Presentor Dr.

ShahinTaj
HISTORY
 Wren used intravenous route for the first time in 1656
using goose quill and bladder to inject wine and ale
into dog’s vein

 Hollow needle in 1843

 Hypodermic needle in 1853

 Pierre-Cyprien Oré performed the first successful

attempt at intravenous anesthesia in 1872 by using
chloral hydrate to anesthetize a human subject.
 Intravenous paraldehyde was briefly used as an
anesthetic during and after World War I.

 By 1900 iv anesthetics came into use

 Hedonal an urethane derivative was the first

anesthetic to be used with moderate safety

 Barbiturates a major breakthrough

THE IDEAL I.V. INDUCTION AGENT
PHYSICAL PROPERTIES
 should be water soluble
 stable in solution
 long shelf life
 no pain on I.V. injection
 no sequelae from arterial injection of small dose
 low incidence of venous thrombosis
THE IDEAL IV INDUCTION AGENT
PHARMACOLOGICAL PROPERTIES
 Cause minimal respiratory and cardiac depression
 Decreases the cerebral metabolism and intracranial pressure
 Does not cause histamine release or hypersensitivity reaction
 Cause induction in one arm brain circulation time with quick
and smooth onset.
 Metabolized to pharmacologically inactive metabolites with
short duration of action and quick, smooth and complete
recovery.
 Absence of postoperative nausea and vomiting, psychomimetic
reactions, dizziness, headache, or prolonged sedation
(“hangover”)..
Types of intravenous agents
 Barbiturates (Thiopentone, methohexitone)
 Phenols (Propofol)
 Benzodiazepines (Midazolam)
 Phencyclidine derivatives (Ketamine)
 Imidazoles (Etomidate)
Barbiturates
HISTORY
 Emil Fischer & Von Mering (1903)- synthesized
first barbiturate, di ethyl barbituric acid.
 Helmut Weese & Scharpff (1932)-introduced ultra
short acting Hexobarbitone.
First drug used to make i.v. anaesthesia popular.
 1934: Thiopentone was introduced by Water &
Lundy.
Classification of barbiturates
Long acting
 Phenobarbitone, mephobarbitone.

Short acting
 Butobarbitone, secobarbitone and pentobarbitone.

Ultra short acting

 Thiopentone, methohexitone and hexobarbitone.
PHYSICOCHEMICAL CHARACTERISTICS
 Derivative of Barbituric acid (pyrimidine
nucleus-hypnotically inactive)
 Hypnotic activity- occurs by adding aryl or alkyl
groups at position 5
 Condensation of malonic acid and urea
 O2 at position 2-oxybarbituate and sulphur at
position 2-thiobarbituate
STUCTURE- ACTIVITY RELATIONS
 Substitution at position 5 with aryl and alkyl
groups
 Hypnotic and sedative effects
 An increase in the length of one or both side
chain of an alkyl group
 Hypnotic potency
 A phenyl group substitution at position 5
 Anticonvulsant activity
 Substitution of sulfur at position 2
 A more rapid onset of action
 Substitution of methyl or ethyl group at
position 1
 A more rapid onset of action but with
excitatory side effects.
Formulation of thiopentone
 Yellow amorphous powder
 Stored in Nitrogen to prevent chemical reaction with
atmospheric CO2
 6% anhydrous sodium carbonate to increase solubility in
water
 Reconstitution with water or normal saline yields 2.5%
solution with pH-10.8.
 Refrigerated solution of thiobarbitone- stable for 1 wk & of
methohexitone- stable for 6 wk
 Pharmacokinetics
 80% protein bound with high lipid solubility
 Thiobarbiturate are more highly protein bound than the
oxybarbiturate
 pKa for thiopentone -7.6. aprox. 50% nonionised fraction at
physiological pH.
 Described in physiological compartmental models
 Rapid mixing of drug with central blood volume
 Quick distribution of the drug to the highly perfused,
low volume tissue (brain)
 Slow redistribution to lean tissue (muscle)
Pharmacokinetics(cont..)
 Continuous infusion – delayed recovery because
termination of action is dependent on slower uptake into
adipose tissue and elimination or clearance through
hepatic metabolism(prolonged context sensitive half life)

 Hepatic clearance is low

 Elimination half life- High (thiopentone- 11.6 hrs)

 More in obese patients due to accumulation in fat due to its
high affinity for fat.
METABOLISM
 Hepatic except for phenobarbitone (which is excreted in
urine in unchanged form)
 Metabolite – inactive, water soluble and excreted in urine.
Four processes
 Oxidation of the aryl, alkyl or phenyl moiety at C-5-most
imp. mechanism producing polar alcohol, ketone , phenols
or carboxylic acid which are excreted in urine or in bile as
glucoronic acid conjugates.
 N-dealkylation
 Desulfuration of the thiobarbiturate at C-2
 Destruction of the barbiturate ring
METABOLISM(Cont..)
 Methohexitone- metabolized by oxidation and N- dealkylation

