Detailed description of iv induction agents

1. INTRAVENOUS INDUCTION
AGENTS
Dr. Atul Ambekar
Guide: Dr. Shalini Saksena

2. WHAT ARE IV INDUCTION AGENTS???
• These are drugs that when given intravenously in an
appropriate dose, cause a rapid loss of consciousness

3. 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.

4. 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

5. 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.

7. 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

8. 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

9. 3. PHARMACOKINETIC
• No organ based metabolism
• Rapid onset & offset of action
• No active metabolites

10. 4.ECONOMIC
• Cheap to produce
• Sustainable supply at low cost
5.PHYSICOCHEMICAL
• High lipid solubility
• High proportion unionised at plasma pH

11. CLASSIFICATION BASED ON CHEMICAL STRUCTURE
BARBITURATES PHENCYCLIDINES
• Thiopental • Ketamine
• Thiamylal
• Methohexital BENZODIAZEPINES
• Midazolam
PHENOLS
• Propofol
IMIDAZOLES
• Etomidate

12. MOST COMMONLY USED ONES
• Thiopental
• Propofol
• Etomidate
• Ketamine

14. THIOPENTAL PROPOFOL ETOMIDATE KETAMINE
CHEMICAL
STRUCTURE
Sodium-5-ethyl-5’-1-
methylbutyl-2-
thiobarbiturate
2,6-di-isopropyl phenol R-1methylimidazole-5’-
ethylcarboxylate
sulphate
2-2-chlorophenyl-2-
methylaminocyclohexan
e hydrochloride
MOLECULAR
WEIGHT
264 178 342 237.5
ACID/BASE Weak acid Weak acid Weak base Weak base
% UNIONISED AT
pH 7.4
61 99.97 99.90 55.7
pKA 7.6 11 4.24 7.5

15. THIOPENTAL PROPOFOL ETOMIDATE KETAMINE
% PROTEIN
BOUND
85 98 76 60
CLEARANCE
(ML/KG/MIN)
4 30 18 19
ELIMINATION
HALF-LIFE
(HRS)
10 6 3 3
ACTIVE
METABOLITES
Pentobarbitone None None Norketamine

17. 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
GABA-A receptor & hyperpolarisation
of pre-& post-synaptic membranes
Similar action
LIPID SOLUBILITY High High
DOSE 3-5mg/kg, effective plasma conc. is
15mcg/ml
Rectally-5 or 10% solution with a dose
of 50mg/kg
1-2.5mg/kg for induction
0.2mg/kg bolus dose followed by
1mg/kg/hr for sedation which
produces a blood conc. of 1.5mcg/ml

18. PHARMACOKINETICS THIOPENTAL PROPOFOL
ABSORPTION Rapid due to high lipid solubility Similar
DISTRIBUTION Initially into highly vascularised organs
& then into the lean tissue
Initial vol. Of distribution is 20-40 L &
initial distribution half-life is 1-8 mins.
CLEARANCE Metabolism & elimination mainly by
liver
Hepatic extraction ratio is less than
20% & clearance during elimination
phase is 250ml/min
CL=1.5 - 2.2 L/min
Metabolised by liver to inactive, water
soluble glucuronide & sulfate
compounds & excreted by kidney

19. PHARMACODYNAMICS THIOPENTAL PROPOFOL
CNS Depression of cerebral activity &
cerebral metabolism,
cerebral vasoconstriction, reduced CBF
& ICP
CPP is usually maintained or slightly
elevated
Reduces CMRO2 & CBF, reduces ICP.
Cerebral autoregulation & reactivity to
CO2 are maintained
CVS Venodilation, reduced preload, & direct
myocardial depressant activity at high
conc.
HR increased
SVR & ABP are relatively unaltered
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
RS Dose dependent ventilatory depression
& apnoea usually follows an induction
dose.
Laryngeal & tracheal reflexes are
depressed to a lesser extent than
propofol
Respiratory depression with a rise in
CO2 tension & a reduced ventilatory
response to both CO2 & hypoxia
Apnoea follows an induction dose

20. THIOPENTAL PROPOFOL
USES • Induction of anaesthesia
• In status epilepticus which is
refractory to BZDs & specialised
anti-convulsant drugs
• Induction & maintenance of
anaesthesia
• Day-case anaesthesia
• Anaesthesia during radiographic
procedures, endoscopy
ADVERSE EFFECTS • Histamine release
• Pain on injection into small veins,
thrombophlebitis
• SC inj.-Pain & tissue necrosis
• Arterial inj.-Painful arterial spasm &
chemical arteritis, irreversible
thrombosis
• Involuntary excitatory movements,
hypertonus, coughing & hiccups
• Pain on inj. into small veins
• Rare anaphylactoid reactions
CI Porphyria -

21. ETOMIDATE KETAMINE
AVAILABILITY Racemic mixture formulated in 35%
propylene glycol as a 0.2%
solution
Racemic mixture, 1%, 5%, or 10%
solution with benzethonium chloride
as preservative
MOA Acts on the GABA-A receptor &
potentiates its inhibitory effect
Non-competitive inhibitor at
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

22. PHARMACOKINETICS ETOMIDATE KETAMINE
ABSORPTION Rapidly absorbed & crosses the
blood brain barrier, producing
peak effect site concs. within 1min
of administration
Very rapid absorption &
penetration of blood-brain barrier
DISTRIBUTION Moderate initial & steady state
vols. of distribution.
Redistribution half-life is 2.7 mins
Rapid early redistribution
t1/2=11-16mins.,
Initial vol. of distribution 20-100L,
& SSVD is 100-400L
CLEARANCE Rapidly metabolized in the liver
primarily by ester hydrolysis to
inactive carboxylic acid derivative
Elimination half-life is 2.9-5.3 hrs,
hepatic extraction ratio is high 0.5-
0.9
Metabolized primarily by liver
CL=1.4 L/min

23. PHARMACODYNAMICS ETOMIDATE KETAMINE
CNS Reduces CBF(36%), cerebral O2
consumption(45%)
ICP & IOP reduced
CPP & cerebrovascular reactivity is
maintained
High incidence of myoclonus
Dissociative anaesthesia
Increases cerebral metabolism,
cerebral O2 consumption, CBF &
ICP
CVS Very minimal effects on
hemodynamic stability & myocardial
function, typically, less than 10%
decrease in cardiac index
Stimulatory effect-increases HR,
ABP & CO
RS Minimal respiratory depression Minimal respiratory depression

24. ETOMIDATE KETAMINE
USES Etomidate is suitable for patients
compromised by trauma, serious
illness, shock or cardiovascular
comorbidity
Anaesthesia for patients with severe
shock or who are cardiovascularly
compromised, asthmatic patients
ADVERSE EFFECTS Pain on inj., thrombophlebitis,
myoclonus, PONV, transient adrenal
suppression
Raises ICP, IOP, emergence
reactions post-op such as vivid
dreams, surreal experiences &
illusions
CI - -

25. FEW OTHER AGENTS
• Midazolam- Facilitates GABA-receptor binding & enhances the chloride ion
conductance across the membrane
• Chloral Hydrate- Used in paediatric patients
• Methohexital
• Thiamylal

26. SUMMARY OF THIOPENTAL
Advantages
• Very rapid onset of anaesthesia
• Potent anti-convulsant
• Tried & tested & cheap
Disadvantages
• Unsuitable for maintenance
• Contraindicated in porphyria
• Antanalgesic

27. 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 PROPOFOL

28. 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

29. 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

30. REFERENCES
• Lee’s synopsis of anaesthesia
• Miller’s anaesthesia
• FRCA website

31. THANK YOU