Nonbarbiturate IV anaesthetics

[Ref: SH(H)2:p151]

Propofol

Structure

Substituted isopropyl phenol
* 2,6-diisopropylphenol

NB:

• Phenyl group = Benzene ring
• Phenol group = hydroxylated benzene ring
• Propyl = 3 carbon alkane

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

• Disodium edetate (0.005%) as preservative
• Sodium hydroxide to adjust pH to 7-8.5
• Also contains soybean oil, glycerin, yolk lecithin

Generic formulation

• Sodium metabisulfite (0.25mg/mL) as preservative
• Lower pH 4.5-6.4

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

• Glucuronide and sulfate conjugates are inactive
  * 40-76%
• 4-hydroxypropofol has about 1/3 the hypnotic activity
  * 24-60%

Elimination

• Elimination half-time = 0.5-1.5 hour
• Vd = 3.5-4.5 L/kg
• Clearance = 30-60 mL/kg/min

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

• Induction of anaesthesia
  * 1.5 to 2.5 mg/kg IV
  * Equivalent to thiopentone 4-5mg/kg IV, or methohexital 1.5mg/kg IV
  * Children require higher dose
  * Elderly require lower dose
• IV sedation
  * 25-100 microgram/kg/min IV
• Maintenance of anaesthesia
  * 100-300 microgram/kg/min IV
• Antiemesis
  * 10 to 15mg IV
  * Mechanism unknown
• Antipruritic effect
  * 10 mg IV
  * Useful against pruritis associated with cholestasis or neuraxial opioid
• Anticonvulsive effect
• Attentuation of bronchoconstriction
  * Decreases prevalence of wheezing after intubation
  * Metabisulfite in generic formulation can CAUSE bronchoconstriction

Advantage

• Minimal residual CNS effect
• Prompt recovery
• Low incidence of PONV

Disadvantage

• Dose dependent hypotension
  * Greater than thiopentone
• Pain on injection
• Neuroexcitatory effects
• Cardiac arrhythmias
• Metabolic acidosis

Actions

CNS

• Decreased cerebral metabolic oxygen requirement (CMRO2)
• Decreased cerebral blood flow
  --> Decreased cerebral blood volume
  --> Decreased ICP
• Cerebrovascular autoregulation unchanged
• Reactivity to pCO2 unchanged

CVS

• Decreased in BP
  * More than thiopentone
  * More marked in hypovolaemia, elderly, and IHD
• HR relatively unchanged
  * c.f. HR increase with thiopentone
• Decreased responsiveness to atropine
  * Possible suppression of sympathetic nervous system activity

Resp

• Dose-dependent depression of ventilation
  * Apnoea occurs in 25-35%
• Bronchodilation
  * But may cause bronchoconstriction in patients with allergy histories

Hepatic and renal function

• No adverse effect on hepatic and renal function

Intraocular pressure

• Significant decreases in intraocular pressure

Coagulation

• No effect on coagulation or platelet function

Side effects

Allergic reactions

• Phenyl nucleous and diisopropyl side chains can be allergenic
• Anaphylaxis to propofol on first exposure possible
  * Especially in patients with allergy history (especially to muscle relaxants)

Lactic acidosis

• Can occur in patients receiving prolonged high-dose infusion (>75 microgram/kg/min over 24 hours)
• Unexpected tachycardia
  --> Prompt investigation for possible metabolic (lactic) acidosis
• Mechanism unclear

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

• Aseptic technique
• Discard if not used after 6 hours

Antioxidant properties

Strong antioxidant properties
* Similar to endogenous vitamin E

Pain in injection

• Mechanism unclear
  * [Lecture] Could be related to structure (phenol)
• Prior injection of 1% lidocaine or strong short-acting opioid may decrease pain

Airway protection

• Upper airway protection impaired
• Risk of aspiration

Miscellaneous

• Does NOT trigger malignant hyperthermia
• Does NOT trigger coproporphyria
• Does NOT influence cortisol secretion

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,

• Involuntary myoclonic movements are common
  * Due to actions on thalamocortical tract
• No analgesic effect
• Transiently depress adrenocortical function
  --> Limits its clinical use

