Thiopental lipophilicity

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

Compounds of similar structure and ionization may have very different partition coefficients. For example, thiopental and pentobarbital are very similar in structure and acidity but have very different lipophilicity (Fig. 3.5), and hence their disposition in vivo is different (see below). 

The difference between the two drugs pentobarbital and thiopental is that thiopental has a sulfur atom at position 2 whereas pentobarbital has an oxygen atom. Consequently thiopental is more lipophilic and therefore will be more readily absorbed and will distribute more rapidly into fat tissue. 

Barbiturates are generally widely distributed throughout the body. The highly lipophilic barbiturates, especially those used to induce anesthesia, undergo redistribution when administered intravenously. Barbiturates enter less vascular tissues over time, such as muscle and adipose tissue, and this redistribution decreases concentrations in the blood and brain. With drugs such as thiopental, this redistribution results in patients waking up within 5 to 15 min after injection of a anesthetic dose. 

In comparing thiopental and penicillin, it is found that thiopental enters the brain more rapidly than muscle the reverse is the case for penicillin. Thiopental is a lipophilic substance, which diffuses easily into both muscle and brain. Because the perfusion of brain is higher than that of muscle, thiopental diffuses more rapidly into the brain. Penicillin is a polar substance, which does not enter the brain at all. However, because the muscle capillaries are porous, they allow many drugs, including penicillin, to diffuse rapidly across the membrane. 

Lipophilic drugs will be enriched in the fat tissue (example Thiopental - see later)... 

Thiopental is a very lipophilic drug that readily crosses the blood brain barrier. Very shortly after injection, the concentration in the brain peaks, and for a few minutes the... 

In general, structural changes in the barbiturate series (see Chapter I4 that favor partitioning into the lipid tissue stores decrease duration of action but increase central nervous system (CNS) depres.sion. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. This latter group of barbiturates both enters and leaves the CN.S more slowly than the more lipophilic thiopental. 

The low concentration of protein in the interstitial fluid has been suggested as another factor which may reduce the distribution of some substances in the central nervous system. Lipid soluble compounds, such as methyl mercury which is toxic to the central nervous system (see Chapter 7). can enter the brain readily, the facility being reflected by the partition coefficient. Another example which illustrates the importance of the lipophilicity in the tissue distribution and duration of action of a foreign compound is afforded by a comparison of the drugs thiopental and pentobarbital (figure 3,5). These drugs are very similar in structure, only differing by one atom. Their pKa values are similar and consequently the... 

Whether given orally or parenterally, drugs are distributed nonuniformly throughout the body. Factors that regulate this distribution are the lipophilic characteristics of the drugs, the blood supply to the tissues, and the chemical composition of various organs and tissues. The distribution of drugs not only influences their onset of action but also at times determines their duration of action. For example, thiopental, an intravenous anesthetic, produces unconsciousness 10 to 20 s after its administration, and consciousness returns in 20 to 30 min. The rapid onset of action is due to the rapid transport of thiopental to the brain. The short duration of action stems from its subsequent redistribution to other tissues, such as muscle and fat. 

Ketamine is an arylcyclohexylamine, a congener of phencyclidine. It is supplied as a racemic mixture even though the S-isomer is more potent with fewer side effects. Although more lipophilic than thiopental, ketamine is water soluble and available as 10-, 50-, and 100-mg/mL solntions in sodium chloride plus the preservative benzethonium chloride. 

Methohexital is more lipophilic than thiopental, and thus has a faster onset of action. It exhibits minimal accumulation in fatty tissues and thus has a shorter duration of action, leading to a faster recovery time. The potency of methohexital is approximately twice that of thiopental. 

Ketamine is a congener of phencyclidine (Figure 13—1). Although more lipophilic than thiopental, ketamine is water soluble. 

The high lipophilicity of thiopental ensures rapid entry to the CNS following an intravenous bolus dose. As the blood level falls, thiopental exits the brain and is redistributed to other highly perfused tissues such as the liver and skeletal muscles. Thus, the brain level of thiopental rapidly declines to the point that consciousness is regained within a few minutes. Ultimately, the elimination of thiopental depends on its metabolism by the liver, but only 10-15% of thiopental is metabolized per hour. The answer is (D). 

Substitution of the 2-oxygen by sulphur converts barbiturates into highly lipophilic, potent hypnotics, with a rapid onset of action and short duration of activity. A notable example of this class is thiopentone (XXIV, thiome-bumal, thiopental, Nesdonal, Penthiobarbital, Pentothal), which is widely employed as an intravenous anaesthetic. 

In moderate doses, the action of the benzodiazepines is remarkably like that of the barbiturates, but they are more selective because larger doses do not introduce the toxicity to the patient seen in barbiturate medication. Intravenous diazepam can be used in place of thiopental for the induction of general anaesthesia. It has been found that barbiturates act on the picrotoxin receptor in the GABA—receptor complex (Olsen, 1982) and, in this way, synergize the action of GABA. This effect is stereospecific for in pentobarbital it is confined to the (5)-isomer (Huang and Barker, 1980). It would seem that this type of activity plays only a minor part in medication with barbiturates which behave on the whole as structure-independent lipophiles (see p. 622). 

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