Inhalational Anaesthetics Flashcards
Nitrous oxide (N2O)
Manufacture
- Careful heating of ammonium nitrate which breaks down to N2O and water vapour
- Contaminants actively removed - NH3, N2, NO, NO2 + HNO3
Storage
- Liquid in blue shoulder and white body cylinders at 51bar and 20oc
- Piped gas
- Critical temp 35.6oc
Chemical
- Low MW, odourless to sweet smelling non-flammable gas
- Low potency
- Poor blood solubility, B:G coefficient 0.47 (rapid onset)
- MAC 104%
- inhibitory action at NMDA glutamate receptors
Effects
CNS
- Incr CBF
- Anaesthesia and analgesia
- Incr SNS activity (central)
RS
- Decr Vt = incr RR -> MV unchanged
- Incr PVR -> incr R to L shunt
- Incr size of air filled cavities (e.g PTX)
- Diffusion hypoxia
- Concentration and 2nd gas effects
CVS
- Direct myocardial depressant (mild)
Other
- Inactivates B12. Oxidation of cobalt ion in Vit B12 (cofactor for methionine synthetase) -> decr synthesis of methionine and DNA -> megaloblastic changes in bone marrow, agranulocytosis, peripheral neuropathy
CNS effects
-Hypnosis
-Analgesia - N2O, xenon
-↓CMRO2 - dose dependent (Iso~sevo~des >halo)
-↑CBF - dose dependent, uncoupling (↑CBF despite ↓CMRO2), halo>iso~sevo~des
-↓cerebral autoregulation - dose dependent, direct arterial vasodilation -> high doses CBF is pressure-passive
-ICP - parallel changes in CBF
-EEG - as ↑depth of anaesthesia -> alpha -> theta -> delta -> burst suppression -> isoelectric. Enflurane - epileptiform activity
-Emergence delirium children - more common after sevo + des
-Neurotoxicity in children (no definitive human evidence)
CVS effects
- ↓contractility
- ↓SVR
- ↓BP
- HR ↑en, iso, des; same - halo, sevo
- Baroreceptor reflex preserved (depressed - halothane)
- ↓PulmVR
- ↓Renal BF
- prolong QTC - iso, sevo, des
- ↑arrhythmias with halothane
Anaesthetic preconditioning
- When volatiles administered before period of prolonged ischaemia -> protect myocardium from ischaemia and repercussion injury, decr infarct size
- Mechanism - activation of sarcolemmal and mitochondrial ATP-dependent K+ channels -> activation of Protein kinase C
Resp effects
Depression of ventilation
- ↓Vt >↑RR -> ↓MV -> ↑PaCO2
- Dose dependent
- En >iso > halo
Depression of ventilatory response to hypoxia
- Dose dependent
- Due to ↓chemoreceptor sensitivity
- Even at MAC 0.1
Depression of ventilatory response to hypercapnia
- Dose dependent
- Due to ↓chemoreceptor sensitivity
- ↑Apnoeic threshold - the PaCO2 at which ventilation resumes after a period of hyperventilation
- N2O no effect
Decreased HPV at MAC >0.6
Depression of upper airway reflexes
Bronchodilation (halo, iso, des, sevo)
Airway irritability (iso, des)
Other effects
- ↓uterine tone - MAC>1, N2O exception
- Augmentation of effects of NDMRs
- MH
- Mutagenic effects - induce DNA damage
- Depression of cell-mediated immunity (potent volatiles), iso > prop
- ?↑incidence of spontaneous abortion in OT personeel
- Impaired glucose tolerance
- PONV
O2
Physicochemical
- Critical temp -119oC
- BP -180oC
- Critical pressure 50bar
- MW 32
- Colourless
- Supports and accelerates combustion
Manufacture
- Fractional distillation of air
- By O2 concentrators using zeolite mesh that absorbs N2 from air leaving 97% O2
Storage
- Gas in all white cylinder at 137bar
- Liquid in vacuum-insulated evaporators (VIE) at 10bar and -180oC
Dangers
- Fire
- Toxicity - caused by free radical
- Absorption atelectasis
- Reduction of hypoxic respiratory drive in pt with COPD
- Retinopathy of prematurity - retinal vasoconstriction
- CNS effects - hyperbaric O2, anxiety followed by nausea + seizures
- Coronary vasoconstriction - after prolonged administration of 100%
Xenon
Physicochemical
- Inert gas
- Part of atmosphere (very small amount)
- Odourless
- Boiling point -108oC
- MAC 71
- B/G coefficient 0.14
- Diffuses freely through rubber and silicon
- Non-flammable
- Does not support combustion
Manufacture
- Fractional distillation of air
- Significantly more expensive than N2O
Effects
- ↑CBF
- Analgesic (NMDA antagonist)
- ↑Vt + ↓RR -> MV unchanged
- ↑Airway resistance - higher density than N2O (3x), higher viscosity than N2O (1.5x)
- CVS stability
- Does not trigger MH
- No diffusion hypoxia
PK
- Not metabolised in the body
- Eliminated via the lungs
Halothane
- Halogenated alkane derivative
- Clear, non-flammable liquid at room temp
- unstable in light
