Barbiturates

Barbiturates
 
Classification

Long acting

  • Phenobarbitone

Short acting

  • Butobarbitone
  • Pentobarbitone

Ultra short acting

  • Thiopentone
  • Methohexitone
 
Pharmacological action
​Barbiturates are general depressants for all excitatory cells, the CNS is most sensitive where effects is almost global, but certain areas are more susceptible.
 
1. CNS
  • Produce dosed dependant effect.
  • Sedation​sleep​​anesthesia ​​coma
  • Hypnotic dose shortens the time taken to fall asleep and increases sleep duration
  • Night awakening are reduced
  • REM and stage 3,4 sleep are decreased; NREM-REM sleep cycle is disrupted
  • A rebound increase in REM sleep and nightmares is often noted when drug is discontinued
  • Hangover (dizziness, distortion of mood, irritability and lethargy) may occur in the morning after a nightly dose
  • Barbiturates can impair learning, short term memory and judgement. Euphoria may be experienced by addicts
  • Barbiturates have anticonvulsant property
  • Higher dose induce a predominance of slow, high voltage EEG activity
  • Animal studies shows that long lasting functional tolerance to to drugs develops following early barbiturate exposure. Although infants become passively addicted following in utero exposure, there are no data on subsequent development of human adult tolerance. Drug related damage must be weighed against therapeutic benefits of drug administration and the results of failure to treat. (1)
  • The receptors of excitatory amino acids can be targets for the actions of barbiturates and alcohols on the central nervous system and may mediate some of the anesthetic and hypnotic effects of these drugs. (2)
  • Since phenobarbital, midazolam and ethanol reproduced the hyperalgesic effect of GABA-A specific agonists which is antagonized by the GABA A antagonist picrotoxin, the GABA-A receptors are tonically involved in the modulation of nociception in the rat central nervous system. (3)
  • The effects of septal area and dorsomedial tegmentum lesions on barbiturate sleeping time are additive. Adrenalectomy ot cortisone replacement fails to abolisj septal sensitivity to barbital. (4)
  • Acute exposure to hypoxia depresses in vivo metabolism of pentobarbital and enhances CNS sensitivity to the barbiturates. (5)
 
2. Other system
 
Respiration
  • Respiration is depressed by relatively high doses
  • Neurogenic, hypercapneic and hypoxic drives to respiratory center are depressed in succession
  • Barbiturates do not have selective antitussive action
 
CVS
  • Hypnotic dose produce a slight decrease in BP and heart rate
  • Toxic dose produce marked fall in BP due to vasomotor centre depression, ganglionic blockade and direct decrease in cardiac contractility
  • Reflex tachycardia can occur, though pressor reflexes are depressed
  • The dose producing cardiac arrest is about 3 times larger than that causing respiratory failure
 
Skeletal muscle
  • Hypnotic dose have little effect
  • Anesthetic doses reduce muscle contraction by action on neuromuscular junction
 
Smooth muscle
  • Tone and motility of the bowel is decreased slightly by hypnotic doses; more profoundly during intoxication
  • Action on bronchial, ureteric, visceral and uterine muscle is not significant
 
Kidney
  • Barbiturates tends to decrease urine flow by decreasing BP and increasing ADH release
  • Oligouria attends barbiturate intoxication
 
Mechanism of action
 
  • Barbiturates act primarily at GABA: BZD receptor Cl channel complex and potentiate GABAergic inhibition by increasing the lifetime of Cl channel opening induced by GABA  
  • They do not bind to BZD receptor, but bind to another site on the same macromolecular complex to exert the GABA facilitatory action
  • Barbiturate site appears to be located on the α or β subunit
  • They also enhance the BZD binding to its receptor
  • At high concentration, barbiturates directly increase Cl conductance and inhibit Ca2+ dependant release of neurotransmitters
  • In addition, they depress glutamate induced neuronal depolarization through AMPA receptor
  • At very high concentration, barbiturate depress voltage sensitive Na+ and K+ channels as well
 
 
 
Pharmacokinetics
 
  • Bariburates are well absorbed from the gi tract
  • They are widely distributed in the body
  • Rate of entry into CNS is dependent on lipid solubility
  • Plasma protein binding varies with the compound: thiopentone 75%; phenobarbitone 20%
  • Barbiturates cross placenta and can produce effects on the fetus and suckling infant

Three processes are involved in termination of action:

