Chemical Properties
Ketamine hydrochloride is Off-White Solid
Originator
Ketanest,Parke Davis,W. Germany,1969
Uses
Anesthetic (intravenous).
Controlled substance (depressant).
Definition
ChEBI: The hydrochloride salt of ketamine.
Definition
ketamine: A vetinary anaesthetic that is used illegally as a club drug. Itis a class A drug in the UK.
Manufacturing Process
The 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine used as an
intermediate is prepared as follows. To the Grignard reagent prepared from
119.0 g of cyclopentyl bromide and 19.4 g of magnesium is added 55.2 g of
o-chlorobenzonitrile. The reaction mixture is stirred for 3 days and thereafter
hydrolyzed in the usual manner. From the hydrolysis there is obtained ochlorophenylcyclopentylketone, BP 96° to 97°C (0.3 mm), nD251.5452. To
21.0 g of the ketone is added 10.0 g of bromine in 80 ml of carbon
tetrachloride.
1-Bromocyclopentyl-(o-chlorophenyl)-ketone, BP 111° to 114°C (0.1 mm) is
isolated in the usual manner. Since it is unstable, it must be used
immediately. The bromoketone (29.0 g) is dissolved in 50 ml of liquid
methylamine. After one hour, the excess liquid methylamine is allowed to
evaporate. The organic residue is dissolved in pentane, and upon evaporation
of the solvent, 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine,
MP 62°C, is isolated.
1-Hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine (2.0 g) is
dissolved in 15 ml of Decalin and refluxed for 2,5 hours. After evaporation of
the Decalin under reduced pressure, the residue is extracted with dilute
hydrochloric acid, the solution treated with decolorizing charcoal, and the
resulting acidic solution is made basic. The liberated product, 2-methylamino-
2-(o-chlorophenyl)-cyclohexanone, after crystallization from pentane-ether,
has MP 92° to 93°C. The hydrochloride of this compound has MP 262° to
263°C.
brand name
Ketalar (Parkdale).
Therapeutic Function
Anesthetic
Biological Functions
Ketamine is a cyclohexanone derivative whose pharmacological
actions are quite different from those of the
other IV anesthetics. The state of unconsciousness it
produces is trancelike (i.e., eyes may remain open until
deep anesthesia is obtained) and cataleptic; it has frequently
been characterized as dissociative (i.e., the patient
may appear awake and reactive but does not respond
to sensory stimuli). The term dissociative
anesthesia is used to describe these qualities of profound
analgesia, amnesia, and superficial level of sleep.
General Description
Ketamine is formulated as an acidic solution, pH 3.5 to 5.5,available with or without 0.1 mg/mL benzethonium chloridepreservative. Ketamine is marketed as the racemic mixtureand some properties of the individual isomers have beenelucidated. Ketamine is a rapid-acting agent that can beused for induction, used as the sole agent for general anesthesiaor combined with other agents. Unlike the proposedmechanism of action for most anesthetics, ketamine doesnot act at the GABAA receptor. Ketamine acts as a noncompetitiveantagonist at the glutamate, NMDA receptor, anonspecific ion channel receptor. The NMDA receptor is locatedthroughout the brain and contains four well-studiedbinding sites. The primary binding site binds L-glutamate,NMDA, and aspartate. The allosteric site binds glycine,which facilitates primary ligand binding. There is also amagnesium binding site that blocks ion flow through thechannel and a phencyclidine (PCP) binding site that blocksthe ion channel when occupied. Ketamine is believed tobind to the PCP site in a stereoselective manner and blockthe ion flow in the channel. By blocking the flow ofcalcium ions into the cell, ketamine prevents the calcium concentration from building and triggering excitatorysynaptic transmissions in the brain and spinal cord.
Biological Activity
Non-competitive NMDA receptor antagonist (EC 50 values are 13.6 and 17.6 μ M for NR1/NR2A and NR1/NR2B subunit combinations respectively). Dissociative anesthetic.
Biochem/physiol Actions
Selective NMDA glutamate receptor antagonist; veterinary anesthetic.
