3. Pharmacology
          3.3. IV anaesthetic agents
 3.3.5. Barbiturate


[SH(H)2:p119; SH4:Chp4]

Commercial preparations

  • Available as sodium salts which dissolves to form alkaline solutions
  • Incompatible to be mixed with drugs such as opioids, catecholamines, muscle relaxants (they are acidic in solution)


  • Barbiturates = Any drugs derived from barbituric acid
  • Barbituric acid
    * No CNS activities
    * Cyclic compound
    * Formed by combination of urea and malonic acid

Structure-activity relationship

  • Substitution at carbon 5
    --> Sedative-hypnotic properties
    * Branched chain --> greater hypnotic activity than straight chain
    * Phenol group (like phneobarbital) --> Greater anticonvulsant activity
  • Carbon 2
    * No substitution (oxygen) = oxybarbiturates
    * Substitution with sulfur = thiobarbiturates
  • Sulfuration at carbon 2 increases lipid solubility
    --> Greater hypnotic potency
    --> More rapid onset, but shorter duration of action
    * e.g. thiopentone has faster onset and shorter duration than pentobarbitone
  • Addition of a methyl group to nitrogen (e.g. methohexitone)
    --> Short duration of action


  • Thiobarbiturates are more lipid soluble than oxybarbiturates
  • Oxybarbiturates include:
    * Methohexitone
    * Phenobarbitone
    * Pentabarbitone
  • Thiobarbiturates include:
    * Thiopentone
    * Thiamylal


  • S(-) isomers are twice as potent as R(+), but only available commercially as racemic mixtures


  • S(-) isomers are 4-5 times more potent.
  • Also only available commercially as racemic mixture

Classification based on duration of action


(Only selected examples are copied)

  • Ultrashort-acting
    * Thiopentone
    * Methohexitone
    * Thiamylal
  • Short-acting
    * Pentobarbitone
    * Secobarbitone
  • Long-acting
    * Phenobarbitone


Mechanism of action


  • Most likely mechanism
    --> Interaction with GABAa receptor
  • GABAa activation
    --> Cl- conductance increase
    --> Cl- flow into cells
    --> Hyperpolarisation
    --> Inhibition of postsynaptic neurons
  • Barbiturates
    * Decreased rate of dissociation of GABA from the receptors (same as propofol)
    * Mimic GABA and directly activate GABAa receptors
    * Depress the reticular activating system
  • Barbiturates may also target
    * Glutamate receptors
    * Adenosine receptors
    * Neuronal nAChRs
  • Barbiturates do not act on
    * Glycine receptors
    * NMDA receptors


Relative potency of barbiturates as IV induction agents

  • Thiopentone 1
  • Thiamylal 1.1
  • Methohexital 2.5


  • Methohexitone is more potent because:
    * Methohexitone is 76% nonionised at physiological pH
    * c.f. Thiopentone = 61% nonionised

Side effects


Cardiovascular system

  • In normovolaemic subjects, thiopentone 5 mg/kg IV
    --> Transient decrease in BP (10-20mmHg)
    * Offset by a compensatory increased HR (15-20 bpm)
    * Minimal myocardial depression
    * Less than that produced by volatile anaesthetics
  • Because carotid sinus-mediated baroreceptor reflex is intact
    --> Baroreceptor-mediated increase in peripheral sympathetic nervous system activity
    --> Increased HR and contractility
    --> Offset some of the effects of peripheral vasodilation
    --> Only mild and transient decrease in BP
  • Decrease in BP is mostly due to peripheral vasodilation
    * Depression of medullary vasomotor centre
    * Decreased sympathetic nervous system outflow from CNS
  • Peripheral vasodilation is mostly of the peripheral capacitance vessels
    --> Pooling of blood in periphery
    --> Decreased venous return


  • Hypovolemic patients are less able to compensate
    --> Blood pressure decrease more marked


  • Histamine release can occur but is rarely of clinical significance
  • Fast or slow injection of thiopentone produce similar decrease in BP and increase in HR
  • Slow incremental injection to achieve an end-point --> Higher dose used than a single dose (not sure about this point. In[SH4:p135], the text said this, but the table on the same page contradicts this point)

