2. INTRODUCTION
• Barbiturates are drugs derived from
barbituric acid.
• Barbituric acid was first created by Adolf
Von Baeyer in 1864 by combining Urea
and Malonic acid.
• Introduced clinically by Water and Lundy in
1934.
3. CLASSIFICATION
A. Long acting barbiturates
Phenobarbitone
Barbitone
Methylphenobarbitone
B. Intermediate acting barbiturates
Amylobarbitone
Butobarbitone
Cyclobarbitone
Pentobarbitone
C. Short acting barbiturates
Quinal barbitone
D. Ultra short acting barbiturates
Thiopentone sodium
Methohexital
Thymilal
4. STRUCTURE ACTIVITY
RELATIONSHIP
• Barbituric acid itself doesn’t have CNS activity.
• Branched chain substitution at C5 leads to
greater hypnotic activity
• Phenyl group at C5 – greater anticonvulsant
activity ( Phenobarbitone )
• Methyl group at C5 – convulsant activity
(Methohexital )
• ‘O’ atom at C2 - oxybarbiturate (
pentobarbitone)
• ‘S’ atom at C2 - thiobarbiturate ( thiopentone )
5. THIOPENTONE SODIUM
• A thiobarbiturate of ultra short acting type
used for intravenous induction of
anaesthesia.
• Its structural name is sodium 5-ethyl,5-
methyl,1-butyl thiobarbiturate, empirically it
is NaSC11H17O2N2.
6. PREPARATION
• Sodium thiopentone (aka thiopental or pentothal) is
prepared by dissolving yellowish powder in sterile
water to provide a 2.5% solution (i.e 25mg/ml)
• Available in 500mg & 1g strength.
• Stability
Powder- indefinite period
Reconstituted –
a) room temperature: 1 week
b) refrigerated: 2 weeks
6
7. • Commercial preparations contain a mixture of six
parts of anhydrous sodium carbonate to prevent
precipitation of insoluble acid form of barbiturate by
atmospheric CO2.
• The solution is alkaline and can be irritating and
painful if accidentally injected into tissues.
• pH of 2.5% solution of thiopentone is 10.5.
7
8. • Should not be mixed in the same syringe with
other drugs, as it may cause formation of a
cloudy precipitate and inactivate the drug.
• Alkaline pH is responsible for their bacteriostatic
properties.
9. • Diluent used for reconstitution for
hygroscopic thiopentone powder
- 0.9% NS
- Sterile water
- 5% dextrose solution
• Routes of administration :
a) Intravenous
b) Rectal
9
10. MECHANISM OF ACTION
Possible mechanisms
• GABA facilitatory action
– The interaction of thiopentone with specific
membrane component of GABAA receptors
decreases the rate of dissociation of GABA from
these receptors, hence increasing the duration
of opening of chloride channels
– Uniquely depress the Reticular Activating
System which is important in maintaining the
wakefulness.
11.
12. • They also mimic action of GABA by directly
activating GABAA receptors – GABA mimetic
action.
• They also target
a) glutamate receptors
b) adenosine receptors
c) neuronal nicotinic acetlycholine receptors.
12
13. PHARMACOKINETICS
• Effect site equilibration time: 30 secs
• Context sensitive half life: prolonged
because drug is stored in fat and skeletal
muscle re-enters the circulation to
maintain plasma concentration.
14. PROTIEN BINDING
• Thiopentone , as a highly lipid soluble
barbiturate, is most avidly bound to plasma
protein ( i.e. 72 – 86 %).
• Higher binding occurs at lower plasma
concentration.
• Changes in pH from 7.35 – 7.5 do not alter
degree of protein binding.
15. • Decreased protien binding of thiopentone
leads to increased free portion of the drug.
• Conditions with decreased protien binding
- Drugs which displace thiopentone from
their binding sites eg. Aspirin ,
Phenylbutazone
- Uraemia
- Cirrhosis of liver
- Neonates
16. DISTRIBUTION
• Depends on :
• Lipid solubility
• Protein binding
• Degree of ionisation
• Tissue blood flow
Volume of distribution (Vd) of thiopentone is 2.5
L/kg
16
17. Brain:
• Max. brain uptake occurs within 30 sec. ( rapid
effect site equilibration )
• Brain receives about 10% of total dose in first 30-40
sec.
• Over next 5 min conc. decreases to half the initial
peak conc. d/t redistribution.
• Redistribution is the principal mechanism for early
awakening.
