Ketamine hydrochloride Chemical Properties

Melting point:

252-254°C

Flash point:

9℃

storage temp. 

2-8°C

solubility 

H₂O: 200 mg/mL

form 

solid

pka

7.5(at 25℃)

color 

white

Water Solubility 

Soluble to 100 mM in water

CAS DataBase Reference

1867-66-9(CAS DataBase Reference)

EPA Substance Registry System

Ketamine hydrochloride (1867-66-9)

Safety Information

Hazard Codes 

Xn,T,F

Risk Statements 

22-36/37/38-39/23/24/25-23/24/25-11

Safety Statements 

26-45-36/37-16-7

RIDADR 

3249

WGK Germany 

3

RTECS 

GW1400000

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

2923900100

Toxicity

LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal)

MSDS

• Language:English Provider:Ketamine hydrochloride

Ketamine hydrochloride Usage And Synthesis

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.

storage

Store at RT

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