 Methohexitone exhibits similar distribution half lives, VD and

protein bindings with thiopentone

 Marked difference exists in plasma disappearance and

elimination half lives of methohexitone(4hrs v/s 12 hrs for
thiopentone) due to three fold greater rate of hepatic
clearance of methohexitone.
MECHANISM OF ACTION
 Enhancement of the synaptic actions of inhibitory neuro-
transmitters (GABA)
 Blockade of the synaptic action of excitatory
neurotransmitters eg. Glutamate and acetylcholine.
 GABAA receptors
 Chloride ion channel
 Five subunits with specific sites of action for GABA, Barbiturate
benzodiazepines.
 At low concentrations- it enhance the effects of GABA by
decreasing the rate of dissociation of GABA from its
receptor
 At high concentrations- it act as agonist itself by directly
activate chloride channels.
Effects on Central nervous system

 Produce CNS depression attended by loss of

consciousness
 Dose related depression in CMRO2
 Progressive slowing of EEG.
 EEG becomes isoelectric (CMRO2- 50%)
-No further decline in CMRO2 due to basal
cerebral metabolism.
-Only Hypothermia can suppress baseline
metabolic activity.
Effects on Central nervous system
( cont..)
 CBF & ICP.
 Ratio of CBF/ CMRO2 is unchanged.
 Preserve CPP (MAP-ICP).(relative fall in ICP is more)
 At low blood levels- antianalgesic
 Amnesic effect less pronounced than benzodiazepines
ONSET OF CNS EFFECTS
Max. brain uptake-30 seconds. It depends on
 Plasma concentration of drug
- Dose and rate of administration.

 Crossing the blood brain barrier

-Degree of lipid solubility, ionization, level of protein
binding & plasma drug concentration

 Acidosis -leads to more nonionized drug ( dose)

TERMINATION OF EFFECTS
 As plasma level decrease brain level also decrease.
 Single dose
-termination depends on rapid redistribution phase -
not metabolism.
-patient is awake after 5-10min(thiopentone)
 Multiple dose or infusion
 Termination depend on metabolism.
 Rate of total-body clearance – higher with methohexitone
 Lead to better early performance of psychomotor skills.
Respiratory system
• Dose dependent resp. depression –Respiratory rate is not reduced
but depth of ventilation is reduced (Apnea 20% , transient < 25 sec.)
• Double Apnea: initial apnea lasting few sec., followed by few breaths
of adequate tidal volume , then followed by lengthier apnoeic period.
• Decreased response of ventilation to hypercapnia or
hypoxia.
• Bronchospasm can occur – mainly due to manipulation in
lighter plane of anaesthesia.
Cause - Histamine release, Direct bronchial smooth
muscle stimulation
• Laryngeal and cough reflexes are not depressed adequately
Cardiovascular system
• Decrease in cardiac output due to
Diminished contractility of heart
Peripheral vasodialation
Transient decrease in symph. outflow from CNS.
• Increase in Heart Rate(10- 36 % ↑).
Baroreceptor reflex remains intact .
• MAP maintained or slightly reduced.
• In CAD patients – increase in heart rate is potentially
deleterious due to increase in myocardial oxygen
consumption.
• It leads to reduced myocardial flow in pts. with narrowed
coronaries. Dangerous in low fixed c.o states like tight
valvular stenosis , complete heart block
Hepatic System
HBF is decreased
Induction of hepatic enzymes
Induction of Aminolevolinic Acid Synthetase- leads to
porphyrin synthesis-can precipitate AIP or variegate
porphyria.
Pregnant Uterus
It crosses placental barrier. conc. in foetal blood is
maximum in 45s & it remains for 5min.
No effect on uterine tone
Kidney
Reduces renal blood flow,
Increases secretion of ADH
USES

 Premedication - Rectal administration in children as

premedication (25-40 mg/kg) – induces sleep.

 Induction and maintenance of anaesthesia

 Methohexitone is superior to thiopental for maintenance

(cleared more rapidly).

 Cerebral protection in patients at risk of developing

incomplete ischemia.
DOSING
 Thiopentone
 Induction dose 3-5 mg/kg(ED50 - 2.2-2.7mg/kg).
 Maintenance 50-100 mg every 10-12 minutes.
 Anticonvulsant 0.5mg/kg i.v.
 Reduction of ICP 1-4 mg/kg
 Methohexitone
 Induction dose 1-2mg(ED50 -1.1mg/kg).
 Maintenance dose 20-40 mg every 4-7 minutes.
SIDE EFFECTS
 Garlic and onion taste(40%)
 Allergic reactions
 Urticarial rash to more severe reaction
 Bronchospasm
 Anaphylaxis
 Mechanism- Sulphur contaning thiobarbiturates- histamine
release- mast cells.
 Excitatory symptoms (> methohexital)
 Cough, hiccups, tremors, twitching
 Pain on injection (> methohexital)
 Phlebitis(5% solution)
 Intra arterial injection
Contraindications
 Absolute-acute intermittent porphyria
 Relative- shocked, debilitated anaemic patients,
Patients with respiratory obstruction,
Asthma,
Hepatic dysfunction,
Fixed low C.O. states.
PROPOFOL

