Ketamine

[SH4:p167-174]

Quick summary

General

• 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

Side-effect:

• Emergence delirium
• Abuse potential
• Bronchorrhoea

Usage

• 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

Structure

Structure

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

Pharmacodynamics

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

CNS

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

Analgesia

• 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

Ketamine

• 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

Others

• Ketamine has little value in neuraxial analgesia

CVS

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 K_ATP 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

Respiratory

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

Bronchodilation

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

Allergy

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

But according [PI],

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

Coagulation

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

Eyes

[PI]

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

Others

• 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]

S&S

• 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]

 

Others:

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

NB:

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

Others

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

Pharmacokinetics (PK)

Absorption

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

Distribution

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

Metabolism

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

Elimination

• <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

[PI]

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

Half-times

Bi-exponential

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

NB:

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

Pharmaceutics

Formulation

• 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

Clinical

Administration

Analgesia

• 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]

Indications/contraindication/precautions

Caution

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

Interactions

• 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

Preparation

• 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

Pregnancy/lactation

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

Paediatrics

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

Trivia

History

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