Hipertermia Maligna

Inhaled agents
* Current - Nitrous Oxide, Halothane, Enflurane, Isoflurane, Sevoflurane, Desflurane
* Previous - Chloroform, Cyclopropane, Methoxyflurane, Trichloroethylene, Fluroxene, Diethylether
* Others - Xenon , Argon, Nitrogen, Compound 485, Thiomethoxyflurane, n-Pentane, Hydrogen, Diosychlorane.
Mechanism of A ction - Uncertain
Anatomy | Site | Comment |Macroscopic | CNS | Transmission disrupted throughout CNS |
  | Brain vs Spinal cord | Decerebration does not alter anaesthetic requirements |
Microscopic | Axon vs Synapse | Axonal disruption needs higher concentration than synaptic disruption |
  | Excitatory vs Inhibitory | Blockage and enhancement of excitatory transmission occurs |
  | Pre vs Post synaptic | Intracellular [Ca 2+]alters pre and other ions alter post |
Molecule | Membrane | The Meyer-Overton rule states that the potency of an anaesthetic is proportional to its lipid solubility.  This suggests a lipophilic site of action. |
  | Lipid vs protein | Both involved |
The most likely site of action are proteins, specifically ion channels, membrane receptors and intracellular enzyme systems. The idea of aunitary theory of anaesthesia must be considered obsolete.  It is clear that drugs that act at multiple sites to produce anaesthesia.
1. The GABA A receptor-chloride channel is a ligand-gated inhibitory complex that contains modulatory sites for benzodiazepines, barbiturates, etomidate, propofol, steroid anaesthetics and volatile anaesthetics.   Intravenous and inhalational anaesthetis alsomodulate the presynaptic release or uptake of GABA
2. There are at least six different classes of voltage-sensitive calcium channels , at least three have been linked to the action of volatile and intravenous anaesthetics
* T-type - T-type calcium channels are important in controlling the state of the postsynaptic membranes in the brain.  Volatile anaesthetics depress this receptor inseveral cell types which, at least in part, accounts for their anaesthetic action.
* L-type - Barbiturates, etomidate, ketamine, propofol and alphaxalone inhibit dihydropyridine binding, but not verapamil binding to this receptor
* N-type
* Isoflurane inhibits neuronal calcium channel currents by enhancing current inactivation and prolonging the recovery time afterinactivation
3. Nitrous oxide, Xenon and ketamine preferentially act on the N-methyl-D-aspartate (NMDA ) receptor
4. The Muscarinic complex is important in memory and consciousness.
* Desflurane has a biphasic effect on m1 signaling, enhancing at a low concentration but depressing at higher concentrations.
* Isoflurane has no effect on m1 signaling, but profoundly inhibits m3signaling
* Sevoflurane depresses the function of m1 receptors in a dose-dependent manner
* Halothane depresses the m1 and m3 receptors in a dose-dependent manner
5. The neuronal nicotinic acetylcholine receptors (nACh) have their slow desensitised conformational state stabilised by all general anaesthetics.
6. Halothane, enflurane, isoflurane, desflurane and sevoflurane, atclinical concentrations, significantly suppress voltage-gated sodium channels.
B iokinetics
  | Halothane | Enflurane | Isoflurane | Desflurane | Sevoflurane | Nitrous | Xenon |
A bsorption D istribution | 1. Factors affecting the rate of delivery of an anaesthetic to the lungs 1. The inspired partial pressure of volatile agent 2. The "second gas effect" *The concentrating effect * The passive increase in alveolar ventilation 3. Alveolar ventilation 2. Factors affecting the uptake of anaesthetic from the lungs 4. The blood gas solubility coefficient (Blood/Gas) 5. The cardiac output 6. The difference between mixed venous and alveolar volatile partial pressure 3. Factors affecting uptake of anaesthetic by the...