Etomidate , ketamine Dr. S. Parthasarathy

MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics- PhD ( physiology), IDRA

Etomidate

• Etomidate is an imidazole derivative whose

structure is unlike that of any other anesthetic

• it is ionized and water soluble at acidic pH and

lipid soluble at physiologic pH.

• It is supplied as a 0.2% solution in 35%

propylene glycol.

Preparation

• emulsion preparation with medium chain triglycerides and soya bean oil (Etomidate Lipuro®).

• Ampoules contain 20 mg of etomidate in 10 mL (2 mg mL–1).

• The pH of the propylene glycol solution is 8.1.

Carbon between two nitrogen is imidazole

Pharmacokinetics

• After an induction dose of 0.3 mg/kg, loss of consciousness and recovery will be similarly rapid, as with thiopental and propofol.

• Redistribution – • Hepatic esterases – carboxylic acid to excrete

in the urine • T-half – 3-5 hours • 78 % protein bound

What is special ?

• Etomidate works via GABA A receptors to produce rapid onset of unconsciousness

• No analgesia • No suppression of autonomic reflexes • But myoclonic jerks

• Respiratory depression as thio • Few episodes of apnea + • At the typical induction dose of 0.3 mg/kg, it

has little effect on arterial or venous vascular tone or on cardiac contractility.

• What is the reason ??

• Not known

• Etomidate is a popular choice for induction of anesthesia

in patients compromised by cardiac dysfunction or

hypovolemia

• Hemodynamic stability after induction with etomidate is

superior to that of any alternative method of induction

• Does not release histamine

• Inpatients with atopy a big OK

• Can we use routinely then ??

Side effects

• High incidence of nausea and vomiting • 30 %• Increased observation of myoclonus • 40 %• Pain on injection • 80 %• Emergence phenomena• Routine use ?

Adrenal suppression

• At clinically relevant concentrations, etomidate inhibits

the mitochondrial CYP isozyme (CYP11B) responsible for

catalyzing the 11β-hydroxylation reaction in cortisol

synthesis

• Even a single dose does

• But clinical relevance ?

• Out of common use

• Evolving septic shock ??

• As infusions in coronary case ??

• Etomidate + glucocorticoid ?? Use

• Porphyria ??

• Significant hemolysis may occur in patients with

fragile red cells, for example spherocytosis or post

transfusion, or by interaction with other drugs or

diseases causing hemolysis

Due to propylene glycol

Newer horizons

• Methoxy carbonyl etomidate (MOC-etomidate) and carboetomidate

• Anesthetic action • Hemodynamic stability • Hemolysis -- no • But no adrenal suppression ?? • Future

Ketamine

• Phencyclidine

• Cyclohexamine

• Ketamine

1960

1970

Chemistry • It is a weak base with a pKa of 7.5 and is supplied in solution as the

hydrochloride salt.

• The 3 concentrations available—10 mg/mL, 50 mg/mL, and 100

mg/ml

• Ketamine is compatible in solution with atropine or glycopyrrolate,

with which it is often mixed.

• The commercial preparations of ketamine contain a racemic

mixture of its 2 isomers.

• S ketamine is available in europe

Images taken from the internet for closed academic purpose only

Pharmacokinetics • Within a minute – action • Redistribution • Elimination itself in around 4 hours • Ketamine

– Liver--- – Diazepam competitively inhibits N-demethylation of ketamine,

decreasing its hepatic clearance• Nor ketamine

– Glucuronide metabolites to the kidney

Tolerance may occur in burn patients receiving more than two short-interval exposures to ketamine.

NMDA antagonism

No GABA A

Other mild actions

• σ receptors • Sodium receptors as local anesthetic • Some muscarinic action

Pharmacodynamics

• Ketamine produces dose-dependent CNS depression leading to a

so-called dissociative ( dissociated from surroundings)

anesthetic state characterized by profound analgesia and

amnesia, even though patients may be conscious and maintain

protective reflexes.(catalepsy)

• The proposed mechanism for this cataleptic state includes

• electro physiologic inhibition of thalamocortical pathways

stimulation of the limbic system.

Dosage – hypnotic

• Intravenous dose 1-2 mg /kg – 30 seconds • IM dose 4-8 mg / kg –2 – 4 minutes • Return of consciousness is around 10 – 20 minutes • burn dressing changes, débridements, and skin-

grafting procedures. • The excellent analgesia and ability to maintain

spontaneous ventilation in an airway that might otherwise be altered by burn-scar contractures are important advantages of ketamine in these patients.

Other uses

• Ketamine 0.5 – 1 mg / kg / hour in Refractory status epilepticus

• 2 -4 mg / kg – used in infants • But attenuation of pain and stress response

may not efficient in kids

• Caudal adjuvant 1 mg /kg – apoptosis risk ??

Which is the end point ?

• Loss of eye lash reflex • Apnea • Verbal contact.

• Not clearly defined

Pharmacodynamics

• Opioid tolerance reversed

• it increases CMRO2, CBF, and ICP

• Propofol prior is useful in blunting ICP increase

• No protection against brain ischemia

• EEG -fast β activity (30 to 40 Hz) followed by moderate-

voltage θ activity, mixed with high-voltage δ waves

recurring at 3- to 4-second intervals.

