Monograph of Thiopental Sodium

Introduction

Thiopental sodium is a short‑acting barbiturate that has been employed extensively as an intravenous anesthetic induction agent and, more recently, as an adjunct in critical care settings. The compound is the sodium salt of thiopental, a derivative of phenobarbital in which the phenolic hydroxyl group is replaced by a nitro group. This modification confers a markedly faster onset of action and a shorter duration of effect relative to other barbiturates, rendering thiopental particularly useful for rapid sequence induction of general anesthesia and for the management of refractory intracranial hypertension.

Historically, thiopental was introduced in the 1940s and quickly became the anesthetic of choice for many surgical procedures due to its rapid onset, high potency, and minimal hemodynamic compromise at induction doses. Over time, the advent of newer agents with more favorable safety profiles has led to a decline in its routine use in many countries; nevertheless, it remains an important drug for emergency and resource‑limited settings, and its pharmacologic principles continue to inform the development of newer anesthetic agents.

For medical and pharmacy students, a thorough understanding of thiopental sodium is essential because it exemplifies key concepts in drug pharmacodynamics, pharmacokinetics, and clinical decision‑making. Mastery of this monograph will facilitate comprehension of barbiturate action, the importance of drug formulation, and the clinical considerations that govern the safe use of potent anesthetic agents.

• Define thiopental sodium and articulate its chemical and pharmacologic classification.
• Describe the historical evolution of thiopental and its current therapeutic roles.
• Explain the mechanisms of action, pharmacokinetic behavior, and dose‑response relationships.
• Identify indications, contraindications, and safety concerns associated with thiopental use.
• Apply knowledge of thiopental to clinical scenarios, including dosing calculations and monitoring strategies.

Fundamental Principles

Core Concepts and Definitions

Thiopental sodium is an intravenous barbiturate characterized by the following core properties:

• Potency: Approximately 100–200 times more potent than phenobarbital.
• Onset of Action: 30–60 seconds following bolus injection.
• Duration of Effect: 5–10 minutes, owing to rapid redistribution.
• Metabolism: Predominantly hepatic via oxidation and conjugation; renal excretion of metabolites.
• Elimination Half‑Life: t_1/2 ≈ 1–2 hours, but clinical effect is limited by redistribution.

The drug is formulated as a sterile, clear solution of sodium salt, typically at a concentration of 5 mg/mL. The sodium ion confers increased solubility in aqueous media, facilitating rapid intravenous administration.

Theoretical Foundations

Barbiturates exert their pharmacologic effects by modulating the gamma‑aminobutyric acid (GABA)_A receptor complex. Binding of thiopental to the barbiturate site on the GABA_A receptor prolongs the opening of the associated chloride channel, thereby increasing chloride influx and hyperpolarizing the neuronal membrane. This action reduces neuronal excitability and produces central nervous system depression. The rapid onset of thiopental is attributable to its lipophilicity, which enables swift diffusion across the blood‑brain barrier.

Pharmacokinetic modeling of thiopental often employs a two‑compartment model. Following intravenous administration, the drug distributes rapidly into a central compartment (plasma and highly perfused tissues) and subsequently redistributes into peripheral tissues. The concentration–time profile can be described by the equation:

C(t) = C₀ × e^−k_el t + A × e^{−k₁₂ t} − B × e^{−k₂₁ t},

where C₀ is the initial concentration, k_el is the elimination rate constant, and k₁₂ and k₂₁ represent intercompartmental transfer rates. The rapid redistribution phase accounts for the brief clinical effect despite a relatively longer elimination half‑life.

Key Terminology

• Induction dose: The initial bolus required to achieve unconsciousness.
• Maintenance dose: Continuous infusion or repeated boluses to sustain anesthesia.
• Rebound hyperthermia: Post‑anesthetic hyperthermia associated with barbiturate withdrawal.
• Drug–drug interaction: Concomitant agents that alter thiopental metabolism or effect.
• Therapeutic index: Ratio of toxic to therapeutic dose; narrow for thiopental.

Detailed Explanation

Mechanisms of Action

Thiopental binds to the barbiturate site on the GABA_A receptor, enhancing the duration of chloride channel opening. This effect is voltage‑dependent and increases the inhibitory postsynaptic potential. The net result is a decrease in neuronal firing rate and suppression of cortical activity. In addition, thiopental exhibits non‑competitive antagonism of N‑methyl‑D‑aspartate (NMDA) receptors, further contributing to its anesthetic properties.