HISTORY
 Work in the early 1970s on substituted
derivatives of phenol with hypnotic
properties resulted in the development of
2,6-diisopropyl phenol
 The first clinical trial was by Kay and Rolly
in 1977
 Insoluble in water and was initially
prepared with Cremophor EL
 Reformulated in emulsion
STRUCTURE OF PROPOFOL
2-6-DI ISO PROPYL PHENOL
PHYSICO-CHEMICAL CHARACTERISTIC
 Alkyl phenols
It Contains
 Propofol 1%,
 10% soybean oil- oil base
 2.25%glycerol
 1.2% purified egg phosphotide – emulsifying agent.
 Disodium edatate(0.005%)- retards bacterial growth.
 pH-7- 8.5, slightly viscous, milky white solution
 Compatible with 5% dextrose in water
Generic prepration uses sodium metabisulfite (0.25 mg/ml ) as
preservative and has a lower pH  4.5 - 6.4

Ampofol
 A low lipid emulsion of propofol which contains
 5% soybean oil
 0.6% egg lecithin
 It doesn't need a preservative or microbial growth
retardant.
 Associated with higher incidence of pain on injection.
 Equipotent to diprivan.
Aquavan(Fospropofol)
 Alternative to emulsion formulation , it is phosphorylated
prodrug prepared to reduce associated side effects (pain on
injection, risk of infection, hypertriglyceridemia)
 Phosphate monoesters or hemisuccinate groups are added to
the parent compound to increase its water solubility
 Propofol is liberated after hydrolysis by endothelial cell
surface alkaline phosphatase
 Compared with propofol ,this prodrug has a large volume of
distribution, prolonged effect and higher potency.
 1mg of fospropofol= 0.54 mg of propofol.
PHARMACOKINETICS
Elimination half time(hours) 0.5-1.5

Volume of distribution(l/kg) 3.5-4.5

Clearance(ml/kg/min) 30-60

Context sensitive half time For an infusion upto 8 hrs is 40

mins
Metabolism Hepatic – cytochrome P450
ring hydroxylation

Extrahepatic-kidney
lung
CONTEXT SENSITIVE HALF TIME
 Rapid clearance accounts for more complete recovery
and less hangover compared to thiopental.

 Single bolus dose : wake – up time usually with in 8 to 10

mins

 Continuous intravenous infusion:

Rapid metabolism coupled with efficient plasma
clearance and
slow redistribution from poorly perfused compartments
to
central compartment makes it suitable for infusion
METABOLISM

 Rapidly metabolized by conjugation to glucuronide and sulfate

 < 1% excreted unchanged in urine and only 2% excreted in
feces.
 metabolite are inactive
 Clearance exceeds H.B.F due to extra hepatic elimination
(lungs: 20-30% uptake and first pass elimination)
EFFECT ON CNS
Hypnotic and Sedative.
 Potentiate the GABA induced chloride current through
binding to beta subunit of the GABAA receptor.
 Inhibition of acetylcholine release in hippocampus
prefrontal cortex.
 Inhibition of NMDA subtype of glutamate receptors.

