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 KATP channel
* c.f. opioids, inhaled AA activates KATP 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