KETAMINE

Moderator: Dr. Prithvi sir

Presenter: Dr. Shaik Nisa(pg)
OVERVIEW
 INTRODUCTION
 PHARMACOKINETICS
 PHARMACODYNAMICS
 MECHANISM OF ACTION
 EFFECTS ON SYSTEMS
 INDICATIONS & CONTRAINDICATIONS
 CLINICAL APPLICATIONS
 ADVANTAGES & DISADVANTAGES
 NON ANAESTHETIC USES
 REFERENCES
 “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
 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

out-of-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
PHARMACOLOGY
 There is a chiral centre with 2 optical isomers
(enantiomers)
 Ketamine has a high lipid solubility (5–10 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 20–30% 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.
 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.

 There are no significant differences in pharmacokinetic

properties between enantiomers and the racemic

mixture.

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

anaesthesia, there are less psychological side-effects.

 Coupled with the quicker recovery, patient acceptance of

S-(+)-ketamine is greater.

 S-(+)ketamine is significantly more expensive than the

generic, racemic ketamine.

PHARMACOKINETICS
 Onset of action:

 IV <30 seconds
 IM/ rectal 3 – 4 minutes

 Peak effects:

 IV 1minute
 IM/ rectal 5 – 20 minutes
 Orally 30 minutes
CONTD..
 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
 Nor ketamine (Metabolite I)
 Has a potency of 30% of the parent drug & longer
half-
PHARMACODYNAMICS

 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
CONTD..

 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

 Thalamo-neocortical 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
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.
CONTD..

 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 ocular 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 5–
30%.
CONTD..

 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 (0.07–0.1 mg /kg), diazepam (0.15– 0.3
mg /kg), and lorazepam (2–4 mg) i.v.
CARDIOVASCULAR EFFECTS

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.

 ketamine inhibits intraneuronal uptake of noradrenaline

CONTD..
 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 anesthetics
 It is possible to reduce the undesirable cardiovascular
effects by giving Ketamine as a continuous infusion and
use of a benzodiazepine.
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 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
instability.
 Severe dehydration.
 Respiratory failure or
bronchospasm.
 Severe anaemia.
 Major thoraco abdominal
procedures.
 Cardiac tamponade and
constrictive pericarditis.
 Obstetric patients
 Rapid sequence induction
 Severe hypovolemia.
 Acute haemorrhage.
 Acute bronchospasm.
 Low dose for analgesia
 Supplement regional technique.
 Transient analgesia at the time of
delivery.
 Adjunct to local or regional
anaesthesia
 Low dose for sedation and
analgesia during the procedure.
 Supplement for inadequate block.
 Outpatient surgery  Diagnostic and
 Paediatric anaesthesia therapeutic procedures.
 Diagnostic and  Reactive airway disease
therapeutic procedures.  Intractable bronchial
 Induction of asthma.
anaesthesia.  COPD with
 Caudal analgesia. bronchospasm.
 Adult anaesthesia  Patients with thermal
injuries
 Brief surgical
procedures.  Debridement and skin
grafting.
 Supplement local or
regional technique.  Dressing changes
 Postoperative analgesia
 As an adjunct with morphine
 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.
CONTRAINDICATIONS
 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).
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.
MISCELLANEOUS CLINICAL
APPLICATIONS BASED ON FEW CASE
REPORTS
 Cardiopulmonary bypass (CPB) surgery: single dose of
ketamine 0.5 mg/kg given upon induction was associated with
lower serum levels of C-reactive protein and lower incidence of
delirium and cognitive dysfunction after cardiac surgery with
CPB. This is because of the neuroprotective and anti
inflammatory effects of ketamine
 Use of dexmedetomidine and ketamine infusions during
scoliosis repair surgery with somatosensory and motor evoked
potential monitoring has been reported in children
 Ketamine sedation during spinal anaesthesia for arthroscopic
knee surgery can reduce the ischemic-reperfusion injury.
Ketamine by inhibition of NMDA receptor activation can
attenuate opioid-induced degeneration of spinal motor neurons
• In electroconvulsive therapy (ECT): A study showed that S-
ketamine given for ECT decreased the number of ECT
sessions, produced lower depression severity scores and
higher cognitive ratings.
• In another study, ketamine appeared to be associated with a
better word recall than etomidate after a course of 6 ECTs.
• A study showed that ketamine-propofol combination (ketofol)
can be an alternative strategy to enhance the seizure quality
and clinical efficiency of ECT
• Ketamine gargle attenuates postoperative sore throat
• By virtue of NMDA antagonism, ketamine in small doses
improves the postoperative depressive state in patients with
mental depression
• A case report describes symptomatic improvement possibly
by inhibition of neuroinflammation in the spinal cord in two
patients with restless leg syndrome treated with oral
ketamine
 Intrathecal administration of ketamine (5-50 mg in 3
ml of saline) produces brief and variable analgesia.
However, its systemic effects occur after systemic
absorption

 It has been used in patients with liver damage, acute

intermittent porphyria and in hiccoughs

 Ketamine co-administered with fentanyl and propofol

anaesthesia for orthopaedic surgery appears to have
potent rapid antidepressant like properties thus
improving the postoperative state of depressed
patients.
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 anaesthetics
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.
NON ANAESTHETIC USES

 Depression:
• A single subanesthetic dose (0.5 mg/kg) of
intravenous (IV) ketamine hydrochloride has been
shown to have a rapid antidepressant effect, which
begins as early as 2 hours after ketamine
administration, peaks at 24 hours, and lasts for up
to 7–14 days .
• This effect has been noted in both unipolar and
bipolar depression although effect duration may be
shorter in patients with bipolar disorder
 KETAMINE-PAIN MANAGEMENT
 patients undergoing cesarean section, a single
postoperative intravenous ketamine bolus
(0.25mg/kg) was shown to reduce the severity of
postoperative pain and decrease an- algesic
requirements. As a result, ketamine can prevent
opioid tolerance and may reduce the rate of opioid-
induced hyperalgesia following surgery
 while also has been shown to reduce nausea and
vomiting in the perioperative period at doses of <0.5
mg/kg . While ketamine has generally been shown to
reduce intraoperative opioid requirements
REFERENCES:

 MILLER’s
 STOELTING’s pharmacology and physiology
in anaesthesia practice
 https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC4258981/
THANK YOU…