Anaesthetics partition coefficients

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. 

General anaesthetics have been in use for the last 100 years, yet their mechanism of action are still not yet clearly defined. For many years it was thought that general anaesthetics exerted their effects by dissolving in cell membranes and perturbing the lipid environment in a non-specific manner. This theory derived from the observation that for a number of drugs which induced anaesthesia, their potency correlated with their oil-water partition coefficients. This Meyer-Oveiton correlation was accepted for a number of years, however in the last 15-20 years evidence has shown that a more likely theory is that of specific interactions of anaesthetics with proteins, particularly those within the CNS that mediate neurotransmission [1]. 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

All inhaled anaesthetic drugs must be soluble in blood and brain in order to pass across the alveolar-capillary membrane and the blood-brain barrier. The term used to quantify solubility is partition coefficient. For anaesthetic purposes this is defined as the ratio of the concentration of dissolved gas/vapour in the blood to the concentration in the alveoli at... 

Halothane was introduced into clinical practice in 1956. It was not the first fluorinated anaesthetic— fluoroxene (Fluoromar) holds that distinction—but it was the first to achieve widespread acceptability. Halothane is a fluorinated alkane 1-bromo, 1-chloro -2,2,2-trifluoroethane (Figure 3.2). It has a characteristic odour, similar to chloroform, and requires a stabiliser, thymol (0.01%), to prevent degradation by light. Halothane has a blood/gas partition coefficient of 2.4 able 3.2) but its lack of irritant qualities makes possible the use of relatively high inspired concentrations (2-4%). For that reason, inhalation induction is characteristically smooth and rapid. Compared to sevoflurane, and possibly isoflurane, recovery from halothane anaesthesia is delayed. 

These are shown in Table 3.3. Xenon (MAC 70%) has a potency of about twice that of nitrous oxide (MAC 104%). Thus, it can be given in anaesthetic concentrations in o> gen with less risk of hypoxia. It is highly insoluble in all body tissues with a blood/gas partition coefficient of 0.14 (nitrous oxide, 0.47 sevoflurane, 0.65 desflurane, 0.42). 

Membranes Inhalation anaesthetics (diethylether, chloroform, and their more modem replacements). The mode of action of these was enshrouded in mystery for a long time, but accumulating evidence now supports direct interaction with several ion channels. Nevertheless, there is a remarkably close correlation between the ability of these agents to partition into lipid membranes, as measured by their oil-water partition coefficients, and their narcotic activity so, in a sense, cell membranes may be considered the targets of these agents. 

An anaesthetic that has high solubility in blood, i.e., a high blood/gas partition coefficient, will provide a slow induction and adjustment of the depth of anaesthesia. This is because the blood acts as a reservoir (store) for the drug so that it does not enter the brain easily imtil the blood reservoir has been filled. A rapid induction can be obtained by increasing the concentration of drug inhaled initially and by hyperventilating the patient. 

Desflurane has the lowest blood/gas partition coefficient of any inhaled anaesthetic agent and thus gives particularly rapid onset and offset of effect. As it undergoes negligible metabolism (0.03%), any release of free inorganic fluoride is minimised this characteristic favours its use for prolonged anaesthesia. Desflurane is extremely volatile and caimot be administered with conventional vaporisers. It has a very pimgent odour and causes airway irritation to an extent that limits its rate of induction of anaesthesia. 

Halothane has the highest blood/gas partition coefficient of the volatile anaesthetic agents and recovery from halothane anaesthesia is comparatively slow. It is pleasant to breathe and is second choice to sevoflurane for inhalational induction of anaesthesia. Halothane reduces cardiac output more than any of the other volatile anaesthetics. It sensitises the heart to the arrhythmic effects of catecholamines and hypercapnia arrhythmias are common, in particular atrioventricular dissociation, nodal rhythm and ventricular extrasystoles. Halothane can trigger malignant hyperthermia in those who are genetically predisposed (see p. 363). 

The oil solubility of an anaesthetic is of interest, not only because it governs the passage of the anaesthetic into and out of the fat depots of the body, but also because there is a well-established correlation between anaesthetic potency and oil solubility. Figure 2.10 shows a linear inverse relationship between log narcotic concentration and log solubility in oleyl alcohol for a series of common anaesthetic gases. The ordinate of the graph represents the minimum alveolar concentration (MAC), which is that concentration of anaesthetic at which 50% of the patients cease to move in response to a stimulus. The abscissa shows the solubility expressed in terms of the oil/gas partition coefficient. Partition coefficients are widely used to express solubility and are the ratios of the concentration of the gas in the two phases in equilibrium at a given temperature. When, as in this case, one of the phases is the gas itself, the partition coefficient expressed as the liquid/gas (note the order of the phases) concentration ratio is equal to the... 