1. Redistribution:
  • Important in case of highly lipid soluble thiopentone
  • After iv injection, consciousness is regained in 6-10 min due to redistribution while ultimate disposal occurs by metabolism (t ½ of elimination phase is 9 hours)
2. Metabolism
  • Drugs with intermediate lipid solubility (short acting) are primarily metabolized in the liver by oxidation, dealkylation and conjugation
  • Their plasma t ½ ranges from 12-40 hours
3. Excretion
  • Barbiturates with low lipid solubility (long acting) are significantly excreted unchanged in urine
  • t ½ of phenobarbitone is 80-120 hours
  • Alkalinization of urine increases ionization and excretion
  • This is most significant in case of long acting agents
 
Uses
  • Phenobarbitine in epilepsy
  • Thiopentone in anesthesia
  • As hypnotic and sedatives, they are superseded by benzodiazepines
  • Occasionally used as adjuvants in psychosomatic disorders
 
Adverse effects
 
Side effects
  • Hangover are common
  • On repeated doses, they produce tolerance and dependence
  • Mental confusion
  • Impaired performance
  • Traffic accidents
 
Idiosyncrasy
  • In occasional patients, barbiturates produce excitement. More common in elderly patients
  • Precipitation of porphyria in susceptible individuals
Hypersensitivity
  • Rashes
  • Swelling of eyelids, lips
  • More common in atopic individuals
Tolerance and dependence
  • Both cellular and pharmacokinetic tolerance develops on repeated use
  • Addicts may present with acute barbiturate intoxication
  • Psychological as well as physical dependence occurs
  • Withdrawal symptoms include: excitement, hallucination, delirium, convulsions and death
Drug interactions
  • Barbiturate induce several CYP isoenzymes including glucoronyl transferase and increases metabolism of many drugs and reduce their effectiveness: Warfarin, steroids (including contraceptives), tolbutamide, griseofulvin, chloramphenicol, theophylline
  • Additive action with other CNS depressants- alcohol, antihistamines, opiods etc
  • Sodium valproate increases plasma concentration of phenobarbitone
  • Phenobarbitone competitively inhibits as well as induces phenytoin and imipramine metabolism: complex interaction
  • Phenobarbitone decreases absorption of griseofulvin from the gi tract
 
 
Acute barbiturate poisoning
 
Manifestations are due to excessive CNS depression:
  • Patient flabby, comatose
  • Shallow and falling respiration
  • Fall in BP and cardiovascular collapse
  • Renal failure
  • Pulmonary complications
  • Bullous eruptions
 
Treatment
  • Gastric lavage
  • Supportive measures: patent airway, assisted respiration, oxygen, maintenance of blood volume by fluid infusion and use of vasopressors (dopamine is preferred)
  • Alkaline diuresis: with sodium bicarbonate 1mEq/Kg iv with or without mannitol
  • Hemodialysis and hemoperfusion is highly effective in removing long and short acting barbiturates
  • There is no specific antidote to barbiturate poisoning

 

Phenobarbitone

  • Statistically significant reduction of bilirubin levels is achieved by phenobarbitone therapy in babies with ABO incompatibility, glucose-6-phosphatase dehydrogenase deficiency, cephalhaematome and non specific causes. (6)
  • A mean intravenous or intramuscular loading dose of 15mg/kg of phenobarbitone safely achieved therapeutic levels within 2 hours of injection and high therapeutic levels is maintaines with a dose of 6 mg/kg a day in patients with neonatal convulsions. (7)
  • Treatment with repeated oral doses of activated charcoal is simple safe and as efefctive as forced alkaline diuresis, haemodialysis and haemoperfusion for the removal of phenobarbitone following overdosage. (8)
  • Phenobarbitone is effective and well tolerated AED. There is distinct improvement in cognition and psychosocial functioning and effective seizure control. (9)
  • Phenobarbital therapy is associated with improvement in organic anion clearance in some patients with cholestatic jaundice and may be benficial to such patients. (10)
  • High dose phenobarbitone is effective in termination of all cases of status epilepticus. Hypotension is a common complication frequently requiring vasopressor therapy. (11)
  • Routine use of combined forced alkaline diuresis and haemodialysis confers no advantage when used among patients with moderate phenobarbitone overdose whose GCS is more than 8 and are haemodynamically stable. (12)
  • Phenobarbital is more selective than pentobarbital in increasing motor cortical thresholds. (13)
  • Drug reaction with eosinophillia and systemic symtoms (DRESS) is a life threatening cutaneous drug reaction with visceral involvement and hematological abnormalities seen with phenobarbital. (14)
  • Phenobarbital may mediate hyperalgesia through GABA-A receptors at supraspinal levels and antonociception through the same kind of receptors at the spinal levels. (15)
  • Phenobarbitone induces urinary excretions of D-glucaric acid and 6β-hydroxycortisol in man. (16)
  • Phenobarbital affects bilirubin metabolism by the induction of enzymes with slow rates of degradation (or rapid rate of degradation with milited capacity). (17)
  • Phenobarbitone may have a role to play in the treatment of parenteral nutrition-associated cholestasis. (18)

