3. Pharmacology
          3.3. IV anaesthetic agents
 3.3.4. Ketamine



Quick summary


  • IV anaesthetic agent, phencyclidine derivative
  • Useful isomer = S(+) isomer

Clinical effect

  • Analgesia at subanaestheisa dose
  • Dissociative anaesthesia
  • CVS stimulation
  • Maintenance of respiratory reflexes and ventilation


  • Emergence delirium
  • Abuse potential
  • Bronchorrhoea


  • Analgesia
    * Acute post-operative pain
    * Change of dressing in burns
  • Sedation
  • Induction of anaesthesia
    * In hypovolaemic patients or CVS unstable patients
    * Can be used as the sole anaesthetic agent if skeletal muscle relaxation is not required
  • Maintenance of anaesthesia



Ketamine is a phencyclidine ("angel dust") derivative

Structure-activity relationship

S(+) isomer is more clinically useful

  • Greater analgesia
    * 4 times the analgesic potency as R(-)
  • More rapid metablism and recovery
  • Less salivation
  • Lower incidence of emergence delirium


Mechanisms of action

  • Ketamine primarily acts on CNS
    * Thalamocortical pathway
    * Limbic system
  • Ketamine binds non-competitively to phencyclidine recognition site on (postsynpatic) NMDA receptors
    * Stereoselective
    * Enters and blocks open channel (i.e. antagonist)

Thus, ketamine:

  • inhibits activation of NMDA receptors by glutamate
    --> inhibits the excitatory effect of glutamate on CNS
  • Reduces presynaptic release of glutamate
  • Potentiate the effects of GABA (inhibitory neurotransmitter)

NMDA receptors

NMDA = N-methyl-D-aspartate

NMDA receptors are:

  • A member of glutamate receptors family
  • Ligand-gated ion channels
  • Unique in that activation requires binding of
    * Glutamate (excitatory neurotransmitter)
    * Glycine (obligatory co-agonist)

Other receptors

Ketamine also interact with the following receptors:

  • Opioid receptors
    * Antagonist at MOP
    * Agonist at KOP
  • Monoaminergic receptors
    * descending inhibitory monoaminergic pain pathway may be involved in ketamine's antinociceptive action
  • Muscarinic receptors
    * Ketamine anaesthesia is partially antagnoised by anticholinergic drugs
    * Ketamine produces some anticholinergic symptoms
    * Thus, ketamine may exert an antagonist action at muscarinic receptors
  • Voltage-sensitive Na+ channel
    * Ketamine shares binding sites with local anaesthetics
    * Responsible for ketamine's mild local anaesthetic effect
  • L-type Ca2+ channel
  • GABAa receptors
    * Only weak actions, unlike propofol and etomidate
  • Direct inhibition of cytokines in blood
    --> May contribute to analgesia

Effects by systems


Dissociative anaesthesia

Dissociative anaesthesia
= A trance-like cataleptic state whereby the patient appears to be dissociated from the environment but not necessarily asleep

Characterised by the following:

  • Profound analgesia
  • Sedation
  • Amnesia
  • Retention of protective airway reflexes
  • Spontaneous respiration
  • Cardiopulmonary stability
  • Slow nystagmic gaze
  • Noncommunicative
  • Varying degree of hypertonus and purposeful movement independent of surgical stimulus
  • Greater effect for somatic pain than visceral pain
  • Primarily due to effect on thalamic and limbic system
  • Ketamine is not recommended as the first line treatment in chronic pain
Spinal cord sensitisation
  • Responsible for pain associated with touching or moving injured body parts
  • Involves the activation of NMDA receptors in spinal cord dorsal horn

Ketamine, Mg2+, and dextromethophan all inhibit NMDA receptors
--> Inhibits spinal cord sensitisation
--> Could decrease post-operative analgesic consumption

Intracranial pressure
  • Ketamine is a potent cerebral vasodilator
    --> Increases CBF by 60% in normocapnia
  • But in studies, patients with traumatic brain injury and mechanically ventilated, ICP DECREASES
  • May increase CMRO2
Neuroprotective effects
  • Activation of NMDA receptors is implicated in cerebral ischaemic damage

In theory,

  • Ketamine inhibits NMDA receptors
    --> Neuroprotective post-ischaemia
    * But not yet proven
EEG effects


  • Abolish alpha rhythm
  • Dominance of theta waves
  • Induces excitatory activities in thalamus and limbic system
    * But no spread to cortex
    --> Unlikely to precipitate generalised convulsion or alter seizure threshold

Thus, SAFE for use in epilepsy

  • Ketamine has little value in neuraxial analgesia


Ketamine has the following effects

  • Central sympathetic stimulation
    * Direct stimulation of CNS --> Increased sympathetic nervous system outflow
  • Vasoconstriction
  • Direct negative inotropic effect on the myocardium
    * But usually overshadowed by central sympathetic stimulation

CVS stimulation effect

Ketamine increases

  • BP
    * SBP increases by 20-40 mmHg in 3-5 minutes, then decreases gradually to pre-dose level in the next 10-20 minutes
  • HR
  • Cardiac output
  • Cardiac work
  • Myocardial oxygen requirement
Blocking the CVS stimulation effect

