Intravenous

induction agents
Dr Sumanth Reddy
Assistant professor in Anesthesiology
SDUAHER, Kolar
 What are i.v induction drugs?
 Drugs, when given intravenously in an appropriate dose, cause rapid loss of
consciousness.
 Rapid onset : Often described as occurring within “ ONE ARM-BRAIN
CIRCULATION TIME”
 The time taken for the drug to travel from the site of injection (usually the arm)
to the brain, where they have their effect.
 History
 HEXOBARBITAL : The first ultra short acting barbiturate
The first successful i.v anesthetic
Introduced by Weese in Germany in 1932.
 THIOPENTAL : Introduced in 1935 by Lundy in Minnesota &
Waters in Wisconsin.
 Thiopental – widely accepted because of lack of excitatory myoclonic
movements seen with hexobarbitone
( contd.. )
 History
 PROPOFOL – launched in 1986 under the brand name DIPRIVAN
 KETAMINE – was first synthesized in 1962 by Calvin Stevens
First human use was in 1969.
 METHOHEXITAL - a shorter-acting barbiturate with central nervous system-
stimulating properties, was introduced in 1956 for
electroconvulsive therapy (ECT).
 USES of Intravenous anesthetics
 Induction and maintenance of anesthesia
 As a sole anesthetic for short procedures
 Intravenous infusion- to maintain anesthesia for longer procedures
e.g. TIVA ( Total intravenous anesthesia)
 To provide sedation in places like ICU
From induction to wake up: what happens to a
bolus of IV induction drug?
Bolus of i.v induction agent enters blood stream

A percentage of drug is bound to plasma proteins & the rest is UNBOUND

(protein binding depends on lipid solubility & degree of ionization)

The drug is carried in the Venous blood to the right side of the heart

( contd.. )
 Drug reaches Left side of the heart through pulmonary circulation

Systemic circulation

High proportion of initial bolus is delivered to CEREBRAL CIRCULATION

( as majority of cardiac output is diverted to brain, liver & kidney- VRG )

( contd.. )
The drug then passes along a concentration gradient from the blood into the
brain.
The rate of this transfer is dependent on a number of factors:
• the arterial concentration of the unbound free drug
• the lipid solubility of the drug
• the degree of ionization.
Unbound, lipid soluble, unionized molecules cross the blood brain barrier the
quickest.
( contd.. )
 Drug starts exerting its effect once it penetrates CNS tissue

Each drug acts at a specific receptor (e.g GABA-A, NMDA and Ach receptors)

The drug then starts to diffuse in to other tissues that do not have such a rich
blood supply ( e.g Skeletal muscle)

( contd.. )
This secondary tissue uptake, causes the plasma concentration to fall, allowing
drug to diffuse out of the CNS down the resulting reverse concentration gradient

This initial REDISTRIBUTION - leads to the rapid wake up seen after a single
dose of an induction drug

Metabolism and plasma clearance have a much less important role following a
single bolus, but are more important following infusions and repeat doses of a
drug.
Drug distribution in various tissues against time following an i.v bolus of thiopental
How is this different in states of reduced
cardiac output?
 When cardiac output is reduced ( Shock, Elderly) the body compensates by
diverting an increased proportion of the cardiac output to the cerebral circulation,
as preservation of cerebral blood flow in these situations is important.
 A greater proportion of any given drug will enter the cerebral circulation
 As a result, the dose of induction drug must always be reduced.

