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 CL_T and V_ss 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⁾

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