 

Butobarbitone 

  • There is redistribution of butobarbitone into the adipose tissue and obesity modifies the pharmacokinetics of the drug. (19)
  • After single 200 mg oral dose of butobarbitone in man, 5.4% is excreted in urine unchanged and 28.2% as the 3i- hydroxy metabolite in 6 days. (20)
  • Enzyme induction of butobarbitone reaches a maximum 3-4 days after single therapeutic dose, but still rises after about 10 days when repititive doses are given. (21)
  • Butobarbitone is more effective than ethinamate and methyprylone as hypnotic and this efficacy is uninfluenced by factors of age, sex or diagnosis. (22)

Pentobarbitone 

  • Pentobarbitone is more effective in lowering blood pressure when injected into the cerebral ventricles than when injcted into the cisterna magna. Pentobarbitone does not act on the structures in the ventricular wall but acts on structures reached from the subarachnoid space. (23)
  • Ketamine and pentobarbitone has opposite effects on Ach release from the rat frontal cortex as seen previously in the rat hippocampus. (24)
  • Benzodiazepines and pentobarbitone potentiate GABA mediated recurrent inhibition in hippocampal neurons in a similar way. (25)
  • Anesthesia with pentobarbitone blocks the progesterone induced luteinizing hormone surge in the ovariectmized rhesus monkey. (26)
  • The continuous thryotropin releasing hormone treatment using TRH-SR causes shortening of pentobarbitone induced sleeping time at doses lower then those required using bolus injection and probably by mechanism involving the central cholinergic system. (27)
  • Pretreatment with baclofen not only prolong pentobarbitone sleeping time but also induce sleep in mice treated wuth a subhypnotic dose of pentobarbitone. (28)
  • 6,7-dimethoxy-4-ethyl-3carbomethoxy-beta-carboline (DMCM) or another benzodiazepine receptor ligand with full inverse agonist qualities could be effective as an antidote for barbiturate intoxication in man. (29)
  • Thiopental is more effective than pentobarbital in controlling intracranial hypertension refractory to first tier measures. (30)
  • Zopiclone is superior to pentobarbitone with regard to sleep quality, judgement of therapy and condition in the morning. (31)
  • The decrease in follicular oestradiol production after pentobarbitone injection is due to inhibition of the serum concentrations of LH rather than the preovulatory surge of prolactin. (32)
  • Pentobarbitone has no effect on ependymal ciliary activity at levels used for anesthesia. (33) 
  • Pentobarbital depressant effects are independent of GABA receptors in auditory thalamic neurons. (34)

 

