4. Ketamine Flashcards
Intro
Unique?
Ketamine is unique amongst anaesthetic agents in that, by causing ‘dissociative
anaesthesia’, a single dose can produce profound analgesia, amnesia and anaesthesia.
It finds its way into the exam more frequently than its clinical use might deserve, but
investigation of the S (+) isomer as an agent with fewer side effects has renewed the
drug’s promise. Its dissimilarity from the other induction agents means that it may be
the sole subject of the oral.
Chemistry:
Cyclohexanone derivative of phencyclidine (PCP),
which is an anaesthetic agent used in veterinary practice
and which is also a drug of abuse (‘angel dust’).
Ketamine is water-soluble and is presented in three different concentrations.
The solution is acidic, at pH 3.5–5.5.
Its pKa is 7.5.
Most formulations now contain preservative,
which precludes its use in central neural blockade, although
preservative-free preparations can be obtained to allow its neuraxial injection
Enantiomer
racemic mixture of two enantiomers, although the pure S (+) enantiomer is available
he S (+) enantiomer is three to four times as potent as the R (−) enantiomer,
and is associated with shorter recovery times and with fewer psychotomimetic reactions.
This is primarily because a lower dose of
S (+) ketamine is required to induce anaesthesia
At equal plasma concentrations the recovery times .
and the incidence of psychological disturbance are the same.
Mechanisms of action
Ketamine is a non-competitive N-methyl-D-aspartate (NMDA)
receptor antagonist at the Ca2+ channel pore.
The NMDA receptor is an L-glutamate receptor in the CNS
(glutamate being the major excitatory neurotransmitter in the brain)
and incorporates a cation channel to which ketamine binds.
In addition, it reduces pre-synaptic glutamate release.
Ketamine also has effects on opioid receptors,
acting as a partial μ (MOP) antagonist and as a partial agonist at
κ (KOP) and δ (DOP) receptors.
It may therefore exert its analgesic effects after intrathecal or extradural injection at spinal κ receptors.
These opioid effects are not antagonized by naloxone.
It also acts as an antagonist at serotoninergic, muscarinic,
nicotinic and monoaminergic receptors.
It may also inhibit sodium channels in neuronal tissue
and so in high doses has local anaesthetic actions.
Onset and duration of action
An induction dose of ketamine does not lead to hypnosis within one arm–brain circulation time.
Consciousness will be lost after 1–2 minutes,
but the patient may continue to move and to make incoherent noises.
Intramuscular administration will take 10–15 minutes to take effect.
The duration of action is between 10 and 40 minutes.
Dose
The reported dose ranges are wide,
but typically an intravenous dose of 1–2 mg kg−1 will induce anaesthesia.
Intramuscular dose is 5–10 mg kg−1.
Subhypnotic doses for sedoanalgesia are usually up to 0.5 mg kg−1.
Pharmacokinetics:
Ketamine is highly lipid-soluble
but weakly protein-bound (25%).
It has high intramuscular bioavailability (93%),
but oral bioavailability is only 20–25%.
Via the nasal route bioavailability is reported as being around 50%.
Metabolism is hepatic;
demethylation and hydroxylation produce norketamine,
which is an active metabolite of one-third the potency of ketamine,
and dehydronorketamine,
which is very weakly active at the NMDA receptor.
Further metabolism produces
conjugates which are excreted in urine.
Central nervous system effects:
dissociative anaesthesia’, which describes what in effect is a state of catalepsy
Corneal and pupillary reflexes, for example, are preserved,
and the patient’s eyes may remain open,
but there is no purposeful response to stimuli.
The ‘dissociation’ is essentially between the thalamus, which relays
afferents from the reticular activating system,
and the cerebral cortex and limbic systems.
potent analgesic at doses much lower than those required to induce anaesthesia.
It is amnesic.
Anecdotally, it is reported that ketamine is less effective in brain-damaged patients. Unlike
other induction agents,
it increases CMRO2, cerebral blood flow and intracranial
pressure, but does not influence autoregulation.
Cardiovascular system:
ketamine is sympathomimetic and increases levels of circulating catecholamines.
On isolated myocardium, however, it acts as a depressant
.
Indirect effects result in tachycardia,
increases in cardiac output and blood pressure,
and a rise in myocardial oxygen consumption.
Respiratory system:
It is a respiratory stimulant which is said to preserve laryngeal reflexes
and tone in the upper airway (this is not always obvious at high doses).
It is an effective bronchodilator.
Gastrointestinal system
: it causes salivation. As with most sympathomimetic anaesthetic
agents, the incidence of nausea and vomiting is increased
Other effects
The use of ketamine has been limited by its CNS side effects.
It is associated both with an emergence delirium
and also with dysphoria and hallucinations.
Emergence delirium is a state of disorientation in which patients may react
violently to minor stimuli such as light and sound.
The psychotomimetic effects are a separate phenomenon,
which can become manifest many hours after apparent
recovery from anaesthesia.
Benzodiazepines may attenuate the problem.
Differences from other induction agents:
as detailed earlier, ketamine is both anaesthetic and analgesic,
producing these effects by actions across a range of receptors.
In contrast to propofol, thiopental and etomidate it is sympathomimetic,
elevating levels of circulating catecholamines and increasing cardiac output and
systemic vascular resistance.
Ketamine is a respiratory stimulant which preserves
laryngeal reflexes and tone in the upper airway.
It antagonizes the effects of ACh and 5-HT on the bronchial tree and causes clinically useful bronchodilatation.
It is used in the management of severe asthma that is refractory to other agents. The R (−)
enantiomer appears to be a more effective antimuscarinic in this regard than the
S (+) form.
It is also different in that it is not limited to the intravenous and rectal
routes but can also be given intramuscularly, orally, nasally, extradurally and intrathecally. Consensus has it that ketamine can probably (with caution) be used in
patients with porphyria
Clinical uses:
Clinical uses:
ketamine can be used for the induction of anaesthesia in adults and
children,
for so-called field anaesthesia as a single anaesthetic agent outside the
hospital setting,
for bronchodilatation and for sedoanalgesia during procedures
performed under local or regional anaesthesia.
Given extradurally or intrathecally it prolongs by three to four times the duration of analgesia provided by local anaesthetic alone.
It is finding increasing use as a perioperative ‘co-analgesic’ when
given in sub-hypnotic doses (for example, 25 mg intravenously)
It can also be used in the treatment of chronic pain syndromes (see under
‘The Complex Regional Pain Syndrome (CRPS)’ in Chapter 3).
Ketamine as an antidepressant
For decades, the monoamine system has been the therapeutic
target of drugs to treat depression (major depressive disorder, MDD)
but around two-thirds of patients have little sustained benefit from treatment.
Interest more recently has shifted to the glutamate system,
as various studies have shown that
a single sub-anaesthetic dose of ketamine can have an immediate and persistent
antidepressive action.
This shows therapeutic promise, but long-term therapy may be
limited by side effects, particularly those affecting the urinary tract.
