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Intravenous Anaesthetics
- 1. Craigavon Area Hospital CT1 Educa.on Series (Intro) Intravenous Anaesthe.cs Dr. Andrew Ferguson
- 2. Overview • Mechanisms of ac.on • Pharmacological principles • Individual agent overviews • Pharmacokine.cs • Induc.on characteris.cs • Organ effects Dr. Andrew Ferguson
- 3. How do they work? • Major inhibitory neuro-‐transmiMer in the CNS = GABA • Ac.ve GABA receptor => Cl-‐ influx => hyperpolarisa.on • Propofol & barbiturates slow GABA/receptor dissocia.on • Benzodiazepines increase GABA to receptor coupling • Ketamine acts at NMDA receptor • These effects lead to seda.ve & hypno.c effects Dr. Andrew Ferguson
- 4. Pharmacodynamics • Increasing dose => seda.on => hypnosis • All iv anaesthe.cs affect other organ systems – Poten.al for respiratory depression – Poten.al for CVS depression – Poten.al for altered CBF/ICP • Hypovolaemia => severe haemodynamic effects seen due to decreased blood pool – Use lower doses! Dr. Andrew Ferguson
- 5. Distribu.on & Elimina.on Dr. Andrew Ferguson
- 6. Single-‐injec.on Kine.cs Dr. Andrew Ferguson
- 7. Context-‐sensi.ve Half-‐Time • Time required for central compartment blood concentra.on to fall by half as a func.on of the dura.on of an infusion (of variable rate designed to maintain steady state) Dr. Andrew Ferguson
- 8. Schema for Discussing Drugs • Chemistry • Structure & structure-‐ac.vity rela.onship • Physical proper.es • Mode of ac.on • Organ effects • CVS • RS • CNS • GIT etc. • Pharmacokine.cs • Distribu.on • Metabolism • Elimina.on • Side-‐effects • Clinical Use Dr. Andrew Ferguson
- 9. Propofol • Very widespread use...know inside out! • 2,6-‐diisopropylphenol • Emulsion with 10% soybean oil, 2.25% glycerol and 1.2% lecithin (egg yolk phospha.de -‐ ? allergen) • Injec.on pain (up to 65%) decreased by lidocaine • Induc.on dose higher in kids, lower in elderly • Metabolised in liver & ? lungs • Wake-‐up due to redistribu.on, not metabolism • Significant vasodilata.on & baroreceptor inhibitor • An.eme.c • Suppresses laryngeal reflexes Dr. Andrew Ferguson
- 10. Etomidate • Imidazole deriva.ve, D-‐(+) isomer • Poorly soluble in H2O => propylene glycol used • Wake-‐up due to redistribu.on • Metabolised by ester hydrolysis to inac.ves • Minimal haemodynamic effects, short half-‐life • High incidence of PONV (35-‐40%) • May ac.vate seizure foci, myoclonus in 50% • Adrenocor.cal suppression • dose-‐dependent 11 β-‐hydroxylase inhibi.on • lasts 4-‐12 hrs aier single dose (much longer in cri.cally ill) Dr. Andrew Ferguson
- 11. Ketamine • Phencyclidine deriva.ve • Racemic mixture: S-‐isomer fewer adverse effects • Effects – Significant analgesia at sub-‐anaesthe.c doses – “Dissocia.ve anaesthesia” -‐ catalep.c state – Blocks NMDA receptor (NOT GABAA ac.ve) – Vivid dreams or hallucina.ons during recovery – EEG changes cannot be used to gauge depth – More stable haemodynamics in unstable pa.ents – Less diminu.on of airway reflexes (less, not none!!) Dr. Andrew Ferguson
- 12. Benzodiazepines • iv prep: midazolam, diazepam, lorazepam • Midazolam has imidazole ring • ring protonated => water soluble at acid pH • In body, ring unprotonated => lipid soluble • solubility NOT due to opening of benzo ring at low pH • At pH 4 only 9% of MDZ rings are open (75% at pH 2) • Bind specific site between α + γ subunits of GABAA receptor • Hepa.c metabolism • Vasodilata.on with MDZ > Diazepam Dr. Andrew Ferguson
