Intravenous Induction

Agents
By Dr Rohith Reddy
Moderator Dr Chashamjot Bawa
 What Are IV 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.
 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

• Induction and maintenance of anesthesia.

• As a sole anesthetic for short procedures.
• Intravenous infusion- to maintain anesthesia for longer procedures.
ex: TIVA ( Total intravenous anesthesia)
• To provide sedation in places like ICU.
 Properties Of An Ideal Induction Drug
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
 Pharmacokinetic Properties

• Rapid onset in one arm-brain circulation time

• Rapid redistribution to vessel rich tissue
• Rapid clearance and metabolism
• No active metabolites
 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
 How The Action Takes Place

• Bolus of i.v induction agent enters blood stream

• A percentage of drug is bound to plasma proteins & the rest is unbound.

• The drug is carried in the Venous blood to the right side of the heart
• 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 ).
• 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.
• Drug starts exerting its effect once it penetrates CNS tissue.

• Each drug acts at a specific receptor (ex: GABA-A, NMDA and Ach receptors).
 Classification

• The commonest drugs currently in use can be classified according to their chemical structure
and are :
• Barbiturates – THIOPENTAL, METHOHEXITAL
• Phenols - PROPOFOL
• Imidazoles - ETOMIDATE
• Phencyclidines - KETAMINE
• Benzodiazepines – MIDAZOLAM, DIAZEPAM, LORAZEPAM
• Opioids - MORPHINE, FENTANYL, NALBUPHINE
 Propofol

• 2,6 Di isopropyl phenol

• 1 or 2% aqueous emulsion (tiny fat droplets in suspension, hence the white color).
• Highly lipid soluble.
• Contains:
-10% Soybean oil,
-1.2% Egg Lecithin and
-2.25% Glycerol ( an osmotic agent).
• 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.
• 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 : 3-5 min.
• Elimination : Propofol is metabolized by conjugation to glucuronide & sulfate by liver.

Propofol also undergoes Extra hepatic metabolism in kidney and lungs.

 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.
• 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.
 Uses

• Induction of anesthesia : 2 – 2.5 mg/Kg in adults ; 2.5 – 3 mg/Kg in children.

• Maintenance of anesthesia : At a dose of 50-150 μg/Kg/min.
• Conscious sedation : @ 50-75 μg/Kg/min.
• Sole anesthetic for short procedures.
• Very useful in Day care anesthesia and surgery.
• Useful in patients susceptible to Malignant hyperthermia.
• Can be used as an Anticonvulsant.
• Total intravenous anesthesia (TIVA) : A plasma concentration of 2.5 to 8μg/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
6mg/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.
 Adverse Effects

• 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 : contents of an opened ampule must be
discarded if they are not used within 6 hours.
• Can cause involuntary epileptiform movements.
• Propofol euphoric reaction:
fast onset of creating a short ecstatic and euphoric feeling, the
capacity to induce sexual delusions, fantasies and disinhibition without many of the side
effects that are associated with other drugs and the fact of not being a controlled substance
are the main reasons for its widespread abuse.
 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

• 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).
 Sodium Thiopental

• 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.
• 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.
• Onset of action : One arm-brain circulation time (15-20 sec).
• Elimination : Metabolized by LIVER & excreted by KIDNEY.
• 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.
 Uses

Induction of anesthesia : 4-5 mg/Kg in adults.

Children require slightly higher doses (5-6 mg/Kg) due to
larger volume of distribution (Vd).
• Status Epilepticus – Single bolus of 3-5 mg/Kg to treat an episode of convulsion
followed by 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.
• Thyroid steal phenomenon:
This method involved in treating the patient with placebo for
several days, inducing them with thiopental in their bed and whisking them away to surgery
without the knowledge.
• These patients would perform significantly better postoperatively in terms of morbidity
and mortality, the anticipation and excitement producing fatal shock are eliminated by
this method.
 Effects On The Body

• CNS:
• 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 pain.
• CVS:
• 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.
• RS:
• 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.
 Adverse Effects

• Inadvertent intraarterial injection of thiopental usually results in immediate, intense

vasoconstriction and excruciating pain that radiates along the distribution of artery. If it
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.
• 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 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.
• 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.
• 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 anesthesia 0.2-0.4 mg/Kg i.v.
 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 cardiovascular compromised patients.
• 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 estrases to yield inactive metabolites. Excretion is
predominantly urinary and the elimination half life varies from 1 – 5 hours.
 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 patients.
 Ketamine

• Phencyclidine derivative.
• Produces DISSOCIATIVE ANESTHESIA – dissociation between thalamocortical &
limbic systems.
• Dissociative anesthesia resembles a cataleptic state in which the eyes remain open with a
slow nystagmic gaze.
• AVAILABILTY : vials containing 10 mg/ml & 50 mg/ml.
 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.
• 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
 Uses

• Induction of anesthesia : 1-2 mg/Kg .

Especially 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)
• 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.
• Neuraxial analgesia: 0.5-1 mg/kg.

Preservative free is used.

