Ketamine

Class:

Phencyclidine derivative, NMDA receptor antagonist, intravenous sedative hypnotic.

History:

Ketamine was discovered in 1962 by Stevens and first used in humans by Corssen and Domino in 1965. It was approved for use in the United States in 1970.

Chemical Structure:

Ketamine is a water-soluble molecule that chemically resembles phencyclidine. It exists as two isomers S(+) and R(-). The S(+) isomer has three to four times more potency as an analgesic with fewer psychomimetic effects but has effects causing cognitive and psychomotor impairment.

Ketamine

Formulation and Administration:

Ketamine can be administered via IV/IM/Oral routes. Its oral potency is limited by high first-pass metabolism (bioavailability of 20-30%). It has also been administered via more unusual methods such as the intranasal route (bioavailability of 50-60%). The drug comes as a clear colorless solution in single-use or multidose amber-colored vials containing l0 mg or 50 mg/ml of Ketamine hydrochloride. It comes as Vials of both sizes -2ml &10 ml.

Diluents Used:

  • Normal Saline
  • DNS
  • 5% Dextrose

Mechanism of Action:

The exact mechanism behind ketamine-induced dissociative anesthesia and analgesia remains unknown. However, it antagonizes the action of N-methyl-D-aspartate (NMDA) receptors through non-competitive binding to its phencyclidine recognition site. Additionally, it acts on opioid muscarinic receptors, voltage-gated sodium & L-type calcium channels, neuronal nAch receptors while depressing neuronal function parts of the cortex/thalamus while stimulating parts of the limbic system.

Pharmacokinetics:

  • Onset time for ketamine is one arm-brain circulation time (15 seconds), which leads to rapid induction due to its high lipid solubility.
  • Peak effect occurs at l min on IV administration or within 5 minutes after IM administration.
  • Protein Binding: Insignificant
  • Initially Rapid redistribution takes place where highly perfused organs like brain get up to .05 times plasma concentration later redistributed throughout other organs too.
  • Therapeutic Half Life lasts from 10 – 20 minutes whereas elimination half-life ranges between two to three hours.
  • Vd=3 lit/kg

Metabolism:

Ketamine primarily undergoes hepatic demethylation forming Nor-ketamine which exhibits one-fifth to one-third potency compared with ketamine itself; excretion occurs mainly through kidneys.

Pharmacodynamics:

CNS Effects – Ketamines potent cerebral vasodilation increases cerebral blood flow up-to sixty percent leading increased CBF, ICP, CMRO2, profound analgesia produced because activity seen thalamus/limbic systems responsible pain perception may cause sustained increase in ICP. Does not affect seizure threshold despite excitatory effects seen those systems anti apoptotic effects noted brain even though evidence seems point towards increasing apoptosis newborns upon awakening produces emergence reactions including vivid dreams feeling floating outside body these are less prominent children benzodiazepines reduce impact marked anti-depressant properties noted dose ranging from .5mg/Kg given over forty-minute infusion excellent sub-anesthetic dosages reducing postoperative requirements thirty-three percent preservative-free S+ enantiomer effective epidural caudal routes management radiculopathy frequently used sedative brief painful procedures

CVS Effects – A direct negative cardiac ionotropic effect overshadowed sympathomimetic actions heart rate mean arterial pressure pulmonary arterial pressure cardiac output work myocardial oxygen requirements all increase making this drug especially useful trauma patients requiring rapid sequence induction preserves hunt flows congenital heart disease ideal anaesthetic agent paediatric cardiac catheterizations inducing children shunt dependent circulations

Respiratory System – Ketamines bronchodilation decreases work breathing potentially preventing bronchospasm induced other anaesthetics proved useful treatment asthma unresponsive conventional treatments preserves tracheobronchial secretions; however administering glycopyrrolate/atropine prevents any increase secretion levels experienced without them present

Other Systems – Minimal impact hepatic renal functions inhibits platelet aggregation suppressed formation Inositol-l,-4,S-triphosphate Increases IOP

Uses&Dosage:

Sub-anesthetic doses achieve intense analgesia range between 0.22 – 0.8mg/Kg while pre-emptive Analgesia requires dosage around 0.15 – 0.25mg/kg Intravenous inductions require dosage range between 0.5 – 2mg/Kg depending on patient condition/intramuscular injections may be better suited in hypovolemic patients/bronchial asthma. Maintenance anaesthesia managed using IV dosages ranging from 0.5 – l mg/kg along with Propofol Total Intravenous Anaesthesia combination propofol reversal opioid tolerance adjunct depression management

Adverse Effects:

Increase Intracranial Pressure Emergence Delirium Chlorobutanoipreservatives neurotoxicity associated usage

Contraindications

include raised intracranial pressure although ventilation maintained ability maintain CBF responsiveness CO2 makes head injury patients good candidates avoid using if experiencing open globe injuries/seizure disorders

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