Thiopentone 

  • Intravenous infusion of thiopentone sodium is used for the treatment of status epilepticus. (35)
  • Thiopentone sodium injected into the artery may cause gangrene. (36)
  • After an accidental intra-arterial injection of thiopentone, good therapeutic results are obtained with a selective intra-arterial injection of urokinase during digital subtraction angiography. (37)
  • Evoked responses are present in comatose patients on continuous thiopentone infusion. Additional amounts of thiopentone producing a full suppression of all spontaneous EEG activity has no effects either on the configuration of evoked responses or on the cental conduction times. (38)
  • Thiopentone infusion in the management of intractable status epilepticus in pediatric patients. (39)
  • Evoked response is present in all comatose patients on continuous thiopentone infusion. Additional amounts of thiopentone producing a full suppression of all spontaneous EEG activity has no effects either on the configuration of the evoked responses or on the central conduction times. (40) 
  • Midazolam is a safe agent than thiopentone on arrhythmias in ischemia and reperfusion conditions. (41)
  • Propofol may be more suitable than thiopentone for dogs with a susceptibility to ventricular arrhythmias or a long QT interval. (42)
  • Propanidid when compared to thiopentone sodium as an anesthetic agent for electro-convulsive therapy is proved to be superior to thiopentone. (43)
  • Midazolam is a suitable alternative to thiopentone and would be of value when the latter is contraindicated as induction agent in general anesthesia. (44)
  • At higher doses (2.5,5,10 mg/kg) both propofol and thiopentone produces a significant and dose dependent increase in the picrotoxin convulsive threshold. (45)
  • Infusion of dexmedetomidine during the laparoscopic cholecystectomy decreases the requirement of thiopentone sodium and pentazocine and leads to early recovery of patients. (46)
  • Propofol is a reasonable alternative to thiopentone during induction of anesthesia in patients with intracranial pathology, provided careful dose titration is done to maintain CPP within the range of autoregulation. (47)
  • Diltiazem inhibits the constriction in response to thiopentone as well as to potassium chloride in a noncompetitive antagonistic manner. Constriction induced by thiopentone may be due in part to activation of the calcium inward channel in the wall of the internal carotid artery. (48)
  • Propofol is superior to thiopentone sodium and can be used as an alternative to thiopentone sodium for induction of general anestehsia in water buffaloes. (49)
  • Rectal thiopentone premedication significantly reduces the incidence and severity of airway complications and quality of induction during inhalational induction with isoflurane. There was significant fall in the preinduction pulse rate following rectal thiopentone premedication. (50)
  • Potentially harmful, yet avoidable, interaction between thiopentone and commonly used muscle relaxants can endanger patients. (51)
  • There is no pharmacokinetic difference of clinical significance between the R-(+) and S-(-)- thiopentone enantiomers. The minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding. (52)
  • Thiopentone induces transient bradycadia in the management of refractory status epilepticus. (53)
  • In the smooth muscle of human epigastric arteries, thiopentone induced relaxation is non-specific and is associated with impairment of Ca2+ supply from both extracellular and intracellular pools. (54)
  • Propofol and thiopental interact in an additive fashion when given at induction of anesthesia. (55)
  • The thiopentone-propofol mixture has the potential advantage of reducing the pain on injection, provides synergistic interaction, does not prolong recovery when used for induction of anesthesia, may reduce the incidence of convulsions and is cost effective. (56)
  • Thiopental is an ultrashort acting anesthetic. The high lipid solubility may be responsible for the rapid equilibration with brain, thus for the ultrashort duration of action. Because of its poor blood supply, depot fat takes up thiopental too slowly to be of great importance in the early events that terminate the anesthetic action of a single small dose of thiopental. (57)
  • The mixtures of propofol and thiopentone at a ratio less than 1:1 do not maintain the bactericidal properties. (58)
  • Continuous infusion of thiopental can be applied effectively and safely for maintenance of anesthesia. In comparison with halothane, it is associated with lower changes of intraoperative hemodynamics and faster anesthesia recovery. (59)
  • Midazolam appears to be at least as acceptable as induction agent as thiopentone in ill patients, from a haemodynamic point of view. (60)
  • Decrease in WBC count is common, while development of leucopenia is rare after thiopentone barbiturate coma. Regular monitoring of WBC counts is recommended. (61)
  • Pre-filled thiopental syringes reduce cost and wastage whilst improve safety. (62)
  • There is facilitation of mechanical ventilation in status asthmaticus with use of early and continuous iv anesthesia induced by thiopental. (63)

Methohexitone 

  • Methohexitone relaxation can be used for desensitising agoraphobic patients. (64)
  • Methohexitone assisted densensitisation is used in the treatment of phobias. (65)
  • Complications after the treatment with methohexitone to relax anxious patients include impaired memory, distorted sense of time, exercise intolerance, drowsiness, euphoria, inappropriate behaviour and barbiturate dependence. (66)
  • The combination of methohexitone with alfentanil is a good regimen for ECT, especially for patients with short seizure duration. (67)
  • Methohexitone activates EEG, thus seems to be valuable in the investigation of petit mal and temporal lobe epilepsy and adds valuable negative evidence in cases of suspected behaviour disorders. (68)
  • Methohexitone is effective in acute blocking of naloxone-precipitated opiate withdrawal symptoms. (69)
  • The administration of effective ECT is possible without the use of methohexitone. (70)
  • In the presence of methohexitone, tetraethylammonium produces contractures of the chick muscle by releasing acetylcholine but also by a direct agonist action on the cholinoceptor. (71)
  • Methohexitone is a useful drug for inducing sleep, especially in out patients. (72)
  • If induced sleep and the appearance of EEG burst suppression are considered as clinical endpoints of anaesthesia, the therapeutic window of methohexitone covers a mean venous serum concentration range of 3.4 to 10.7 µg/ml. (73)
  • Diazepam injected after induction of methohexitone improves the quality of methohexitone anesthesia, reduce the supplementary doses of methohexitone and minimize the incidence of nausea and vomiting. It is recommended that patients should avoid driving a motor vehicle or using dangerous tools or machines for 12-24 hours following recovery from methohexitone anaesthesia. (74)
  • Methohexitone antagonises kainate and epileptiform activity in rat neocortical slices. (75)
  • Thiopentone and methohexitone enantiomers do not act stereoselectively on the oxidative respinse in human neutophills in vitro. (76)
  • Thiopentone and propofol and not methohexitone nor midazolam inhibit nutrophil oxidative response t the bacterial peptide FMLP. (77)
  • Ten percent rectal methohexitone 25 mg/kg and one percent rectal methohexitone 15 mg/kg are equally effective for induction of anaesthesia in children and both are significantly more effective than ten percent methohexitone 15 mg/kg. (78)
  • The use of infusions of methohexitone and succinylcholine probides adequate safe anesthesia and prompt recovery for diagnostic fiberoptic bronchoscopic procedured under general anesthesia. (79)