- 13. Thiopental • Thiobarbiturate • Sodium salt + anhdrous NaHCO3 => pH 10-‐11 • Precipitates with acidic drugs e.g. NMBs • Extravascular injec.on => pain + .ssue injury • Intra-‐arterial injec.on => crystals + ischaemia • Dose dependent CNS depression • Decrease CBF, ICP, CMRO2, seizure ac.vity • Less BP fall at induc.on than propofol • Compensatory heart rate increase offsets vasodilata.on effects • Cau.on in hypovolaemia, tamponade, IHD, heart failure • Wake-‐up due to redistribu.on Dr. Andrew Ferguson
- 14. Management of intra-‐arterial injec1on of Thiopental Stop injec1on but leave needle or cannula in place Dilute with immediate injec.on of saline Give intra-‐arterial LA + vasodilator Lidocaine 50mg (5 ml of 1% solu.on) Phenoxybenzamine (α blocker) 0.5 mg bolus or 50-‐200 µg/minute infusion Consider systemic papaverine 40-‐80 mg Consider sympathe.c blockade (stellate ganglion or brachial plexus block) Start iv heparin infusion Consider intra-‐arterial hydrocor.sone Postpone non-‐urgent surgery Liaise with vascular surgeon Dr. Andrew Ferguson
- 15. Single dose pharmacokine.cs Redistribu.on Protein VdSS Clearance Elimina.on Drug T1/2 (min) binding % l/kg ml/kg/min 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 Dr. Andrew Ferguson
- 16. Induc.on Characteris.cs Induc.on dose Onset Dura.on Injec.on Heart Drug (mg/kg) (secs) (mins) Excita.on pain 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 ++ ++ Dr. Andrew Ferguson
- 17. CNS effects of IV anaesthe.cs Drug CMRO2 CBF CPP ICP An1convulsant Thiopental -‐-‐ -‐-‐ + -‐-‐ Yes Methohexital -‐-‐ -‐-‐ + -‐-‐ No Propofol -‐-‐ -‐-‐ -‐ -‐ Yes Etomidate -‐-‐ -‐-‐ + -‐-‐ No Benzodiazepines -‐ + 0 -‐ Yes Ketamine + ++ + + No CMRO2 = cerebral metabolic rate for oxygen CBF = cerebral blood flow CPP = cerebral perfusion pressure ICP = intracranial pressure Dr. Andrew Ferguson
- 18. CVS Effects of IV Anaesthe.cs Drug MAP HR CO Contrac.lity SVR Venous dilata.on Thiopental -‐ + -‐ -‐ + ++ Methohexital -‐ ++ -‐ -‐ + + Propofol -‐-‐ -‐ -‐ -‐ -‐-‐ ++ Etomidate 0 0 0 0 0 0 Diazepam 0/-‐ + 0 0 -‐/0 + Midazolam 0/-‐ + 0/-‐ 0 -‐/0 + Ketamine ++ ++ + + + 0 Dr. Andrew Ferguson
- 19. RS Effects of IV Anaesthe.cs Drug Ven1la1on Respiratory rate CO2 response Hypoxia response Propofol -‐-‐-‐ -‐-‐ -‐-‐/-‐-‐-‐ Thiopental -‐-‐ -‐ -‐-‐ Ketamine Unchanged Unchanged Unchanged ? Midazolam Unchanged Unchanged -‐ -‐ Etomidate -‐ -‐ -‐ Dr. Andrew Ferguson
- 20. Propofol Thiopental Midazolam Ketamine Etomidate SBP Decrease Decrease 0/Decrease Increase Decrease CVS Heart rate 0/Decrease Increase Unchanged Increase Decrease SVR Decrease Decrease Unchanged/ Increase Decrease Decrease Ven1la1on Decrease Decrease Unchanged Unchanged Unchanged RESP Resp rate Decrease Decrease Unchanged Unchanged Unchanged CO2 response Decrease Decrease Unchanged Unchanged Unchanged CBF Decrease Decrease Unchanged Unchanged/ Unchanged Increase CMRO2 Decrease Decrease Unchanged Unchanged/ Unchanged/ increase Decrease CNS ICP Decrease Decrease Unchanged Unchanged/ Unchanged Increase An1convulsant Yes? Yes Yes Unclear Anxiolysis No No Yes No Yes? Analgesia No No No Yes No? Emergence delirium No No No Yes No Dr. Andrew Ferguson N&V Decrease Unchanged Unchanged Increase Increase Adrenal suppression No No Yes? No No