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 H2O => 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 GABAA 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 GABAA receptor

• Hepatic metabolism• Vasodilatation with MDZ > Diazepam

Dr. Andrew Ferguson

Thiopental• Thiobarbiturate

• Sodium salt + anhdrous NaHCO3 => 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, CMRO2, 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 redistributionDr. 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

Dr. Andrew Ferguson

Single dose pharmacokinetics

DrugRedistribution

T1/2 (min)Protein

binding %VdSSl/kg

Clearanceml/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

Dr. Andrew Ferguson

Induction Characteristics

DrugInduction 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 ++ ++

Dr. Andrew Ferguson

CNS effects of IV anaestheticsDrug CMRO2 CBF CPP ICP Anticonvulsant

Thiopental -- -- + -- Yes

Methohexital -- -- + -- No

Propofol -- -- - - Yes

Etomidate -- -- + -- No

Benzodiazepines - + 0 - Yes

Ketamine + ++ + + No

CMRO2 = cerebral metabolic rate for oxygenCBF = cerebral blood flowCPP = cerebral perfusion pressureICP = intracranial pressure

Dr. Andrew Ferguson

CVS Effects of IV AnaestheticsDrug 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

Dr. Andrew Ferguson

RS Effects of IV AnaestheticsDrug Ventilation Respiratory rate CO2 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

CO2 response Decrease Decrease Unchanged Unchanged Unchanged

CBF Decrease Decrease Unchanged Unchanged/Increase

Unchanged

CMRO2 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

Dr. Andrew Ferguson