Barbiturates

Barbiturates

Barbiturates are derivatives of barbituric acid. Depending upon the presence of oxygen or sulphur atom with 2^nd carbon they are called

· Oxybarbiturates (eg. Methohexitol) – Oxygen at 2^nd position

· Thiobarbiturates (eg. Thiopentone) - Sulphur at 2^nd position

Thiobarbiturates are more lipid soluble, more potent and having shorter duration of action than oxybarbiturates.

Substitution at 5^th carbon atom with phenyl group increases anticonvulsant activity. (Phenobarbitone)

Thiopentone

Thiopental was introduced clinically by Waters and Lundy. It is an ultra short-acting barbiturate that depresses the central nervous system (CNS) to produce hypnosis and anaesthesia without analgesia.

Preparation

Thiopentone sodium is available as white powder (mixed with6 % anhydrous sodium carbonate) in nitrogen environment. (I.e. Air in vial is replaced by nitrogen.)

It should be reconstituted with either water or normal saline to produce a 2.5% solution of thiopental. This solution is highly alkaline (pH >10) and relatively unstable (2 week shelf life when refrigerated). Injections should be freshly prepared and used within 24 hours after reconstitution. Solutions of higher concentration are not recommended as it causes pain on injection and venous thrombosis.

Any factor or condition that tends to lower the pH of thiopental injections, such as diluents that is too acid (Ringer Lactate) or the absorption of carbon dioxide, which combines with water to form carbonic acid, causes precipitation of thiopental acid. 6% anhydrous sodium carbonate is added to prevent precipitation of thiopentone due to CO2 absorption.

Thiopentone should not be mixed with medications that have an acid pH like succinylcholine, tubocurarine. They cause precipitation.

Pharmacokinetics and pharmacodynamics

After i.v. injection onset of action is within one arm brain circulation time (15 sec) patient become unconscious within 30-40 sec and patients awaken within 20 minutes. Termination of action is due to rapid redistribution of the drug to peripheral compartment (mainly muscle) and reduction of concentration in brain. From muscle it is redistributed to adipose tissue.

Time to peak concentration after Intravenous administration: Brain: within 30 seconds. Muscles: 15 to 30 minutes. Fat: Several hours. Very highly perfused tissues such as the brain, heart, liver, and kidneys achieve concentrations equal to peak plasma concentrations. Rapid induction is due to high lipid solubility and higher initial brain concentration.

The elimination half life of thiopentone is 12 hours. So it takes about 48 hours for complete elimination of the drug and patient is drowsy. So thiopentone is not preferred for day care surgery. (Propofol is the choice)

· Distribution: Because of their high lipid solubility and low degree of ionization, thiopentone rapidly cross the blood-brain barrier and are rapidly redistributed from the brain to other body tissues, first to highly perfused visceral organs (liver, kidneys, heart) and muscle, and later to fatty tissues.
When barbiturate anesthetics are administered repeatedly or by continuous infusion, accumulation in and slow release from lipoidal storage sites may result in prolonged anesthesia, somnolence, and respiratory and circulatory depression. Concentrations of thiopental in fatty tissues may be six to twelve times greater than in plasma.

· Volume of distribution: 1.7 to 2.5 L/kg

· Protein binding: 72 to 86%.

· Onset of action: Intravenous—30 to 40 seconds, Rectal—within 8 to 10 minutes.

Following intravenous administration of induction doses of thiopental, muscle relaxation occurs about 30 seconds after unconsciousness is attained, the depth of anaesthesia increase for up to 40 seconds and then decrease progressively until consciousness returns. Hypnosis occurs Within 10 to 40 seconds of intravenous injection.

· Duration of action: 10 to 30 minutes

· Half-life: Redistribution half life: 4.6 to 8.5 minutes, Elimination half life: 3 to 8 hours after a single intravenous dose, the elimination half-life is longer after prolonged administration (10 to 12 hours). The elimination half-life increases with increasing age, during pregnancy at term and in obese patients. At low doses it follow 1^st order kinetics but at higher doses it follow zero order kinetics.

· Biotransformation: Primarily hepatic; also, biotransformed to a small extent in other tissues, especially the kidneys and brain. Although most of thiopental's metabolites are inactive, about 3 to 5% of a dose is desulfurated to pentobarbital, which is cleared from the body much more slowly than thiopental.

Action on Central Nervous system –

Thiopentone is CNS depressant; it causes sedation, hypnosis, unconsciousness. It has anticonvulsant property.

It has antanalgesic property and lowers the pain threshold.

No muscle relaxation.

Mechanism of action –

· Thiopentone depresses the reticular activating system in brainstem which is responsible for consciousness.

· It (1) enhances the synaptic actions of inhibitory neurotransmitters (mainly acts on GABA_A receptor), and (2) blocks the synaptic actions of excitatory neurotransmitters (glutamate and acetylcholine).

Thiopentone is cerebro-protective and the induction agent of choice in neurosurgery.

