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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
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
( 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
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
( 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.
( 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
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