Thiopental
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3 sources
Collated from TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.
Barbiturate that kicks in very quickly, that is used to Anesthesia, Medical induced comas among other things.TS
🧬 Receptor activityDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| GABA-A receptor alpha-1/beta-2/gamma-2 (GABRA1) | Positive allosteric modulator | — | DRUGCENTRAL | TargetGABA-A receptor alpha-1/beta-2/gamma-2 (GABRA1) ActionPositive allosteric modulator Affinity— SourceDRUGCENTRAL |
| Potassium voltage-gated channel subfamily C member 4 (Kcnc4) | Gating inhibitor | 4 IC50 | DRUGCENTRAL | TargetPotassium voltage-gated channel subfamily C member 4 (Kcnc4) ActionGating inhibitor Affinity4 IC50 SourceDRUGCENTRAL |
| GABA-A receptor; anion channel (Gabrp) | — | 4.53 IC50 | DRUGCENTRAL | TargetGABA-A receptor; anion channel (Gabrp) Action— Affinity4.53 IC50 SourceDRUGCENTRAL |
Mechanism of actionPH
Thiopental binds at a distinct binding site associated with a Cl<sup>-</sup> ionopore at the GABA<sub>A</sub> receptor, increasing the duration of time for which the Cl<sup>-</sup> ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged.
The exact mechanism(s) by which barbiturates exert their effect on the CNS, has not been fully elucidated. However, it is believed that such effects are related, at least partially, to the drugs' ability to enhance the activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS, by altering inhibitory synaptic transmissions that are mediated by GABAA receptors. /Barbiturates General Statement/
Although the drugs act throughout the CNS, a site of particular sensitivity is the polysynaptic midbrain reticular formation which is concerned with the arousal mechanism. Barbiturates induce an imbalance in central inhibitory and facilitatory mechanisms influencing the cerebral cortex and the reticular formation. The significance of the effect of barbiturates on neurotransmitters is unclear. It appears that the drugs decrease the excitability of both presynaptic and postsynaptic membranes. It has not been determined which of the various actions of barbiturates at cellular and synaptic levels are responsible for their sedative and hypnotic effects. /Barbiturates General Statement/
Relatively low doses of the barbiturates depress the sensory cortex, decrease motor activity, and produce sedation and drowsiness. In some patients, however, drowsiness may be preceded by a period of transient elation, confusion, euphoria, or excitement, especially after subhypnotic doses of aprobarbital, pentobarbital, or secobarbital. /Barbiturates General Statement/
Larger doses distort judgment, cloud perception, suppress motor activity, and produce drowsiness and sleep. Still larger doses induce anesthesia. Barbiturate-induced sleep differs from physiologic sleep. Barbiturates reduce the rapid eye movement (REM) or dreaming stage of sleep. Stages III and IV sleep are also decreased. Although tolerance develops to the REM-suppressant effects during chronic administration, REM rebound occurs when the drugs are withdrawn, and the patient may experience markedly increased dreaming, nightmares, and/or insomnia. /Barbiturates General Statement/
For more Mechanism of Action (Complete) data for Thiopental (16 total), please visit the HSDB record page.
PharmacodynamicsPH
Thiopental, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate Pentothal in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia
Pharmacokinetics
Half-lifePH
3-8 hours
Following small iv doses of thiopental, the drug appears to decline in a monoexponential (first order) fashion, with an elimination half-life of about 3-22 hours. Following a rapid iv ('bolus") injection, pharmacokinetics of thiopental can be described by a triexponential equation; the drug appears to undergo a rapid and slow distribution phase followed by a terminal elimination phase. In the rapid distribution phase, thiopental equilibrates rapidly in highly perfused organs (CNS, viscera), while in the slow distribution phase the drug equilibrates between highly perfused organs and the adipose tissue. In adults, the mean plasma half-lives in the initial distribution phase and slow distribution phase are about 1.7-13.2 and 39.5-161.4 minutes, respectively.
... At high therapeutic concentrations, pharmacokinetics of thiopental can be characterized by Michaelis-Menten kinetics, with a first-order elimination half-life of 9.72-49.4 hours.
In pediatric patients (5 months to 13 years of age), the elimination half-life of thiopental was about one-half the elimination half-life in adults (about six hours); however the elimination half-life in neonates was increased two-fold compared with their mothers (about 15 hours).
AbsorptionPH
Rapidly absorbed.
Following iv administration of usual induction doses of thiopental sodium in adults, onset of action (hypnosis or unconsciousness) reportedly occurs rapidly, within 10-40 seconds, with maximal effects occurring in about 1 minute and the duration of anaesthesia persisting 5-8 minutes.