Pharmacokinetics

After intravenous administration, the drug displays a biphasic plasma concentration profile. The first phase (distribution) is characterized by a rapid decline (k₁₂) as the drug partitions into highly perfused tissues such as the brain, heart, and liver. The second phase (elimination) is governed by hepatic metabolism and renal excretion (k_el). The apparent volume of distribution (V_d) is approximately 0.3 L/kg, indicating extensive tissue binding. Clearance (Cl) can be expressed as:

Cl = Dose ÷ AUC,

where AUC denotes the area under the concentration–time curve. In healthy adults, Cl averages 1.5–2 L/h/kg. The elimination half‑life (t_1/2) is calculated as:

t_1/2 = 0.693 ÷ k_el,

and typically ranges from 1 to 2 hours. However, the clinical effect is limited to the redistribution phase, which lasts 5–10 minutes.

Dosing Calculations

Induction dose is commonly 2.5–5 mg/kg administered over 30–60 seconds. For a 70‑kg adult, the recommended dose is 175–350 mg. Maintenance dosing may involve a continuous infusion at 0.5–1 mg/kg/h or repeated boluses of 50–100 mg every 10–15 minutes, depending on the desired depth of anesthesia and patient characteristics. Dose adjustments are necessary for patients with hepatic impairment, reduced cardiac output, or concomitant CNS depressants.

Factors Affecting Pharmacokinetics and Dynamics

• Age: Elderly patients exhibit decreased hepatic clearance, prolonging the elimination phase.
• Body composition: Obesity increases the volume of distribution, potentially necessitating higher induction doses.
• Genetic polymorphisms in cytochrome P450 enzymes may alter metabolic rate.
• Concurrent medications such as anticonvulsants or alcohol can induce hepatic enzymes, increasing clearance.
• Physiological state (e.g., hypovolemia, sepsis) may affect drug distribution and clearance.

Safety Profile and Adverse Effects

Thiopental is associated with several adverse effects, some of which are dose‑dependent:

• Cardiovascular depression: Bradycardia, hypotension, and decreased cardiac output may occur at higher doses.
• Respiratory depression: Apnea or hypoventilation is a common consequence of CNS depression.
• Post‑anesthetic hyperthermia: Occurs within 4–12 hours after drug clearance, particularly in children.
• Hypersensitivity reactions: Rare, but may include anaphylaxis.
• Hepatotoxicity: Chronic exposure has been linked to hepatic injury in susceptible individuals.

Monitoring of hemodynamic parameters, oxygenation, and depth of anesthesia is essential to mitigate these risks. The use of adjunct agents (e.g., opioids, benzodiazepines) can reduce required thiopental doses, thereby lowering the incidence of adverse effects.

Drug Interactions

Thiopental is a potent inducer of several cytochrome P450 isoenzymes (CYP3A4, CYP2B6, CYP2C9). Co‑administration with drugs metabolized by these enzymes can lead to reduced plasma concentrations and therapeutic failure. Conversely, inhibitors of CYP3A4 (e.g., ketoconazole) may prolong thiopental action and increase the risk of toxicity. Additionally, concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, alcohol) may produce additive effects, heightening the risk of respiratory arrest and hypotension.

Clinical Significance

Relevance to Drug Therapy

Thiopental’s rapid onset and short duration make it an invaluable agent for induction of general anesthesia, especially in procedures requiring quick airway control and rapid recovery. Its use in critical care includes management of refractory intracranial hypertension, where controlled barbiturate coma can reduce cerebral metabolic demand and intracranial pressure. Although newer agents have largely supplanted thiopental in many settings, its continued availability ensures preparedness for emergencies and resource‑constrained environments.

Practical Applications

In the operating room, thiopental is often combined with short‑acting opioids (e.g., fentanyl) and neuromuscular blocking agents (e.g., succinylcholine) to achieve rapid sequence induction. In intensive care units, continuous infusion protocols may be employed for patients with severe traumatic brain injury, with careful titration to maintain a target mean arterial pressure and cerebral perfusion pressure. In addition, thiopental is occasionally used as a rescue agent for seizures refractory to benzodiazepines, owing to its potent GABAergic activity.

