The membrane concentrations of neutral and positive anesthetics (alcohols, chloropromazine, morphine) fit the meyer-overton rule of anesthesia; negative narcotics do not

Abstract

1. 1. The anti-hemolytic action of 44 anesthetics, and the adsorption of most of these anesthetics to erythrocyte membranes, synaptosomes and sarcoplasmic reticulum were compared. Neutral, positive and negative anesthetics all reduced hypotonic hemolysis at concentrations known to cause local anesthesia. 2. 2. The membrane/buffer partition coefficients of anesthetics in the nerve or muscle membranes were the same as those for the erythrocyte membranes. 3. 3. The membrane/buffer partition coefficients for the neutral anesthetics were independent of the free drug concentration or the ionic strength; the coefficients for the positive anesthetics decreased at higher free concentrations and higher ionic strength; the coefficients of the negative anesthetics were independent of the free concentration but increased with ionic strength. 4. 4. The membrane/buffer partition coefficients for the neutral anesthetics were invariably one-fifth of the octanol/water partition coefficients, indicating that the membrane is much less hydrophobic than octanol. The good correlation justifies and facilitates the calculation of the membrane/buffer partition coefficients for neutral molecules directly from the octanol/water system. There was no correlation between the two sets of coefficients for the positive anesthetics. 5. 5. For all the neutral and positively charged anesthetics, the concentrations in the membrane phase (for equi-effective anti-hemolytic action) fell in the range predicted by the Meyer-Overton rule of anesthesia, all values being of the order of 0.04 mole anesthetic per kg dry membrane. The membrane concentrations of the negatively charged anesthetics (barbiturates and fatty acids) were 20- to 40-fold lower than the Meyer-Overton range. 6. 6. The anesthetic molecular volume occupying the membrane (at equi-effective anti-hemolytic action) was calculated as 2–3 ml/kg dry membrane for all the neutral and positive anesthetics; the negative molecules occupied around 0.1 ml/kg dry membrane. It is concluded that the negative molecules have a 20- to 40-fold higher intrinsic efficacy in the membrane phase.