Neural blockade by local anesthetics.

The bimolecular phospholipid membrane that separates axoplasm from extracellular fluid holds the key to nerve excitability: and so to local anesthesia. Local anesthetics block impulse propagation by preventing membrane depolarization. They do this by occluding the sodium pores (probably by plugging the channel's internal axoplasmic mouth). The positively charged local anesthetic $\text{cation}$ binds to oppositely charged anionic channel components, whereas the uncharged lipid soluble anesthetic $\text{base}$ furnishes the carrier species that penetrates the membrane.Dissolved in water, local anesthetic salt crystals dissociate to yield anesthetic cation and base whose proportions are governed by the drug's fixed pK_a and the tissue's variable pH. The more acid the surroundings, the more cation and the less base coexist. The cation/base concentration ratio is critical to optimal blockade. Too little base, and few anesthetic molecules manage to reach the neural target; too little cation, and few sodium channels will be plugged.     

Inhalation Therapy

Joint Accord on the Role of Respiratory (Inhalation) Therapy Personnel in Airway Management and Endotracheal Intubation endorsed by the California Medical Association, the California Hospital Association, the California Society for Respiratory Therapy, the California Society of Anesthesiologists and the California Thoracic Society.     

Effects of local anesthetics on bacterial cells.

The membrane effects of chlorpromazine, nupercain, tetracain, and procain were studied using Bacillus cereus, B. megaterium, B. subtilis, and Streptococcus faecalis, protoplasts from S. faecalis, and isolated membranes from B. subtilis. Chlorpromazin, nupercain, and tetracain produced characteristic micromorphological alterations after treatment for 5 to 30 min at pH 7.0 and 20 degrees C; the membrane staining pattern changed from asymmetric to symmetric, complex mesosome-like structures appeared, and membrane fractures and solubilization occurred. Procain at concentrations up to 100 mM did not induce detectable alterations. Protoplasts were quickly lysed by 10 mM tetracain. A rapid and extensive leakage of K+ was induced by chlorpromazin, nupercain, and tetracain. Procain (100 mM) induced a slight K+ leakage. The membrane respiratory activity of intact B. cereus cells (as measured by the triphenyl tetrazolium reduction) and the succinic dehydrogenase activity of B. subtilis isolated membranes were found to be inhibited by the four local anesthetics. The concentrations that produced 50% inhibition of those activities are correlated with the hydrophobicities of the anesthetic molecules.     

Interactions between anesthetics and lipid mixtures. Normal alcohols.

The effects of normal alcohols up to 1-dodecanol on phase transitions in phosphatidylcholines and phosphatidylethanolamines have been studied using chlorophyll a as fluorescent probe. With the phosphatidylcholines, alcohols up to octanol cause a lowering of the transition temperature, and a broadening of the transition, whereas for dipalmitoylphosphatidylethanolamine, only a lowering of the transition is observed. The lowering of the phase transition temperature in dipalmitoylphosphatidylcholine by butanol and hexanol is close to that expected for ideal behavior, but the behavior of the longer chain alcohols becomes less ideal. The effects of these alcohols on mixtures of lipids have been studied, and they illustrate the care necessary if these plots of temperatures of onset and completion of gel phase formation are to be called "phase diagrams". The effect of 1 -octanol on mixtures of lipids is to increase the proportion of lipid present in the lipid-crystalline state. In contrast, 1-decanol causes an increase in the phase transition temperature for dimyristoylphosphatidylcholine, although it lowers the transition temperature for dipalmitoylphosphatidylcholine, and 1 -dodecanol raises the transition temperature for both of these phosphatidylcholines, although it lowers that for dipalmitoylphosphatidylethanolamine. Dodecanol appears to behave in these lipid bilayer membranes as a lipid with a phase transition temperature of ca. 55 degrees C. Anesthesia is discussed as a phenomenon of liquidus extension: alcohols up to 1 -octanol increase the proportion of lipid in the liquidus state and result in anesthesia, whereas the longer alcohols do not, and result in catalepsy.     

Effects of local anesthetics on the Chara plasmalemma.

The effects of lidocaine, tetracaine, procaine and bupivacaine (less than 1000 microM) on the Chara corallina internodal cell were studied. These local anesthetics depolarized the membrane at rest, while they affected the rising phase and the peak level of action potential not appreciably. Instead, they prolonged the time course of the falling phase of action potential as slowly as the repolarization was imperfect, even after enough lapse beyond the refractory period. Consequently, an action potential appeared to enhance the degree of depolarization at rest. Such a depolarization with stimulus/excitation was named use-dependent depolarization, while the depolarization without excitation, the resting one. The order of the potency of the use-dependent depolarization almost coincided with that of the nerve-blocking potency. During depolarization the change in membrane conductance was not simple. However, the conductance-voltage (Gm-Vm) relationship curve in the presence of local anesthetic suggested that depolarization was due to, not only the decrease in the electrogenic H(+)-pump, but also the increase in the diffusion conductance.     

