Thiopental tissue distribution

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... 

As soon as a drug finds its way into the blood stream, it tries to approach the site of biological action. Hence, the distribution of a drug is markedly influenced by such vital factors as tissue distribution and membrane penetration, which largely depends on the physico-chemical characteristics of the drug. For instance, the effect of the ultra-short acting barbiturate thiopental may be explained on its dissociation constant and lipid solubility. It is worthwhile to observe here that the dmation of thiopental is not influenced by its rate of excretion or metabolism, but by its rate of distribution. 

Bioavailability of ketamine is 90-93% after intramuscular injection, 16% after oral administration, and 77% after epidural injection. Protein binding of ketamine is 47%, and it is initially distributed to highly perfused tissues such as brain, heart, and the lungs. There the concentration can reach up to five times the plasma concentration. Redistribution is similar to thiopental. The distribution half-life after intravenous administration is 7 tol7 minutes, and the volume of distribution is 2 to 3 L/kg. 

The distribution of thiopental in body tissues and organs following intravenous injection. Note the redistribution of the drug, with time, to tissues with lower rates of blood flow. (Reprinted with permission from Price HL et al. The uptake of thiopental by body tissues and its relation to the duration of narcosis. Clin Pharmacol Ther 1 16,1960.)... 

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. 

Barbiturates are absorbed orally and distributed widely throughout the body. All barbiturates redistribute in the body from the brain to the splanchnic areas, to skeletal muscle, and finally to adipose tissue. This movement is important in causing the short duration of action of thiopental and similar short-acting derivatives (see p. 115). Barbiturates are metabolized in the liver, and inactive metabolites are excreted in the urine. 

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. 

Barbiturates are distributed widely and readily cross the placenta. Following initial distribution to the CNS of an intravenous dose, the highly lipid-soluble barbiturates undergo redistribution to less vascular tissues, especially muscle and fat, leading to a decline in the concentration of barbiturate in the plasma and brain. With thiopental and methohexital, this results in the awakening of patients within 5-15 minutes of the injection of the usual anesthetic doses (see Chapter 13). 

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