Intravenous Anaesthetics (Intro)

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Intravenous Anaesthetics (Intro)

  1. 1. Intravenous Anaesthetics Craigavon Area Hospital CT1 Education Series (Intro) Dr. Andrew Ferguson
  2. 2. Overview <ul><li>Mechanisms of action </li></ul><ul><li>Pharmacological principles </li></ul><ul><li>Individual agent overviews </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Induction characteristics </li></ul><ul><li>Organ effects </li></ul>Dr. Andrew Ferguson
  3. 3. How do they work? <ul><li>Major inhibitory neuro-transmitter in the CNS = GABA </li></ul><ul><li>Active GABA receptor => Cl - influx => hyperpolarisation </li></ul><ul><li>Propofol & barbiturates slow GABA/receptor dissociation </li></ul><ul><li>Benzodiazepines increase GABA to receptor coupling </li></ul><ul><li>Ketamine acts at NMDA receptor </li></ul><ul><li>These effects lead to sedative & hypnotic effects </li></ul>Dr. Andrew Ferguson
  4. 4. Pharmacodynamics <ul><li>Increasing dose => sedation => hypnosis </li></ul><ul><li>All iv anaesthetics affect other organ systems </li></ul><ul><ul><li>Potential for respiratory depression </li></ul></ul><ul><ul><li>Potential for CVS depression </li></ul></ul><ul><ul><li>Potential for altered CBF/ICP </li></ul></ul><ul><li>Hypovolaemia => severe haemodynamic effects seen due to decreased blood pool </li></ul><ul><ul><li>Use lower doses! </li></ul></ul>Dr. Andrew Ferguson
  5. 5. Distribution & Elimination Dr. Andrew Ferguson
  6. 6. Single-injection Kinetics Dr. Andrew Ferguson
  7. 7. Context-sensitive Half-Time <ul><li>Time required for central compartment blood concentration to fall by half as a function of the duration of an infusion (of variable rate designed to maintain steady state) </li></ul>Dr. Andrew Ferguson
  8. 8. Schema for Discussing Drugs <ul><li>Chemistry </li></ul><ul><ul><ul><li>Structure & structure-activity relationship </li></ul></ul></ul><ul><ul><ul><li>Physical properties </li></ul></ul></ul><ul><li>Mode of action </li></ul><ul><li>Organ effects </li></ul><ul><ul><ul><li>CVS </li></ul></ul></ul><ul><ul><ul><li>RS </li></ul></ul></ul><ul><ul><ul><li>CNS </li></ul></ul></ul><ul><ul><ul><li>GIT etc. </li></ul></ul></ul><ul><li>Pharmacokinetics </li></ul><ul><ul><ul><li>Distribution </li></ul></ul></ul><ul><ul><ul><li>Metabolism </li></ul></ul></ul><ul><ul><ul><li>Elimination </li></ul></ul></ul><ul><li>Side-effects </li></ul><ul><li>Clinical Use </li></ul>Dr. Andrew Ferguson
  9. 9. Propofol <ul><li>Very widespread use...know inside out! </li></ul><ul><ul><li>2,6-diisopropylphenol </li></ul></ul><ul><ul><li>Emulsion with 10% soybean oil , 2.25% glycerol and 1.2% lecithin (egg yolk phosphatide - ? allergen) </li></ul></ul><ul><ul><li>Injection pain (up to 65%) decreased by lidocaine </li></ul></ul><ul><ul><li>Induction dose higher in kids, lower in elderly </li></ul></ul><ul><ul><li>Metabolised in liver & ? lungs </li></ul></ul><ul><ul><li>Wake-up due to redistribution, not metabolism </li></ul></ul><ul><ul><li>Significant vasodilatation & baroreceptor inhibitor </li></ul></ul><ul><ul><li>Antiemetic </li></ul></ul><ul><ul><li>Suppresses laryngeal reflexes </li></ul></ul>Dr. Andrew Ferguson
