Thiopentone Sodium

Class

Barbiturate

History

Discovered in 1930s by Ernest Volwiler and Donalee Tabern, who were working for Abbott Laboratories. First administered to humans in 1934 by Dr Ralph M Waters and Lundy. Famously associated with many anaesthetic deaths during the Pearl Harbour attack, wherein large doses were given to patients in shock by nurse anaesthetists. However, once it was realised that the fault lay not with the drug but with the failure to give titrated doses and continued resuscitation in patients with shock, the drug was back in use.

Chemistry

Thiopentone

Sulphur analogue of sodium pentobarbital. The alkyl group at C5 confers hypnotic and sedative effects while the addition of a methyl (as in Methohexitone) or sulphur (as in Thiopental) radicle at C2 produces more rapid effect. Thiopental lacks the excitatory effects of Methohexitone.

Formulation and Administration

Available as a pale-yellow powder in vials containing 0.5 gm and 1 gm Thiopentone. Given by Intravenous route. “Basal narcosis” with rectally administered Thiopentone was used for paediatric induction in the past.

Diluents

  • NS,
  • 5% Dextrose or
  • Sterile Water

Preparations

25mg/ml for adults and 10 mg/ml for paediatric patients

Physical Properties

The drug is a yellowish, hygroscopic powder, stabilized with 6% anhydrous sodium carbonate as a buffer in an atmosphere of nitrogen. The pH of reconstituted solution containing 25 mg/ml of Thiopentone is 10.4.

Mechanism of Action

Thiopental binds at a distinct binding site associated with a Cl-ionopore at the GABA-A receptor, increasing the duration of time for which the Cl-ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is therefore, prolonged. It also has action on nAChR, glutamate and adenosine channels.

Pharmacokinetics

Onset: One brain-arm circulation time (15 sec); (Rapid induction due to high lipid solubility and non-ionization)

Peak Effect: 60 sec

  • Protein Binding: 80%
  • Elimination Half Life: 3-22 hours (Average 10 hrs)
  • Follows zero order kinetics when delivered as an infusion
  • Therapeutic Half Life: 15 – 20 mins
  • Distribution: Occurs in 3 phases- Alpha- 1 phase (distribution to highly perfused organs; 1.7- 6.5 mins), Alpha-2 phase (redistribution to other body tissues; 23 – 71 mins; may be the cause of prolonged respiratory depression or anaesthesia), and Beta-1 phase (elimination by metabolism; 206-1321 mins)
  • Metabolism: Primarily hepatic, to inactive metabolites by oxidation of the alkyl moiety (most important pathway), N-dealkylation, desulfuration and destruction of the barbituric ring. The only barbiturate which is predominantly renally excreted.

Pharmacodynamics

  • CNS: Easily crosses the blood brain barrier as it is a lipophilic molecule. Causes anaesthesia and hypnosis. Has an excellent anticonvulsant property. Decreases ICP (by decreasing cerebral blood volume through drug induced cerebral vasoconstriction and an associated decrease in cerebral blood flow), CMRO2 and cerebral oxygen consumption. Causes nausea and vomiting due to stimulation of CTZ.
  • CVS: Decrease in Cardiac Output is due to direct negative inotropic action, decreased ventricular filling due to increase in capacitance vessels and transiently decreased outflow from CNS. It also prolongs Q.T interval.
  • Respiratory: Dose dependant respiratory depression by depression of medullary and pontine ventilatory centres (first depth, then rate). Causes decrease sensitivity of respiratory centre to hypercapnia. Induction doses cause apnoea in 30-40% cases.
  • Other Systems: Causes constriction of splanchnic and renal blood vessels resulting in reduced renal blood flow and GFR. Decreases peristalsis. Decreases IOP, and causes loss of eyelash reflex (end point for induction of anaesthesia with Thiopentone)

Uses and Dosage

  • Induction of Anaesthesia (3-4 mg/Kg)
  • Drug of choice for cerebral protection
  • Sole anaesthetic agent for short (<15 mins) procedures
  • Treatment for raised ICP (3mg/Kg)
  • For the control of convulsive states (3 mg/Kg)
  • Narcoanalysis in psychiatric patients
  • IV maintenance 50-100mg every 10-12 mins

Contraindications

  • Hypotension
  • Respiratory or airway obstruction (Thiopental may worsen obstruction)
  • Status asthmaticus/Bronchial asthma
  • Porphyria
  • Absence of proper induction or airway equipment
  • Allergy to sulpha drugs

Adverse Effects

  • Drowsiness
  • Laryngospasm
  • Extravascular infiltration causing tissue necrosis and sloughing

  • Intra-Arterial Injection:

Highly alkaline Thiopentone may cause the precipitation of the Hb and Thiopentone crystals. This may cause arteriospasm and severe pain along the course of the artery, later leading to oedema and gangrene of the arm and finger. It is advisable never to use more than 2.5% concentration to limit the damage caused in this eventuality.

* Treatment: Leave the needle in place and inject 5000 U of heparin through the same needle, along with 5 m) of 2% Lignocaine. Administer a dilute solution of 40 – 80 mg papaverine. Consider local infiltration of Alpha – adrenergic blocking agents such as phentolamine into the vasospastic area. Brachial plexus block on the side of intra-arterial injection can also be given to break the arterial spasm.

Drug Interactions

  • Like all barbiturates – Thiopentone is an enzyme inducer and causes accelerated metabolism of a wide variety of drugs including anticoagulants, phenytoin and tricyclic antidepressants.
  • Concurrent administration with other CNS/ respiratory depressants may cause profound and prolonged depression of the same.
  • Ketamine may cause antagonism of the hypnotic effects of Thiopentone. ,
  • Unsuitable for mixture with drugs in acidic solutions such as opioids, NMBAs and catecholamines.

Special points

  • Myocardial depression
  • Respiratory depression
  • Extreme anaemia, burns, malnutrition, uraemia, ulcerative colitis and intestinal obstruction all require smaller doses.

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