Respiratory system

  • Dose-dependent depression of medullary and pontine ventilatory centre
  • Laryngeal reflex and cough reflex are not depressed until large doses have been given
    * (???) Needs more than the hypnotic dose
  • Resumption of spontaneous breathing
    * Slow frequency and decreased tidal volume (characteristic)


  • At 4mg/kg of thiopentone
    --> Isoelectric EEG
    --> Near maximal decrease in cerebral metabolic oxygen requirement
    * About 55%
    * Does not decrease the basal requirement
  • Hypothermia is the only reliable way of decreasing the basal cerebral metabolic requirement of oxygen


  • Thiopentone alone causes modest decrease in hepatic blood flow
  • Induction dose of thiopentone does not alter postoperative LFT
Enzyme induction
  • Barbiturates causes hepatic microsomal enzyme induction
    * 2-7 days after sustained administration
    * May persists for up to 30 days
    * Phenobarbitone is the most potent enzyme inducer among barbiturates


Barbiturate induces hepatic microsomal enzyme, resuting in:

  • Accelerated metabolism of other drugs
    * e.g. oral anticoagulants, phenytoin, tricyclic antidepressant
  • Accelerated metabolism of endogenous substances
    * e.g. corticosteroids, bile salts, vitamin K
  • Barbiturate also induces a mitochondrial enzyme (D-aminolevulinic acid synthetase)
    --> Increased production of heme
    * Can exacerbate acute intermittent porphyria
  • Enhanced metabolism of barbiturate
    --> Contribute to tolerance


  • Modest decrease in renal blood flow and GFR
    * Most likely to be due to decreased BP and CO

Tolerance and physical dependence

  • Acute tolerance to barbiturate occurs earlier than microsomal enzyme induction
  • Required effective dose may be increased 6-fold
    * More than accounted for by enzyme induction
  • Tolerance to the sedative effect occur sooner and is greater than tolerance to anticonvulsant and lethal effects
  • With tolerance, therapeutic index decreases
    * i.e. risk of toxicity is increased
  • Withdrawal syndrome severity depends on
    * Degree of tolerance
    * Rate of elimination
  • Generally slow elimination of barbiturates allows time for CNS to adjust and decrease its compensatory excitatory response
    * But phenobarbital discontinuation can lead to status epilepticus in epilepsy patients

Intraarterial injection

  • Intra-arterial injection results in
    * Intense vasoconstriction
    * Excruciating pain along the distribution of the artery
  • Vasoconstriction is sufficient to cause blanching, even gangrene and permanent nerve damage
  • Risk of vascular damage increases with concentration
  • Likely to be due to precipitation of thiopentone crystals in the artery
    --> Inflammation, arteritis, microembolisation
    --> Occlusion of distal circulation
  • NOT due to the high pH
  1. Immediate attempt at dilution by injecting saline
  2. Injection of lidocaine, papaverine, or phenoxybenzamine to produce vasodilation and pain-relief
  3. Sympathectomy or regional nerve block (e.g. brachial plexus block) may also relieve vasoconstriction
  4. Heparinisation to prevent thrombosis [RDM6:p333]


  • Urokinase may improve distal blood flow after accidential intraarterial injection of thiopentone

Venous thrombosis

  • Possibly due to deposition of barbiturate crystal in the vein
  • Less hazardous because of the ever-increasing diameter of veins
  • Extravasation can also cause local tissue necrosis

Allergic reaction

  • Allergic reaction is most likely anaphylaxis in nature
  • Incidence of allergyic reaction to thiopentone = 1:30,000
  • Mortality after an allergic reaction to barbiturates is unusually high
    --> Need to be aggressively managed


Possible immunosuppression

  • Long term use of high dose thiopentone is associated with increased nosocomial infection
  • Long term use of thiopentone for ICP treatment is associated with:
    * Bone marrow suppression
    * Leukopenia
  • Midazolam and thiopentone impair neutrophil functions
    * May be an advantage in decreasing autoimmune injury and organ dysfunction
    * May be a disadvantage in allowing bacterial infection