It reduces the cerebral oxygen requirement (CMRO2) and reduces intra cranial tension (ICT) and thus increases cerebral perfusion.

It shunts blood from non ischemic to ischemic areas of brain so it protects brain from focal ischemia (But not from global ischemia). This phenomenon is called reverse still phenomena or Robin Hood effect. (Inhalational anaesthetics like halothane causes the opposite effect ie. Shunts blood from ischemic to non ischemic areas and it is called still phenomena or Luxury perfusion.)

Action on other body systems

Cardio Vascular System -

· On i.v. administration it causes hypotension and tachycardia. Too rapid injection may cause a severe drop in blood pressure, possibly to shock levels, especially in patients who are hypovolemic.

Respiratory System -

· Barbiturate anaesthetics are potent respiratory depressants, apnea may occur immediately after intravenous injection, especially in the presence of hypovolemia, cranial trauma, or opioid premedication.

· During induction of anaesthesia or in lightly anesthetized patients, laryngospasm may be induced by a variety of stimuli such as surgical stimulation, the premature insertion of the laryngoscope blade or airway. Laryngospasm is treated with IPPV and small dose of scholine

Hepatic-

Thiopentone induces of amino levulinic acid synthetase, which stimulates the formation of porphyrin, and may precipitate acute intermittent porphyria or variegate porphyria in susceptible patients.

Action on thyroid – thiopentone depress thyroid function. (So it is preferred in patients with increased thyroid activity)

Immunological –

In vitro thiobarbiturates may release histamine from mast cell. So oxybarbiturates (methohexitone) or propofol is preferred over thiopentone in asthmatic and atopic patients. True anaphylaxis has been reported to occur with barbiturate but it is rare.

Barbiturate anaesthetics rapidly cross the placenta; also, after administration of large doses, thiopental is distributed into breast milk.

Indications

1. Thiopentone is indicated primarily for the induction of general anaesthesia.

2. Sole anaesthetic as intramuscular, intravenous, or rectal anaesthesia for brief surgical procedures with minimal painful stimuli and to produce hypnosis during balanced anaesthesia with other agents such as analgesics or muscle relaxants

3. It is used as the sole sedative agent for diagnostic procedures (e.g., computerized axial tomography [CAT] scans or magnetic resonance imaging [MRI]) in children.

4. Treatment of convulsions —Thiopentone is used for short-term control of status epilepticus resistant to other drugs and to control convulsive states during or following inhalation anaesthesia, local anaesthesia, or other causes

5. To reduce ICT — It is indicated in the treatment of increased intracranial pressure if adequate ventilation is provided. It is useful in the management of conditions associated with acutely increased intracranial pressure, such as Reye's syndrome, cerebral edema, acute head injury and during neurosurgical procedures.

6. Cerebo-protection - Thiopental for injection is indicated to protect the brain from the effects of hypoxia and ischemia following head injuries and other related conditions

7. Narcoanalysis—it is used for narcoanalysis.

Accidental Intra-arterial injection of thiopentone is a serious complication and can lead to significant morbidity

Commonly occurs at anticubital vein accidentally injected to ulnar artery. Many patients complain of immediate discomfort (often within seconds), ranging from local irritation to intense pain distal to the site of injection. Patients may report sensory problems such as tingling, burning, and paresthesias; altered motor function (involuntary muscle contractures and muscle weakness) and cutaneous manifestations (flushing, mottling).

There is crystal formation of thiopentone, which blocks the microcirculation and causes vasospasm ieading to necrosis and gangrene

Management:

1. STOP the injection

2. LEAVE the cannula/needle in place

3. Immediately inject 0.9% SALINE into the artery to dilute the drug

4. Administer Local Anaesthetic to relieve pain. e.g. lignocaine 50mg ( 5ml 1%); procaine 50-100mg (10-20 ml 0.5%)

5. Administer Vasodilator to reduce vasospasm. e.g. papaverine 40-80mg (10-20 ml 0.4%)

6. Consider Stellate ganglion or brachial plexus block to encourage vasodilation hence improve circulation & tissue oxygenation

7. Start IV HEPARIN to reduce subsequent thrombosis

8. Consider intra-arterial injection of HYDROCORTISONE.

9. Urokinase infusion.

10. Postpone surgery.

Dosage should be reduced and the medication administered slowly if barbiturate anaesthetics are used in the presence of the following medical problems.

1. Addison's disease, severe anaemia, Hepatic function impairment, Myxedema

2. Renal function impairment (hypnotic effect may be prolonged or potentiated)

3. Severe Cardiovascular disease, Congestive heart failure, hypotension or shock (barbiturate anesthetics produce cardiovascular depressant effects; condition may be exacerbated)

4. Myasthenia gravis and other neuromuscular disorders, other, such as muscular dystrophies and myotonias (respiratory depression may be prolonged; dosage should be carefully titrated)

5. Respiratory disease involving dyspnea or obstruction, particularly status asthmaticus

6. Sensitivity to barbiturates

Absolute contraindication – Acute intermittent porphyria or or variegate porphyria.