2. INTRODUCTION
Sulphur derivative of Barbituric Acid.
i.e. Thio barbiturate.
Ultra short acting barbiturate.
Synthesised by Tabern and Volwiler in 1935.
Introduce clinically by Ralph waters and John Lundy
for induction of anaesthesia.
4. Fig : Chemical Structure of
Thiopentone
Sulphur make it more lipid soluble and more potent
Sulphur at second carbon atom position.
5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid
5. PROPERTIES
Highly soluble in water / NS yielding highly
alkaline solution,stable for 48 hrs.
Must be prepared freshly.
Powder form stable at room temperature.
Refrigerated solution stable up to 2 week.
6. PROPERTIES
pH of 2.5% solution is 10.5.
Commercial preparation contain it sodium
salt with anhydrous sodium carbonate to
prevent ppt.of acid form.
Available as 0.5 gm and 1 gm powder for
reconstitution.
• Refrigerated solutions- stable upto 2
weeks
7. PHARMACOKINETICS
Onset of action of i.v. injection - 10-20 sec.
peak 30-40 sec. duration for awakening 5-15
min.
Prompt awakening after single i.v. inj. is due to
rapid redistribution to lean body tissue (muscle)
Volume of distribution is 2.5 Lit. per Kg.
8. Ultimate elimination due to hepatic metabolism.
Effect site equilibration time is rapid.
Brain – 30 Sec. Muscle – 15 Min. Fat > 30 Min.
Context sensitive half life is prolonged.
9. TERMINATION OF ACTION
1) Redistribution
a) Lipid solubility (most important factor)
High Lipid Solubility makes it to cross blood brain
barrier & lean body tissue rapidly.
b) Protein Binding
Highly bound to albumin & other plasma protein.
72 – 86% Binding.
Only unbound fraction crosses Blood-Brain-Barrier.
10. Affected by physiological PH. Disease state &
parallels lipid solubility
Hepatic disease & chronic renal disease decrease
protein Binding, increase free form.
c) Ionization
Only non-ionized part crosses Blood-Brain-Barrier.
Thiopentone has PKA 7.6 so 61% of it is
non-ionized at physiologic PH
As PH decreases (acidosis) non-ionized form
increases.
Metabolism induced changes in PH affect more.
11. Rapid distribution half life – 8.5 Min.
Slow distribution half life – 62.7 Min
12. 2)Metabolism
By liver microsomal
enzymes mainly, Slightly
in CNS & kidney.
10 – 24 % Metabolised
each hour.
13. By oxidation, dealkylation & conjugation to
hydroxy Thiopental & carboxylic acid derivatives
more water soluble & excreted rapidly.
Affect by hepatic enzyme activity more than
blood flow.
Metabolism at 4-5 mg./Kg. dose exhibits first
order kinetics.
At very high doses (300-600 mg/Kg.)
exhibit zero order kinetics.
15. Elimination Half Life 11.6 Hours
Low elimination clearance(3.4ml/kg/min)
Prolonged in obese patient & pregnancy.
Short in paediatric patient.
16. MECHANISM OF
ACTION Sedation & Hypnosis by interaction with
inhibitory neurotransmitters GABA on GABAA
receptor.
GABA facilitatory & GABA mimetic action.
GABAA receptor has 5 glycoprotein sub unit.
Increases GABA mediated
transmembrane conductance of Cl– ion,
Causes hyperpolarization & inhibition of post
synaptic neuron.
17. ↓↓ rate of dissociation of GABA from receptor.
It high doses itself activate GABA receptor.
Fig. GABAA
Channel
Complex
Inhibit synaptic transmission of excitatory
neurotransmitter via glutamate & neuronal nicotinic
acetylcholine receptors.
23. Respiratory system .
Neurogenic, Hypercapnic
& hypoxic drive
depressed.
Depression of medullary &
pontine ventilatory
centres.
Apnoea likely in presence
of narcotics.
24. Cough & laryngeal reflexes not depressed
until high doses given.
Bronchospasm & laryngospasm likely in
light plane, added by sympathetic depression
25. Cardiovascular system
At 5 mg/Kg doses, 10-20
mmHg ↓↓ in BP due to
sympathetic blockade.