 

References:
 
  1. Rachelle HB Fishman, Joseph Yanai. Long lasting effects of early barbiturates on central nervous system and behaviour. Neuroscience & Biobehavioural Reviews. SPring 1983;7(1):19-28. 
  2. VI Teichberg, N Tal, O Goldberg, A Luini. Barbiturates, alcohols and the CNS excitatory neurotransmission: SPecific effects on the kainate and quisqualate receptors. Brain Research. Jan 1984;291(2):285-292. 
  3. MAKF Tatsuo, CM Yokoro, JV Salgado, SMS Pesquero, MAP Santana, JN Francischi. Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement. Braz J Med Res. FEb 1997;30(2):251-256. 
  4. John A Harvey, ALfred Heller, Robert Y Moore, Howard F Hunts, Lloyd J Roth. Effect of central nervous system lesions on barbiturate sleeping time in the rat. JPET. April 1964;144(1):24-36. 
  5. Irwin Baumel, John J DeFeo, Harbans Lal. Effect of acute hypoxia on brain sensitivity and metabolism of barbiturates in mice. Psychopharmacologia.1970;17(2):193-197. 
  6. CY Yeung, C Elaine Field. Phenobarbitone therapy in neonatal hyperbilirubinemia. The Lancet, July 1969;294(7612):135-139. 
  7. RA Ouvrier, R Goldsmith. Phenobarbitone dosage in neonatal convulsions. Arch Dis Child. Sept 1982;57(9):653-657. 
  8. DAR Boldy, JA Vale, LF Prescott. Treatment of phenobarbitone poisoning with repeated oral administration of activated charcoal. QJM 1986;61(2):997-1002. 
  9. P Satischandra, SL Rao, S Ravat, S Jayalakhsmi et al. The effect of phenobarbitone on cognition in adult patients with new onset epilepsy: A multi-centric prospective study from India. Epilepsy Research. July 2014;108(5):928-936. 
  10. JOseph R Bloomer, James L Boyer. Phenobarbital efefcts in cholestatic liver disease. Ann Intern Med. 1975;82(3):310-317. 
  11. HC Chua, AKY Tan, CB Tan, H Tjia. High dose phenobarbitone for status epilepticus in adults. Neurol J Southeast Asia 1999;4:25-29. 
  12. S Srinivas, Sunil Karanth, V Nayyar. Does it matter how we treat phenobarbitone overdose of moderate severity? IJCCM 2004;8(3):153-156. 
  13. Robert N Straw, CL Mitchell. A comparison of the effects of phenobarbital and pentobarbital on motor cortical threshold and tighting reflex response in the cat. JPET. June 1967;156(3):598-601. 
  14. Navreet K Natt, Tarseem Singh, Harmanjit Singh, Manu Sharma, Gagandeep Singh. Phenobarbitone induced drug reaction with eosinophilia and systemic symptoms (DRESS): a case report. Int J Basic Clin Pharmacol. 2013;2(3):333-335. 
  15. CM Yokoro, SMS Pesquero, RMMM Turchetti-Maia, JN Francischi, MAKF Tatsuo. Acute phenobarbital administration induces hyperalgesia: pharmacological evidence for the involvement of supraspinal GABA-A recpetors. Braz J Med Biol Res. March 2001;34(3):397-405. 
  16. AN Latham, P TUrner, C FRanklin, W Maclay. Phenobarbitone-induced urinary excretions of D-glucaric acid and 6β-hydroxycortisol in man. Canadian Journal of Physiology and Pharmacology. 1976;54(5):778-782. 
  17. John F Crigler, Norman I Gold. Effect of sodium phenobarbital on bilirubin metabolism in an infant with congential, nonhemolytic, unconjugated hyperbilirubinemia and kernicterus. J Clin Invest. 1969;48(1);42-55. 
  18. Michael South, Ashley King. Parenteral nutrition associated cholestasis: recovery following phenobarbitone. J Parenter Enteral Nutr. March 1987;11(2):208-209. 
  19. G Cheymol, C Bernheim, J Besson, J Dry, R Portet. Study of urinary excretion of butobarbitone in man in relation to the percentage of ideal body weight. Br J Clin Pharmacol. 1979;7(3):303-309. 
  20. J Grove, PA Toseland, GH Draffan, RA Clare, Faith M William. Butobarbitone metabolism in man: identiication of 3i-ketobutobarbitone. Journal of Pharmacy and Pharmacology. March 1974;26(3):175-178. 
