Ziconotide is a non-opioid, non-NSAID, non-local anesthetic used for the amelioration of chronic pain. In December 2004 the FDA approved ziconotide for intrathecal administration. The drug is derived from a marine snail toxin. Its mechanism of action has not yet been elucidated. Due to serious side effects or lack of efficacy when delivered through more conventional routes ziconotide must be administered in-trathecally. It s use is considered appropriate only for management of severe chronic pain in patients for whom intrathecal therapy is indicated. 

Among the earliest proposals to explain the mechanism of action of anesthetics is the concept that they interact physically rather than chemically with lipophilic membrane components to cause neuronal failure. However, this concept proposes that all anesthetics interact in a common way (the unitary theory of anesthesia), and it is being challenged by more recent work demonstrating that specific anesthetics exhibit selective and distinct interactions with neuronal processes and that those interactions are not easily explained by a common physical association with membrane components. Proposals for the production of anesthesia are described next. 

Mechanism of Action A local anesthetic that blocks nerve conduction in the autonomic, sensory, and motor nerve fibers. Competes with calcium ions for membrane... 

Mechanism of Action A non-narcotic antitussive that anesthetizes stretch receptors in respiratory passages, lungs, andp ema TherapeuticEffect Reduces cough production. 

Mechanism of Action A general anesthetic and antiemetic agent that antagonizes dopamine neurotransmission at synapses by blocking postsynaptic dopamine receptor sites partially blocks adrenergic receptor binding sites. Therapeutic Effect Produces tranquilization, antiemetic effect. 

Mechanism of Action An anticholinergicthat relaxes detrusor and other smooth muscle by cholinergic blockade, counteracting muscle spasm in the urinary tract, Thera-peuticEffect Produces anticholinergic, local anesthetic, and analgesic effects, relieving urinary symptoms. 

Mechanism of Action An amide anesthetic that inhibits conduction of nerve impulses. Therapeutic Effect Causes temporary loss of feeling and sensation. Also an... 

Mechanism of Action An antiarrhythmicthat prevents sodium current across myocardial cell membranes. Has potent local anesthetic activity and membrane stabilizing effects. Slows AV and His-Purkinje conduction and decreases action potential duration and effective refractory period. Therapeutic Effect Suppresses ventricular arrhythmias. 

Mechanism of Action A surface or local anesthetic which is not chemically related to the "caine" types of local anesthetics. Decreases the neuronal membrane permeability to sodium ions, blocking both initiation and conduction of nerve impulses, therefore inhibiting depolarization of the neuron. Therapeutic Effect Temporarily relieves pain and itching associated with anogenital pruritus or irritation. 

Mechanism of Action Tetracaine causes a reversible blockade of nerve conduction by decreasing nerve membrane permeability to sodium. Therapeutic Effect Local anesthetic. 

Mechanism of Action An amide-type local anesthetic that shortens the action potential duration and decreases the effective refractory period and automaticity in the His-Purkinje system of the myocardium by blocking sodium transport across myocardial cell membranes. Therapeutic Effect Suppresses ventricular arrhythmias. Pharmacokinetics Very rapidly and completely absorbed following PO administration, Protein binding 10%, Metabolized in liver. Excreted in urine. Half-life 15 hr. 

---