KETAMINE

MODERATOR: Dr. D.MADHUSUDHAN REDDY D.A. PRESENTER : Dr. V.SUJATHA P.G

HISTORY
It was synthesized as Ketalar by Stevens ,in 1962.

First used in humans by Corsen and Domino in

1965.
First used- American soldiers during Vietnam War. Released for civilian use in 1970. In recent past its use on humans dramatically

curtailed emergence phenomena including outof-body experiences in clinical practice.

Physical & Chemical Properties

It is phencylidine derivative {2-(O-chlorophenyl)-2-methylamino

cyclohexanone}. Mol wt =238 pH =3.5 to 5.5 Freely water soluble pKa =7.5

ORGANIC CHEMISTRY
Phencyclidine derivative

skeletal formula of (S)ketamine

PHARMACOLOGY
There is a chiral centre with two optical isomers

(enantiomers) Ketamine has a high lipid solubility (510 times that of thiopental) crosses the blood-brain barrier faster. It undergoes demethylation and hydroxylation of the cyclohexanone ring. The metabolites are conjugated to water soluble glucoronide derivatives and excreted in the urine. Norketamine has 2030% of the activity of the parent compound.

Isomers
The chiral centre of the cyclohexanone ring permits the existence of two enantiomers. S-(+)-ketamine has greater affinity than R (-) ketamine at phencyclidine binding sites on the NMDA receptor. There are no significant differences in

pharmacokinetic properties between enantiomers and the racemic mixture. S-(+)-ketamine has twice as potent as the racemic mixture in producing anaesthesia and analgesia, and thrice as potent as R-( - ) ketamine

 The recovery time is reduced with S (+) ketamine

compared with the racemic mixture.

smaller dose of S-(+)-ketamine is required for

anaesthesia, there are less psychological sideeffects.

Coupled with the quicker recovery, patient

acceptance of S-(+)-ketamine is greater.

S-(+)ketamine is significantly more expensive than

the generic, racemic ketamine.

skeletal formula of (R)ketamine

skeletal formula of (S)ketamine

PHARMACKINETICS
Onset of action:
IV <30 seconds IM/ rectal 3 4 minutes

Peak effects:
IV 1minute IM/ rectal 5 20 minutes Orally 30 minutes

Duration of action:
IV 5 - 15minute IM/ rectal 12 25 minutes Epidural 4 hours

Metabolism:
Demethylation & hydroxylation by hepatic CYP One of the produced metabolites is active

Norketamine (Metabolite I) Has a potency of 30% of the parent drug & longer halflife

PHARMACODYNAMICS
Dosing: Sedation/Analgesia

IV: 0.5 1.0 mg/kg IM/ rectal: 2.5 5.0 mg/kg Orally: 5 6 mg/kg
Induction IV: 1.0 2.5 mg/kg IM/ rectal: 5 10 mg/kg Infusion 15-80 mcg/kg/min Augment with midazolam IV 1 -2 mg Epidural/ Caudal 0.5 mg/kg Dilute in saline or local anesthetic (1 mL/kg)

Site of action: Thalamoneocortical projection. Depresses the thalamus, stimulates part of limbic system (Hippocampus) Causes functional disorganization of nonspecific pathways in mid brain and thalamus Medullary reticulary formation is depressed

Mechanism of action
acts on the central nervous system and has local anaesthetic

properties. Its effects are mediated primarily by noncompetitive antagonism at the N-methyl-D aspartate(NMDA) receptor Ca+2 channel pore. NMDA channel block appears to be the primary mechanism of the anaesthetic and analgesic action of ketamine (at the CNS and also at spinal cord receptors). It reduces the presynaptic release of glutamate. The S (+) enantiomer has a three- to four-fold greater affinity for the NMDA receptor than the R(-) form.

Other mechanisms of action of ketamine

Include interaction with opioid receptors,

With a preference for mu and kappa receptors;.

The affinity of ketamine for these receptors is 10

times less than that for the NMDA channel,

Naloxone does not antagonize the analgesic

effects of Ketamine

 ketamine has an antagonistic interaction with

monoaminergic, muscarinic, and nicotinic

receptors.
ketamine produces anticholinergic symptoms

(e.g. tachycardia and bronchodilatation).