Compensated by carotid sinus
baroreceptor mediated ↑↑ in
peripheral sympathetic nervous
system activity.
26. Leads to unchanged myocardial contractility &
15 – 20 beats/min ↑↑ in Heart Rate.
Direct myocardial depression occurs at doses used
to ↓↓ intracranial pressure.
27. Depression of sympathetic nervous
system & medullary vasomotor center
↓
Dilatation of peripheral capacitance
vessel
↓
Pooling of blood
↓
↓↓ venous return
↓
↓↓ cardiac output
↓
↓↓ Blood Pressure
28. Changes exaggerated in hypovolemic patient,
patient on B-blocker drugs & centrally acting anti
hypertensive.
Skeletal muscle
↓↓ Neuro muscular excitability.
29. 5) Kidney
↓↓ blood flow & GFR .
6) Suppression of adrenal cortex &
↓↓ cortisol level, but it is reversible.
31. Placental transfer occurs but drug
metabolised by foetal liver & diluted by its
blood volume so less depression.
32. CLINICAL USES
1) Induction
3 – 5 mg/Kg. produces unconsciousness in 30 sec.
with smooth induction & rapid emergence.
Loss of eyelid reflex & corneal reflex used for
testing induction.
Consciousness regained 10-20 Min. but residual
CNS depression persist for more than 12 Hours.
Dose requirement ↓↓ in early pregnancy, ↑↑ child
with thermal injury.
33. Patient with sever anaemia, burns, malnutrition,
malignant disease, wide spread uraemia,
ulcerative colitis, intestinal obstruction requires
lower doses.
adult child infant
Induction dose 3-5 mg/Kg. 5-6 mg/Kg 6-8Mg/Kg.
Anaesthesia supplementation - i.v. 0.5 – 1 mg/Kg
Thiopental infusion seldom used
long context- sensitive half-time
prolong recovery period
34. 2) Anticonvulsant
for rapid control of status epilepticus
dose 0.5 – 2 mg/kg. repeated as needed
36. 4) Cerebral Protection
In focal ischemia eg. Carotid endarterectomy,
thoracic aneurysm resection, profound
controlled-hypotension, Incomplete cerebral
emboli.
Barbiturate narcosis – i.v. bolus 8 mg/Kg.
EEG burst suppression – mean total dose 40
mg/Kg.
Infusion – 0.05 to 0.35 mg/Kg/min with
inotropic & ventilatory support.
37. SIDE EFFECTS
Garlic onion taste.
Allergic reaction.
Local tissue reactions & necrosis.
Urticarial rash, facial edema, hives, bronchospasm
& anaphylaxis.
Pain at injection site.
38. Cardiovascular system
Cardiovascular depression
a) Peripheral vasodilation & pooling of blood - ↓↓ BP.
b) ↓↓ availability of Ca++ to myofibrils-↓↓ contractility.
c) Direct negative inotropic action, ↓↓ ventricular filling.
These changes more when i.v. bolus given
If given to hypovolemic patient, reduces cardiac output
(69%), in patient without compensatory mechanism
cardiovascular collapse.
39. Respiratory System
Dose related respiratory depression
Transient apnea, patient with chronic lung
disease more susceptible.
Laryngospasm, bronchospasm.
Central nervous system
Emergence delirium, prolonged somnolence &
recovery, Headache
45. Thiopentone solution is highly alkaline
incompatible
for mixture with drug such as opioid
catecholamines neuromuscular blocking drugs as
these are acidic in nature.
Probenecid prolongs action, aminophylline
antagonize.
CNS depressant eg. narcotics, sedative, hypnotic,
alcohol, volatile anaesthetic agent prolongs &
potentiate its actions.
INTERACTIONS
46. Induces metabolism of oral anticoagulants,
digoxin, B-blocker, corticosteroids, quinidine,
theophylline.
Action prolonged by MAO inhibitors,
chloramphenicol.
47. Dose should be reduced
In geriatric- 30- 40% decrease central
compartment volume & slowed redistribution
Hypovolemic Patient,
High risk surgery patient with concomitant
use of narcotic & sedatives