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(+)

• Racemic formulation most common
• S(+) isomer also available

S(+) vs R(-)

• Both isomers inhibit uptake of catecholamines back into postganglionic sympathetic nerve endings
  * Cocaine-like activity

S(+)

• More intense analgesia
• More rapid metabolism and recovery

R(-)

• More salivation
• Higher incidence of emergence delirium

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

• Ligand-gated
• Voltage sensitive
• Glutamate sensitive
• Requires glycine as a obligatory co-agonist
• Blockade by Mg2+ ion

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

• 0.2-0.5 mg/kg IV
• Probably greater for somatic than visceral pain
• Not useful as neuraxial analgesia

Dissociative anaesthesia

Cataleptic state, where...

• Eyes remain open
• Slow nystagmic state
• Noncommunicative
• May appear wakeful

Also, there would be...

• Some hypertonus
• Some purposeful skeletal muscle movement
• Amnesia
• Intense analgesia

Induction of anaesthesia

• 1-2 mg/kg IV OR 4-8 mg/kg IM

Fast action

• Lost of consciousness in 30-60 seconds (IV) or 2-4 min (IM)
• Consciousness returns in 10-20min

Recovery

• Full orientation in another 60-90in
• Amnesia persists for 60-90 min after regaining consciousness
• No retrograde amnesia
• Normal pharyngeal or laryngeal reflex (or only slightly depressed)

Other uses

• Reversal of opioid tolerance
• Improvement of postoperative depressive state

Evaluation of ketamine

Advantage

• Water soluble
  * No need for lipild emulsion
  * Unlike propofol and etomidate
• Strong analgesia at subanaesthetic dose
  * Unlike propofol and etomidate
• Fast onset
• Cardiovascular-stimulating effect
  * Unlike propofol and etomidate
• Bronchodilatory effect
• Does not trigger malignant hyperthermia

Disadvantage

• Loss of cardioprotective effect (preconditioning) with racemic ketamine
• Abuse potential
• Possible emergence delirium
• Tolerance may occur when dosing interval too short

Caution

Use cautiously or avoid in

• Systemic HTN
• Pulmonary HTN
• Increased ICP

Side effect

CNS

• Increases cerebral blood flow and CMRO2
• Possible neuroprotection via antagonism at NMDA receptors
• Does not alter seizure threshold in epileptic patients
  * Abolition of alpha-rhythm on EEG
  * Dominance of theta-activity on EEG

Emergence delirium

• Incidence = 5-30%
• May be associated with visual, auditory, proprioceptive, and confusional illusions
  --> May progress to delirium
• May have transient cortical blindness
• Dreams and hallucination can occur up to 24 hours afterwards

Mechanism

• Depression of inferior colliculus and medial geniculate nucleous
  --> Misinterpretation of auditory and visual stimuli
• Loss of skin and musculoskeletal sensation
  --> Decreased ability to perceive gravity
  --> Floating sensation or detachent sensation

Risk factors for emergence delirium

• >15 y.o.
• Female gender
• >2 mg/kg IV
• History of frequent dreaming

Prevention of emergence delirium

• Midazolam before use of ketamine
• Inclusion of thiopentone or inhaled AA

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

• Does not produce significant ventilation depression
• Carbon dioxide response maintained
• Upper airway skeletal muscle tone maintained
• Upper airway reflex intact
• Salivery and mucous secretion are increased
  * May need antisialagogue
• Bronchodilation
  * Mechanism unclear

Coagulation

• Ketamine inhibits platelet aggregation

Other systems

• No impact on hepatic or renal function
• Does not cause histamine release
• Allergic reactions to ketamine are very rare
• Loss of ischaemic preconditioning
  * R(-) isomer prevents activation of K_ATP channel
  * c.f. opioids, inhaled AA activates K_ATP channel, mimicking ischaemic preconditioning

Dextromethorphan

• d-isomer of levorphanol
• Low affinity NMDA antagonist
• Common cough suppressant ingredient
• Equally potent as codeine in antitussive effect
• Lacks analgesia or physical dependency properties