Anesthetics blocking potency

Tab. 5.1 Relative blocking potency of local anesthetics on natural membranes and various physicochemical effects of local anesthetics on artificial phospholipid membranes. (Reprinted from Tab. 1 of ref.

The effect of pH changes on the potency of local anesthetics has been extensively investigated (30). Based on these studies, it was concluded that local anesthetics block the action potential by first penetrating the nerve membrane in their un-ionized forms and then binding to a site within the channels in their onium forms. Perhaps the most direct support for this hypothesis comes from the experimental results of Narahashi et al. (31,32), who studied the effects of internal and external perfusion of local anesthetics (both tertiary amines and quaternary ammonium compounds), at different pH values, on the sodium conductance of the squid axon. The observation that both tertiary amines and quaternary ammonium compounds produce greater nerve blockage when applied internally indicates an axoplasmic site for these compounds. 

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. 

General anesthetics are usually small solutes with relatively simple molecular structure. As overviewed before, Meyer and Overton have proposed that the potency of general anesthetics correlates with their solubility in organic solvents (the Meyer-Overton theory) almost a century ago. On the other hand, local anesthetics widely used are positively charged amphiphiles in solution and reversibly block the nerve conduction. We expect that the partition of both general and local anesthetics into lipid bilayer membranes plays a key role in controlling the anesthetic potency. Bilayer interfaces are crucial for the delivery of the anesthetics. 

Bupivacaine is more cardiotoxic than equi-effective doses of Udocaine. Clinically, this is manifested by severe ventricular arrhythmias and myocardial depression after inadvertent intravascular administration of large doses of bupivacaine. Bupivacaine dissociates slowly during diastole, so a significant fraction of No channels at physiological heart rates remains blocked with bupivacaine at the end of diastole. Thus, the block by bupivacaine is cumulative and substantially more than would be predicted by its local anesthetic potency. Bupivacaine-induced cardiac toxicity can be very difficult to treat, and its severity is enhanced by coexisting acidosis, hypercarbia, and hypoxemia. The S-enantiomer and the racemate are equally efficacious and potent, but levobupivacaine may be less cardiotoxic. 

Procaine (novocain), the first synthetic local anesthetic, is an amino ester (see Figure 14-1) with low potency, slow onset, and short duration of action. Its use now is confined to infiltration anesthesia and occasionally for diagnostic nerve blocks. Its hydrolysis in vivo produces para-aminobenzoic acid which inhibits the action of sulfonamides. Thus, large doses should not be administered to patients taking sulfonamide drugs. 

Local anesthetics are widely used in many primary care settings. Techniques for their administration in these settings include topical application, local infiltration, field block, and peripheral nerve block. Their use can be maximized by an understanding of their potencies, durations of action, routes of administration, and their pharmacokinetic and side effect profiles. The generic, trade name, and recommended application are given in Table 16.1, and the chemical structures of these agents can be found in Table 16.2. 

They antagonize the positive inotropic and chronotropic effects of catecholamines. Cardiac arrhythmias associated with excessive adrenergic stimulus, released endogenous catecholamines or sensitization of the heart by anes-thetics or cardiac glycosides may effectively be treated by 6-blockade. Some B-blockers also possess membrane or local anesthetic action and are effective against arrhythmias due to ischemia or cardiac glycoside toxicity as well. This membrane action was shown to be independent of 6-blockade since resolved isomers of B-blockers possessed equal antiarrhythmic potency but unequal B-blocking action. 

An analog (ICI 46037) structurally similar to propranolol was shown to possess local anesthetic and antiarrhythmic activity similar to propranolol in the dog. No -blocking action and a lower level of myocardial depressant action was observed . Other analogs have been reported recently having antiarrhythmic activity similar to quinidine in potency. These include 1,5-dimorpholino-3-(l-naphthyl)pentane (DA-1686) 2-propyl amino-1-naphthylpropane (S-931) ethoxamine (BW 62-235) and xipranolol (BS-79770)28. 

Local anesthetics are able to depress or block nerve conduction at low dosage Davis has demonstrated a relationship between antiarrhythmic potency, local anesthesia and neuromuscular transmission . The actions of antiarrhythmic agents to slow conduction can be explained by their depression of neuromuscular transmission. Slowed conduction can be explained through a retardation of the nerve impulse propagation, by increasing the electrical excitation threshold and reducing the rate of rise of the action potential . ... 

Like all local anesthetics, ropivacaine binds directly to the intracellular voltage-dependent sodium channels. It blocks primarily open and inactive sodium channels. Thus, this blocks the generation and conduction of nerve impulses. Lipid solubility appears to be the primary determinant of intrinsic anesthetic potency and toxicity. The more lipid-soluble, the greater is the potency of the local anesthetic. Hence, ropivacaine is less potent and less toxic than bupivacaine. In addition, the progression of blockade is affected by the diameter, myelination, and conduction velocity of the nerve fibers. 

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