  10. 10. Etomidate <ul><li>Imidazole derivative, D-(+) isomer </li></ul><ul><li>Poorly soluble in H 2 O => propylene glycol used </li></ul><ul><li>Wake-up due to redistribution </li></ul><ul><li>Metabolised by ester hydrolysis to inactives </li></ul><ul><li>Minimal haemodynamic effects, short half-life </li></ul><ul><li>High incidence of PONV (35-40%) </li></ul><ul><li>May activate seizure foci, myoclonus in 50% </li></ul><ul><li>Adrenocortical suppression </li></ul><ul><ul><ul><li>dose-dependent 11  -hydroxylase inhibition </li></ul></ul></ul><ul><ul><ul><li>lasts 4-12 hrs after single dose (much longer in critically ill) </li></ul></ul></ul>Dr. Andrew Ferguson
  11. 11. Ketamine <ul><li>Phencyclidine derivative </li></ul><ul><li>Racemic mixture: S -isomer fewer adverse effects </li></ul><ul><li>Effects </li></ul><ul><ul><li>Significant analgesia at sub-anaesthetic doses </li></ul></ul><ul><ul><li>“ Dissociative anaesthesia” - cataleptic state </li></ul></ul><ul><ul><li>Blocks NMDA receptor (NOT GABA A active) </li></ul></ul><ul><ul><li>Vivid dreams or hallucinations during recovery </li></ul></ul><ul><ul><li>EEG changes cannot be used to gauge depth </li></ul></ul><ul><ul><li>More stable haemodynamics in unstable patients </li></ul></ul><ul><ul><li>Less diminution of airway reflexes (less, not none!!) </li></ul></ul>Dr. Andrew Ferguson
  12. 12. Benzodiazepines <ul><li>iv prep: midazolam, diazepam, lorazepam </li></ul><ul><li>Midazolam has imidazole ring </li></ul><ul><ul><ul><li>ring protonated => water soluble at acid pH </li></ul></ul></ul><ul><ul><ul><li>In body, ring unprotonated => lipid soluble </li></ul></ul></ul><ul><ul><ul><li>solubility NOT due to opening of benzo ring at low pH </li></ul></ul></ul><ul><ul><ul><li>At pH 4 only 9% of MDZ rings are open (75% at pH 2) </li></ul></ul></ul><ul><li>Bind specific site between  +  subunits of GABA A receptor </li></ul><ul><li>Hepatic metabolism </li></ul><ul><li>Vasodilatation with MDZ > Diazepam </li></ul>Dr. Andrew Ferguson
  13. 13. Thiopental <ul><li>Thiobarbiturate </li></ul><ul><ul><ul><li>Sodium salt + anhdrous NaHCO 3 => pH 10-11 </li></ul></ul></ul><ul><ul><ul><li>Precipitates with acidic drugs e.g. NMBs </li></ul></ul></ul><ul><ul><ul><li>Extravascular injection => pain + tissue injury </li></ul></ul></ul><ul><ul><ul><li>Intra-arterial injection => crystals + ischaemia </li></ul></ul></ul><ul><li>Dose dependent CNS depression </li></ul><ul><ul><ul><li>Decrease CBF, ICP, CMRO 2 , seizure activity </li></ul></ul></ul><ul><li>Less BP fall at induction than propofol </li></ul><ul><ul><ul><li>Compensatory heart rate increase offsets vasodilatation effects </li></ul></ul></ul><ul><ul><ul><li>Caution in hypovolaemia, tamponade, IHD, heart failure </li></ul></ul></ul><ul><li>Wake-up due to redistribution </li></ul>Dr. Andrew Ferguson