  21. John NT Gilbert, JOhn W Powell. Enzyme induction effects in the human metabolism of butobarbitone. European Journal of Drug Metabolism and Pharmacokinetics. Oct-Dec 1976;1(4):188-193. 
  22. IC Lodge Patch, MD Eilenberg, EH Hare. Ethinamate and Methyprylone as hypnotics: A comparative trial. The British Journal of Psychiatry. 1960;106:1455-1458. 
  23. W Feldberg, PG Guertzenstein. A vsodepressor efefct of pentobarbitone sodium. J Physiol. Jul 1972;224(1):83-103. 
  24. T Kikuchi, Y Wang, H Shinbori, K Sato, F Okumura. Effects of ketamine and pentobarbitone on acetylcholine release from the rat frontal cortex in vivo. Br J Anaesth. 1997;79(1):128-130. 
  25. Toshiro Tsuchiya, Hideaki Fukushima. Effects of benzodiazepines and pentobarbitone on the GABA-ergic recurrent inhibition of hippocampal neurons. European Journal of Pharmacology. April 1978;48(4):421-424. 
  26. E Terasawa, J Noonan, WE Bridson. Anaesthesia with pentobarbitone blocks the progesterone induced luteinizing hormone surge in the ovariectomized rhesus monkey. J Endocrinol. March 1982;92:327-339. 
  27. Tadatoshi Hashimoto, Takeo Wada, Naohisa Fukuda, AKinobu Nagaoka. Effect of thyrotropin releasing hormone on pentobarbitone induced sleep in rats: continuous treatment with a sustained release injectable formulation. Journal of Pharmacy and Pharmacology. Feb 1993;45(2);94-97. 
  28. VV Joshi, JJ Balsara, AG Chandorkar. Effect of baclofen treatment on pentobarbitone sleep in mice. Indian Journal of Pharmacology. 1982;14(4):341-344. 
  29. H Havoundjian, GF Reed, SM Paul, P Skolnick. Protection against the lethal effects of pentobarbital in mice by a benzodiazepine receptor inverse agonist, 6,7-dimethoxy-4-ethyl-3-carbomethoxy-beta-carboline. J Clin Invest. 1987;79(2):473-477. 
  30. Jon Perez Barcena, Juan A Llompart-Pou, Javier Homar, Josep M Abadal et al. Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial. Critical Care 2008;12:R112. 
  31. Mello de Paula AJ. Comparative study of zopiclone and pentobarbitone as hypnotics. Pharmacology. 1983;27:188-195. 
  32. J Th J Uilenbroek. Effect of pentobarbitone sodium and bromocriptine on follicular oestradiol production in the rat. J Reprod Fertil. May 1989;86:327-333. 
  33. Chris O'Callaghan, Kulvinder Sikand. The effect of halothane and pentobarbital sodium on brain ependymal cilia. Cilia 2012;1:12. 
  34. Xiang Wan, Ernest Puil. Pentobarbital depressant effects are independent of GABA receptors in auditory thalamic neurons. Journal of Neurophysiology. Dec 2002;88:3067-3077. 
  35. AS Brown, JM Horton. Status epilepticus treated by intravenous infusions of thiopentone sodium. Br Med J. Jan 1967;1(5531):27-28. 
  36. JH Burn. Why thiopentone injected into an artery may cause gangrene. Br Med J. Aug 1960;2(5196):414-416. 
  37. M Vangerven, G Delrue, E Brugman, P Cosaert. A new therapeutic approach to accidental intra-arterial injection of thiopentone. Br J Anaesth. 1989;62(1):98-100. 
  38. T Ganes, T Lundar. The effect of thiopentone on somatosensory evoked responses and EEGs in comatose patients. J Neurol Neurosurg Psychiatry. 1983;46:509-514. 
  39. R Govindarajan, M Sathyamoorthy, J Aronsohn. Role of thiopentone infusion for management of intractable status epilepticus in pediatric patients. Critical Care 2004;8(Suppl 1):P319. 
  40. T Ganes, T Lundar. The effect of thiopentone on somatosensory evoked responses and EEGs in comatose patients. J Neurol Neurosurg Psychiatry. 1983;46:509-514. 
  41. Oner Suzer, Sabahat Koselglu, Vildan Senses. Midazolam is a safe agent by comparison with thiopentone on arrhythmias in ischemia and reperfusion conditions in isolated perfused rat hearts. Pharmacological Research. June 1998;37(6):461-468. 
