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)

Structure

• 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

NB:

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

Thiopentone

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

Methohexital

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

Classification based on duration of action

[RDM6:p328]

(Only selected examples are copied)

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

Pharmacodynamics

Mechanism of action

[SH4:p128]

• 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

Potency

Relative potency of barbiturates as IV induction agents

• Thiopentone 1
• Thiamylal 1.1
• Methohexital 2.5

NB:

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

Side effects

[SH4:p134]

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

Thus,

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

NB:

• 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)

EEG

• 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

Liver

• 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

Kidney

• 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

Mechanism

• 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

Treatment

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]

NB:

• 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

Immunosuppression

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

Others

• 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]

 

Pharmacokinetics

[SH4:p128]

Distribution

• 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

[SH4:p129]

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

Brain

• 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)

Fat

• 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

NB:

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

Ionisation

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

Thus,

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

NB:

• 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

[SH4:p136]

• 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

Metabolism

• 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

Elimination

[SH4:P130]

Renal excretion

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

Thus,

• <1% of thiopentone, thiamylal, or methohexital are excreted unchanged in urine

Phenobarbitone

• 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

[SH4:p131]

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

Clearance

• Thiopentone = 3.4 mL/kg/min
• Methohexital = 10.9 mL/kg/min

Vd

• Thiopentone = 2.5 L/kg
• Methohexital = 2.2 L/kg

NB:

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

Thiopentone

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

Pharmaceutics

Thiopentone

Presentation

• 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]

Composition

• 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

NB:

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

Methohexitone

• Used as 1% solution

 

Clinical

Usage

[SH4:p131]

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

NB:

• 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

[SH4:p131]

• 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)

Administration

• 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

NB:

• 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]

Thus,

• Benzodiazepines have replaced barbiturates in some clinical settings

Interactions

[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

Trivia

History

 

Others

Thiopentone brand name = Pentothal