Interfacial ionization and partitioning of membrane-bound local anesthetics.

Consideration of the interfacial protonation equilibria of membrane-associated amphiphiles indicates that the partition coefficients of the protonated and unprotonated species will differ considerably. The partition coefficients of the charged and uncharged forms of spin-labelled myristic acid in dimyristoylphosphatidylcholine bilayer dispersions have been measured by EPR spectroscopy and found to be approximately 140-fold higher for the protonated acid than for the dissociated salt form. This ratio of partition coefficients is found to be in good agreement with that predicted from the interfacial shift in pKa of the fatty acid on its partitioning into the membrane. The latter was determined from the changes in the EPR spectra of the membrane-associated fatty acid with pH and was found to be +2.1 pH units. The interfacial shifts in pKa for a series of spin-labelled analogues of tertiary amine local anaesthetics have been determined from the pH dependence of the partition coefficients in dimyristoylphosphatidylcholine bilayer dispersions and are found mostly to be in the range of approx. -1.0 to -1.5 pH units, corresponding to a 10- to 30-fold higher partition coefficient of the uncharged base compared with that of the charged ammonium form.     

The penetration of local anesthetics into phosphatidylcholine monolayers.

The penetration of tetracaine into monolayers of phosphatidylcholine and trioctanoin at different surface pressures, and the penetration of dibucaine, tetracaine, butacaine, lidocaine, and procaine into monolayers of didecanoylphosphatidylcholine at II = 10 mN/m was determined by the use of a modified Gibbs adsorption equation. These data were shown to fit a geometric model and compared favorably with data determined by a method based on the geometric model. The penetration of tetracaine into phosphatidylcholine monolayers was pressure dependent. At II = 10 mN/m, the local anesthetics penetrate into a phosphatidycholine monolayer in the order: dibucaine greater than tetracaine greater than butacaine greater than lidocaine greater than procaine. This correlates with their potencies in blocking nerve conduction and inhibiting phospholipase A2.     

Interaction of fluorinated ether anesthetics with artificial membranes.

Fluorine-19 nuclear magnetic resonance spectroscopy is applied to the study of the environment of dipalmitoyl phosphatidylcholine-bound fluorinated ether anesthetics (enflurane, fluoroxene and methoxyflurane) both below and above the lipid gel to liquid crystal phase transition temperature. Line widths and spin-lattice relaxation time (T1) measurements are consistent with substantial immobilization of the lipid-bound anesethetic molecules. Heating anesthetic/lipid mixtures above the lipid transition temperature leads to narrowing of the lipid-bound anesthetic fluorine resonances accompanied by little or no change in anesthetic fluorine-19 chemical shifts, suggesting that although the mobility of the bound anesthetic increases at the higher temperature, the nature of the anesthetic-lipid interaction changes little as a result of this phase change. Differential scanning calorimetric studies of the effects of these anesthetics on the phase transition behavior of the phospholipid indicate that the regions of the bilayer in which volatile anesthetics partition at lower concentrations are different from the regions in which they partition at higher concentrations.     

Structure activity relationship of lidocaine type local anesthetics.

The structure activity relationship of nine compounds were studied and compared to lidocaine. The extent of local anesthetic activity was ascertained by the tail pinch method in mice, and by the isolated frog sciatic nerve method. The effective and lethal dose in 50% of the animals was also determined. Three of the nine compounds appeared to possess significant local anesthetic activity in the $\text{in vivo}$ studies and thus were selected for further investigation $\text{in vitro}$. The $\text{in vivo}$ studies also indicated that two of the three were more toxic than lidocaine. The $\text{in vitro}$ results demonstrated that methyl substitution at positions 2,3 and 5 on the benzene ring produced a compound of slightly more anesthetic potency in an acid medium. At pH 7.8 all three compounds approached the potency of lidocaine. These data indicate that methyl substitution at other than the ortho position of the benzene ring generally results in compounds of lesser local anesthetic activity while tending to increase the toxicity.     

Inhalation injury caused by the products of combustion.

Inhalation injury results from a type of chemical burn (tracheobronchitis) of the respiratory tract. When this injury occurs in patients with serious cutaneous burns the mortality is exceedingly high- 48% to 86%. The injury can be divided into three types according to the level at which the damage occurs; upper airway, major airway and terminal airway. The early signs and symptoms may be complicated by carbon monoxide poisoning. The patient''s condition usually follows a staged progression that is proportional to the extent and severity of the tracheobronchitis. Indirect laryngoscopy, bronchoscopy, scintiscanning of the lung with xenon 133 and serial analysis of arterial blood gases are useful diagnostic techniques. Treatment must be expeditious, and it depends on the severity of the injury. The prophylactic use of antibiotics and steroids is contraindicated.