Ketamine at high doses has local anaesthetic

properties through its ability to inhibit

neuronal sodium channels

DISSOCIATIVE ANESTHETIC
Ketamine produces the dissociative anaesthetic state that

has been described as functional and electrophysiological dissociation between the thalamo-neocortical and limbic systems Produces an atypical behavioral state. State of sedation Immobility Amnesia Marked analgesia Feeling of dissociation from the environment Without true unconsciousness

CNS effects
The EEG demonstrates a dominant theta activity with abolition of alpha rhythm. The unique clinical state produced by ketamine is typically a state of catalepsy in which the eyes remain open with a slow nystagmic gaze, whereas the corneal and light reflexes remain intact.

Varying degrees of hypertonus and occasional purposeful movements unrelated to painful stimuli are noted in the presence of adequate surgical anaesthesia.
excitatory activity in both the thalamus and limbic systems without clinical evidence of seizure activity

after ketamine administration.

 Ketamine has anticonvulsive and even neuroprotective properties. Analgesia occurs at considerably lower blood concentrations than does the loss of consciousness.. Ketamine increases cerebral metabolism, cerebral blood flow , and intracranial pressure, cerebral O2

consumption. Pupillary dilatation, nystagmus, salivation, and lacrimation are common, Intra occular pressure rises Increased skeletal muscle tone with coordinated but purposeless movements of arms , legs, trunk and head

Emergence reactions
Psychic sensations after ketamine emergence can be

alterations in mood state and body image, floating sensations, vivid dreams or illusions, and occasional frank delirium.
These dreams and illusions usually disappear on full wakening.
The incidence of psychic effects is approximately 530%. A higher incidence is associated with factors such as

increasing age, female gender, patients who normally dream, rapid intravenous administration, and large doses.
Ketamine has been observed to activate psychoses in patients

with schizophrenia.
Premedication can attenuate psychic reactions: midazolam

(0.070.1 mg /kg), diazepam (0.15 0.3 mg /kg), and lorazepam (24 mg) i.v.

Cardiovascular effects
Stimulates CVS and associated with tachycardia, increased

blood pressure, SVR and PVR and increased cardiac output

and myocardial O2 consumption.

centrally mediated sympathetic response .. Ketamine has a direct myocardial depressant effect, in

presence of sympathetic depression.

It is possible to reduce the undesirable cardiovascular

effects by giving Ketamine as a continuous infusion and use

of a benzodiazepine.
ketamine inhibits intraneuronal uptake of noradrenaline

Cardiovascular effects
Drug of choice in congenital heart disease Increases SVR and CO Does not worsen RIGHT to LEFT shunt Correction of fallots tetralogy

CVS effects are supressed by Benzodiazepines, Clonidine , fentanyl and Volatile anaesthetics

Respiratory effects
Ketamine has minimal effect on central respiratory

drive,
A transient decrease in ventilation can occur after

bolus administration.
Ketamine is a bronchial smooth muscle relaxant, so it

has a special role in intractable asthma.

It improves pulmonary compliance and is as effective

as halothane in preventing bronchospasm..

 Ketamine increases salivary secretions, which can produce

potential problems in children by causing upper airway obstruction.

Although swallowing, cough, sneeze, and gag reflexes are

relatively intact with ketamine, silent aspiration can occur.

Laryngospasm is frequent laryngospasm during ketamine sedation is usually caused

by stimulation of the vocal cords by instrumentation or

secretions.
Secretions can be reduced by giving glycopyrrolate

premedication.

Effects on other systems

Ketamine has not been shown to have any adverse effects on hepatic and renal systems. Intraocular pressure is slightly increased after Ketamine administration. Ketamine produces an increase in muscle tone and

sometimes muscle spasms, although it has been safely used in myopathies and malignant hyperthermia.
Variable effects on uterine tone have been reported.
Other effects include emesis, transient rash, and agitation.