  • 40% patients may experience a taste sensation of onion or garlic on induction with thiopentone
    * [RDM6:p333; PI on MIMs]
  • Thiopentone may decrease lower oesophageal sphincter tone
    * [PI on MIMs]





  • After single dose (of thiopentone, thiamylal, or methohexital)
    --> Prompt redistribution from brain to inactive tissues
  • Discontinuation of an infusion
    --> Inactive tissues stores some drugs
    --> Drugs diffuse back into the blood
    --> Context-sensitive half-time is prolonged
  • Elimination almost completely depends on metabolism
    * <1% excreted unchanged in urine
  • Thiopentone Vd = 2.5L/kg

Protein binding

  • High lipid solubility is associated with higher protein binding

For example,

  • Thiopentone is highly lipid soluble and highly protein bound
  • Thiobarbiturates have higher protein-binding than oxybarbiturates
  • Protein-binding (to albumin)
    = 72-86% [SH4:p129]
    = 80% [PI per MIMs]

Factors influencing protein-binding


Decreased protein-binding
--> increased free thiopentone
--> Increased drug effect

  • Protein-binding percentage is higher at lower plasma concentration of thiopentone
  • Protein-binding is decreased by displacement by other drugs:
    * e.g. aspirin, phenylbutazone
  • Protein-binding is also reduced in
    * Uraemia (competition with nitrogenous waste products)
    * Liver cirrhosis (with resultant hypoalbuminaemia)
    * Neonates (about half that in adults)



Factors influencing distribution

  • Depends on
    * Lipid solubility
    * Protein binding
    * Degree of ionisation
    * Blood flow
  • Lipid solubility is the most important factor for:
    * Thiopentone
    * Thiamylala
    * Methohexitone
  • Tissue blood flow is very important
    * In hypovolaemia, decreased blood flow to muscles and unchanged blood flow to brain
    --> Less dilution
    --> Greater effect of thiopentone


  • Receives about 10% of the total dose
  • Maximal brain uptake within 30 seconds
    * Due to blood flow of CNS and lipid solubility of barbiturates
    * Prompt onset of action
  • Redistribution to other tissues
    --> Brain concentration halves after 5 minutes
    --> About 10% remains in brain after 30 minutes

Skeletal muscles

  • The most prominent site for initial redistribution of highly lipid-soluble barbiturates
  • Equilibrium with skeletal muscle is reached in about 15 minutes after IV thiopentone
  • Thiopentone dosage should be reduced when
    * Skeletal muscle perfusion is reduced (e.g. in shock)
    * Decreased skeletal muscle mass (e.g. in elderly)


  • Due to high storage capacity and low blood flow
    --> Thiopentone concentration still continues to increase 30min after injection
  • Thiopentone dose should be calculated based on lean body mass
  • Due to the low blood flow
    --> Redistribution to fat does NOT contribute much to early awakening after single dose


  • Fat:blood partition coefficient for thiopentone = 11
    --> Fat can take up to 11 times the amount of thiopentone as blood does


  • Thiopentone pK = 7.6 (weak acid)
    --> Close of blood pH
    --> 60% unionised at physiological pH


  • Acidosis decreases ionisation
    --> Nonionised fraction increase
    --> Greater entry into CNS
    --> Increased intensity of barbiturate effect
  • Alkalosis
    --> Decreased effect


  • pH changes due to metabolic causes are associated with normal intracellular pH in brain
    * Ventilation-induced changes in pH are associated with changes in intracellular pH as well
    --> Metabolic acidosis increases barbiturate effect more than respiratory acidosis

Placental transfer


  • Barbiturate is transfered readily from maternal circulation to foetal circulation
  • But, foetal plasma level of barbiturate is lower than maternal
  • And foetal brain level of barbiturate is lower than foetal plasma level
    * Due to clearance in foetal liver and dilution effect
    * Generally innocuous


