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

CHEMICALSTRUCTURE

Sodium-5-ethyl-5’-1-methylbutyl-2-thiobarbiturate

2,6-di-isopropyl phenol

R-1methylimidazole-5’-ethylcarboxylate sulphate

2-2-chlorophenyl-2-methylaminocyclohexane hydrochloride

MOLECULARWEIGHT

264 178 342 237.5

ACID/BASE Weak acid Weak acid Weak base Weak base

% UNIONISED ATpH 7.4

61 99.97 99.90 55.7

pKA 7.6 11 4.24 7.5

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

ACTIVEMETABOLITES

Pentobarbitone None None Norketamine

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/mlRectally-5 or 10% solution with a dose of 50mg/kg

1-2.5mg/kg for induction0.2mg/kg bolus dose followed by 1mg/kg/hr for sedation which 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 & 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 liverHepatic extraction ratio is less than 20% & clearance during elimination phase is 250ml/min

CL=1.5 - 2.2 L/minMetabolised by liver to inactive, water soluble glucuronide & sulfate compounds & excreted by kidney

PHARMACODYNAMICS

THIOPENTAL PROPOFOL

CNS Depression of cerebral activity & cerebral metabolism,cerebral vasoconstriction, reduced CBF & ICPCPP 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 increasedSVR & ABP are relatively unaltered

Reduced ABP, CO, SVR, VFPHR is usually unchangedCoronary 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 & hypoxiaApnoea follows an induction dose

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 -

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/kgIM – 4-6 mg/kgRectal – 8-10 mg/kg

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 derivativeElimination half-life is 2.9-5.3 hrs, hepatic extraction ratio is high 0.5-0.9

Metabolized primarily by liverCL=1.4 L/min

PHARMACODYNAMICS

ETOMIDATE KETAMINE

CNS Reduces CBF(36%), cerebral O2 consumption(45%)ICP & IOP reducedCPP & cerebrovascular reactivity is maintainedHigh incidence of myoclonus

Dissociative anaesthesiaIncreases 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

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 - -

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

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

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

• Lee’s synopsis of anaesthesia• Miller’s anaesthesia• FRCA website

THANK YOU