Intravenous Anaesthetics (Intro)

Intravenous Anaesthetics Craigavon Area Hospital CT1 Education Series (Intro) Dr. Andrew Ferguson

Overview Mechanisms of action Pharmacological principles Individual agent overviews Pharmacokinetics Induction characteristics Organ effects Dr. Andrew Ferguson

How do they work? Major inhibitory neuro-transmitter in the CNS = GABA Active GABA receptor => Cl - influx => hyperpolarisation Propofol & barbiturates slow GABA/receptor dissociation Benzodiazepines increase GABA to receptor coupling Ketamine acts at NMDA receptor These effects lead to sedative & hypnotic effects Dr. Andrew Ferguson

Pharmacodynamics Increasing dose => sedation => hypnosis All iv anaesthetics affect other organ systems Potential for respiratory depression Potential for CVS depression Potential for altered CBF/ICP Hypovolaemia => severe haemodynamic effects seen due to decreased blood pool Use lower doses! Dr. Andrew Ferguson

Distribution & Elimination Dr. Andrew Ferguson

Single-injection Kinetics Dr. Andrew Ferguson

Context-sensitive Half-Time 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) Dr. Andrew Ferguson

Schema for Discussing Drugs Chemistry Structure & structure-activity relationship Physical properties Mode of action Organ effects CVS RS CNS GIT etc. Pharmacokinetics Distribution Metabolism Elimination Side-effects Clinical Use Dr. Andrew Ferguson

Propofol Very widespread use...know inside out! 2,6-diisopropylphenol Emulsion with 10% soybean oil , 2.25% glycerol and 1.2% lecithin (egg yolk phosphatide - ? allergen) Injection pain (up to 65%) decreased by lidocaine Induction dose higher in kids, lower in elderly Metabolised in liver & ? lungs Wake-up due to redistribution, not metabolism Significant vasodilatation & baroreceptor inhibitor Antiemetic Suppresses laryngeal reflexes Dr. Andrew Ferguson

Etomidate Imidazole derivative, D-(+) isomer Poorly soluble in H 2 O => propylene glycol used Wake-up due to redistribution Metabolised by ester hydrolysis to inactives Minimal haemodynamic effects, short half-life High incidence of PONV (35-40%) May activate seizure foci, myoclonus in 50% Adrenocortical suppression dose-dependent 11  -hydroxylase inhibition lasts 4-12 hrs after single dose (much longer in critically ill) Dr. Andrew Ferguson

Ketamine Phencyclidine derivative Racemic mixture: S -isomer fewer adverse effects Effects Significant analgesia at sub-anaesthetic doses “ Dissociative anaesthesia” - cataleptic state Blocks NMDA receptor (NOT GABA A active) Vivid dreams or hallucinations during recovery EEG changes cannot be used to gauge depth More stable haemodynamics in unstable patients Less diminution of airway reflexes (less, not none!!) Dr. Andrew Ferguson

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  +  subunits of GABA A receptor Hepatic metabolism Vasodilatation with MDZ > Diazepam Dr. Andrew Ferguson

Thiopental Thiobarbiturate Sodium salt + anhdrous NaHCO 3 => pH 10-11 Precipitates with acidic drugs e.g. NMBs Extravascular injection => pain + tissue injury Intra-arterial injection => crystals + ischaemia Dose dependent CNS depression Decrease CBF, ICP, CMRO 2 , seizure activity Less BP fall at induction than propofol Compensatory heart rate increase offsets vasodilatation effects Caution in hypovolaemia, tamponade, IHD, heart failure Wake-up due to redistribution Dr. Andrew Ferguson

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 Lidocaine 50mg (5 ml of 1% solution) Phenoxybenzamine (  blocker) 0.5 mg bolus or 50-200  g/minute infusion 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

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

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 ++ ++

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

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

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 - - -

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

Intravenous Anaesthetics (Intro)

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Intravenous Anaesthetics (Intro)