 Since global cardiac output is reduced, the time taken for an induction drug to
reach the brain and exert its effect is prolonged

 Key to SAFE INDUCTION : SLOW titration of a REDUCED dose of drug

Properties of an IDEAL induction agent
Physical properties
• Water soluble & stable in solution
• Stable on exposure to light
• Long shelf life
• No pain on intravenous injection
• Painful when injected into an artery
• Non-irritant when injected subcutaneously
• Low incidence of thrombophlebitis
• Cheap ( contd.. )
Properties of an IDEAL induction agent

Pharmacokinetic properties
• Rapid onset in one arm-brain circulation time
• Rapid redistribution to vessel rich tissue
• Rapid clearance and metabolism
• No active metabolites

( contd.. )
Properties of an IDEAL induction agent
Pharmacodynamic properties
• High therapeutic ratio ( ratio of toxic dose : minimally effective dose )
• Minimal cardiovascular and respiratory effects
• No histamine release/hypersensitivity reactions
• No emetic effects
• No involuntary movements
• No emergence nightmares
• No hang over effect
• No adrenocortical suppression
• Safe to use in porphyria
 Classification
The commonest drugs currently in use can be classified according to their
chemical structure and include:
 Barbiturates – THIOPENTAL, METHOHEXITAL
 Phenols - PROPOFOL
 Imidazoles - ETOMIDATE
 Phencyclidines - KETAMINE
 Benzodiazepines – MIDAZOLAM, DIAZEPAM, LORAZEPAM
 Classification
They can also be classified based on the onset of their action as :
 Rapidly acting ( within one arm brain circulation time)
Thiopentone
Propofol
Etomidate
 Slow acting (those that take longer than one arm-brain circulation time)
Ketamine
Midazolam
 PROPOFOL
 2,6 Di isopropyl phenol
 1 or 2% aqueous emulsion (tiny fat droplets
in suspension, hence the white colour)
 Highly lipid soluble
 Contains 10% Soybean oil,
1.2% Egg Lecithin and
2.25% Glycerol ( an osmotic agent)
 PROPOFOL
 The emulsion is an excellent medium for bacterial growth
 EDTA or Sodium Benzoate are added to impede bacterial growth
 Propofol causes pain on injection
 PROPOFOL LIPURO – preparation of propofol containing both long &
medium chain triglycerides in 1:1 ratio. Reduces pain on injection
 FOSPROPOFOL- A water soluble methylphopshorylated prodrug of propofol
No Pain on injection
But slow onset of action
 PROPOFOL
Physicochemical & pharmacokinetic properties
 pKa – 11
 Volume of distribution – 4.6 L/Kg
 Clearance – 25 ml/Kg/min
 Protein binding - 98%
 Water solubility – No
 pH 7.0 – 8.5
 PROPOFOL
 Mechanism of action – Activation of chloride channels of GABA receptors
thus enhancing inhibitory synaptic transmission. It also inhibits NMDA subtype
of glutamate receptors.
 Onset of action – One arm brain circulation time ( 15 -20 seconds)
 Duration of action – 3 to 5 min when given i.v
 Half life : α half life – 3-5 min
β half life – 20-50 min
γ half life – 200-500 min
 PROPOFOL
 Context sensitive half time : Appox. 10 minutes when infused for less than
3 hours & less than 40 minutes when infused for upto 8 hours
 Elimination : Propofol is metabolized by conjugation to glucuronide
& sulfate by liver.
Propofol also undergoes Extra hepatic metabolism in kidney
and lungs (30%)
 PROPOFOL : Effects on the body
 CNS : Dose dependent depression of CNS
End point for induction – Loss of response to verbal commands
Can be used an anti-convulsant
