Thiopental redistribution

The ultra-short acting thiopental, exclusively used in anesthesia, rapidly reaches CNS depressant concentrations due to its high lipid solubility and high blood flow to brain. Redistribution to muscle and other sites is responsible for its short duration of... 

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.)... 

Redistribution of thiopental after an intravenous bolus administration. Note that the time axis is not linear. 

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. 

Redistribution of thiopental from brain to muscle and adipose tissue. 

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).

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. 

Propanidid is a nonbarbiturate ultra-short-acting anesthetic agent that may cause hypotension and tachycardia. Unlike thiopental, which is redistributed, propanidid is metabolized rapidly by pseudocholinesterases. 

The ultra-short-acting barbiturates, thiopental, thiamylal, and methohexital, quickly cross the blood-brain barrier but are rapidly redistributed from the brain to other body tissues, first to highly perfused visceral organs (liver, kidneys, heart) and muscle, and later to fatty tissues. 

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). 

Figure 25-4. Redistribution of thiopental after intravenous bolus administration. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

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). 

Thiopental sodium. A single induction dose of 3 to 5 mg kg may cause unconsciousness within a short span of 30 to 40 seconds. Its action is, however, terminated by the immediate redistribution of drug away from the brain. It has been observed that there exists a transient decrease in blood pressure (20%), and a simultaneous compensatory enhancement in the heart rate on injection. Thiopental is largely metabolized in the liver, although the kidney and muscle tissue may participate concurrently. 

Thiopental injected intravenously induces anaesthe.sia in les.s than 30 seconds because the very lipid-soluble drug quickly dissolves in the rapidly perfu-sed brain. Recovery from thiopental is rapid because of redistribution into less perfused tissues (bottom right figure). The liver... 

Thiopental sodium is rtq>idly and efficiently absorbed following either oral or rectal administration [63,64]. However, clinically thiopental is administered as an intravenous injection whereupon it is extremely rrq>idly taken up by the brain. Equilibrium of brain and plasma thiopental is achieved within about one minute [65,66] and is followed by a speedy decrease in the brain concentration, approximately half the maximal concentration remaining after five minutes [65,66]. The rapid decline in brain and plasma concentration has been attributed to the redistribution of die drug to other body tissues [58, and references therein] and is responsible for its extremely short duration of action. 

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. 

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