Injectable anaesthetics

Injectable anaesthetics

1. Barbiturates – Thiopentone, phenobarbitone

2. Phenol derivative – Propofol

3. Imidazole derivative – Etomidate, Metomidate

4. Steroid derivative – Alphaxalone, Althesin

5. Chloral derivative – Chloral hydrate

6. Miscellaneous - Propanidid, Chloralase, Urethane, Guaiphenesin

Injectable anaesthetics

·         The rate and onset of anesthesia depends on several factors like type of anaesthetic agent, dose, route of administration and condition of the animal.

·         Though the depth or level of anaesthesia is difficult to control due to their slow detoxification and elimination, yet the Injectable anaesthetics offer several advantages over inhalation anaesthetics like,

1.       They produce easy and very rapid induction of anaesthesia

2.       Do not require costly and specialized equipments for administration

3.       There is no chance of fire or explosion

4.       Lesser degree of myocardial depressant and hypotensive effects when compared with many inhalant anaesthetics.

5.       Will not pollute atmosphere and are safe to anaesthetist and other personnel.

6.       Useful for surgery on respiratory tract or about head.

Barbiturates

·         Barbiturates are widely used and very versatile group of therapeutic agents.

·         Barbituric acid itself has no CNS depressant effect.

·         For creation of the effect, substitutions on its structure at various positions, especially at carbon-5 are required.

·         All barbiturates are derived from barbituric acid.

              NH    C              H                                                              

O =C                       C

             NH    C               H

      

        Barbituric acid

              R₃

              

              N      C              R₁

1        6

X =C 2                 5C

               3        4

             NH    C               R₂

       Barbiturate

Structure activity relationship

C2 substitution X

·         Oxygen molecule at C2 – Oxybarbiturates – Pentobarbitone, Phenobarbitone

·         Sulphur molecule at C2 – Thiobarbiturates – Thiopentone, Thiamylal

·         Thiobarbiturates are more lipid soluble and more highly protein bound than oxybarbiturates.

C5 substitution at R₁ and R₂

·         Substitution at both R₁ and R₂ with alkyl or aryl radicals are required for CNS depressant activity

·         Change in R₂ substitution can markedly affect lipid solubility of the drug and there by influence onset, duration of action and fate in the body.

·         Eg: Phenobarbitone – long acting

Pentobarbitone – Short acting

N1 substitution at R₃

·         Substitution of alkyl group in R₃ position leads to increased potency and speed of action and greater incidence of excitatory side effects.

·         Eg: Methohexitone – Methyl group at R₃

Classification of barbiturates

1.       Long acting – Phenobarbitone

2.       Short acting – Pentobarbitone

3.       Ultra short acting – Thiopentone, Thiamylal, Methohexitone

Mechanism of action

·         They activate GABA_A receptors and cause opening of chloride channel that allows more chloride to enter the cell.

·         This produces hyperpolarization and hence decreases the excitation.

·         Barbiturates enhance GABA induced chloride current by prolonging the periods of channel opening.

Pharmacology of barbiturates

·      Barbiturates are quite good muscle relaxants but they are poor analgesics.

·      They depress respiratory rate and depth. Over dosage results in death due to paralysis of central respiratory control mechanism.

·      They depress the cardiovascular system. Rapid intravenous administration results in transient hypotension.

·      Large doses may also increase spleenic uptake of erythrocytes and results in haemodilution. Enlargement of the spleen is commonly seen when Pentobarbitone is used for euthanasia.

·      Spasmolytic action on gastrointestinal tract decreases intestinal peristalsis and delay gastric emptying.

·      Liver and renal functions are not directly affected but if hypoxia develops there may be cellular damage.

·      Central nervous system – Dose dependant CNS depression. Decrease cerebral blood flow and reduce intracranial pressure.

·      Rapid intravenous administration results in placental transfer.

·      Barbiturate specific antagonist - Bemegride

Ultra short acting barbiturates

·         Highly lipid soluble in nature. Duration of action – 10-30 minutes

Thiobarbiturates – Thiamylal and Thiopental

·         Thiamylal is more potent than thiopental.

·         Thiopentone is used as an induction agent and for short surgical procedures.

·         Drug of choice for induction of anesthesia in animals with suspected increased intracranial pressure, glaucoma and epilepsy.

·         Prolonged recovery (3-5 hrs) in thin and heavily muscled animals, as their body reservoirs are saturated earlier and their recovery depends on metabolism. Eg: Greyhounds – Thiobarbiturates should not be used in these animals

Methohexitone

·         More potent than Thiopentone

·         Rapidly metabolized than thiobarbiturates

·         Safe to use in Greyhounds – as rapidly metabolized by liver and recovery is quick.

·         Excitement occurs during induction and recovery.

Short acting barbiturates

·         Less lipid soluble in nature. Longer duration of action (30-60 minutes).

·         Very low margin of safety.

·         Primarily used as a euthanizing agent.

·         Recovery is not smooth.

Long acting barbiturates

·         Least lipid soluble in nature.

·         Slowest onset and long duration of action (6-12 hrs).

·         Primarily used as an anticonvulsive agent at sub anesthetic dose and not used as general anaesthetic.

Propofol

·         It is a substituted phenol.

·         Can be used as an anaesthetic induction agent as well as for maintenance of short term general anaesthesia in dogs and cats.

·         In cardiovascular system it causes hypotension and respiratory depression

·         It is rapidly metabolized.

·         It is useful in case of head trauma and intracranial pressure

·         Better used in greyhounds due to lesser side effects.

·         Propofol contains no preservatives and the emulsion promotes bacterial growth. So it should be used up within 6 hours following its opening from the container.

Chloral hydrate

·         This drug is used in large animals as hypnotic.

·         Can be administered intravenously in horse to produce surgical anaesthesia.

·         It volatizes on exposure to air and has an aromatic penetrating odour.

·         It can be administered orally in the form solution or capsule.

Althesin

·         It is a steroidal preparation which produces immediate induction with short duration of action.

·         It is contraindicated in dogs as they may exhibit a potentially fatal anaphylacticoid reaction to the castor oil which is used as a vehicle.

·         Can be administered intravenously or intramuscularly in cats, birds and other small laboratory animals.

·         Contraindicated to use with barbiturates.

·         Provides good muscle relaxation.

·         Produces mild respiratory depression and cardiovascular depression.

·         Cross placental barrier and cause fetal depression.

Chloralose

·         This drug is metabolized to chloral hydrate and chloral.

·         Anaesthesia and hypnosis produced by chloral hydrate and chloralose are similar.

Propanidid

·         Used intravenously in human beings

Metomidate

·         Recommended for use in birds of prey

Etomidate

·         It is an ultra short acting intravenous anaesthetic drug.

·         Rapid hepatic metabolism resulting in rapid recovery.

·         No cardiovascular side effects except in dogs especially in greyhounds.

·         Cause respiratory depression.

·         It is expensive.

·         Pain upon injection due to its propylene glycol preparation

·         Sneezing, retching and myocardial twitching noticed during induction.

Hemolysis and hematuria reported in dogs and cats.