- Intermediate solubility in blood, B/H coefficient 2.4
- Susceptible to decomposition to hydrochloric acid, hydrobromic acid, chloride, bromide and phosgene
Hepatic toxicity
Reversible form
- Subclinical
-↑hepatic transaminases
Fulminant hepatic necrosis (halothane hepatitis)
- Tri-fluoro-acetyl chloride + hepatic proteins -> antibody formation
- High mortality rate
- Incidence
=> 1:35000 after single exposure
=> 1:3000 after multiple exposures
- Risk factors
- Multiple exposures within short period
- Obesity
- Female
- Middle age
- Genetic predisposition
- Pre-existing liver disease
(In theory may be caused by any of the other commonly used volatiles)
Desflurane
- Fluorinated methyl ethyl ether
=> Fluorination - ↑vapour pressure, enhances stability, decr potency - Can boil at room temp (boiling point 23.5C) - uses vaporiser that convert desflurane to gas, heated and pressurised vaporiser
- Low solubility, B/G coefficient 0.45, mod potency MAC 6
- Potent odour -> airway irritation (breathing holding, coughing, laryngospasm)
- CO results from degradation of des by strong base present in desiccated CO2 absorbent
Sevoflurane
- Fluorinate methyl isopropyl ether
- Stored in polythylene naphthalate bottles as glass -> toxic hydrofluoric acid
- Non-pungent, has minimal odour, produce bronchodilation, and causes least degree of airway irritation
- B/G coefficient 0.69, MAC 2
- 100x more vulnerable to metabolism than desflurane
Sevoflurane toxicity
- Hexa-fluoro-acetylated liver proteins - no formation of tri-fluoro-acetylated proteins -> extremely low potential for hepatotoxicity
- Inorganic fluoride
=> Theoretical risk of nephrotoxicity
=> Rapid pulmonary elimination -> less availability for metabolism
=> Minimal additional intra-renal production of fluoride
- Compound A (vinyl halide) - nephrotoxic in rats
=> Sevo + CO2 absorbent => compound A
=> Factors increasing rate of production
- Low FGF
- Prolonges exposure
- Closed circuit
- Baralyme > soda lime
- Higher absorbent temperatures - fresh absorbent
- Dehydration of soda lime - ↓compound A
- Dehydration of baralyme - ↑compound A
Enflurane
- Halogenated methyl ethyl ether
- Clear, non-flammable volatile liquid at room temp
- Pungent odour
- B/G coefficient 1.8, MAC 1.7
- Decreases threshold for seizures
- Oxidised in the liver to produce inorganic fluoride ions that can be nephrotoxic
Isoflurane
- Halogenated methyl ethyl ether
- Clear, non-flammable liquid at room temp
- Pungent odour
- B/G coefficient 1.4, MAC 1.15
- Extreme physical stability - easy storage
Metabolism and degradation
Primary by CYP2E1 in liver
- Agents that induce CYP2E1 (ethanol, barbiturates) increases metabolism
- Metabolism is inhibited by the agents at the higher concentrations present during anaesthesia, but is enhance during elimination of residual anaesthetic during recovery phase
- Halo (20% metabolised) > sevo >enf >iso >des >N2O + xenon (0.002% metabolised)
- Magnitude of metabolism is too small to influence rate of equilibration (exception is methoxyflurane)
Chemical degradation
- Sevo undergoes base catalysed degradation when exposed to CO2 absorbents
=> Forms compound A and B (compound A renal tubular necrosis in rats)
CO production
- Passage of volatiles through dry CO2 absorbents can produce CO (severe CO poisoning with des)
- Insignificant with sevo + halo, intermediate with iso, highest with des and enf
Recovery and elimination
- Most eliminated by exhalation
- Other routes include transcutaneous and visceral losses
- Also agent-specific metabolic component
- Biodegradation (methoxy»_space; halo»_space;> sevo >en, iso, des (extensive metabolism of methoxy (75%) and halothane (20%) contributes to faster decay in alveolar concentration
- Washout follow multiexponental decay time course, lower solubility = faster elimination
Inhalational MoA
Exact mechanism unknown
Meyer and Overton Hypothesis
- Interaction with lipid membranes
- Solubility proportional to potency
- However many soluble drugs are not anaesthetics
Protein interaction
- Pre and post synaptic effects on neurotransmission have been demonstrated, and various membrane proteins are affected by volatiles
- Inhibitory receptors - GABAA, glycine
- Two-pore-domain potassium (K2P) channels
- Excitatory receptors - antagonism NMDA, AMPA and kainite receptors
- Voltage gated ion channels
- 5-HT3 receptors
- NAChR
- Calcium channels