Antiemetic
serotonin level in the area postrema.
Sense of well being
dopamine concentration in the nucleus accumbens
 Onset of hypnosis
 One arm brain circulation time
 Peak effect: 80-100 sec.
 Duration: 5 to 10min
 Induction dose: with increasing age
 At subhypnotic doses: sedation and amnesia
 Propofol infusion
-should be at least 2mg/kg/hr to provide amnesia
-Extremely higher rate are required to prevent
awareness during surgical procedures.
INTRACRANIAL PRESSURE
 ICP in normal and with elevated ICP patients. It also
decrease cerebral blood flow and CMRO2
 Cerebral autoregulation is maintained
INTRA OCCULAR PRESSURE
Larger in IOP( 30-40%) and more effective in preventing a
rise in IOP secondary to scoline and endotracheal intubation
than thiopentone.
NEUROPROTECTIVE EFFECTS - Controversial
EFFECTS ON RESPIRATORY SYSTEM
 Initially reduction in tidal volume with tachypnea followed by
Apnea(25-30% incidence)
 Incidence and duration depends on dose, speed of injection
and premedication(eg opiates)
 Duration of apnea lasting>30 sec. is more common as
compared to other i.v.agents.
 Depresses the ventilatory response to hypercarbia and
hypoxia.
 Induces brochodilation: COPD patients
 Direct action on muscarinic receptors.
 Attenuates the magnitude of H.P.V
 Does not alter basal pulmonary vascular tone and flow
EFFECT ON CVS
 Decrease in Arterial BP (25-40%)
-due to vasodilation ( sympathetic activity, effect on
calcium mobilization in smooth muscle, decreased
prostacyclin synthesis in endothelial cells, stimulation of nitric
oxide)
and direct myocardial depression.
Fall in BP depends on dose and plasma concentrations
 Heart Rate- does not change significantly because it resets or
inhibits the baroreflex.
 It decreases sympathetic tone in greater proportion than
parasym. tone resulting in a predominance of parasym.
activity.
 Heart rate responses to IV administration of atropine are
attenuated in pt. receiving propofol compared to awake pt.
 Minimal direct effect on SA ,AV node and accessory
pathway conduction.
 It cause significant reduction in myocardial blood flow and
myocardial consumption thus, global oxygen supply and
demand ratio is maintained.
OTHER EFFECTS
 Does not alter hepatic , haematologic or fibrinolytic
function Hovever lipid emulsion per se reduces in vitro
platelet aggregation.
 Antiemetic – at low doses.
 Antipruritic- at subhypnotic doses.
 Excretion of green urine, reflecting the presence of phenols
USES
 Induction and maintenance of anaesthesia
 It cause quicker recovery and early return of psychomotor function
than barbiturate
 Agent of choice for day care surgery.
 Sedation
 during surgical procedures.
 In ICU. Advantage- antioxidant properties
-Rapid recovery after termination of infusion.
Disadvantage-altered hemodynamic effects
-need of analgesic
-hypertriglyceridemia
- propofol infusion syndrome
so, maintain with lowest possible dose with sedation holidays.
• Antiemetic.
Doses
 Induction of GA- 1-2.5 mg/kg I.V.
 Maintainance of GA- 50- 150μg/kg/min combined with
nitrous oxide or an opiate.
 Sedation- 25-75 μg/kg/min
 Antiemetic- 10-20 mg I.V. can be repeated every 5- 10 min
or start infusion at 10 μg/kg/min
SIDE EFFECTS
 Pain on injection
Can be reduced by using a large vein, avoiding veins of
dorsum of the hand, adding lignocaine to propofol solution ,
changing propofol formulation.
Other drugs and distraction techniques like pretreatment with
small dose of propofol, opiates , NSAIDS, Ketamine, esmolol,
metoprolol, magnesium, dexamethasone, metoclopramide
have been used with variable efficacy.
 Mycolonus
etomidate>propofol>thiopentone
 Apnea
 Hypotension
 Thrombophlebitis, anaphylactoid reactions.
 Hypertriglyceridemia-pacreatitis.
Propofol infusion syndrome

 rare but lethal syndrome associated with infusion of propofol

at 4 mg/kg/hr or more for 48 hours or longer.

 The clinical features are acute refractory bradycardia leading

to asystole, in the presence of one or more of the following:
metabolic acidosis (base deficit >10 mmol/L-1),
rhabdomyolysis,
hyperlipidemia,
enlarged or fatty liver.
 Other features include cardiomyopathy with acute cardiac
failure, skeletal myopathy, hyperkalemia, hepatomegaly, and
lipemia.
 Pathogenesis-Various theories include mitochondrial toxicity,
mitochondrial defects, impaired tissue oxygenation, and
carbohydrate deficiency.
 The major risk factors
poor oxygen delivery,
sepsis,
serious cerebral injury,
high propofol dosage.
In some cases, an increasing lipemia was the first indication of
impending propofol infusion syndrome ,so it should not be
viewed as a benign sign
BENZODIAZEPINES
HISTORY
 1959; Diazepam was synthesized, described for
intravenous anesthetic induction in 1965
 1961; Oxazepam, a diazepam metabolite was synthesized
 1971; Lorazepam was synthesized
 1976; synthesis of midazolam ,the first clinically used
water-soluble benzodiazepine, produced primarily for use
in anesthesia.
 1971; benzodiazepine receptor were postulated by
Barnett and Fiore
 1977; specific benzodiazepine receptors were described
BENZODIAZEPINES
The term “BENZODIAZEPINE” refers to the portion of the chemical
structure composed of a benzene ring fused to a seven member
diazepine ring.