  42. SG Dennis, PR Wotton, A Boswood, D Flaherty. COmparison of the effects of thiopentone and propofol on the electrocardiogram of dogs. Veterinary Record. 2007;160:681-686. 
  43. Katre AM, Pandya SH. Comparative evaluation of propanidid with thiopentone as an anesthetic agent for electro-convulsive therapy. JPGM 1980;26(3):171-7. 
  44. Yudhvir Suri. COmparison of midazolam and thiopentone as induction agents in general anesthesia. Medical Journal Armed Forces India. July 2001;57(3):213-214. 
  45. Zyheir Hasan, Said Khatib, Ayman Abu-Laban. Effects of popofol and thiopentone on picrotoxin convulsive threshold in the rabbit. Canadian Journal of Physiology and Pharmacology. 1995;73(6):714-717. 
  46. Suchit Khanduja, Anil Ohri, Manoj Panwar. Dexmedetomidine decreases requirement of tiopentone sodium and pentazocine followed with improved recovery in patients undergoing laparoscopic cholecystectomy. Journal of anesthesiology Clinical Pharmacology. 2014;30(2):208-212. 
  47. Sankari Santra, Bibhukalyani Das. Effect of propofol and thiopentone on intracranial pressure and cerebral perfusion pressure in patients undergoing elective craniotomy - a comparative study. Indian Journal of Anaesthesia. 2007;51(3):211-215. 
  48. T Tsuji, S Chiba. Blocking effect of diltiazem on thiopentone induced vasoconstriction in isolated canine internal carotid arteries. Journal of Cerebral Blood Flow & Metabolism. 1985;5:446-450. 
  49. Deepti Bodh, Kiranjeet Singh, Jitender Mohindroo et al. Propofol and thiopentone sodium as induction agents in water buffaloes (Bubalas bubalis): a comparative study. Journal of Applied Animal Research. 2013;41(3):370-373. 
  50. Madona Stephen, Radhesh Hegde. Effect of rectal thiopentone as premedication for inhalational induction with isoflurane in children. IJHSR. 2013;3(4):36-41. 
  51. Shahab Khan, Naina Stannard, Jeff Greijn. Precipitation of thiopental with muscle relaxants: a potential hazard. JRSM Open. JUly 2011;2(7):58. 
  52. DJ Cordato, AS Gross, GK Herkes, LE Mather. Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone. British Journal of Clinical Pharmacology. April 1997;43(4):355-362. 
  53. Sushma Sharma, Pradeep P Nair, Aditya Murgai Raja J Selvaraj. Transient bradycardia induced by thiopentone sodium: a unique challange in the management of refractory status epilepticus. Case Reports 01/2013;2013(oct15_1). DOI: 10.1136/bcr-2013-200484. 
  54. NE Olele, AE Ehigiegba, AB Ebeigbe. Vasorelaxant effect of thiopentone in isolated human epigastric arteries. Experimental Physiology. July 1998;83:461-468. 
  55. W Wong, T Lim, K Lim. Interaction between propofol and thiopental: Isobolographic analysis using dose, central compartment and effect compartment concentrations. The internet Journal of anesthesiology. 2007;17(1). 
  56. HGW Paw, M Garrood, AJ Fillery Travis, GT Rich. Thiopentone and propofol:  a compatible mixture? European Journal of anaesthesiology. JUly 1998;4:409-413. 
  57. Avram Goldstein, Lewis Aronow. The durations of action of thiopental and pentobarbital. JPET. Jan 1960;128(1):1-6. 
  58. KE Joubert, J Picard, M Sethusa. Inhibition of bacterial growth by different mixtures of propofol and thiopentone. Journal of the South African Veterinary Association. 2005;76(2):85-89. 
  59. Mehrdad Shoroghi, Farshid Farahbakhsh, Mehrdad Sheikhvatan, Mahmood Sheikhfathollahi, ALi Abbasi, Azam Talebi. Anesthetic recovery and hemodynamic effects of continuous thiopental infusion versus halothane for maintenance anesthesia in patients undergoing ocular surgery. Acta Cir. Bras. May/June 2011;26(3). 