  • Oxybarbiturates
    * Only metabolised in hepatocytes
  • Thiobarbiturates
    * Also break down in extrahepatic sites (e.g. kidney, possibly CNS)
  • Oxidation of the side chain at C5 is the most important initial step
    --> It terminates the pharmacologic activity of barbiturate
    * Occurs in the endoplasmic reticulum of hepatocytes
  • Reserve capacity of the liver for oxidation is large
    --> Metabolism is only decreased when extreme hepatic dysfunction
  • Metabolites often more water soluble
    --> Better renal excretion

Metabolism of thiopentone

  • Slow rate
  • 10-24% metabolised by liver each hour
  • Eventually almost all (99%) metabolised
  • Metabolites include:
    * Hydroxythiopentone
    * Carboxylic acid
    --> More water soluble and very little CNS activity
  • Principle site of metabolism
    * Oxidation of C5
    * Desulfuration of C2
    * Hydrolytic opening of barbituric acid ring
  • At large doses of thiopentone, desulfuration at C2 can produce pentobarbitone
  • Hepatic clearance of thiopentone
    * Low hepatic extraction ratio
    * Capacity-dependent elimination (i.e. influenced by enzyme activity, not perfusion)
  • However, enzyme induction or inhibition does not change duration of action of thiopentone in animals

Metabolism of methohexitone

  • Methohexitone
    --> Lower lipid solubility
    --> More drug in plasma for metabolism
    --> Metabolised faster than thiopentone
    * Hepatic clearance is 3-4 times that of thiopentone
  • Early awakening still depends mostly on redistribution
  • Hepatic clearance of methohexitone is more dependent (than thiopentone) on:
    * Cardiac output
    * Hepatic blood flow
    * i.e. more perfusion-dependent



Renal excretion

  • High protein-binding
    --> Limited filtration
  • High lipid solubility
    --> Increased reabsorption of filtered drugs


  • <1% of thiopentone, thiamylal, or methohexital are excreted unchanged in urine
  • Phenobarbitone has lower protein-binding and lipid solubility
    --> the ONLY barbiturate that undergoes significant renal excretion in unchanged form
  • Renal excretion of phenobarbitone is increased by:
    * Osmotic diuresis
    * Alkalinisation of urine

Elimination half-time

  • Obesity
    --> Increased Vd
    --> Increased elimination half-time for thiopentone
  • Advanced age
    --> Slower transfer of thiopentone from central to peripheral compartment (30% slower)
    --> Decreased thiopentone dose requirement
    * But initial Vd is unchanged
  • In paediatric patients, thiopentone has shorter elimination half-time
    * Due to more rapid hepatic clearance
    * No difference in Vd or protein-binding
  • In pregnancy, thiopentone has longer elimination half-time
    * Due to increased protein-binding
  • Hypothermia is associated with a significant decrease in systemic clearance
    * [SH4:p129]

Action profile

Thiopentone vs methohexitone


Rapid distribution half-time
  • Thiopentone = 8.5 min
  • Methohexital = 5.6 min
Slow distribution half-time
  • Thiopentone = 62.7 min
  • Methohexital = 58.3 min
Elimination half-time
  • Thiopentone = 11.6 hour
  • Methohexital = 3.9 hour
    * Much lower than thiopentone
  • Thiopentone = 3.4 mL/kg/min
  • Methohexital = 10.9 mL/kg/min
  • Thiopentone = 2.5 L/kg
  • Methohexital = 2.2 L/kg


According to James' notes [???]

