Intravenous induction agents ppt001

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Detailed description of iv induction agents

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Intravenous induction agents ppt001

  1. 1. INTRAVENOUS INDUCTION AGENTS Dr. Atul Ambekar Guide: Dr. Shalini Saksena
  2. 2. WHAT ARE IV INDUCTION AGENTS??? • These are drugs that when given intravenously in an appropriate dose, cause a rapid loss of consciousness
  3. 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. 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. 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.
  6. 6. 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
  7. 7. 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
  8. 8. 3. PHARMACOKINETIC • No organ based metabolism • Rapid onset & offset of action • No active metabolites
  9. 9. 4.ECONOMIC • Cheap to produce • Sustainable supply at low cost 5.PHYSICOCHEMICAL • High lipid solubility • High proportion unionised at plasma pH
  10. 10. CLASSIFICATION BASED ON CHEMICAL STRUCTURE BARBITURATES PHENCYCLIDINES • Thiopental • Ketamine • Thiamylal • Methohexital BENZODIAZEPINES • Midazolam PHENOLS • Propofol IMIDAZOLES • Etomidate
  11. 11. MOST COMMONLY USED ONES • Thiopental • Propofol • Etomidate • Ketamine
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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 -
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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 - -
  22. 22. FEW OTHER AGENTS • Midazolam- Facilitates GABA-receptor binding & enhances the chloride ion conductance across the membrane • Chloral Hydrate- Used in paediatric patients • Methohexital • Thiamylal
  23. 23. SUMMARY OF THIOPENTAL Advantages • Very rapid onset of anaesthesia • Potent anti-convulsant • Tried & tested & cheap Disadvantages • Unsuitable for maintenance • Contraindicated in porphyria • Antanalgesic
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. REFERENCES • Lee’s synopsis of anaesthesia • Miller’s anaesthesia • FRCA website
  28. 28. THANK YOU

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