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

Mechanisms of action

Pharmacological principles

Individual agent overviews

Pharmacokinetics

Induction characteristics

Organ effects

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

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

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

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!

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

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)

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

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

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

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

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

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)

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

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!!)

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

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

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

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 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

Lidocaine 50mg (5 ml of 1% solution)

Phenoxybenzamine (  blocker) 0.5 mg bolus or 50-200  g/minute infusion

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