Effects are due to both spinal and systemic effects and possibly interaction with
local anesthetic binding sites on voltage gated sodium ion channels.
• 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.
 Effects On The Body

• CNS:
• Produces “ Dissociative anesthesia” 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.
• CVS:
• 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.
• RS: Very good BRONCHODILATOR, but does not obtund airway reflexes well.
• GIT : Increases secretions especially Salivary & bronchial.
 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.
Benzodiazepines

• MIDAZOLAM
• 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.
• It doesn’t cause pain on injection.
• 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.
 Uses

• Induction of anesthesia : 0.1-0.2 mg/Kg intravenously.

• SEDATION: effective for sedation during regional anesthesia as well as for brief therapeutic
procedures in a dose of 1-2.5mg/kg iv.
• PREMEDICATION : 0.5 mg/Kg ORALLY, administered 30 min before induction of anesthesia,
provides reliable sedation and anxiolysis in children without producing delayed awakening.
• Also used as an anticonvulsant.
• Paradoxical vocal cord motion: is a cause of nonorganic upper airway obstruction and stridor
that may manifest postoperatively. 0.5 – 1mg/kg intravenously can be used.
• Postoperative sedation:
loading dose - 0.5 to 4mg/kg iv
maintenance dose - 1 to 7mg/kg iv
• Maintenance of anesthesia:
Used as supplement to opioids and propofol.
It produces gradual awakening which is rarely associated with nausea or
emergence reactions.
 Effects On The Body

• CNS:
• Cerebral oxygen consumption, cerebral blood flow, and intracranial pressure –
decrease.
• Anti seizures properties.
• Antegrade amnesia--- premedication.
• Mild muscle-relaxant property.
• Slower loss of consciousness and a longer recover.
• CVS:
• Minimal cardiovascular depressant effects even at induction doses.
• Arterial blood pressure
• Cardiac output decreases slightly.
• Peripheral vascular resistance
• Heart rate : slightly increases.
• Midazolam tends to reduce blood pressure and peripheral vascular resistance more than
diazepam.
• RS:
• Depress the ventilatory response to CO2
Apnea may be less common after benzodiazepine induction than after barbiturate
induction.
• Ventilation must be monitored in all patients receiving intravenous benzodiazepines,
and resuscitation equipment must be immediately available.
 Opioids

• On the basis of source

• Naturally occuring
• Phenanthrene :Morphine, Codeine ,Thebaine
• Benzylisoquinoline: Papaverine ,Noscapine ,Narcine
• Semisynthetic
• Heroin
• Dihydromorphone /morphinone
• Thebaine derivatives: Etorphine, Buprenorphine.
 Opioids

• Synthetic
• Phenylpiperidines: Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil.
• Morphinan compounds : Levorphanol, Butorphanol.
• Phenyl-heptylmines : Methadone, Propoxyphene, Dextropropoxyphene
Diphenylpropylamine.
• Benzomorphans: Pentazocine
 On The Basis Of Action

• Opioid Agonists Opioid Agonist- • Opioid Antagonists

• Oxycodone
Antagonists
• Morphine • Propoxyphene • Naloxone
• Pentazocine
• Meperidine • Methadone • Naltrexone
• Butorphanol
• Fentanyl • Tramadol • Nalmefene
• Nalbuphine
• Sufentanil • Heroin
• Buprenorphine
• Remifentanil • Codeine
• Nalorphine
• Alfentanil • Hydromorphone
• Bremazocine
• Oxymorphone
• Dezocine
 Fentanyl

• Phenylpiperidine derivative synthetic opioid structurally related to meperidine.

• 75 to 125 times as potent as morphine.
• Rapid onset and shorter duration due to greater lipid solubility.
• Rapidly redistributed to inactive storage sites such as fat and skeletal muscles.
• 75% of the initial dose undergoes first-pass pulmonary uptake.
 Uses

• Analgesia: Low IV dose 1-2 μg/kg

• Adjuvant to anesthetics: (2-20 μg/kg) to blunt circulatory response to Intubation of the
trachea and to decrease requirement of inhalational agents.
• As a component of Total Intravenous Anesthesia (TIVA) – Dose 50-150 μg/kg.
• Intrathecal fentanyl may be used to provide labor analgesia and as an adjuvant for spinal
and epidural anesthesia.
• Oral transmucosal fentanyl 5- 20 μg/kg may be used to decrease pre-operative anxiety
and facilitate induction.
• Transdermal fentanyl patch delivering 75 - 100 μg/hr may be used for treatment of
chronic pain in cancer patients.
• As a Sole Anesthetic Agent
• Advantages:
• Lack of direct myocardial depressant effects.
• Absence of histamine release.
• Suppression of stress response to surgery.
• Disadvantages:
• Failure to prevent sympathetic response to surgical stimulation.
• Possible patient awareness.
• Postoperative ventilatory depression.
 Adverse Effects

• Persistent/ recurrent respiratory depression.

• Bradycardia is more prominent.
• Allergic reactions are rare.
• Myoclonus may produce clinical picture of seizure activity in the absence of EEG
changes.
• Modest increases in ICP in head injury patients in-spite of an unchanged PaCO2.