  14. 14. Dr. Andrew Ferguson Management of intra-arterial injection of Thiopental Stop injection but leave needle or cannula in place Dilute with immediate injection of saline Give intra-arterial LA + vasodilator <ul><ul><li>Lidocaine 50mg (5 ml of 1% solution) </li></ul></ul><ul><ul><li>Phenoxybenzamine (  blocker) 0.5 mg bolus or 50-200  g/minute infusion </li></ul></ul>Consider systemic papaverine 40-80 mg Consider sympathetic blockade (stellate ganglion or brachial plexus block) Start iv heparin infusion Consider intra-arterial hydrocortisone Postpone non-urgent surgery Liaise with vascular surgeon
  15. 15. Single dose pharmacokinetics Dr. Andrew Ferguson Drug Redistribution T1/2 (min) Protein binding % VdSS l/kg Clearance ml/kg/min Elimination T1/2 (hrs) Thiopental 2-4 85 2.5 3.3 11 Methohexital 5-6 85 2.2 11 4 Propofol 2-4 98 2-10 20-30 4-23 Midazolam 7-15 94 1.1-1.7 6.4-11 1.7-2.6 Diazepam 10-15 98 0.7-1.7 0.2-0.5 20-50 Lorazepam 3-10 98 0.8-1.3 0.8-1.8 11-22 Etomidate 2-4 75 2.5-4.5 18-25 2.9-5.3 Ketamine 11-16 12 2.5-3.5 12-17 2-4
  16. 16. Induction Characteristics Dr. Andrew Ferguson Drug Induction dose (mg/kg) Onset (secs) Duration (mins) Excitation Injection pain Heart rate BP Thiopental 3-6 <30 5-10 + 0/+ + - Methohexital 1-3 <30 5-10 ++ + ++ - Propofol 1.5-2.5 15-45 5-10 + ++ 0/- -- Midazolam 0.2-0.4 30-90 10-30 0 0 0 0/- Diazepam 0.3-0.6 45-90 15-30 0 +/+++ 0 0/- Lorazepam 0.03-0.06 60-120 60-120 0 ++ 0 0/- Etomidate 0.2-0.3 15-45 3-12 +++ +++ 0 0 Ketamine 1-2 45-60 10-20 + 0 ++ ++
  17. 17. CNS effects of IV anaesthetics CMRO 2 = cerebral metabolic rate for oxygen CBF = cerebral blood flow CPP = cerebral perfusion pressure ICP = intracranial pressure Dr. Andrew Ferguson Drug CMRO 2 CBF CPP ICP Anticonvulsant Thiopental -- -- + -- Yes Methohexital -- -- + -- No Propofol -- -- - - Yes Etomidate -- -- + -- No Benzodiazepines - + 0 - Yes Ketamine + ++ + + No
  18. 18. CVS Effects of IV Anaesthetics Dr. Andrew Ferguson Drug MAP HR CO Contractility SVR Venous dilatation Thiopental - + - - + ++ Methohexital - ++ - - + + Propofol -- - - - -- ++ Etomidate 0 0 0 0 0 0 Diazepam 0/- + 0 0 -/0 + Midazolam 0/- + 0/- 0 -/0 + Ketamine ++ ++ + + + 0
  19. 19. RS Effects of IV Anaesthetics Dr. Andrew Ferguson Drug Ventilation Respiratory rate CO 2 response Hypoxia response Propofol --- -- --/--- Thiopental -- - -- Ketamine Unchanged Unchanged Unchanged ? Midazolam Unchanged Unchanged - - Etomidate - - -
  20. 20. Dr. Andrew Ferguson Propofol Thiopental Midazolam Ketamine Etomidate SBP Decrease Decrease 0/Decrease Increase Decrease Heart rate 0/Decrease Increase Unchanged Increase Decrease SVR Decrease Decrease Unchanged/Decrease Increase Decrease Ventilation Decrease Decrease Unchanged Unchanged Unchanged Resp rate Decrease Decrease Unchanged Unchanged Unchanged CO 2 response Decrease Decrease Unchanged Unchanged Unchanged CBF Decrease Decrease Unchanged Unchanged/Increase Unchanged CMRO 2 Decrease Decrease Unchanged Unchanged/increase Unchanged/Decrease ICP Decrease Decrease Unchanged Unchanged/Increase Unchanged Anticonvulsant Yes? Yes Yes Unclear Anxiolysis No No Yes No Yes? Analgesia No No No Yes No? Emergence delirium No No No Yes No N&V Decrease Unchanged Unchanged Increase Increase Adrenal suppression No No Yes? No No

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