Ketamine's CVS stimulation effects may be blunted or prevented by

  • Inhaled anaesthetic agents
  • Ganglionic blockade
  • Cervical epidural
  • Spinal cord transection
  • Benzodiazepine


Ketamine's myocardial depression may also be unmasked when

  • Sympathetic nervous system compensatory response impaired
  • Depletion of endogenous catecholamine store

Other CVS effects
  • Ketamine may maintain BP by vasoconstriction
    --> Impaires tissue perfusion
    --> Increases plasma lactic acid level
  • R(-) negates the cardioprotective effect of ischaemic pre-conditioning
    * S(+) does not affect pre-conditioning
    * Ischaemic pre-conditioning is also mimiced by activation of KATP channels
  • Ketamine's effect on cardiac rhythm is inconclusive
  • Inhibits reuptake of catecholamines back to postganglionic sympathetic nerve endings
    * Cocaine-like effect
    * Associated with an increase in plasma catecholamine


Ventilation not depressed

Ketamine does not cause significant depression of ventilation

  • RR may be decreased for 2-3 minutes
  • Apnoea can still occur with rapid IV ketamine or when used with opioid

Ketamine induces bronchodilation

  • Useful for rapid sequence induction in asthma
  • Mechanism is unclear, possible ones include:
    * Increased circulating catecholamine
    * Inhibition of catecholamine uptake
    * Voltage-sensitive Ca2+ channel blockade
    * Inhibition of postsynaptic nicotinic or muscarinic receptors
Reflex and muscle tone
  • Upper airway skeletal muscle tone and reflex are well maintained with ketamine
Secretions (bronchorrhoea)
  • Ketamine increases salivery and tracheobronchial mucous gland secretion
    --> Co-administration of antisialagogue is frequently recommended
  • Increased airway secretion could increase the risk of bronchospasm and laryngeal spasm

Hepatic and renal

  • Ketamine does NOT affect hepatic function or renal function tests


  • Does NOT evoke histamine release
  • Allergic reactions to ketamine is very rare

But according [PI],

  • Transient rash incidence = 15%
    * Predominantly on face and neck


  • Ketamine inhibits platelet aggregation
  • Mechanism: Ketamine suppresses formation of inositol 1,4,5-triphosphate
    --> Inhibition of cytosolic free calcium concentration



  • Transient increase in intraocular pressure
  • Nystagmus and eye movement is common
  • Corneal reflex usually preserved


  • Safe for use in malignant hyperthermia
  • Caution in acute intermittent porphyria
    * Can increase aminolevulinic acid synthetase activity in animal
  • Reversal of opioid tolerance
    * Subanaesthetic dose --> prevents and reverses morphine-induced tolerance
    * Mechanism unknown
  • May increase the risk of N&V, although usually not severe
  • May activate psychoses in schizophrenic patients
  • May cause significant reduction in leucocyte activation during sepsis

Adverse reactions

Ketamine is unique in that it produces

  • Emergence delirium
  • Stimulation of CVS

Emergence delirium

Incidence of emergence delirium
= 5-30% [SH4]
= 12% [PI]

  • Disorientation
  • Visual, auditory, and proprioceptive illusions
  • Cortical blindness may be present transiently
  • Dreams and hallucination can occur up to 24 hours after ketamine

Mechanism of emergence delirium
  • Probably due to depression of inferior colliculus and medial geniculate nucleus
    --> Misinterpretation of auditary and visual stimuli
  • Loss of skin and musculoskeletal sensation
    --> Decreased ability to preceive gravity
    --> Bodily detachment or floating sensation
Risk factors

Risk factors include:

  • Age > 15 y.o.
  • Female gender
  • Ketamine dose > 2 mg/kg IV
  • History of personality problem or frequent dreaming
  • Atropine and droperidol increase incidence
  • Rapid IV administration [PI]


Factors that decrease incidence of emergence delirium

  • Benzodiazepine is the most effective prevention
  • Thiopentone or inhaled anaesthetics also decrease incidence
  • Occurs less when ketamine is used repeatedly
  • Young (<15 y.o.) or old (>65%)
  • IM administration [PI]



  • There is NO evidence that quiet area for awakening decreases emergence delirium
    * [SH4:p174]
    * [PI] Still recommends quiet area for awakening


  • Inhaled anaesthetic agents also produce some emergence delirium, but much less than ketamine


  • Transient rash
  • Laryngospasm
  • Hypersalivation
  • Increased muscle tone
  • Nystagmus

Pharmacokinetics (PK)


  • IM bioavailiabilty = 93%
  • IM absorption halflife = 2-17 min


  • Vd = 2.5 - 3.5 L/kg
  • Protein binding = 20 - 50%
    * Lowest protein binding of all IV anaesthetic agents


Several metabolic pathways

  • Extensive metabolism by hepatic microsomal enzymes
  • Demethylation by CYP450 --> Norketamine
  • Norketamine (metabolite I)
    * 1/5 - 1/3 the potency of ketamine (Or 1/6 [PI])
    * Eventualy hydrolysed and glucuronidated into inactive metabolites
    * Concentration is similar to the parent compound
    * Does not penetrate BBB enough to cause hypnosis

