Anesthetics membrane localization

FIGURE 12-3 Schematic diagram showing mechanism of action of local anesthetics on the nerve membrane. Local anesthetics appear to bind directly to a site within the sodium channel, thereby locking the channel in a closed position, thus preventing sodium entry and action potential propagation. 

Local anesthetic activity Local anesthetic activity ( membrane stabilizing activity ) is a disadvantage when beta-blockers are used topically in the eye because it decreases protective reflexes and increases the risk of corneal ulceration. Local anesthetic effects are absent from timolol and several other beta-blockers. 

Local Anesthetic - Membrane Active Antiarrhythmics - Many established anti-arrhythmic agents have been found to possess local anesthetic activity which parallels their effectiveness against a variety of cardiac arrhyth-rnias. These agents include quinidine, procaine amide, lidocaine and propranolol. They appear to act by depressing impulse conduction and by restoring normal automaticity to the myocardium. 

C. North andD.S. Cafiso. Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the meyer-overton hypothesis of general anesthetic potency. Biophys. J., 72 (1997) 1754-1761. 

Note that the relative spatial arrangement of the phenyl, amine, and hydroxyl functionahties are identical for (R)-alprenolol and (5)-sotalol. In addition to P-blocking activities, some of these compounds also possess potent local anaesthetic activity (see Anesthetics). The membrane stabilizing activity, however, is not stereoselective and correlates directly with the partition coefficient (hydrophobicity) of the compound. 

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory, as well as motor nerve, fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics act by inhibiting the channel s opening they bind to a receptor located in the channel s interior. The degree of blockage on an isolated nerve depends not only on the amount of dmg, but also on the rate of nerve stimulation (153—156). 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Toxic Reactions of the Skin Irritation is the most common reaction of the skin. Skin irritation is usually a local inflammatory reaction. The most common skin irritants are solvents dehydrating, oxidizing, or reducing compounds and cosmetic compounds. Acids and alkalies are common irritants. Irritation reactions can be divided into acute irritation and corrosion. Necrosis of the surface of the skin is typical for corrosion. Acids and alkalies also cause chemical burns. Phenols, organotin compounds, hydrogen fluoride, and yellow phosphorus may cause serious burns. Phenol also causes local anesthesia, in fact it has been used as a local anesthetic in minor ear operations such as puncture of the tympanous membrane in cases of otitis. ... 

Treatment of 2,6-dimethylaniline (121) with phosgene and triethylamine affords the corre-S]ionding isocyanate (122). Condensation of that reactive intermediate with N-isopropylpropyl-cne-1,3-diamine leads to formation of urea 123. This product, recainam (123), acts as membrane Stabilizing agent and thus exhibits both local anesthetic and antiarrhythmic activity [30]. 

Topical anesfliesia involves die application of die anes-flietic to die surface of the skin, open area, or mucous membrane The anesthetic may be applied wifli a cotton swab or sprayed on the area This type of anesthesia may be used to desensitize the skin or mucous membrane to the injection of a deeper local anesthetic. In some instances, topical anesthetics may be applied by the nurse ... 

Topical anesthetics temporarily inhibit the conduction of impulses from sensory nerve fibers. These drug s may be used to relieve itching and pain due to skin conditions, such as minor bums, fungus infections, insect bites, rashes, sunburn, and plant poisoning, such as poison ivy. Some are applied to mucous membranes as local anesthetics. Examples of local anesthetics include benzocaine (Lanacane), dibucadne (Nupereainal), and lidocaine (Xylocadne). 

Starmer C.F. Grant A.O. and Strauss, H.C. Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J 46 5-21, 1984. 

Local anesthetics interact with peripheral nerve cell membranes and exert a pharmacological effect [34]. Potential oscillation was measured in the presence of 20 mM hydrochlorides of procaine, lidocaine, tetracaine, and dibucaine (structures shown in Fig. 16) [19]. Amplitude and the oscillatory and induction periods changed, the extent depending on the... 

In this section, we focus on how to determine DD sites by NMR. The specification of the DD sites in bilayers can be done by utilizing the NMR signals of both drugs and membrane lipids. An example of the delivery site determination is given for the case of two benzene derivatives, propylbenezene (PrBe) and benzyl alcohol (BzOH) in egg phosphatidylcholine (EPC) bilayers [46]. Alkylbenzenes are suspected to be endocrine disruptors, and BzOH is one of the local anesthetics. 

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. 

Most recently, we have applied and H NMR to the delivery of local anesthetics from water to phospholipid bilayer membranes [48]. Preferential locations of the four drugs DBC-H+, PRC-H+, TTC-H+, and LDC-H+ in EPC SUV have been specified and compared. To specify the delivery sites of drugs on the atomic-site level from their... 

It has been proposed that local anesthetics pass nerve membrane by neutral species despite the clinical adminsitration of the cationic form. Experimental molecular information is required for a better understanding of the mechanism. Thus the NMR information can be useful to the anesthetic discharging in membranes. 

Miyazaki, J. Hideg, K. Marsh, D., Inerfacial ionization and partitioning of membrane-bound local anesthetics, Biochim. Biophys. Acta 1103, 62-68 (1992). 

---