Indications
Aged and poor risk patients Shock and cardiovascular Acute haemorrhage. Acute bronchospasm. Low dose for analgesia

instability.
Severe dehydration.
Respiratory failure or

Supplement regional

technique.
Transient analgesia at the

bronchospasm.
Severe anaemia. Major thoraco abdominal

time of delivery.
Adjunct to local or regional

procedures. Cardiac tamponade and constrictive pericarditis.

Obstetric patients Rapid sequence induction Severe hypovolaemia.

anaesthesia Low dose for sedation and analgesia during the procedure.
Supplement for inadequate block.

 Outpatient surgery Paediatric anaesthesia Diagnostic and

Diagnostic and

therapeutic procedures.
Reactive airway disease

therapeutic procedures. Intractable bronchial asthma. Induction of anaesthesia. COPD with bronchospasm. Caudal analgesia.
Adult anaesthesia Brief surgical Patients with thermal

injuries
Debridement and skin

procedures.
Supplement local or

grafting.
Dressing changes

regional technique.

 Postoperative analgesia
As an adjunct with morphine Recovery room. Intensive care units. Procedural sedation in intensive care Paediatric cannulation, central lines. Adult central lines, endoscopies, dressing changes.

Developing countries and field hospitals

Chronic pain For patients in whom airway management may be

difficult
Unstable cervical spine. Trapped casualties.

Contra indications
A high predisposition to laryngospasm or apnoea (e.g. active

pulmonary infection, patients younger than 3 months).

Severe cardiovascular disease, such as angina, heart failure, or

malignant hypertension (because of cardiostimulant effects of ketamine, although this is controversial).

CSF obstructive states (e.g. severe head injury, central

congenital or mass lesions).

Intraocular pressure pathology (e.g. glaucoma, acute globe

injury).
Previous psychotic illness (potential activation of psychoses) Hyperthyroidism or thyroid medication use (possibility of

severe tachycardia or hypertension).

Porphyria (possibility of triggering a porphyric reaction).

Clinical applications
Sedation Ketamine is appropriate for children undergoing

procedures in isolated situations. Emergence reactions in children are less intense, so it can be used for both sedation and general anaesthesia in procedures such as cardiac catheterization , radiotherapy, radiological investigations, and burns dressings. Generally, sub anaesthetic doses are required for minor procedures. Ketamine is often combined with premedication (e.g. benzodiazepines) to reduce the dose requirement and emergence reactions, and an antisialogogue (e.g. glycopyrrolate) to reduce salivary secretions.

 In both adults and children, ketamine can be used

as a supplement (i.v. or i.m.) during regional anaesthesia. It can also be given via the epidural route as an adjunct to a local anaesthetic to extend the duration of analgesia. Low-dose ketamine has also been used along with propofol to improve the quality of sedation. administration of ketamine results in reduced postoperative opioid requirements6 (4060% on an average). Ketamine-treated patients also experienced less post operative nausea and vomiting

ADVANTAGES & USES

Induction agent of choice for Asthmatics Shock Children as an alternative to inhalational induction. Constrictive pericarditis, cardiac tamponade, right to left

shunt like TOF, Used as sole agent for minor procedures, burns and dressings Safely used at remote places since it does not depress respiration and heart
Depressed pts as they have better recovery In neuromuscular diseases- as a sole anaesthetic

DISADVANTAGES
Incidence of hallucinations and emergence

reactions is very high

Increased muscle tone Pharyngeal and respiratory secretions are

increased which can cause laryngospasm

Increases myocardial O2 demand

All pressures like intra ocular, intra gastric,

intracranial markedly raised

Ketamine in regional Anaesthesia: Should be preservative free as Benzethonium is neurotoxic. After caudal or epidural anaesthesia Duration of analgesia is longer Ketamine caudal block is similar to post OP analgesia of bupivacaine. Chlorobutanol used as preservative for ketamine is neurotoxic.

References
Miller 7th edition Ketamine & Kids an update - Paediatric

anaesthesia 2005, 15:91- 97 Ketamine CEACCP reviews vol 7, no.2,2007.

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