  • 8 hour-context sensitive half-life = 3 hours
  • c.f. Propofol 8 hour CSHF = 30 min (clearance = 30-60 mL/kg/min)


Thiopentone [RDM6:p319]

  • Elimination half-time = 7-17 hours
  • Clearance = 3-4 mL/kg/min
  • Vd = 1.5-3 L/kg

Physicochemical properties


  • pKa
    = 7.6 [SH4:p130]
    = 7.4 [PI per MIMs]
  • Weak acid
  • Undissociated acid extremely insoluble in water




  • Available as sodium salts, which dissolves to form alkaline solutions
  • High pH --> bacteriostatic
  • At room temperature of 22C, reconstituted solution remain stable and sterile for at least 6 days
    * [SH4:p127]


  • Active
    = Thiopentone 2.5% (25mg/mL)
  • Inactivate:
    * Anhydrous sodium carbonate 60mg/g (i.e. 6%, or 30 mg in a 500mg vial)
    * Nitrogen to exclude atmospheric CO2 --> To prevent carbonic acid formation
  • pH 10.5


  • Thiamylal are usually used as 2.5% solution too
    * [SH4:p127]


  • Used as 1% solution





Main clinical application

  • Induction of anaesthesia
  • Treatment of increased ICP

Other clinicial uses

  • Treatment of hyperbilirubinaemia and kernicterus
    * Phenobarbital
    * Via induction of hepatic glucuronyl transferase enzyme activity
  • Treatment of grand mal seizures
    * Benzodiazepines are probably superior


  • Unlikely to be of benefit in cerebral protection after global ischaemic (due to cardiac arrest)
    * EEG is flat already, adding barbiturate will not decrease metabolic oxygen demand further

Induction of anaesthesia


  • Thiopentone has been used exclusively for IV induction since 1934 until introduction of propofol in 1989
  • Methohexitone is another alternative choice for induction
    * Faster recovery
    * But greater incidence of excitatory phenomena (e.g. myoclonus, hiccups)
  • Thiamylal is indistinguisable from thiopentone when used for IV induction
  • Factors affecting the induction dose of thiopentone
    * Patient age --> Dose requirement decreases with age
    * Weight
    * Cardiac output
    * Early pregnancy --> Decreased dose requirement (by 18%)
    * Children > 1 y.o. after thermal injury --> Increased dose requirement

Treatment of increased ICP

  • Barbiturates
    --> Decrease cerebral metabolic requirement
    --> Cerebral vascular vasoconstriction
    --> Decreased cerebral blood flow
    --> Decreased cerebral blood volume
    --> Decreased ICP
  • But better outcome after head trauma has not been demonstrated in trials
  • High doses of thiopentone or methohexitone are required to suppress EEG activity
    --> Risk of hypotension and ventricular fibrillation
    * But these CVS effects are smaller than that caused by the dose of isoflurane required to suppress EEG activity (2 MAC)


  • Thiopentone = 3 - 5 mg/kg IV
    --> Unconsciousness within 30 seconds [SH4:p132]
    = 3-4 mg/kg [RDM6:p333]
  • Methohexitone = 1 - 1.5 mg/kg IV
    --> Onset = 10-30 seconds
  • Methohexitone can be administered rectally as well as IV


  • ED50 for thiopentone = 2.2-2.7mg/kg IV
    * [RDM6:p333]

Disadvantage of barbiturates

  • Lack of specificity of effect in CNS
  • Lower therapeutic index than benzodiazepines
  • Higher chance of tolerance than benzodiazepines
  • Greater abuse potential
  • Great risk of drug interaction
  • Paradoxical excitement (instead of sedation)
    * Especially in presence of pain, or in the elderly
  • Hang-over effect after a sedative-hypnotic dose
  • Increased laryngeal/pharyngeal reflexes
    * [Prof Kam lecture 2006]
  • Increased pain perception
    * [Prof Kam lecture 2006]
    * Said to be unproven [SH4:p132]


  • Benzodiazepines have replaced barbiturates in some clinical settings


[PI per MIMs]

  • Probenecid --> Prolonged action of thiopentone
  • Opioid analgesics --> Thiopentone may be antianalgesic
  • Diuretics, hypotensive medications --> Additive hypotensive effects
  • Mg2+ --> Increased CNS depressant effect
  • Aminophylline --> Thiopentone antagonism
  • Benzodiazepine --> Synergism

Contraindication of thiopentone


  • Lack of IV access
  • Lack of resuscitation equipments
  • Porphyria
  • Status asthmaticus





Thiopentone brand name = Pentothal





Table of contents  | Index