1. Pharmacology
        1.1. IV anaesthetics
1.1.2. Nonbarbiturate IV anaesthetics

Nonbarbiturate IV anaesthetics

[Ref: SH(H)2:p151]

Propofol

Structure

Substituted isopropyl phenol
* 2,6-diisopropylphenol

NB:

Not a chiral compound
* Unlike thiopentone, etomidate, ketamine

Pharmaceutics

Propofol is insoluble
--> Requires lipid vehicle for emulsification

Emulsifying agent is of long-chain triglyceride
* Supports bacterial growth
* Increases plasma triglyceride concentration

Diprivan
Generic formulation

Mechanism of action

Relative selective modulator of GABAa receptor
--> Increased transmembrane Cl- conductance
--> Hyperpolarisation of postsynaptic cell membrane

Pharmacokinetics

Distribution

Propofol crosses placenta but is rapidly cleared from foetal circulation

Metabolism

Hepatic metabolism

Metabolite
Elimination
Clearance

Clearance of propofol exceeds hepatic blood flow
--> Hepatic metabolism is not the only mechanism of clearance
* Tissue uptake (possibly into the lungs) also contributes

Rapid clearance
--> Context-sensitive half-time minimally affected by duration of infusion

Clearance does not seem be be affected by liver cirrhosis or renal dysfunction

Clearance = 25mL/kg/min
* c.f. thiopentone = 3mL/kg/min

Clinical use

Advantage
Disadvantage

Actions

CNS
CVS
Resp
Hepatic and renal function
Intraocular pressure
Coagulation

Side effects

Allergic reactions
Lactic acidosis

Differential diagnosis include
* Hyperchloremic metabolic acidosis (associated with large volume of NS infusion)
* Metabolic acidosis (e.g. diabetic acidosis)

Proconvulsant activity

Small incidence of spontaneous excitatory movements of subcortical origin during induction or emergence

Does NOT produce seizure activity in known seizure patient
* Considered safe for use in epilepsy
* Same as thiopentone

Bacterial growth

Strongly supports growth of
* Escherichia coli, and
* Pseudomonas aeruginosa

Thus

Antioxidant properties

Strong antioxidant properties
* Similar to endogenous vitamin E

Pain in injection
Airway protection
Miscellaneous

Etomidate

Carboxylated imidazole-containing compound

Pharmaceutical

Fat emulsion preparation
* Pain on injection unlikely
* Venous irritation unlikely

Mechanism of action

Administered as R(+) isomer
* 5 times as potent as S(-) isomer

Acts on GABAa receptor
* Binds directly on the receptor
* Enhance the affinity of GABA for these receptors

Pharmacokinetics

Vd is large

Cross BBB rapidly
* Peak level within 1 min of IV administration

Fast recovery
* Rapid redistribution
* Rapid metabolism

Metabolism

Rapid metabolism

Hydrolysis of ethyl ester side chain
--> Carboxyli acid ester
* Water soluble and inactive

Clearance of etomidate is about 5 times that for thiopentone

Short elimination half-time (2-5 hours)

Context sensitive half-time not increased much by infusion duration

Clinical uses

Induction of anaesthesia
* 0.2-0.4 mg/kg IV
* Alternative to propofol or barbiturates
* Stable for CVS
* Little hangover or cumulative effect

However,

Side effects

CNS

Direct cerebral vasoconstrictor
--> Decrease CBF and CMRO2

Can activate seizure foci or excitation spikes on EEG
--> Use with caution in epilepsy (general or focal)

CVS

Cardiovascular stability at 0.3 mg/kg

Very minimal myocardial depressant effect at induction dose
--> Good for patients with little CVS reserve

Hypotension is more likely in hypovolaemic patient

Ventilation

Less ventilatory depression than barbiturate

Apnoea may result from rapid IV administration

Pain on injection

No pain on injection with lipid emulsion formulation

But still pain with the propylene glycol formulation (not used)

Myoclonus

Myoclonus spontaneous movement occurs in 50-80% of patients receiving etomidate without premedication

Mechanism
* Disinhibition of subcortical structures which normally suppress extrapyramidal motor activity
* May also be associated with seizure activity

Adrenocortical suppression

Dose-dependent inhibition of the coversion of cholesterol to cortisol

Enzyme inhibition last 4-8 hours after IV induction

May adversely affect patients with sepsis or haemorrhage

Allergic reaction

Very rare

Ketamine

Phencyclidine derivative

Structure-activity relationship

Two isomers
--> R(-) and S(+)

S(+) vs R(-)
S(+)
R(-)

Mechanism of action

Binds noncompetitively to NMDA receptors
* Phencyclidine recognition site on NMDA receptor

Only weak actions at GABAa receptors
* Unlike propofol and etomidate

Interaction with other receptors

Antagonist effect at muscarinic receptors
* Anticholingeric symptoms (emergence delirium, bronchodilation, sympathomimetic action)

Interaction with voltage-gated sodium channel
* Shares a binding site with local anaesthetics
* Mild local anaesthetic action

NMDA receptor

NMDA = N-methyl-D-aspartate

NMDA recept is

Pharmacokinetics

Rapid onset

Relatively short duration

High lipid solubility
--> Rapid transfer rate into CNS

Metabolism

High hepatic extraction ratio
* Alteration in hepatic blood flow can change ketamine clearance

Metabolised by hepatic microsomal enzymes
--> (Demethylation)
--> Norketamine

Norketamine
* 1/5 to 1/3 potency of ketamine
* Contribute to prolonged ketamine analgesic effect
* Eventually hydroxylated, conjugated, then excreted in urine (as inactive metabolite)

Clinical use

Analgesia
Dissociative anaesthesia

Cataleptic state, where...

Also, there would be...

Induction of anaesthesia
Fast action
Recovery
Other uses

Evaluation of ketamine

Advantage
Disadvantage

Caution

Use cautiously or avoid in

Side effect

CNS
Emergence delirium
Mechanism
Risk factors for emergence delirium
Prevention of emergence delirium
CVS

Ketamine has intrinsic myocardial depressant effect

But ketamine directly stimulates CNS
--> Increased sympathetic outflow
--> Overrides the depressant effect

Overall effects

Similar to sympathetic stimulation
--> Increased BP, HR, CO, myocardial O2 requirement

Exception to the cardiovascular stimulation

Depression of CNS with inhaled AA or diazepam
--> Prevention of sympathetic stimulation
--> Haemodynamic depression instead of stimulation

In critically ill patients
* Depletion of endogenous catecholamines stores
--> Haemodynamic depression

Respiratory system
Coagulation
Other systems

Dextromethorphan



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