Three commonly used benzodiazepine in anesthesia are:

midazolam, diazepam, and lorazepam
PHYSICO-CHEMICAL CHARACTERISTICS

 All molecules are relatively small and lipid soluble at

physiological pH.
 They are highly lipophilic.
 Rapid CNS effects and large VD

 Midazolam
 Is most lipid soluble of all benzodiazipines in vivo
 Water soluble when formulated in a buffered acidic
medium (pH 3.5)
 Imidazole ring- accounts for its stability in solution and
rapid metabolism
PHARMACOKINETICS
 According to their metabolism and plasma clearance they are
divided into short lasting (midazolam), intermediate lasting
(lorazepam) and long lasting (Diazepam)
 Midazolam (and diazepam) have a more rapid onset of
action (usually within 30 to 60 seconds) than lorazepam
(60 to 120 seconds) due to higher lipid solubility
 Hepatic clearance of midazolam is 5 times >than Lorazepam
and 10times > than Diazepam as the imidazole ring of
midazolam is oxidized much more rapidly than the methylene
group of the others.
PHARMACOKINETICS (cont..)
 Termination of action- redistribution from CNS to other
tissues.
 The short duration of action of midazolam is due to rapid
lipid solubility, leading to rapid redistribution from brain
to inactive tissues and rapid hepatic clearance
 The t1/2 of midazolam is 1-4 hrs.
 T½ of lorazepam is 10-20 hrs and that of diazepam is 21-
27 hrs
Metabolism
 In liver
1)hepatic microsomal oxidation ( N-dealkylation or aliphatic
hyroxylation)
2)glucoronide conjugation
 midazolam undergoes extensive hydroxylation by hepatic
microsomal oxidative mechanisms (cyt P-4503A) to form 1 and
4 hydroxymidazolam which are pharmacologically active (20-
30%) and can accumulate if infused for longer time.
 Rapid oxidation accounts for the greater hepatic clearance of
midazolam than diazepam
 They are excreted largely by the kidneys as glucuronide
conjugates and can cause profound sedation in patients with
renal impairment
PHARMACOLOGICAL EFFECTS
 Hypnotic, sedative, anxiolytic, amnesia, anticonvulsant and
centrally produced muscle relaxant properties.
 Anxiolysis effect: 20% receptor occupancy
 sedation : 30-50% receptor occupancy
 unconsciousness:60% or higher receptor occupancy
 Occupies BDZ site on GABAa receptor that modulate GABA
mediated chloride channels.
 Sedation, anterograde amnesia and anticonvulsant: α1-
receptor
 Anxiolysis and muscle relaxation: α2 receptor
 Receptor affinity: lorazepam >midazolam> diazepam
 GABAA Receptor
 Transmembrane pentamer
composed of 2 , 2 , and 1  or
 subunits
 Each has a binding site for
GABA
 Benzodiazepines
 Bind a cleft of  and  subunits
 Increases frequency of channel
opening
 Barbiturates, propofol
 Bind  subunit
 Increase duration of channel
opening
 Barbiturates also have GABA
mimetic action at higher doses
EFFECTS ON CNS
 Reduce CMRO2 and CBF in a dose-related manner with a
relatively normal CBF/CMRO2 ratio
 Cerebral vasomotor responsiveness to carbon dioxide is
preserved during midazolam anesthesia.
 It does not prevent increases in ICP associated with
laryngoscopy and intubation.
 It is a potent anticonvulsant used in the treatment of status
epilepticus and increases the seizure initiation threshold of
local anesthetics
 Midazolam (> diazepam) have a dose-related protective
effect against cerebral hypoxia.
EFFECTS ON THE RESPIRATORY SYSTEM
 It produces dose dependent central respiratory system
depression
 Patients with COPD more susceptible
 Transient apnoea may occur after rapid injection of large doses
of midazolam(>0.15mg/kgIV). Peak onset of ventilatory
depression is about 3 mins and significant depression remains
for about 60-120mins
 Benzodiazepines and opioids produce additive or supra-
additive (synergistic) respiratory depression
 BZDs may depress upper airway activity and also the
swallowing reflex.
EFFECT ON C V SYSTEM
 The predominant hemodynamic change is a slight
reduction in arterial BP that results from a ↓ in SVR,
which is dose dependent.
 Despite this, midazolam is safe and effective for induction
of anesthesia even in patients with severe aortic stenosis.
 Midazolam with fentanyl or sufentanil produce a greater
↓ in BP than each drug does alone
 It does not prevent BP and HR responses evoked by
intubation.
USES
 Intravenous sedation: It has rapid onset of action with in 2-3
minutes
 As premedication
 Intraoperative sedation
 Regional or LA provides reliable amnesia
 Postoperative sedation
 Oral sedation
 Diazepam: 5-10mg in adults
 Midazolam: 0.5mg/kg in children
strawberry flavoured preparation is available which
provides reliable amnesia with in 10 minutes
USES( cont..)

