Ketamine

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Pharmacology Index | Intravenous anaesthetics


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Ketamine

Ketamine_2D_Structure.3555.gif


Contents

Introduction

Ketamine is a phencyclidine derivative which is used as an intravenous agent for induction of general anaesthesia. It has potent analgesic activity. It may also be:

  • given by intramuscular injection
  • used as a sole anaesthetic agent, typically for short operations.
  • used by infusion for relief or acute or chronic pain conditions

It acts by blocking the NMDA glutamate receptors in the central nervous system.

It produces a distinctly odd sort of anaesthesia commonly referred to as "dissociative anaesthesia". The patient seems to be in a cataleptic state with eyes open and muscular hypertonus though this appearance may be greatly modified by concomitant administration of other drugs such as midazolam or non-depolarising relaxants.

In Western countries it is not commonly used for induction of anaesthesia but often has a niche use in certain clinical scenarios. Particular problems mitigating against widespread acceptance of the drug in routine anaesthetic practice are the "emergence reactions" that occur during recovery and the unpleasant dreaming and nightmares that patients may experience the night after surgery. These adverse reactions can be minimised by use of ketamine with midazolam and this combination has even been touted as the ideal for induction of anaesthesia.

Other important points to note are excessive salivation (which can be blocked by atropine), nystagmus, "relative sparing" of upper airway protective reflexes, the indirect sympathetic stimulation (resulting in hypertension and tachycardia) and the increase in cerebral metabolism and blood flow. It is generally considered to be contraindicated in neuroanaesthesia, and is patients with significant ischaemic heart disease.


Ketamine - Key Points
  • Ketamine is an anaesthetic and analgesic which produces "dissociative anaesthesia"
  • Unlike most anaesthetics, but like nitrous oxide, its site of action is the NMDA receptor
  • It is associated with indirect sympathetic stimulation (causing increases in BP and heart rate) and relatively less depression of protective airway reflexes
  • Its major side-effects are emergence reactions, and postoperative unpleasant dreams and nightmares
  • It may have a useful role in pain management and seems to interfere with the development of opioid tolerance
  • ..............

History

Ketamine was first described in 1965 and introduced into clinical practice in the 1970s.

Physical Properties

  • state
  • odour, taste
  • White crystalline powder or clear liquid.
  • MW 274.2
  • solubility - Ketamine is freely soluble in water and methyl alcohol and is soluble in alcohol.
partition coefficient
  • melting point, boiling point, valour pressure at 20C
  • specific gravity of liquid or vapour
  • inflammability in air or oxygen

Chemical Properties

  • Preparation: Ketamine hydrochloride. Formulated as an acid (pH 3.5 to 5.5) solution for intravenous or intramuscular injection. Vials, 200 mg (base)/2 ml.

Racemic ketamine is the most common commercially available formulation. This contains a mixture of the two enantiomers S(+) ketamine and R(-) ketamine. In some countries a formulation containing only (S+) ketamine is now available.

S(+) ketamine has four times the affinity of R(-) ketamine for the NMDA receptor and also binds to mu and kappa opioid receptors. Its anaesthetic potency is three times that of the racemic mixture.

The incidence of side-effects is the same at equal plasma concentrations for both enantiomers, but as lower doses of S(+) ketamine are required due to its higher potency, fewer side-effects and shorter recovery times are seen with the single enantiomer preparation.

The R(-) enantiomer has a greater effect on airway smooth muscle relaxation and for this reason the racemic mixture may be more suited for patients with bronchospasm.

  • Formula: C13 H16 Cl NO.HCl

dl-2-(ortho-chloro-phenyl)-2-(methylamino) cyclohexanone hydrochloride

  • Stability & preservatives;

Benzethonium chloride (phemerol) (not more than 0.1 mg/mL) as a preservative, water for injections

  • exclusion of light; decomposition products & their effects; tests for decomposition
  • class of the compound; acid, base, ester, simple compound
  • structure-activity relationships - ionised (water-soluble), unionised (lipid soluble); molecular size; similarity to other drugs

Pharmacokinetics

Absorption

Distribution

  • Mean volume of distribution is reported to range from approximately 1 to 3 L/kg
  • plasma protein binding, tissue affinities

Elimination

  • Biotransformation, metabolic products & their actions
  • Excretion
  • Special features - enzyme induction, cumulation, effects of age

Pharmacodynamics

Desired effects

  • target organs/sites

Side effects

Toxic effects

System effects

  • CNS
  • Autonomic nervous system
  • CVS
  • Respiratory system
  • Skeletal system
  • GIT
  • Blood
  • Metabolism
  • Genitrourinary system
  • Endocrine system
  • Immune system

Clinical Uses

  • Dosage & administration
  • Blood levels - Peak plasma levels averaged 0.75 microgram/mL and cerebrospinal fluid (CSF) levels were about 0.2 microgram/mL one hour after dosing,
  • The plasma half-life is in the range of two to four hours.
  • Expected duration

Advantages & disadvantages

Indications

Contraindications

Antagonists

Drug Interactions

Controversies

recent research

Related material & references

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