The correlation between anaesthetic potency and lipid solubility shown in Fig. 2.10 is valid for most inhaled anaesthetics and the product MAC X oil/gas partition coefficient (which should of course be a constant) varies by only a factor of 2 or 3 for potencies ranging over 100 000-fold. This constancy implies that inhaled anaesthetics act in the same manner at a specific hydrophobic site (the so-called unitary theory of anaesthesia). This has been challenged by more recent work that has identified compounds, including alkanes and poly-halogenated and perfluorinated compounds, which do not obey the Meyer- Overton hypothesis. It has been suggested that a contributory cause of deviation from this hypothesis may be the choice of lipid to represent the anaesthetic site of action of these compounds, implying that there may be multiple sites of action for inhaled anaesthetics. 

Figure 2.10 Narcotic concentrations of various anaesthetic agents plotted against solubility in oleyl alcohol (expressed as oil/gas partition coefficient).

Temperature also influences anaesthetic solubility temperature increase leads to a decrease in solubility as expected from section 2.4.1. Table 2.4 shows the temperamre coefficients of the both water/gas, 2water/gas d oil/gas, Aoii/gas partition coefficients for a range of anaesthetic gases. 

These data are relevant clinically because of possible wide variation of body temperature in the surgical patient. Body temperature may be lowered as a result of preoperative sedation, by cutaneous vasodilation, by the infusion of cold fluids and by reduced metabolism under operating conditions. The increase in oil/gas partition coefficient with decreasing temperature means that the effective concentration at the hydrophobic site of action is increasing and hence the apparent potency of the anaesthetic increases. 

The aqueous solubilities of several volatile anaesthetics can be related to the osmolarity of the solution. The inverse relationship between solubility (expressed as the liquid/gas partition coefficient) of those anaesthetics and the osmolarity is shown in Table 3.4. 

Table 3.4 Liquid/gas partition coefficients of anaesthetics in four aqueous solutions at 37°C°...

With this equation, it is now possible to predict the anaesthetic activity of other ether structures, given their partition coefficients. 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and non-volatile anaesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anaesthesia are not fully understood, although various theories have been proposed. Many of these have centred on the correlation between certain physicochemical properties and anaesthetic potency. Thus the oil water partition coefficient, the ability to reduce surface tension and the ability to induce the formation of... 

There exists a direct relationship between the anaesthetic activity of an agent and its lipid solubility. It offers a reasonably acceptable correlation between anaesthetic activity (pharmacologic) of a compound and its oil/water or oil/gas partition coefficient (physical). This hypothesis rightly advocates that the site of action of anaesthetics is usually hydrophobic in nature. It may be anticipated that the greater the lipid solubility of an anaesthetic agent the higher would be its potency. 

Analyses of nerve membranes have brought to light the unusually high ratio of cholesterol to phospholipid, namely about 1 to 3 Chdicko et al. 1976). Because the spinal cord and brain are clad in lipid-rich membranes, a lower dose of a depressant is effective for the central nervous system as compared with the musculature. Thus the partition coefficient of halothane is 6.80 for brain (grey matter), but only 2.92 for muscle (tissue/gas, 37°C) (Lowe, 1968). In detail, the site of action of a general anaesthetic in the central nervous system is not exactly known, some workers favouring the polysynaptic sites, others the cytoplasmic membrane. The physical and molecular nature of this site will be discussed later in this chapter. 

Regardless of structure, anaesthetics and hypnotics have a lipophilicity that approximates to log P = 2.0, the property being lost when this figure is raised or lowered (Hansch, 1971, p. 300). Table 15.1 presents a cross-section of relevant data. In addition, many anaesthetic gases have had partition coefficients determined by gas chromatography (Hansch et al., 1975, Leo et aL, 1975) agreement was excellent. For general information on partition coefficients, see Sections 3.3 and 17.1.. 

Table 15.1 Partition coefficients of anaesthetics and hypnotics used in human medicine (See Table 17.3 for coefficients of other substances)...

Table 17.3 Partition coefficients of drugs between octanol and water. (See Table 15.1 for coefficients of hypnotics and general anaesthetics which average logP = 2.0)...

Figure 1.2. Correlation between the biological potency of local anaesthetics, given as the minimum blocking concentration MBC), and activated carbon adsorption (a, filled squares) or octanol-water partition coefficient P (open squares) (data from ref. (3a))...

Perhaps the most famous examples of early QSAR are seen in the linear relationships between the narcotic action of organic compounds and their oil/water partition coefficients (Meyer 1899 Overton 1899). Table 1.3 lists the anaesthetic activity of a series of alcohols along with a parameter, which describes their partition properties (see Box 1.2 in this chapter for a description of 7t). The relationship between this activity and the physicochemical descriptor can be expressed as a linear regression equation as shown below. 

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