No iso electric EEG –

Cant monitor EEG

RS • Ketamine has well-characterized broncho dilatory activity.-

no ventilatory drive effect

• In the presence of active bronchospasm, ketamine is

considered to be the IV induction agent of choice.

Ketamine has been used in subanesthetic dosages to treat

persistent bronchospasm in the OR and ICU.

• Increase secretions– ( glyco as additive)

• Airway reflexes preserved but -----

• Effective intravenous ketamine anesthesia permits high inspired oxygen concentrations

• Functional residual capacity, minute volume, tidal volume, and the coordinated contribution of intercostal muscle function to inspiration are maintained

CVS • Ketamine has prominent cardiovascular-stimulating

effects secondary to direct stimulation of the

sympathetic nervous system. Ketamine is the only

anesthetic that actually increases peripheral arteriolar

resistance.

• As a result of its vasoconstrictive properties, ketamine

can reduce the magnitude of redistribution hypothermiaHypovolemic ok ---- but no use in

sympathetically exhausted patients

Other clinical pearls

• Rapid Sequence Intubation of the Shock Patient

• In sub hypnotic doses (0.15-0.3 mg/kg), ketamine is

commonly used for monitored anesthesia care.

• It produces profound analgesia without the concurrent

ventilatory depression produced by opioids

• Children

• Anesthetic doses of ketamine increase uterine tone and the intensity of uterine contraction

• We have a case of atonic PPH and hypotension

• The ideal drug would be ??

All routes

• IV • IM

oral • Nasal • Rectal • Epidural • Intra thecal • IVRA • Adjuvant to blocks

• Ketamine is commonly used, either alone or in

combination with midazolam, as an oral medication

in children, especially as the sole agents for

conscious sedation for a short but noxious procedure

• No iv line also is OK

• No pain on injection

Side effects • high incidence of psychomimetic reactions (namely,

hallucinations, nightmares, altered short-term memory, and

cognition) during the early recovery period.

• Usually 10 – 20 %

• The incidence of these reactions is dose-dependent and can

be reduced by co administration of benzodiazepines,

barbiturates, or propofol

• ( upto 75 % described )

Emergence phenomena • Start from one hour after recovery

• One third of adults

• Adults and women higher

• Many times pleasant in children

• Previous psychological problems

• Atropine increases

• Benzodiazepines decrease

• Promethazines

Music makes it pleasant

Eye and MH

• A parallel increase in intraocular pressure may be detrimental in patients with open eye injuries or glaucoma, or during vitreo retinal surgery

• Ketamine has been safely used for patients with malignant hyperthermia and acute intermittent and variegate porphyria.

Heart , TCADs and ketamine

• ketamine can produce adverse effects when

administered in the presence of tricyclic

antidepressants because both drugs inhibit

norepinephrine reuptake and could produce severe

hypotension, heart failure, and/or myocardial

ischemia

Resurgence

• Low doses

• Anesthetic adjuvant • Analgesia • Spinal comfort • Post operative pain reduction • Ketamine is effective in decreasing the incidence of

emergence agitation in children undergoing dental repair under sevoflurane general anesthesia.

Intranasal ketamine• attenuates pain in the emergency room in children and adults.

• also reduces the severity of pain in migraine.

• Wink et al reported a 29-year-old woman with autism who

was treated with intranasal ketamine (20–60 mg) on 12 dosing

occasions across 6 weeks.

• She showed improvements in mood, social interactions,

flexibility, tolerance of changes in routine, motivation, and

concentration.

• Rectal Ketamine, 10 mg/kg, has a delayed onset but is as effective as 1 mg/kg midazolam for sedating healthy children before general anesthesia.

• Anesthesiology. 1992 Jan;76(1):28-33.• Oral ketamine preanesthetic medication in

children- 6 mg / kg

• Long-term ketamine subcutaneous continuous infusion in neuropathic cancer pain. 150 mg / day tapered

• subcutaneous injection of low dose ketamine at the incision site to reduce cesarean section pain.( 0.5 mg / kg )

Epidural PCEA

• A combination of low-dose epidural ketamine and

morphine results in effective postoperative analgesia

and also reduces morphine requirement, thereby

decreasing morphine-related side-effects.

Nerve blocks

• Addition of 2 mg / kg – possible improvement in block characters after supra clavicular nerve blocks

• Ketamine as an adjuvant in sympathetic blocks for management of central sensitization following peripheral nerve injury

IVRA or sublingual or local • 0.5 mg/kg of body weight ketamine to

lignocaine for IVRA improves quality of anesthesia and perioperative analgesia without causing side effects.

• Better than dexmed in a few studies• ------------------------------------------------------• Sublingual ketamine 25 mg for chronic

neuropathic pain • Ketamine ointment for neuropathic pain

Summary

• Etomidate – imidazole • GABA A -0.3 MG/ KG- iv • Thio like • Nausea, myoclonus pain • Hemodynamics • Adrenal suppression

• Phencyclidine • Dissociative , analgesia • Increase cmro2, EEG ? • 1-2 mg/ kg , NMDA ant.• Subanesthetic doses • All routes • Sympathetic stimulation • Bronchospasm , • emergence • IOP, ICP, IHD, HT -- ?? • PPH !!