• After 30 min, drug is further redistributed and only
10% remains in brain.
17
18. Skeletal muscles:
• Skeletal muscles are the most prominent sites of
initial redistribution
• Equilibrium with skeletal muscles is reached in
about 15 min. after iv injection
• Dose of thiopentone is reduced when skeletal
muscle perfusion is reduced ( shock) or when
skeletal muscle mass is reduced ( elderly).
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19. Fat:
• Drug content continues to increase 30min. after
injection
• Fat : blood partition coefficient is about 11.
• Thiopentone will move from blood to fat as long as
conc. in fat is less than 11 times that of blood.
• Max. deposition in fat is present after 2.5 hrs and
this tissue becomes potential reservoir for
maintaining plasma conc.
19
20. • Large or repeated doses of thiopentone produces a
cumulative effect because of storage capacity of fat.
• When this occurs , usual quick awakening
characteristic of these drugs is absent.
• For this reason, dose of thiopentone is best
calculated according to the lean body mass to avoid
an overdose.
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21. IONISATION
• Thiopentone is a weak acid with a pka of 7.6
• Acidosis favours non-ionised fraction of drug and
alkalosis has opposite effect.
• The non-ionised form has greater access to CNS
than ionised form
• Acidosis will thus increase and alkalosis decrease
the intensity of effect.
21
22. METABOLISM
• Metabolism occurs at a slow rate, 10 – 24 % of the
drug being metabolized by the liver each hour ( low
hepatic extraction ratio of 0.15 )
• After several hours , most of the drug stores are in
the fat and the fraction of the drug delivered to the
liver is far less than in first few min after injection
• Metabolised in liver to hydroxythiopental &
carboxylic acid derivatives.
22
23. • The metabolites are more water soluble and have
less CNS activity.
• Principal sites of metabolism being:
– Oxidation at C5
– Desulfuration at C2
– Hydrolytic opening of barbituric acid ring
23
24. EXCRETION
• Thiopentone is filtered by the kidneys but
– High protein binding limits the magnitude of
filtration
– High lipid solubility favours reabsorption
• <1% is excreted unchanged in urine.
• Alkalinization of urine hastens renal excretion
because of shift towards ionised state caused by pH
change.
Clearance
• Adults 3 mL/kg/min
• Children 6 mL/kg/min
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25. Elimination half life:
• High d/t low hepatic clearance.
Thiopentone- 11.6hrs
Methihexitone- 3.6 hrs.
• More in obese patients.
• Increase with age- intercompatmental shift is slow.
• Greater effect in old with same amount of drug.
• Pediatric patients –opposite effect i.e. rapid hepatic
clearance
25
26. SYSTEMIC EFFECTS
Effects on CNS :
• Depression directly proportional to plasma level .
• 3 - 4 mg/kg produces sleep
• Dose related reduction in CMR
– progressive slowing of the EEG,
– a reduction in the rate of ATP consumption, and
– protection from focal cerebral ischemia
26
27. • With the reduction in CMRO2 comes a parallel
reduction in cerebral perfusion, which is seen as
– Decreased cerebral blood flow (CBF) and ICP.
• With reduced CMRO2
– cerebral vascular resistance increases and
CBF decreases.
• Potent anticonvulsant activity
27
28. Effects on CVS:
• Cardiovascular depression from barbiturates is a
result of both central and peripheral effects.
• There is peripheral vasodilation resulting in
pooling of blood in the venous system.
• A decrease in contractility is another effect and is
related to reduced availability of calcium to
myofibrils.
28
29. • Mechanisms for the decrease in cardiac output
include
(1) direct negative inotropic action,
(2) decreased ventricular filling because of
increased capacitance, and
(3) transiently decreased sympathetic outflow
from the CNS.
• The increase in heart rate (10% to 36%)
– results from baroreceptor-mediated
sympathetic reflex stimulation of the heart in
response to the drop in output and pressure.
29
30. • The cardiac index is unchanged or reduced.
• Mean arterial pressure is maintained or slightly
reduced.
• When thiopental is given to hypovolemic patients,
there is a significant reduction in cardiac output,
as well as a decrease in blood pressure.
30
31. Effects on respiratory system
• Dose related central respiratory depression
– respiratory acidosis
• Transient apnea
• Minute ventilation is diminished
• Patients with chronic lung disease are slightly
more susceptible to the respiratory depression
associated with thiopental
31
32. • The initial apnea that occurs during drug
administration lasts a few seconds and is
succeeded by a few breaths of reasonably
adequate tidal volume, followed by a more lengthy
apneic period.