Clinical Examples

1. Rapid Sequence Induction in a 60‑kg adult: Induction dose of 150 mg (2.5 mg/kg) is administered over 45 seconds. Following confirmation of loss of consciousness, succinylcholine 1.5 mg/kg is given to facilitate intubation. Monitoring of heart rate and blood pressure is maintained throughout the procedure.

2. Barbiturate Coma for Refractory Intracranial Hypertension: A 45‑kg patient with severe traumatic brain injury receives an initial bolus of 112 mg (2.5 mg/kg) followed by a continuous infusion of 0.5 mg/kg/h. Cerebral perfusion pressure is monitored via intracranial pressure transducer, and infusion rate is adjusted to maintain target values.

3. Seizure Management: A patient with status epilepticus unresponsive to benzodiazepines receives a bolus of 50 mg thiopental, resulting in cessation of seizure activity within 30 seconds. A maintenance infusion of 25 mg/h is continued until seizure recurrence is prevented.

Clinical Applications/Examples

Case Scenario 1: Emergency Airway Management

A 52‑year‑old male presents with severe upper airway obstruction. Rapid sequence induction is indicated. The anesthesiologist calculates the induction dose based on weight (70 kg), administering 175 mg of thiopental over 60 seconds. Following adequate sedation, succinylcholine is given to achieve rapid neuromuscular blockade. The patient is intubated successfully, and ventilation is maintained with controlled ventilation. Hemodynamic monitoring reveals a transient drop in blood pressure, which is managed with intravenous fluid bolus and vasopressor support.

Case Scenario 2: Intracranial Hypertension Management

A 30‑year‑old female with severe traumatic brain injury demonstrates persistent intracranial hypertension despite osmotherapy. The critical care team initiates a thiopental infusion at 0.75 mg/kg/h, targeting a mean arterial pressure of 85 mmHg and intracranial pressure <20 mmHg. The infusion is titrated over 48 hours, with continuous EEG monitoring to detect burst suppression. After 72 hours, the infusion is weaned, and the patient remains stable.

Problem‑Solving Approaches

• Dosing in Renal Impairment: Since thiopental is primarily metabolized hepatically, renal dysfunction has limited impact on clearance. Nevertheless, caution is warranted due to potential accumulation of metabolites.
• Managing Hypotension: Adjunctive agents such as phenylephrine or ephedrine may be administered to counteract thiopental‑induced vasodilation.
• Preventing Post‑Anesthetic Hyperthermia: In pediatric patients, active cooling measures (ice packs, antipyretic administration) are recommended within 6 hours post‑infusion.
• Addressing Drug Interactions: Prior to induction, a medication review is essential. If a CYP3A4 inhibitor is present, the induction dose may be reduced by 25–30 % to avoid prolonged sedation.

Summary/Key Points

• Thiopental sodium is a highly potent, short‑acting barbiturate with rapid onset and brief duration of action.
• Its pharmacologic effects are mediated through GABA_A receptor potentiation and NMDA receptor antagonism.
• Standard induction dosing is 2.5–5 mg/kg intravenously over 30–60 seconds; maintenance may involve continuous infusion or repeated boluses.
• Key safety concerns include cardiovascular and respiratory depression, post‑anesthetic hyperthermia, and potential hepatotoxicity.
• Thiopental is a strong CYP450 inducer, necessitating careful consideration of drug interactions.
• Clinical applications encompass rapid sequence induction, barbiturate coma for intracranial hypertension, and refractory seizure management.
• Monitoring of hemodynamic status, depth of anesthesia, and temperature is essential to mitigate adverse effects.
• Adjustments for special populations (elderly, obese, hepatic impairment) should be guided by pharmacokinetic principles and clinical judgment.
• Despite newer anesthetic agents, thiopental remains a valuable drug in emergency and resource‑limited settings.

Clinical pearls for students: When using thiopental, always calculate doses based on ideal body weight in obese patients; anticipate rapid redistribution; and remain vigilant for post‑anesthetic hyperthermia, particularly in children. Employ adjunctive agents judiciously to minimize required thiopental dose and reduce the risk of adverse events.

References

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