High hepatic extraction ratio
--> Sensitive to changes in hepatic blood flow


  • <4% excreted unchanged in urine
  • <5% excreted unchanged in faeces
  • Inactive metabolites are excreted by kidney
  • Clearance
    = 16-18 mL/min/kg [SH4]
    = 10-20 mL/min/kg [PI]

Action profile


IV induction

  • Onset of action: < 1min
  • Duration of action = 6-15 min
  • IV recovery period = 60-90 min

IM induction

  • Onset of action
    = 2-4 min [SH4]
    = 3-5 min [PI]
  • Duration of action = 12-25 min (dose dependent) [PI]
  • Mean recovery time = 90 - 150 min


According to [SH4] (which does not differentiate between IM and IV)

  • Return of conscienceness in 10 - 20 minutes
  • Full orientation and takes additional 60-90 minutes
  • Amnesia lasts about 60-90 minutes after return of conscienceness



  • Alpha phase half-time = 10-15 minutes
  • Beta phase half-time = 2-3 hours


  • Duration of alpha phase = 45 min [PI]
  • Generally alpha phase represent anaesthetic action



  • Acid solution: pH 3.5 - 5.5
  • 200 mg in 2mL = 100 mg/mL
  • Racemic or single isomer (S(+))

Content of an ampule

  • Ketamine hydrochloride 100 mg/mL
  • Benzethonium chloride
    = 0.1 mg/mL = 0.01%
    * As preservative
    * ?? aka phemerol

Physicochemical properties

  • pKa = 7.5
  • High lipid solubility
    * 5-10 times that of thiopentone
    * Crosses BBB easily
  • Freely soluble in water and methyl alcohol. Also soluble in ethanol




  • Analgesic dose
    = 0.2 - 0.5 mg/kg IV [SH4]
  • Ketamine 100mg with haloperidol 2.5mg, run over 24 hours, could be a good starting point for ketamine infusion
    * [Anthony Colby]


Induction of anaesthesia

  • Induction dose
    = 1 - 2 mg/kg IV (slowly over 1-2 min)
    = 4 - 8 mg/kg IM [SH4]
  • Surgical anaesthesia IM dose
    = 6.5-13 mg/kg IM [PI]
    = 9 - 13 mg/kg IM (paediatric) [PI]


Useful adjuncts

  • Benzodiazepines
    * To reduce emergence delirium
  • Anti-cholinergic drugs (e.g. glycopyrrolate)
    * To reduce hypersalivation, thus risk of coughing and laryngospasm
    * Glycopyrrolate is preferred because atropine and scopolamine can cross BBB and cause delirium
  • Haloperidol
    * For sedation when ketamine is used at analgesic dose [Dr Anthony Colby]



When ketamine is used in patients with

  • CVS disease or hypovolaemia
  • Stroke
  • Increased ICP, intracranial haemorrhage
  • Higher risk of laryngospasm ie.
    * Age < 3 months
    * Stimulation of posterior pharynx
    * Respiratory infection (due to sensitised gag reflex)
    * [PI]
  • Increased intraocular pressure
  • Hyperthyroidism
    * Excessive BP and HR increase
  • Acute intermittent porphyria
  • Psychiatric illness
  • Seizure
    * [PI], but not according to [SH4]
  • Coagulopathy

When giving as IV, ketamine needs to be given slowly to avoid excessive pressor response and apnoea


  • With inhaled anaesthetic agents and benzodiazepines, ketamine can cause hypotension
    * Due to blunting or prevention of its CVS-stimulating effects
    * Halothane and benzodiazepines also prolong the halflife of ketamine [PI]
  • With verapamil, ketamine causes
    * Less increase in BP
    * Greater increase in HR
  • Ketamine also enhance the effect of non-depolarising neuromuscular blocker
    * Possibly due to actions on Ca2+ binding
  • Alternatively, ketamine may DECREASE sensitivity of postjunctional membrane to neuromuscular blocker
  • Duration of apnoea after suxamethonium is INCREASED with ketamine
    * Possibly due to inhibition of plasma cholinesterase
  • Combination of aminophylline and ketamine may decrease seizure threshold
  • Other CNS depressants
    * Potentiation of CNS depression
    * Higher risk of respiratory depression


  • Do not mix diazepam with ketamine in the same syringe [PI]

Special consideration

  • Dose reduction in severe hepatic impairment
  • Not reversed by naloxone
  • Wide therapeutic index
  • Ketamine causes enzyme induction
    --> Tolerance occurs in repeated dosing
  • High abuse potential


  • Crosses placenta easily
  • Plasma level similar in maternal and foetal circulation
  • Pregnancy safety category B3
  • Excreted in milk


  • Absorption after IM is more rapid than in adults
  • Pharmacokinetic profile similar to adults



  • First synthesized in 1962
  • First used on American soldiers during the Vietnam War
  • Recreational use increased through the end of the 20th century

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