Reduces Cerebral metabolic rate
Reduces Cerebral blood flow through auto-regulation
Reduces Intracranial pressure
Can cause some involuntary movements during induction
( contd.. )
 PROPOFOL : Effects on the body
 CVS : Causes hypotension due to peripheral vasodilatation
The fall in blood pressure is dose dependent and is most marked in the
elderly and in shocked patients. This can be minimized by slow injection
– avoiding inadvertent overdose.
 RS : Causes transient apnea
Obtunds airway reflexes well
 GIT : Propofol has antiemetic properties
 Propofol : Uses, Dose & Route
 Induction of anaesthesia : 2 – 2.5 mg/Kg in adults ; 2.5 – 3 mg/Kg in children
 Maintenance of anaesthesia : At a dose of 50-150 μg/Kg/min
 Conscious sedation : @ 50-75 μg/Kg/min
 Sole anaesthetic for short procedures e.g. Cardioversion
 Very useful in Day care anaesthesia and surgery
 Useful in patients susceptible to Malignant hyperthermia
 Can be used as an Anticonvulsant
( contd.. )
 Propofol : Uses, Dose & Route
 Total intravenous anaesthesia (TIVA) : A plasma concentration of 2.5 to 8
μg/ml is required. This can be achieved as follows –
1 mg/Kg bolus 10 mg/kg/hr for 10 min 8 mg/kg/hr for next
10 minutes 6 mg/kg/hr thereafter.
This is expected to give a plasma conc. of propofol of 3 μg/ml.
 Sedation of critically ill patient in ICU : 1-3 mg/kg/hr.
 Can also be used as antipruritic & antiemetic.
 Safe in patients susceptible to porphyrias.
 PROPOFOL: Adverse effects & Caution
 Hypotension
 Allergic reaction to Egg protein
 Pain on injection ( can be reduced with lignocaine 20 mg added to 20ml )
 Caution in patients who are hypovolemic
 Susceptible to growth of micro-organisms : Tubings and unused propofol
injectable emulsions should be discarded after 12 hours.
 Can cause involuntary epileptiform movements.
( contd.. )
 Propofol Infusion Syndrome
 Occurs due to prolonged infusion in small children and infants
 Usually when used in excess of 4 mg/kg/hr for > 48 hours
 Propofol interferes with mitochondrial mechanisms
 Features : METABOLIC ACIDOSIS , hyperkalemia , RHABDOMYOLYSIS,
Renal failure, hepatomegaly, cardiac failure ( RBBB & asystole )
Hyperlipidemia.
 Management : Cardiorespiratory support
Hemodialysis.
Barbiturates
 Barbiturates- broadly classified as
a) Thiobarbiturates : Sulphur at C2 e.g. Thiopental, thiamylal
b) Oxybarbiturates : Oxygen at C2 e.g. Methohexital
 Formulated as racemic mixtures of their water soluble sodium salts
 Use “Sodium carbonate” to maintain alkaline pH 10-11
 High alkalinity – Severe tissue damage (intra arterial injections)
Precipitation of drugs that are weak bases(vecuronium)
 Thiopentone Sodium
 Ultra-short acting barbiturate
 Available as Hygroscopic,
pale YELLOW powder
 Ampoules commonly contain- 500mg of sodium thiopental +
6% sodium carbonate in an inert atmosphere of nitrogen.
( to prevent precipitation of insoluble acid form of barbiturate by atmospheric CO2)
 Reconstituted with 20ml of water - 2.5% solution (25mg/ml) with a pH of 10.8.
 The alkaline solution is bacteriostatic and safe to keep for 48 hours
 Thiopentone Sodium
Mechanism of action :
 Mainly through interaction with inhibitory neurotransmitter – GABA in CNS
 GABAA receptor has 5 glycoprotein subunits
 Activation of GABAA receptor Increase in transmembrane Chloride
channel conductance Hyperpolarization of post-synaptic neurons