Following iv administration, thiopental is rapidly distributed to all tissues and fluids with high concentrations in brain and liver. Lipid solubility of thiopental, and to a lesser extent its protein binding, are the dominant factors in the drugs distribution in the body. Following iv administration of thiopental sodium to rats, the drug distributes into brain, heart, intestines, spleen, pancreas; peak concentrations are reached in about 1minute.
Thiopental equilibrates rapidly in highly perfused organs and tissues (eg, CNS, viscera), while the uptake is delayed in less perfused organs and tissues (eg, muscle, adipose tissue). In rats, peak tissue concentrations occur in about 6, 30, and 60-120 minutes in muscle, or testes, skin, and adipose tissue, respectively. Thiopental penetrates the blood-brain barrier rapidly, and its rate of entry into the brain is limited only by the rate of cerebral blood flow. CSF concentrations of the drug are slightly lower than those in plasma.
The steady-state volume of distribution (Vss) of thiopental following iv administration is reportedly is about 0.4-4 L/kg in adults. The Vss may vary according to dosage and mode of administration (single- or multiple-dose); the pharmacokinetic model (eg, 1-,2-,3-, or 4-compartment) used to describe the drug; and gender, age , or weight of the patient. Limited data indicate that the average Vss is greater in women 20-40 years old (1.2 L/kg) than in men of the same age (0.417 L/kg). It has been suggested that the initial volume of distribution (Vd) may change with age; however, these changes may be associated with the pharmacokinetic model used. The Vss is 3-4 times higher in obese patients compared with lean patients possibly because of the highly lipophilic nature of the drug.
For more Absorption, Distribution and Excretion (Complete) data for Thiopental (13 total), please visit the HSDB record page.
MetabolismPH
Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, [pentobarbital], that exists in concentrations approximately 3-10% that of the parent concentration. Thiopental and pentobarbital are also subject to both oxidation and hydroxylation to carboxylic acids and alcohols, respectively, all of which are pharmacologically inert. While many of the specifics regarding thiopental biotransformation have not been elucidated, including the enzymes responsible, the oxidation of thiopental to its carboxylic acid may be the major driver of thiopental detoxification as this product appears to account for 10-25% of renally excreted drug.
Thiopental is metabolized mainly in the liver and to a lesser extent in other organs and tissues (eg, kidneys and brain). Thiopental undergoes desulfuration to form pentobarbital, an active metabolite. However, both thiopental and pentobarbital undergo oxidation and hydroxylation to form corresponding carboxylic acid metabolites and alcohols, respectively; all detected metabolites have been found to be pharmacologically active.
Barbiturates are slowly metabolized, chiefly by hepatic microsomal enzymes. Phenobarbital and probably other barbiturates induce hepatic microsomal enzymes and thus may accelerate metabolism of other concomitantly administered drugs metabolized by these enzymes. /Barbiturates General Statement/
... Under clinical trials thiopental and two metabolites namely 5 ethyl-5 (1' methyl-3' hydroxy-butyl) 2 thiobarbituric acid and 5 ethyl-5 (1' methyl-3' carboxy-propyl) 2 thiobarbituric acid have been determined by high performance liquid chromatography and mass spectrometry. In human plasma high concentrations of thiopental and 5 ethyl-5 (1' methyl-3' hydroxy-butyl) 2 thiobarbituric acid and a lower concentration of 5 ethyl-5 (1' methyl-3' carboxy-propyl) 2 thiobarbituric acid have been found. In urine samples these metabolites are excreted in large and approximately equal quantities, whereas small amounts of thiopental were recovered.
The desulfuration of thiopental to pentobarbital has previously been shown to be a relatively minor pathway of thiopental metabolism. In two cases, /investigators/ observed significant conversion, resulting in blood pentobarbital concentrations up to 50 percent of total blood barbiturate (thiopental and pentobarbital) concentrations. Both patients received continuous infusions of thiopental and had present a condition (hypothermia) or drug (cimetidine) known to inhibit hepatic microsomal enzyme activity. It is suggested that inhibition of hepatic microsomal enzyme activity may prevent thiopental's metabolism to its major metabolite, a carboxylic acid analogue, and increase the amount of thiopental desulfurated to pentobarbital. Inhibition of hepatic microsomal metabolism also decreases the metabolism of pentobarbital. Until further elucidation of the causes of altered thiopental metabolism is available to identify patients more likely to have elevated concentrations of pentobarbital, monitoring of blood drug concentrations in patients receiving thiopental should include determination of both thiopental and pentobarbital concentrations.
Primarily hepatic. Biotransformation products of thiopental are pharmacologically inactive and mostly excreted in the urine.
Half Life: 3-8 hours
Protein bindingPH
Approximately 80% of the drug in the blood is bound to plasma protein.
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.