  60. Philip W Lebowitz, M Elizabeth Cote, ALfred L Daniels, JA Jeevendra Martyn, Richard S Teplick, J Kenneth Davison, N Sunder. Cardiovascular effects of midazolam and thiopentone for induction of anesthesia in ill surgical patients. Canadian Anaesthetists Society Journal. Jan 1983;30(1):19-23. 
  61. Shin Yi Ng, Ki Jinn Chin, Tong Kiat Kwek. Decrease in white blood cell counts after thiopentone barbiturate therapy for refractory intracranial hyprtension: A common complication. Journal of Neurosciences in rural practice. 2013;4(5):31-34. 
  62. H Murdoch, L Jordan, J Tuckey. Pre-filled thiopental syringes reduce cost and wastage whilst improving safety. International Journal of Obstetric Anesthesia. Oct 2012;21(4):384-385. 
  63. G Grunberg, JD Cohen, J Keslin, S Gassner. Facilitation of mechanical ventilation in status asthmaticus with continuous intravenous thiopental. Chest 1991;99(5):1216-1219. 
  64. NJ Yorkston, HGS Sergeant, S Rachman. Methohexitone relaxation for desensitising agoraphobic patients. The Lancet. Sept 1968;292(7569):651-653. 
  65. AB Mawson. Methohexitone-assisted desensitisation in treatment of phobias. The Lancet. May 1970;295(7656):1084-1086. 
  66. HGS Sergeant, NJ Yorkston. Some complications of using methohexitone to relax anxious patients. The Lancet. Sept 1968;292(7569):653-655. 
  67. TT Nguyen, AK Chhibber, SJ Lustik, JW Kolano, PJ Dillon, LB Guttmacher. Effect of methohexitone and propofol with or without alfentanil on seizure duration and recovery in electroconvulsive therapy. Br J Anaesth. 1997;79(6):801-803. 
  68. John Gumpert, Ronald Paul. Activation of the electroencephalogram with intravenous Brietal (methohexitone): the findings in 100 cases. J Neurol Neurosurg Psychiatry. 1971;34:646-648. 
  69. N Loimer, R Schmid, K Lenz, O Presslich, J Grunberger. Acute blocking of naloxone-precipitated opiate withdrawal symptoms by methohexitone. THe British Journal of Psychiatry. 1990;157:748-752. 
  70. Chris Aldridge, Mandy Assin, Safwat Elyas. Alternatives to methohexitone. Psychiatric Bulletin. 2000;24:31-32. 
  71. RC Eliott. Contractures elicited by tetraethylammonium in avian muscle treated with methohexitone. British Journal of Pharmacology. July 1979;66(3):391-395. 
  72. George W Fenton, Leila Scotton. The use of methohexitone in sleep electroencephalography. Electroencephalography and clinical neurophysiology. Sept 1967;23(3):273-276. 
  73. PM Lauven, H Schwilden, H Stoeckel. Threshold hypnotic concentration of methohexitone. European Journal of Clinical Pharmacology. 1987;33(3):261-265. 
  74. Matti AK Manila, Harry M Larni. The effect of diazepam on methohexitone short anesthesia: a clinical double blind investigation. Current Medical Research and Opinion. 1981;7(3):171-178. 
  75. Palmer AJ, Zeman S, Lodge D. Methohexitone antagonises kainate and epileptiform activity in rat neocortical slices. European Journal of Pharmacology. 1992;221(2-3):205-209. 
  76. Wittmann S, Daniels S, Ittner Kp, Frohlich D. Thiopentone and methohexitone enantiomers do not act stereoselctively on the oxidative response in human neutophils in vitro. Pharmacology. 2004;72(1). 
  77. D Frohlich, G Rothe, B Schwall, G Schmitz et al. Thiopentone and propofol but not methohexitone nor midazolam inhibit neutrophil oxidative response to the bacterial peptide FMLP. European Journal of Anaesthesiology. Nov 1996;6:582-588. 
  78. RS Laishley, AC O'Collaghan, J Lerman. Effects of dose and concentration of rectal methohexitone for induction of anestehsia in children. Canadian Anaesthetists Society Journal. July 1986;33
  79. M Heifetz, S De Myttenaere, J Lemer. Intermittent positive pressure inflation during fiberoptic bronchoscopy. Chest 1977;72(4):480-482.