Thiopental distribution

Figure 2.13. Kinetics of thiopental distribution. Thiopental is a very hydrophobic barbiturate that is used for transient narcosis. Duration of the narcosis is limited by redistribution of thiopental from the brain to other body compartments (which is very fast) rather than elimination of the drag (which is very slow).

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.)... 

What is the difference between the drugs thiopental and pentobarbital and how would it affect their absorption and distribution ... 

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. 

Changes in drug effects are often delayed in relation to changes in plasma concentration. This delay may reflect the time required for the drug to distribute from plasma to the site of action. This will be the case for almost all drugs. The delay due to distribution is a pharmacokinetic phenomenon that can account for delays of a few minutes. This distributional delay can account for the lag of effects after rapid intravenous injection of central nervous system (CNS)-active agents such as thiopental. 

Other sites In pregnancy, the fetus may take up drugs and thus increase the Vd. Drugs such as thiopental (see p. 115), which are stored in fat, may also have unusually high volumes of distribution. 

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. 

The above considerations on drug partitioning mainly apply to the equilibrium of drug distribution. However, it is important to realize that it may take some time until a drug that is applied rapidly (e.g., by injection or inhalation) actually reaches equilibrium. A practically important example of non-equilibrium distribution is provided by the drug thiopental, which is a barbiturate used for short-duration narcosis (Figure 2.13). 

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... 

Figure 7.9 A. Illustrates the differences in perfusion rate on the proposed distribution and redistribution of thiopental. (Redrawn from http //www.cvm.okstate.edu/Courses/vmed5412/LECT006.htm) B. Drug equilibration in the cerebrospinal fluid with plasma water for various drugs in the dog (redrawn from Figure 5-11 in Rowland and Tozer, 2006, and Brodie et al., 1960. Plasma drug concentration was kept constant throughout the study. Thiopental displays perfusion limited distribution whereas the distribution of salicylic acid is permeability rate limited.

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 hepatically metabolized to norketamine, which has reduced CNS activity norketamine is fnrther metabolized and excreted in urine and bile. Ketamine has a large volume of distribution and rapid clearance that make it snitable for continuous infusion withont the drastic lengthening in duration of action seen with thiopental. Protein binding is much lower with ketamine than with the other parenteral anesthetics. 

All three barbiturates are primarily eliminated by hepatic metabolism and renal excretion of inactive metabolites a small fraction of thiopental undergoes desulfuration to the longer-acting hypnotic pentobarbital. Each drug is highly protein bound (Table 13-2). Hepatic disease or other conditions that reduce serum protein concentration will decrease the volume of distribution and thereby increase the initial free concentration and hypnotic effect of an induction dose. 

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). 

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. 

A drug-induced change in the distribution and renal excretion of sulfonamides, JPET, 134, 291-303 (1961). Mayer et al. also reported values for thiopental (7.6), aniline (4.6), aminopyrine (5.1), 4-aminoantipyrine (4.1), acetanilide (1.0), barbital (7.8), N-acetyl-4-aminoantipyrine (NAAP 0.5), salicylic acid (3.0). With the exceptions of acetanilide and NAAP, all additional pKa values were obtained by the potentiometric method. The barbital value is lower than the best value and suggests that carbon dioxide absorption interfered, however, the remaining values should not be affected by this factor. 

A study in 532 healthy patients, aged from 20 to over 80 years, found that those who normally drank aleohol (more than 40 g weekly, roughly 400 mL of wine) needed more thiopental to aehieve anaesthesia than non-drinkers. After adjusting for differenees in age and weight distribution, men and women who were heavy drinkers (more than 40 g aleohol daily) needed 33% and 44% more thiopental, respeetively, for induetion than non-drinkers. Chronie aleohol intake is known to inerease barbiturate metabolism by eytoehrome P450 enzymes. ... 

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