• During induction of anesthesia with thiopental,
ventilation must be assisted .
32
33. Effects on hepatic system:
• Modest decrease in blood flow.
• Stimulate increase in liver microsomal enzyme
induction after 2 – 7 days of sustained drug
administration.
Effects on renal system:
• Decreased renal blood flow
• Decrease GFR
– oliguria
33
34. Immunological effects
• Anaphylactic reactions may occurs in 1:30,000. This
may be due to sulfur, which may evoke mast cell
histamine release.
• Majority of reported cases are in patients with the
history of chronic atopy , who often have received
thiopentone previously without adverse responses.
• Long term administration of thiopentone is associated
with increased incidence of nosocomial infection due
to bone marrow suppression and leucopenia.
34
35. Other actions :
• Pupillary response is lost with surgical
anaesthesia.
• Loss of eyelash reflex commonly used as a clinical
endpoint for an adequate induction dose.
• Skeletal muscle tone fall more than smooth
muscle tone.
• Uterine tone is unaffected.
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36. Placental transfer
Readily cross placenta but fetal plasma
concentration is less than those of maternal
plasma concentration
– Clearance by fetal liver
– Dilution by blood from fetal viscera &
extremities.
36
37. THERAPEUTIC USES
• Induction of anesthesia
• Treatment of increased intracranial tension
• Anticonvulsant
• As a sole agent for short surgical
procedures
• As a supplement during regional block
37
38. Induction of anaesthesia: 3-5 mg/kg iv of
2.5% solution until loss of eyelash reflex
• Rectal dose for induction is 20-30 mg/kg
• Thiopentone infusion is not used because of
long context sensitive half time and
prolonged recovery period.
39. Treatment of raised ICT : thiopentone
causes cerebral vasoconstriction leading to
decrease in CBF and CBV.
• Dose: 35-40mg/kg
• Cerebral protection with barbiturates is seen
only after focal ischaemia and not after global
ischaemia.
40. Anticonvulsant agent : used in treatment of
- convulsions due to local anaesthetic toxicity
- status epilepticus
- eclamptic convulsions
41. CONTRAINDICATIONS
Absolute
• Acute intermittent porphyria
• Hypersensitivity to barbiturates/sulpha drugs
Relative
• Respiratory obstruction,inadequte airway, status
asthamaticus
• Previous immune reaction
• Fixed and low cardiac output states ( tight MS)
• Severe cardiovascular instability & shock
• Without proper i.v line and airway equipment
41
42. DRUG INTERACTIONS
• Ethanol, Opioids, Antihistaminics potentiate the
sedative effect of thiopentone.
• Contrast media, sulphonamides occupy same
protein binding sites thus increases the free drug
available and potentiate the sedative effect of
the drug.
42
43. COMPLICATIONS
Vascular injury
• due to chemical nature of drug
• venous
–5% of patients
–thickening of vein wall
–resolves after several weeks
• arterial
–severe pain and thrombosis
–ischaemic injury
43
44. Mechanism :
• Precipitation of thiopentone microcrystals in arterial
vessels → inflammatory response and arteritis
• Endothelial damage → Platelet aggregation →Aseptic
thrombosis
Clinical features :
• Immediate , intense vasoconstriction & excruciating
pain that radiates along the course of the artery.
• Blanching of extremity followed by cyanosis
• Gangrene & permanent nerve damage may occur.
44
45. Treatment:
• Dilution of drug
– By injection of saline through the needle
which still remains in the artery.
• Prevention of arterial spasm
– Injection of lidocaine, papaverine or
phenoxybenzamine may be administered to
produce vasodilatation
• General measures to sustain adequate blood
flow
45
46. If needle is removed-
– inject vasodilator drug in proximal artery
• Direct injection of heparin in the artery may be
considered.
• Sympathectomy- stellate ganglion block or
brachial plexus block.
• Urokinase
46
47. Side-effects
• Involuntary movements
• Immunosuppression
• Cough, laryngeal spasm, bronchospasm,
apnea
• Allergic reactions (1:30,000)
• Hypotension, tachycardia
• Loss of vasomotor control
47
48. Effects on gravid uterus:
• Readily crosses the placenta
• When used in doses below 5mg/kg
concentration in fetal brain tissue is minimal.
