General anesthetics solubility

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. 

It was at the turn of the twentieth century that the importance of lipid solubility in drug action was also independently described by Meyer and Overton (the significance of the oil/water partition coefficient was discussed in Chapter 2). The importance of lipid solubility in drug action subsequently became manifested in the lipoid theory of cellular depression. In essence, this theory correlated a pharmacological effect (e.g., CNS depression) with a physical property (i.e., lipid solubility) rather than a structure-activity relationship. In the process, the theory was attempting to explain the diverse chemical structures that exist within the hypnotic and general anesthetic classes of drugs (see Chapter 11). Today, we realize the limitations of the lipoid theory and appreciate that the distinction between physical and chemical factors is illusory, since chemical structure is a determinant of physical properties. 

General anesthetics are soluble in lipids. Only a few are soluble in water. Furthermore, there is a well known correlation between anesthetic potency and lipid solubility. It is the Meyer-Overton rule that has been known for 80 years to researchers in anesthesia.. This relationship was thoroughly studied and reexamined in recent years (See ). In its most modem form the lipid solubility or oil/water partition coefTicient is plotted against the so-called righting reflex taken for a measure of anesthetic potency. It is log 1/p where p is the effective anesthetic pressure in atmospheres required to suppress the righting reflex of mice in half of the experimental animals On this relationship arc based the unitary hypothesis and the hydrophobic site theory which state that all general anesthetics act by the same mechanism at the same molecular or sub-cellular sites of the membrane and that the sites are hydrophobic. 

Intravenous anesthetics are also relatively lipid-soluble, which helps account for their rapid onset. This high degree of lipid solubility allows them to rapidly cross the blood-brain barrier and partition into the brain. Barbiturates such as thiopental and methohexitol and the nonbarbiturates etomidate and propofol are often used to induce anesthesia, but only propofol is commonly used today as a general anesthetic by continuous infusion, thus only propofol will be discussed. 

That the lipid solubility versus anesthetic potency relationship is not above criticism has been intimated for a number of years by a number of authors. Summaries of the relevant facts and comments are found in the reviews of Halsey and Kaufman . It is only since 1974, however, that the possible importance of polar interactions has become a target of intense discussions. General anesthetics have widely different chemical structures and it has never been possible to classify them on chemical grounds. Xenon, nitrous oxide, ethylene, cyclopropane, ether, chloroform, C Fg, SFg, CFj—CHClj, CFj-CHClBr (halothane), CHjOCF.CHCf, (methoxyflurane) can all exert anesthetic action. (This aspect will be discussed in more detail in the next section). Looking at the formulas of these different molecules it is hard to believe that they all associate with the same site and with the same type of forces. A series of observations have been made in recent years that substantiate this scepticism. 

The concentrations of general anesthetics in the brain depend on their solubility, their concentration in the inspired air, the rate of pulmonary ventilation, the rate of pntmonary blood flow, and the concentration gradient of the anesthetic between arterial and mixed venous blood. 

FIGURE 13-4 Uptake of inhalational general anesthetics. The rise in end-tidal alveolar (F ) anesdietic concentration toward the inspired (Fj) concentration is most rapid widi die least soluble anesdietics, nitrous oxide and desflurane, and slowest with the most soluble anesdietic, halodiane. 

Methoxyflurane (Fig. 18.6) is seldom used beoause of its propensity to cause renal toxicity. It is the most potent of the agents discussed here, and it has the highest solubility in blood. Induotion and recovery would be expected to be slow. Chemically, it is rather unstable, and as much as 50% of an administered dose can be metabolized. Toxic metabolites significantly limit its utility as a general anesthetic (Fig. 18.7). 

The body also has a blood-brain barrier that enables only lipid soluble dmgs—such as general anesthetics and barbiturates— into the brain and cerebral spinal fluid (CSF). The only way for nonlipid soluble dmgs to enter the brain is if they are instilled intrathecally, that is, injected directly into the CSF, bypassing the blood-brain barrier. 

Certain respiratory tract irritants, including a number of fluorocarbons, can produce cardiac arrhythmias. Such effects may be attributed to the reduction of coronary blood flow, depression, or contractility and sensitization of the heart to epinephrine and several other factors. Many lipid-soluble substances can depress cardiac contractility. These include organic solvents, many general anesthetics, and aminoglycoside antibiotics. 

We have found that general anesthetics (that are lipid-soluble molecules) induce some fluidization of the lipid bilayer in liposomes prepared from mitochondrial lipids, but the effect is rather small except when high concentrations of anestetics are used. However, in mitochondrial membranes we have found a large disordering effect induced by anesthetics (17). 

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