“FUNCTIONAL INHIBITION OF POST-SYNAPTIC NEURONS”

Thiopentone Sodium – Uses & Dose
 Always given intravenously (i.v)
 Can be given through rectal route for sedation, but the
absorption is erratic.
 For induction of anaesthesia : 4-5 mg/Kg in adults.
Children require slightly higher doses (5-6 mg/Kg) due to
larger volume of distribution (Vd)

( contd.. )
Thiopentone Sodium – Uses & Dose
 Status Epilepticus – Single bolus of 3-5 mg/Kg to treat an episode of
convulsion f/b INFUSION ( 3-5 mg/Kg/hr) in status epilepticus
refractory to conventional treatment.

 Cerebral protection – Bolus of 3 mg/Kg followed by an infusion

of 5-6 mg/Kg/hr to protect ischemic brain in neurosurgical patients
 Thiopentone Sodium
 Onset of action : One arm-brain circulation time (15-20 sec)
 Duration of action : α Half life - 10 min
β Half life - 45 min
γ Half life - 6-20 hrs
 Elimination : Metabolized by LIVER & excreted by KIDNEY
 Clearance : 3.4 ml/Kg/min
 Volume of distribution : 2.5 liters/Kg
 Thiopentone Sodium
 Following repeated doses or infusions of thiopental, metabolism follows zero
order kinetics i.e., a constant amount of drug is being eliminated per unit time,
irrespective of the plasma concentration.
 Some drugs are metabolized by first order kinetics; a constant fraction of drug is
eliminated per unit time, i.e. dependent on plasma concentration.
 Zero order kinetics occur when the metabolic pathways become saturated
leading to an accumulation of the active drug and delayed recovery
 Effects on the body
Central Nervous System :
 Dose dependent depression of CNS
 End point of induction- Loss of “EYELASH REFLEX”
 Reduces CMRO2 & CBF thereby reducing ICP
 It is a potent anti-convulsant
 It is an ANTANALGESIC – decreases the threshold to pain
( contd.. )
 Effects on the body
Cardiovascular system :
 Causes Hypotension due to peripheral vasodilatation
 Causes increase in Heart rate – Baroreceptor reflex
mediated sympathetic stimulation
 Higher doses have negative inotropic effect & should be
used with caution in hypovolemic and IHD patients

( contd.. )
 Effects on the body
Respiratory system :
 Causes transient apnea
 Produces dose dependent decrease in both tidal volume &minute ventilation
 The medullary center ventilator responses to both hypoxia & hypercapnia
are reduced
 May not obtund airway reflexes well – hence unsuitable for use while inserting an
LMA ( can cause coughing & laryngospasm)
 Histamine release can occur – can precipitate bronchospasm
 Thiopentone – Adverse effects
 Inadvertent intra-arterial injection of thiopentone – causes intense spasm
of the artery & therefore must be avoided. If occurs,
a) Stop further injection but keep cannula in place
b) Inject saline into the cannula & flush it
c) Inject through same cannula, preservative free LIGNOCAINE to reduce pain,
PAPAVERINE 40-80 mg to provide local vasodilatation, HEPARIN to prevent
thrombus formation
d) Stellate ganglion block or brachial plexus block to achieve sympatholysis if intense
pain & if tissue perfusion is in jeopardy.
 Thiopentone – Adverse effects
 Thiopentone is contraindicated in Patients with PORPHYRIAS
 Stimulation of mitochondrial enzyme – “δ Amino levulinic acid Reductase”,
the rate limiting enzyme in porphyrin biosynthesis, can exacerbate AIP
 Manifestations : 1. Abdominal pain
2. Psychiatric symptoms like hysteria
3. Motor neuropathies.
4. CNS symptoms like seizures, mental status changes,
cortical blindness & coma
 Thiopentone – Adverse effects
 Thiopentone should be avoided in patients with sulpha drug allergy
 Extravasation of thiopentone at i.v site can cause local tissue
destruction
 Thiopentone can be used safely in cesarean deliveries
 But doses greater than 8 mg/Kg can cause neonatal depression
due to placental transfer of the drug
 Etomidate
 Carboxylated IMIDAZOLE ester.
 Weak Base & poorly water soluble
 Formulated as a Hyperosmotic solution in 35% Propylene glycol
 Prepared as pharmacologically active R(+) isomer
 Available as lipid emulsion at a conc. of 2mg/ml
 Pain on injection is common and there is a high rate of
thrombophlebitis in the post operative period.
 Etomidate
 Mechanism of action : Activation of Chloride channels of
GABAA receptors