INDUCTION AND MAINTENANCE OF ANAESTHESIA

 Midazolam is the drug of choice of all benzodiazepines due to
faster onset and lack of various complications
 Onset is less rapid than with thiopentone
 Amnesia is more reliable
 Rapidity of onset depends on dose, speed of injection, degree
of premedication, age, ASA status and concurrent anaesthetic
drugs
 Lacks analgesic properties and must be used with another
drug to provide sufficient analgesia.
Doses
SIDE EFFECTS AND CONTRA-INDICATIONS
 Safe drugs with relatively high margin of safety.
Lorazepam and diazepam can cause venous irritation
and thrombophlebitis
 Undesirable degree of post operative amnesia,
sedation and respiratory depression can occur.
 can be reversed with flumazenil.
FLUMAZENIL
 Competitive antagonist

 It is very specific to BZD receptor

 Acts in a dose dependent manner

 Metabolism: hepatic microsomal enzymes

 Dose: 0.2 mg (8-15 ug/kg) reverses effect in 2 min

 Further doses can be administered @ 60 sec
intervals

 Duration of action: 30-60 min

 No pharmacological drug interactions noted

CLINICAL USE
 A slow intravenous injection of flumazenil can be
used to reverse the benzodiazepine induced
sedation as well as to diagnose or treat
benzodiazepine overdose.
INITIAL DOSE 0.2MG

FURTHER DOSE 0.1-0.2MG(30-60

SEC)
MAXIMUM DOSE 1MG

INFUSION 0.1-0.4MG
PHENCYCLIDINE DERIVATIVES
(KETAMINE)
HISTORY
 1958,59; Phencyclidine was the first drug of its class used for
anesthesia. It produced unacceptably high adverse psychological
effects
 1959; Cyclohexamine, a congener of phencyclidine, was tried
clinically
 1962; Ketamine was synthesized by stevans
 1965 ; First used in humans by corssen and domino.
 1970; Ketamine was released for clinical use
PHYSICO-CHEMICAL PROPERTIES
 It is partially water soluble and supplied as an aqueous soln in
several concentrations (10, 50, and 100-mg /ml of NaCl soln
containing the preservative benzethonium chloride) and
formulated as a weak acid (pH 3.5 - 5.5).
 5 to 10 times more lipid soluble than thiopental.
 Ketamine occurs as two resolvable optical isomers or
enantiomers [S(+) and R(-)]. The racemic mixture of the two
stereo-isomers is the most frequently used clinically though
the S(+) form is commercially available.
S(+) KETAMINE
 More intense analgesia (2 times of racemic ketamine and 4
times R(-) ketamine)
 More rapid metabolism and recovery
 Less salivation
 Lower incidence of emergence delirium

Ketamine isomers induce less fatigue and cognitive

impairment than equianalgesic doses of the racemic form.
PHARMACOKINETICS
 It has rapid onset of action of 1min after IV and 5min after IM
dose. Duration of anesthesia after single dose is 10-15 min.
and full orientation occurs in 15-30 minutes.
 Highly lipid soluble drug
 Rapid distribution half life (11 to 16 min)
 Elimination half life: 2.5-2.8 hrs.
 High clearance rate of 12-17ml/kg/min
 Total body clearance: equal to HBF.
METABOLISM
 Metabolized by hepatic microsomal enzymes

 Major pathway is N-demethylation by cytochrome P-450

to norketamine (metabolite I), which is then hydroxylated
to hydroxynorketamine and excreted in urine as water-
soluble glucuronide derivatives.

 Norketamine has 20% - 30% activity of ketamine.

 MECHANISM OF ACTION
 The primary site of CNS action is the THALAMONEOCORTICAL
projection system. It depresses cortex and thalamus while
simultaneously stimulating parts of limbic system, thus creates
functional disorganization or dissociative anesthesia.
 Ketamine inhibits activation of NMDA receptors by glutamate, ↓
its presynaptic release, and also potentiates the effects of the
inhibitory neurotransmitter, GABA. This may mediate general
anesthetic effects as well as some analgesic action.
 Ketamine may also have agonist action on μ receptors.
 Inhibition of dorsal horn of spinal cord may be another
mechanism for its analgesic effect.
 CENTRAL NERVOUS SYSTEM EFFECTS
 Potent cerebral vasodilator capable of increasing CBF by 60% and
also increases ICP, in the presence of normocapnia. It also
increases CMRO2 though less than CBF.
 Cerebrovascular responsiveness to CO2 appears to be preserved
with ketamine.
 Leads to dose related unconsciousness and analgesia.
 Ketamine administration causes a cataleptic state with intense
analgesia but eyes are left open. Pupils dilate moderately and
nystagmus also occurs.
 Patients have no recall of surgery or anesthesia, but amnesia is not
as prominent as with benzodiazepines.
 CENTRAL NERVOUS SYSTEM EFFECTS (cont..)

 Lacrimation and salivation are common

 Skeletal muscle tone is increased , often with coordinated but

seemingly purposeless movement of the arms, legs, trunk, and
head.