Pharmacology
Slow IV administration of ketamine does not cause
gradual loss of airway reflexes, apnea, or general muscular
relaxation.The onset of the ketamine-induced “anesthetic
state” is accompanied by a gradual, mild increase
in muscle tone (which greatly resembles catatonia), continued
maintenance of pharyngeal and laryngeal reflexes,
and opening of the eyes (usually accompanied by
nystagmus). Although reflexes may be maintained, the
airway still must be protected, since ketamine sensitizes
laryngeal and pharyngeal muscles to mucous or foreign
substances, and laryngospasm may occur.
Ketamine also can be contrasted to other intravenous
drugs in its ability to cause cardiovascular stimulation
rather than depression. The observed increases
in heart rate and blood pressure appear to be mediated
through stimulation of the sympathetic nervous system.
In a healthy, normovolemic, unpremedicated patient,
the initial induction dose of ketamine maintains or stimulates
cardiovascular function. In contrast, patients with poor cardiac reserve, compromised autonomic control,
or hypovolemia may undergo a precipitous fall in blood
pressure after induction of anesthesia with ketamine. If
selection of the patient and preoperative preparation
are carefully done, however, ketamine may be an excellent
drug for the induction of anesthesia in individuals
who cannot tolerate compromise of their cardiovascular
system.
The analgesia induced by ketamine also is a property
that separates it from other IV anesthetic drugs.
Analgesia is obtained without a deep level of anesthesia.
When subdissociative doses of ketamine are given
either IV or intramuscularly (IM), they provide adequate
analgesia for postoperative pain relief as well as
analgesia for brief operations on the skin, such as debridement
of third-degree burns. Because it can be regarded
as a nearly complete anesthetic (hypnosis and
analgesia), does not require anesthesia equipment, and
is relatively protective of hemodynamics, ketamine also
can be very useful outside of normal operating room
conditions, such as may be found during painful radiographic
procedures.
A most important advantage of ketamine over other
anesthetic agents is its potential for administration by
the IM route.This is particularly useful in anesthetizing
children, since anesthesia can be induced relatively
quickly in a child who resists an inhalation induction or
the insertion of an IV line. Ketamine has a limited but
useful role as an IM induction agent and in pediatrics.
Clinical Use
Like other dissociative anesthetics, ketamine isabused for its hallucinatory effects. Most of the illegallyused ketamine comes from stolen legitimate sources, particularlyfrom veterinary clinics or smuggled in fromMexico.
Ketamine is metabolized via N-demethylation to formthe main metabolite norketamine. Norketamine has aboutone third the potency of the parent compound. Minor metabolicpathways include hydroxylation of the cyclohexanonering; hydroxylation followed by glucuronide conjugation,and hydroxylation followed by dehydration to the cyclohexenonederivative.
Side effects
The most serious disadvantage to the use of ketamine is
its propensity to evoke excitatory and hallucinatory
phenomena as the patient emerges from anesthesia.
Patients in the recovery period may be agitated, scream
and cry, hallucinate, or experience vivid dreams. These
episodes may be controlled to some extent by maintaining
a quiet reassuring atmosphere in which the patient
can awaken or if necessary by administering tranquilizing
doses of diazepam.
Other reported side effects include vomiting, salivation,
lacrimation, shivering, skin rash, and an interaction
with thyroid preparations that may lead to hypertension
and tachycardia. Ketamine also may raise intracranial
pressure and elevate pulmonary vascular resistance, especially
in children with trauma or congenital heart disease.
Increases in intraocular pressure also may occur,
and vigilance is required if ketamine is used in ocular
surgery.
Safety Profile
Poison by
intramuscular, intraperitoneal, and
intravenous routes. Moderately toxic by
ingestion. Human systemic effects by
intravenous and possibly other routes:
analgesia, coma, hallucinations and distorted
perceptions, dyspnea. An experimental
teratogen. An anesthetic. When heated to
decomposition it emits very toxic fumes of
Cland NOx.
Drug interactions
Potentially hazardous interactions with other drugs
Adrenergic-neurone blockers: enhanced hypotensive
effect.
Antihypertensives: enhanced hypotensive effect.
Antidepressants: stop MAOIs 2 weeks before
surgery; increased risk of arrhythmias and
hypotension with tricyclics.
Antipsychotics: enhanced hypotensive effect.
Memantine: increased risk of CNS toxicity, avoid
concomitant use.
Muscle relaxants: enhances effects of atracurium.