Enhancing inhibitory synaptic transmission

 Onset of action : One arm-brain circulation time (15-20 sec)
 Duration : 3-5 minutes when given i.v
 Dosage : For induction of anaesthesia 0.2-0.4 mg/Kg i.v
 Etomidate : Effects on the body
 CNS : Dose dependent depression of CNS
Can produce involuntary movements during induction.
Recovery is RAPID due to REDISTRIBUTION.
 CVS : IV agent with LEAST cardiovascular depression
Only small reduction in BP & HR- very CARDIOSTABLE
Used in shock, elderly and cardiovascularly compromised
patients.
( contd.. )
 Etomidate : Effects on the body
 RS : Transient apnea occurs with induction doses
Can cause cough or hiccups. Hence not ideal for
insertion of supraglottic airway devices
 GIT : Increased incidence of Nausea & Vomiting
Metabolized by hepatic and plasma esterases to yield inactive
metabolites. Excretion is predominantly urinary and the
elimination half life varies from 1 – 5 hours
 Etomidate : Adverse effects
 Pain on injection & Thrombophlebitis
 Recovery is frequently unpleasant and accompanied by
nausea and vomiting
 Adreno-cortical suppression –
Etomidate inhibits 11-β-hydroxylase, an enzyme important
in adrenal steroid production. A single induction dose blocks the
normal stress-induced increase in adrenal cortisol production for
4-8 hours, and up to 24 hours in elderly and debilitated patients.
( contd.. )
 Etomidate : Adverse effects
 Continuous infusion of etomidate for sedation in critically ill
patients has been shown to increase mortality.
 No increase in mortality has been identified following a single dose
during induction of anesthesia
 Ketamine Hydrochloride
 Phencyclidine derivative
 Produces DISSOCIATIVE ANAESTHESIA – dissociation between
thalamocortical & limbic systems
 Dissociative anaesthesia resembles a cataleptic state in which the eyes remain
open with a slow nystagmic gaze.
 AVAILABILTY : vials containing 10 mg/ml & 50 mg/ml
 Preservative free ketamine is available for use for Central neuraxial blockade.
 Structure activity relationships
 Presence of asymmetric carbon atom results in the existence
of two OPTICAL ISOMERS of ketamine: S(+) & R(-) forms
 Most frequently used preparation of ketamine – Racemic mixture
 S(+) ketamine produces ( when compared to R(-) form):
a) More intense analgesia
b) More rapid metabolism & thus recovery
c) Less salivation
d) Lower incidence of emergence reactions
 Preservative used – BENZETHENIUM CHLORIDE
 Stereo isomers of ketamine