 Corneal, cough and swallowing reflexes are present but may not
be protective.
EMERGENCE DELIRIUM
 Undesirable psychological reactions during awakening from
anesthesia in patients who receive ketamine as a sole or major
part of the anesthetic technique
 Incidence range of 10% - 30% of adult patients
 Common manifestations are vivid dreaming, hallucination
(visual, auditory and proprioceptive), transient cortical
blindness, extracorporeal experiences (sense of floating out of
one's body), and illusions (misinterpretation of a real, external
sensory experience)
 Often associated with excitement, confusion, euphoria, and
fear.
EMERGENCE DELIRIUM ( cont..)
 Occur in the first hour of emergence and usually abate within
1 to several hours. Decreased incidence seen with repeated
anesthesia.
 Factors affecting the incidence of emergence reactions are;
1) age (>15yrs),
2) dose( >2mg/kg and if rapidly administered),
3) gender (F>M),
4) a history of psychological problems or frequent dreaming.
 The benzodiazepines esp. midazolam is the most effective
drugs for attenuation or treatment
EFFECTS ON RESPIRATORY SYSTEM
 Minimal effects on central respiratory derive
 Transient in MV after bolus administration can occur.
 Apnea is seldomly seen
 It is a bronchial smooth muscle relaxant
 Mechanism-Sympathomimetic response
 As effective as halothane or enflurane
 salivation in children- can lead to upper airway
obstruction, larygospasm & silent aspiration.
 EFFECTS ON THE CVS
 ↑ HR, BP, CO, myocardial O2 demand and catecholamine levels
by a generalized increase in CNS sympathetic activity.

 Direct myocardial depression counteracts the increased

sympathetic activity and may leave stroke volume unaffected.

 The direct myocardial depressant effects of ketamine (large

doses) are unmasked by sympathetic blockade or in patients
who are catecholamine depleted (as in patients with
hypovolemic shock of long duration)
 USES
 Induction and maintenance of anaesthesia
 In bronchospastic airway disease
 Haemodynamically compromised patients
 Septic shock,
 cardiomyopathies
 Cardiac temponade, restrictive pericarditis
 CHD: Rt to Lt shunt
Can be Combined with propofol for TIVA.
 Maintain stable hemodynamics and cause minimal
ventilatory depression
 USES (cont..)
Sedation For paediatric patient- has fewer emergence reactions
 Cardiac catheterization
 radiation therapy,
 dressing changes
 dental work.

Supplement or adjunct to RA.

Prevention and treatment of opiate tolerance and hyperalgesia.
Useful in chronic pain states like cancer pain , neuropathic pain
 DOSES OF KETAMINE
 Induction of General Anesthesia
0.5–2 mg/kg IV or 4–8 mg/kg IM
 Maintenance of General Anesthesia
15–45 µg/kg/min IV with 50%–70% N2O in O2
30–90 µg/kg/min IV without N2 O
 Sedation and Analgesia
0.2–0.8 mg/kg IV over 2–3 min
2–4 mg/kg IM
 Preemptive/Preventive Analgesia
0.15–0.25 mg/kg IV
CONTRA INDICATIONS
 Patients with ICP & with intracranial mass lesion
 Open eye injury
 IHD, vascular aneurysms
 Schizophrenia or a h/o adverse reaction to ketamine.
 When there is a possibility of postop delirium from other
causes e.g., delirium tremens
 ETOMIDATE
 Synthesized in 1971.
 A carboxylated imidazole
 Exists as 2 isomers, only the R(+)isomer is active as
hypnotic.
 It is water insoluble and unstable in a neutral solution.
It is supplied as a 2-mg/mL propylene glycol solution
with a pH of 6.9.
 A new lipid emulsion solution is also available.
PHARMACOKINETICS
 Protein binding- 75%.
 Three compartment model
Initial distribution half life of 2.7min
A redistribution half life of 29min
An elimination half life 2.9-5.3 hrs
 Redistribution is the mechanism whereby the effect of a
bolus of etomidate is dissipated.
 Hepatic clearance- very high(18-25ml/kg/min).
 VDss 2.5 to 4.5 L/kg
 The relatively short elimination half-life and the rapid
clearance of etomidate make it suitable for administration
in multiple doses, or in a continuous infusions
 METABOLISM
 Metabolized in liver primarily by ester hydrolysis to the
corresponding carboxylic acid of etomidate (major metabolite)
or by N-dealkylation.

 The main metabolite is inactive.

 Only 2% of the drug is excreted unchanged, the rest being

excreted as metabolites by the kidney (85%) and in bile (13%)
 EFFECTS ON THE CNS
 The primary action of etomidate on the CNS is hypnosis, which
is achieved in one arm-brain circulation after a normal
induction dose. The mechanism of action is similar to
propofol. It mimics the inhibitory effects of GABA. β2,β3
subunits of GABA receptor are more imp. for its action than α
subunit.
 It reduces CBF (by 34%) and CMRO2 (by 45%) without altering
MAP.
 CPP is maintained or↑, and there is a beneficial net ↑ in the
cerebral O2 supply-demand ratio.
 Myoclonus- due to activity either in brain stem or in deep
cerebral structures.
 EFFECTS ON THE CVS
 Minimal effect on CVS due to its unique lack of effect on both
the sympathetic nervous system and baroreceptor function, sets
it apart from other rapid-onset induction agents even in large
doses and in patients with impaired left ventricular function or
valvular disease
 After induction and infusion it produces a 50% decrease in
myocardial blood flow and O2 consumption and a 20% to 30%
increase in coronary sinus blood oxygen saturation.
 Myocardial oxygen demand supply ratio is well maintained.
 Etomidate lacks analgesic efficacy, may not totally ablate the
sympathetic response to laryngoscopy and intubation.
 EFFECTS ON THE RESPIRATORY SYSTEM
 It has less effect on ventilation than other indution agents.

