Date post: | 20-Jan-2015 |
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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