The pharmacokinetics and pharmacodynamics of thiopental as used in lethal injection.

• Author: Dershwitz, Mark
• Position: The Lethal Injection Debate: Law and Science

Thiopental (sometimes called, although inaccurately, Sodium Pentothal) was the most commonly used intravenous anesthetic agent for about fifty years, beginning in the mid-1940s. (1) As states began to discuss and develop protocols for lethal injection in the 1970s, thiopental was the logical choice as the medication to render the inmate unconscious prior to the administration of subsequent medications, most commonly pancuronium (a medication that paralyzes skeletal muscle and results in cessation of breathing) followed by potassium chloride (a salt that is a necessary component of the diet but when given intravenously in large doses results in the cessation of electrical activity in the heart).

It is virtually unanimously accepted by physicians, particularly anesthesiologists, that the administration of lethal doses of pancuronium and/or potassium chloride to a conscious person would result in extreme suffering. For this reason, all of the protocols for lethal injection that we have reviewed precede the administration of pancuronium and potassium chloride with a dose of thiopental intended to render the inmate unconscious for a period of time far in excess of that necessary to complete the execution. (2) When implemented as written, meaning the correct doses of the correct medications are administered in the correct order into a properly functioning intravenous delivery system and with sufficient time for thiopental to produce its effect, all of the protocols we have reviewed are intended to result in the rapid death of the inmate without undue pain or suffering.

This paper will concentrate on the pharmacokinetics and pharmacodynamics of thiopental. As applied here, pharmacokinetics is the study of the concentration of thiopental as a function of time in tissues (particularly brain), while pharmacodynamics is the study of the effects of thiopental (particularly the production of unconsciousness and impairment of the heart's ability to circulate blood). (3) By using generally accepted computer modeling techniques, and considering the wealth of published studies on the pharmacology of thiopental, we can prepare predictions of such relevant parameters as the onset (how long it takes for the inmate to become unconscious) and duration (how long the inmate would remain unconscious) of the pharmacological effects of thiopental. (4)

Thiopental is usually described as an "ultra-short acting" sedative/hypnotic agent in pharmacology and anesthesiology texts. (5) This description is semantically correct, but only when thiopental is compared to other barbiturates. Indeed, when thiopental was used to induce (i.e., begin) a general anesthetic, the typical adult dose was about 300 mg and the typical patient would remain unconscious for 5 to 10 minutes. (6) The usual anesthetic regimen would involve the subsequent administration of anesthetic gases that would keep the patient unconscious for the duration of the surgical procedure. The protocols for lethal injection mandate doses of thiopental ranging from 2000 to 5000 mg, i.e., about seven to sixteen times higher than those used to begin a typical anesthetic. (7) However, the relationship between the dose of thiopental and its duration of action is not linear. For example, as the dose of thiopental is increased sevenfold to 2000 mg, the duration of unconsciousness is not also increased sevenfold but actually much more, as described later. The pharmacological term "sedative/hypnotic" means that at low doses (e.g. 25-100 mg), thiopental causes sedation (i.e., sleepiness), while at higher doses it produces hypnosis (i.e., unconsciousness). (8) At sedative doses, it produces no analgesia (pain relief) and in fact probably increases the perception of painful stimuli. When a person is rendered unconscious by thiopental, the conscious perception of pain is abolished. The body may, however, react in a reflex manner to pain and exhibit such phenomena as movement, a fast heart rate, sweating, or tearing. Additionally, the state of consciousness produced by a drug is also affected by the strength of applied stimuli. Thus, at the threshold of unconsciousness pain may reverse the state and produce consciousness, making it difficult to distinguish between reflex responses to pain and conscious response. Therefore, it has been argued by some that deep unconsciousness, as defined by burst suppression on the electroencephalogram ("LEG"), be the level of unconsciousness produced in lethal injection. (9)

We will present models to describe the onset and duration of unconsciousness as a function of the dose of thiopental. For example, with the administration of 2000 mg of thiopental to an 80-kg person, loss of consciousness will occur within approximately 1.0 to 1.5 minutes, while duration of unconsciousness will last approximately two hours. The time for onset of burst suppression in the same individual would be approximately 1.5 to 2.5 minutes and would reliably last only seven minutes. Larger doses of thiopental will be shown to result in further prolongation of the duration of unconsciousness and burst suppression.

There is an enormous body of anesthesiology literature supporting the use of mathematical modeling of the pharmacokinetic and pharmacodynamic behavior of intravenous anesthetic agents like thiopental. (10) Such modeling underlies the commonly utilized technique of target-controlled intravenous drug infusions. Mathematical modeling of intravenous anesthetics has been extensively studied and has been validated in the real world practice of target-controlled infusions ("TCI"). (11) TCI couples a small computer with an infusion pump so that multi-compartment models are used to predict and adjust anesthetic drug infusion rates on a second-by-second basis to reach and maintain plasma concentrations determined by the practitioner. (12) TCI devices are in common use in anesthetic practice worldwide. Median absolute performance errors for TCI of predicted versus actual drug concentrations are in the range of [+ or -] 30% when literature values for pharmacokinetic parameters are used to drive the TCI device. (13) Therefore, similar errors can be expected when applying the simulations presented here to any given individual. Thus the methodology employed in performing the pharmacological simulations employed herein has undergone peer review and its application to the actual practice of anesthesia is well studied.

1. THE ONSET TIMES FOR THIOPENTAL ADMINISTERED AT VARIOUS RATES

   No drug, including thiopental, has an effect the moment it is injected. It must first be transported by circulating blood to the site of action, i.e., the brain in the case of thiopental. The drug must then cross the blood-brain barrier to reach drug receptors in the neural cells of the brain. The drug-receptor interaction then triggers a cellular response resulting in the drug effect. As thiopental concentrations at the site of action continue to rise, more intense drug responses are seen. The interval between injecting the drug, and seeing an effect, i.e. the process of accumulating adequate drug concentrations in the blood and subsequently the brain, is called hysteresis. (14) A good way to think about hysteresis is to compare it to using a stove. Turning the flame on is akin to injecting the drug; transporting the heat to the surface of the pan is analogous to the circulation delivering the drug to the site of action; and cooking the food in the pan is akin to producing the drug effect. Your dinner can range from undercooked to well done, depending on how long it's exposed to the flame "dose" the stove is delivering. Similarly the heating effect continues for some time even after the flame is turned off. Therefore, with hysteresis it is possible to have the same effect at two different plasma drug concentrations just as it is possible for a pan to be at the same temperature at two different flame settings, once during heating and again during cooling. Pharmacokinetic-pharmacodynamic modeling is able to mathematically describe this hysteresis and fully explain how the same blood drug concentration can produce variable effects. (15)

   In a lethal injection setting, once an injection of thiopental has begun, the drug must pass through the IV tubing from the "injection room" to the "death chamber" before reaching the vein of the condemned inmate. For instance, if the tubing is ten feet long with a typical tubing volume of 1.8 mL/foot, then the total volume is 18 mL. Assuming fluid traveling in a tube as a perfect cylinder and an injection speed of 2 mL/sec, it would take a full 9 seconds for the drug to reach the vein.

   After entering the bloodstream the drug must circulate with the blood to reach the brain before concentrations at the site of effect can begin to rise. Depending on where the intravenous catheter is placed in the inmate, it could take up to 15 seconds for the drug to reach the right-sided chambers of the heart and thus be considered within the central circulation where the flow of blood is at its greatest. From the right side of the heart, the...