INTRAVENOUS INDUCTION

AGENTS

Dr. Atul Ambekar

Guide: Dr. Shalini Saksena
 WHAT ARE IV INDUCTION AGENTS???

These are drugs that when given intravenously in an

appropriate dose, cause a rapid loss of consciousness
 HISTORY OF IV ANAESTHESIA

Born in 1932- Wesse & Schrapff published their report into the use of
hexobarbitone, the first rapidly acting iv drug.
1934- Sodium thiopental was introduced into clinical practice by Waters & Lundy.
Consequently a number of other drugs were developed with propofol being
introduced as late as in 1990.
PHARMACODYNAMICS OF IV INDUCTION AGENTS- AN OVERVIEW
ADMINISTRATION OF DRUG

DRUG ENTERS THE BLOODSTREAM

PLASMA
PROTEIN FREE
BOUND FORM

VESSEL RICH ORGANS

BRAIN, LIVER & KIDNEY

ACT ON GABA-A, ACH & NMDA RECEPTORS

A high proportion of the initial bolus is delivered to the cerebral
circulation, & later on the drug passes along a concentration gradient from
the blood into the brain.

The rate of transfer is dependent on a number of factors-

The arterial conc. 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.
 PROPERTIES OF AN IDEAL INDUCTION AGENT

1. PHARMACEUTICAL-
Needs no mixing or diluting
Long shelf life without refrigeration
pH close to plasma
No preservatives needed
2. PHARMACODYNAMIC
Affects only CNS
No excitatory phenomena
No unwanted effects, particularly respiratory or cardiovascular
Good correlation between plasma conc. & clinical effects
High therapeutic index
Analgesic
No important drug interactions
No pain on injection
No histamine release or anaphylactic reactions
3. PHARMACOKINETIC

No organ based metabolism

Rapid onset & offset of action

No active metabolites
4.ECONOMIC

Cheap to produce
Sustainable supply at low cost

5.PHYSICOCHEMICAL

High lipid solubility

High proportion unionised at plasma pH
 CLASSIFICATION BASED ON CHEMICAL STRUCTURE

BARBITURATES PHENCYCLIDINES
Thiopental Ketamine
Thiamylal
Methohexital BENZODIAZEPINES
Midazolam
PHENOLS
Propofol

IMIDAZOLES
Etomidate
MOST COMMONLY USED ONES

Thiopental
Propofol
Etomidate
Ketamine
 THIOPENTAL PROPOFOL ETOMIDATE KETAMINE

CHEMICAL Sodium-5-ethyl-5-1- 2,6-di-isopropyl phenol R-1methylimidazole-5- 2-2-chlorophenyl-2-

STRUCTURE methylbutyl-2- ethylcarboxylate methylaminocyclohexan
thiobarbiturate sulphate e hydrochloride
MOLECULAR 264 178 342 237.5
WEIGHT

ACID/BASE Weak acid Weak acid Weak base Weak base

% UNIONISED AT 61 99.97 99.90 55.7

pH 7.4

pKA 7.6 11 4.24 7.5

 THIOPENTAL PROPOFOL ETOMIDATE KETAMINE

% PROTEIN 85 98 76 60
BOUND

CLEARANCE 4 30 18 19
(ML/KG/MIN)

ELIMINATION 10 6 3 3
HALF-LIFE
(HRS)
ACTIVE Pentobarbitone None None Norketamine
METABOLITES
 THIOPENTAL PROPOFOL

AVAILABILITY Sodium salts in lyophilised form 1% & 2% solutions of an aqueous

emulsion of soyabean oil, glycerol &
purified egg phosphatide

MOA Potentiaition of inhibitory effects of Similar action

GABA-A receptor & hyperpolarisation
of pre-& post-synaptic membranes

LIPID SOLUBILITY High High

DOSE 3-5mg/kg, effective plasma conc. is 1-2.5mg/kg for induction

15mcg/ml 0.2mg/kg bolus dose followed by
Rectally-5 or 10% solution with a dose 1mg/kg/hr for sedation which
of 50mg/kg produces a blood conc. of 1.5mcg/ml
PHARMACOKINETICS THIOPENTAL PROPOFOL

ABSORPTION Rapid due to high lipid solubility Similar

DISTRIBUTION Initially into highly vascularised organs Initial vol. Of distribution is 20-40 L &
& then into the lean tissue initial distribution half-life is 1-8 mins.

CLEARANCE Metabolism & elimination mainly by CL=1.5 - 2.2 L/min

liver Metabolised by liver to inactive, water
Hepatic extraction ratio is less than soluble glucuronide & sulfate
20% & clearance during elimination compounds & excreted by kidney
phase is 250ml/min
PHARMACODYNAMICS THIOPENTAL PROPOFOL