 The ventilatory response to CO2 is depressed minimally.

Induction produces a brief period of hyperventilation
followed by a similarly brief period of apnea.

 Hiccups or coughing may accompany induction.

ENDOCRINE EFFECTS

 Induction doses of etomidate transiently inhibit enzymes

involved in cortisol and aldosterone synthesis. It is dose
dependent and reversible inhibition.
 It inhibits 11-β-hydroxylase and to a minor extent 17 α
hydroxylase ,which results in inhibition of corticosteroid
and mineralocorticoid synthesis.
 The suppression of steroid synthesis (part of the stress
response to surgery) lasts for 3-6 hr after a single dose, but
it is only of clinical significance when infusion is used.
 It is no longer licensed for use by infusion.
Pathway for the biosynthesis of cortisol and aldosterone.
The sites at which etomidate affects cortisol-aldosterone
synthesis by its action on 11β-hydroxylase (major site)
and 17α-hydroxylase (minor site) are illustrated
 USES AND DOSES OF ETOMIDATE
INDUCTION OF GENERAL ANESTHESIA
 Useful in sick and shocked patient
 Due to CV stability and rapid recovery
0.2–0.6 mg/kg IV
IV MAINTENANCE OF GENERAL ANESTHESIA
10 µg/kg/min IV with N2 O and an opiate
SEDATION
5–10 µg/kg/min IV

(Prolonged periods of sedation are contraindicated because of

inhibition of corticosteroid synthesis by Etomidate)
 Side effects
 Nausea and vomiting 30-40% incidence
 Pain on injection similar incidence with propofol.
Lipid formulation has much lower incidence of pain on
injection,thrombophlebitis, and histamine release.
 Myoclonus.
Can be reduced by premedication with midazolam
0.015mg/kg 90 seconds before injection.
 Hiccups
 It enhances the NM blockade of NDMRs.
 Propylene glycol toxicity.
Comparative Pharmacologic Effects of IV Agents

Propofol Thiopental Etomidate Ketamine

Systemic BP ↓↓ ↓ ↔ or ↓ ↑

Heart Rate ↔ or ↓ ↑ ↔ or ↓ ↑

SVR ↓ ↓ ↔ or ↓ ↑

CMRO2 ↓ ↓ ↓ ↑

ICP ↓ ↓ ↓ ↑

CPP ↓ ↓ or ↔ 0 ↑

Respiratory Yes Yes Yes No

Depression
Comparative Pharmacologic Effects of IV Agents contd.

Propofol Thiopentone Etomidate Ketamine

Analgesia No No No Yes
Emergence No No No Yes
Delirium
Nausea/ ↓ ↔ ↑ ↔
Vomiting
Adrenocortical No No Yes No
Suppression
RECENT ADVANCES
 Target-controlled infusion of propofol
 Introduction of prefilled and ‘tagged’ propofol syringes
and commercial equipment led to the rapid
popularization of target-controlled infusion (TCI) in
most parts of the world
 The use of target-controlled infusion (TCI) has been
extended to include paediatric anaesthesia and
sedation
 Application of TCI to remifentanil is now licensed
 Closed loop anaesthesia with propofol
 Using derivatives of the electroencephalogram (EEG)
as a measure of hypnotic effect and a model of drug
distribution, it is possible to use feedback control to
alter the rate of propofol administration and maintain
a constant level of sedation or anaesthesia.
 The availability of stereoisomer ketamine and
improved understanding of its pharmacology have
increased non-anaesthetic use of ketamine as an
adjunct analgesic.
 It may be useful in subhypnotic doses for postsurgical
patients with pain refractory to morphine
administration .
 Remifentanil is now well established for maintenance
of anaesthesia, with a number of trials illustrating its
safety and efficacy.
 Nevertheless, the high price of remifentanil and its
rapid elimination have, in practice, restricted its use to
procedures where intense peroperative opioid effect
(and associated haemodynamic stability) may be
combined with mild or moderate postoperative pain.
REFERENCES
 STOELTING PHARMACOLOGY:5TH EDITION
 MILLERS:8TH EDITION
 BARASCH:7TH EDITION
 MODERN ANESTHETICS:HANDBOOK OF
EXPERIMENTAL PHARMACOLOGY