Hallucinogen Anesthetic
 Ketamine Hydrochloride
 Mechanism of action :
a) Inhibits N-methyl-D-aspartate (NMDA) receptors which have been activated by
Glutamate, an excitatory neurotransmitter.
b) Also inhibits SEROTONIN & MUSCARINIC receptors
c) It is an agonist of μ type of opioid receptors
 Onset of action : 30-60 sec when given i.v, 5 min when given i.m &
25-45 min when given orally
 Duration of action : 10-15 min when given i.v
( α half life – 10-15 min , γ half life – 2-3 hours)
 Ketamine : Uses, Dose & Route
 Induction of anaesthesia : 1-2 mg/Kg .
Particularly useful in a) Bronchial asthma – Bronchodilatory effect
b) Tetralogy of fallot – Maintains SVR
c) Hypovolemic patients.
 Analgesia : 0.5 mg/Kg bolus followed by infusion @ 3μg/Kg/min
 Premedication : I.m – 3-5 mg/Kg ( onset time – 5 min)
Nasal – 3-6 mg/Kg ( onset time- 5 min)
Orally – 3-10 mg/Kg ( onset – 20-45 min) ( contd.. )
 Ketamine : Uses, Dose & Route
 As a Bronchodilator : for treatment of Status asthmaticus @ 30-40 μg/Kg/min
 As a sole anesthetic for short procedures – Can be given as infusion
@ 15-45 μg/Kg/min with 50% Nitrous oxide
@ 30-90 μg/Kg/min without Nitrous oxide
POINTS TO REMEMBER WITH USE OF KETAMINE :
 Ketamine can produce “ Hallucinations & Increase in secretions”
 Hence ketamine administration should be preceded by a benzodiazepine
like midazolam & an anti-sialogogue like Glycopyrrolate
 Ketamine : Effects on the body
Central Nervous system :
 Produces “ Dissociative anaesthesia” resembling a cataleptic state.
 Causes Functional & Electrophysiological dissociation of Thalamocortical
system (depressed) from Limbic system (stimulated).
 This produces intense analgesia & amnesia as the sensory impulses from
the body do not reach the cortex.
 Increases CMRO2, CBF and thereby increases Intracranial pressure.
 Also increases the intraocular pressure.
 Ketamine : Effects on the body
 Cardiovascular system : DUAL EFFECT
a) HYPERTENSION & TACHYCARDIA – by indirect stimulation of
sympathetic system causing release of catecholamines.
b) In larger doses or patients with depressed sympathetic system, can cause
hypotension due to direct myocardial depression
 Respiratory system : Very good BRONCHODILATOR,
But does not obtund airway reflexes well.
 GIT : Increases secretions especially Salivary & bronchial
 Ketamine : Adverse effects
 Hallucinations : also called “ Emergence reactions”
- Occur due to ketamine induced depression of auditory and
visual relay nuclei, leading to misperception/misinterpretation
of auditory and visual stimuli.
 Muscle rigidity due to increased muscle tone
 Hypertension and tachycardia.
 Midazolam Hydrochloride
 Water soluble Benzodiazepine with an IMIDAZOLE ring in its structure,
that accounts for stability in aqueous solutions & rapid metabolism
 The solubility of midazolam is pH dependent.
 At pH 3.5, imidazole ring is open WATER SOLUBLE
 At body pH imidazole ring closes LIPID SOLUBLE RAPID ONSET
 Availability : 5 ml vials containing 1 mg/ml & 1 ml ampoules containing 5 mg/ml
 It doesn’t cause pain on injection.
Reversible Ring opening of Midazolam
TAUTOMERISM
 Midazolam
 Mechanism of action : Activation of Chloride channels of
GABA receptors enhancing inhibitory synaptic transmission
 Onset of action : 30-60 seconds
 Duration of action : 1 hour when given i.v
 Elimination : Metabolized in liver by hydroxylation & conjugation
 The metabolite “ HYDROXYMIDAZOLAM” has no clinically
significant side effects.
 Midazolam : Uses, Dose & Route
 Induction of anesthesia : 0.1-0.2 mg/Kg intravenously
 Commonly used to supplement to regional anesthesia for SEDATION
 For PREMEDICATION : Midazolam is given in a dose of 0.5 mg/Kg ORALLY,
upto a maximum dose of 10 mg, to easily separate children from parents. This is
usually possible in 15 to 30 minutes
 Popular drug for sedating critically ill patients in the ICU as it is cardiostable.
 Also used as an ANTICONVULSANT
 Midazolam : Effects on the body
 CNS : Dose dependent depression of the CNS
 CVS : Relatively CARDIOSTABLE
Doesn’t affect Heart rate and Blood pressure much
 RS : doesn’t produce change in respiration at usual doses

CAUTION : To be used with caution in patients with

HYPOVOLEMIA as it may aggravate hypotension
 Flumazenil
 Competitive benzodiazepine antagonist
 Available in vials containing 0.1 mg/ml
 Usually given in 100 μg boluses
 Onset of action : 2 min
 Duration : about an hour
 Adverse effects : Nausea, Vomiting,
Agitation, seizures.
 References
 Robert K.Stoelting, Simon C Hillier. Pharmacology and physiology
in anesthetic practice. 5th Edition.
 Morgan & Mikhail’s Clinical Anesthesiology.5th Edition.
 Ronald D Miller, Elske sitsen, Marije reekers. Intravenous
Anesthetics. 8th edition.
 Lupton T, Pratt O. Intravenous drugs used for induction of
anesthesia.Anesthesia tutorial of the week.Aug 2008
 Hugh C Hemmings. The pharmacology of intravenous anesthestic
induction agents. Anesthesiology news. October 2010.