CNS Depression of cerebral activity &
cerebral metabolism,
cerebral vasoconstriction, reduced CBF
& ICP
CPP is usually maintained or slightly
elevated
CVS Venodilation, reduced preload, & direct
myocardial depressant activity at high
conc.
HR increased
SVR & ABP are relatively unaltered
RS Dose dependent ventilatory depression
& apnoea usually follows an induction
dose.
Laryngeal & tracheal reflexes are
depressed to a lesser extent than
propofol
Reduces CMRO2 & CBF, reduces ICP.
Cerebral autoregulation & reactivity to
CO2 are maintained
Reduced ABP, CO, SVR, VFP
HR is usually unchanged
Coronary perfusion pressure is reduced,
but LV stroke work is also reduced, so
myoc. O2 supply-demand ratio is
preserved
Respiratory depression with a rise in
CO2 tension & a reduced ventilatory
response to both CO2 & hypoxia
Apnoea follows an induction dose
 THIOPENTAL
USES Induction of anaesthesia
In status epilepticus which is
refractory to BZDs & specialised
anti-convulsant drugs
PROPOFOL
Induction & maintenance of
anaesthesia
Day-case anaesthesia
Anaesthesia during radiographic
procedures, endoscopy

ADVERSE EFFECTS Histamine release Pain on inj. into small veins

Pain on injection into small veins, Rare anaphylactoid reactions
thrombophlebitis
SC inj.-Pain & tissue necrosis
Arterial inj.-Painful arterial spasm &
chemical arteritis, irreversible
thrombosis
Involuntary excitatory movements,
hypertonus, coughing & hiccups

CI Porphyria -
 ETOMIDATE KETAMINE
AVAILABILITY Racemic mixture formulated in 35% Racemic mixture, 1%, 5%, or 10%
propylene glycol as a 0.2% solution with benzethonium chloride
solution as preservative

MOA Acts on the GABA-A receptor & Non-competitive inhibitor at

potentiates its inhibitory effect NMDA-receptor, & as a ligand at
opioid u & k receptors

LIPID SOLUBILITY High High

DOSE 0.3 mg/kg IV induction-1-2mg/kg

IM 4-6 mg/kg
Rectal 8-10 mg/kg
PHARMACOKINETICS ETOMIDATE KETAMINE
ABSORPTION Rapidly absorbed & crosses the Very rapid absorption &
blood brain barrier, producing penetration of blood-brain barrier
peak effect site concs. within 1min
of administration

DISTRIBUTION Moderate initial & steady state Rapid early redistribution

vols. of distribution. t1/2=11-16mins.,
Redistribution half-life is 2.7 mins Initial vol. of distribution 20-100L,
& SSVD is 100-400L

CLEARANCE Rapidly metabolized in the liver Metabolized primarily by liver

primarily by ester hydrolysis to CL=1.4 L/min
inactive carboxylic acid derivative
Elimination half-life is 2.9-5.3 hrs,
hepatic extraction ratio is high 0.5-
0.9
PHARMACODYNAMICS ETOMIDATE KETAMINE

CNS Reduces CBF(36%), cerebral O2 Dissociative anaesthesia

consumption(45%) Increases cerebral metabolism,
ICP & IOP reduced cerebral O2 consumption, CBF &
CPP & cerebrovascular reactivity is ICP
maintained
High incidence of myoclonus
CVS Very minimal effects on Stimulatory effect-increases HR,
hemodynamic stability & myocardial ABP & CO
function, typically, less than 10%
decrease in cardiac index

RS Minimal respiratory depression Minimal respiratory depression

 ETOMIDATE KETAMINE

USES Etomidate is suitable for patients Anaesthesia for patients with severe
compromised by trauma, serious shock or who are cardiovascularly
illness, shock or cardiovascular compromised, asthmatic patients
comorbidity

ADVERSE EFFECTS Pain on inj., thrombophlebitis, Raises ICP, IOP, emergence

myoclonus, PONV, transient adrenal reactions post-op such as vivid
suppression dreams, surreal experiences &
illusions

CI - -
 FEW OTHER AGENTS

Midazolam- Facilitates GABA-receptor binding & enhances the chloride ion

conductance across the membrane

Chloral Hydrate- Used in paediatric patients

Methohexital

Thiamylal
 SUMMARY OF THIOPENTAL

Advantages
Very rapid onset of anaesthesia
Potent anti-convulsant
Tried & tested & cheap

Disadvantages
Unsuitable for maintenance
Contraindicated in porphyria
Antanalgesic
 SUMMARY OF PROPOFOL
Advantages
Pleasant sedation & recovery
Rapid onset & easy titration to effect
Suitable for both induction & maintenance
Suppression of airway reflexes
Anti-emetic effects
Safe in porphyria

Disadvantages
Pain on injection
Lipid emulsion carrier-which supports bacterial growth
Vasodilation causes hypotension, especially with low cardiac reserve
Expensive
 SUMMARY OF ETOMIDATE

Advantages
Hemodynamic stability
Reduction in CMRO2,CBF & ICP, with maintenance of CPP
Very rapid onset of hypnosis & recovery

Disadvantages
Hyperosmolar propylene glycol carrier causes pain on injection,thrombophlebitis &
hemolysis
Profound but transient inhibition of steroidogenesis
Excitatory effects & myoclonus are common
Postoperative nausea & vomiting
 SUMMARY OF KETAMINE

Advantages
Dissociative anaesthesia & marked analgesia
Very rapid onset of effects
Cardiorespiratory stability
Relative preservation of airway reflexes
Safe in patients with porphyria

Disadvantages
Unpleasant & troublesome psychomimetic emergence reactions
Tachycardia & hypertension, undesirable with ischemic heart disease
Contraindicated in raised ICP
 REFERENCES

Lees synopsis of anaesthesia

Millers anaesthesia
FRCA website
THANK YOU