Anaesthesia and surgery
Agents used to induce anaesthesia work by modifying the function of ligand-gated ion channels in nerve cell membranes; the exact mechanism is still controversial.
Anaesthetics also suppress muscle tone and induce relaxation, though nowadays additional muscle relaxants are often administered as well. Use of muscle relaxants gives the surgeon easier access to the surgical site. The prevention of the patient's muscle stretch reflex and the suppression of muscle resting tone facilitates intubation and mechanical ventilation.
The route of anaesthetic administration may be either 1) intravenous or 2) inhalational.
1) Intravenous agents may be opioid or non-opioid. They include the newest intravenous anaesthetic, propofol (C12H18O; introduced into clinical practice 1989: tradename Diprivan), a rapidly-metabolised induction and maintenance anaesthetic which structurally resembles the neurotransmitter GABA and suppresses activity in the wakefulness-promoting tuberomammillary nucleus; etomidate (C14H16N2O2; introduced 1972: Amidate), an induction agent causing minimal cardiovascular depression on account of its unique lack of effect on the sympathetic nervous system; barbiturates such as thiopentone (Pentothal) and methohexital (Brevital); benzodiazepines such as diazepam (introduced as an anaesthetic 1966: Valium), midazolam (Versed) and lorazepam (Ativan), used both for pre-anaesthesia sedation and induction anaesthesia; and ketamine (C13H16CINO; Ketalar).
2) Inhalational anaesthetics include the gas nitrous oxide (N2O); and potent volatile liquids such as the halogenated derivative of alkane, halothane (CF3CHClBr; introduced in 1956; tradename Fluothane); and the halogenated derivatives of ethers, notably enflurane (CHClFCF2OCHF2; introduced 1972: Ethrane); the malodorous isoflurane (CF3CHClOCHF2; introduced 1981: Forane); the more volatile but equally malodorous desflurane (CF3CHFOCHF2; introduced 1992: Suprane); and the non-irritating, sweet-tasting, highly insoluble sevoflurane (C4H3F7O; introduced 1990: Ultane).
The inert gas xenon (Xe) is under active investigation. It is a safe and effective inhalation anaesthetic and analgesic with potent hypnotic properties and a fast recovery time. Xenon is not a cardiac depressant, an important advantage. It's extremely insoluble in plasma; hence its onset of action is rapid. However, xenon is expensive.
Anaesthetists in a few countries continue to use "Nature's Quaalude", the demonised gamma-hydroxybutyrate (GHB; Xylem).
In contemporary surgery, both fast-acting intravenous induction agents and inhalational anaesthetics with complementary properties are normally combined. Anaesthetists commonly aim at so-called balanced anaesthesia rather than relying on a single agent. Modern practice strives for "anaesthesia, analgesia, amnesia, areflexia and autonomic stability". No single drug achieves this all at once. Moreover the use of separate drugs to modulate each desired effect allows both the anaesthetist and the surgeon a greater measure of control. Unless a fast-acting intravenous agent is used at the outset, the induction of anaesthesia may precipitate a brief initial delirious and excitatory phase in the patient, especially in the case of nitrous oxide or, historically, ether; this phase is followed by sedation and a dose-dependent increase in anaesthetic depth. An opioid analgesic is typically added. Inhaled anaesthetics themselves activate descending supra-spinal pain-inhibitory systems, but at low, sub-anaesthetic doses they can sometimes even increase sensitivity to pain. The additional opioid acts on the opioid receptors in the spinal cord to ensure noxious stimuli don't reach the brain, where their intensity might wake or partially rouse the lightly anaesthetised patient.
Major surgery without anaesthesia is now unthinkable: even so, after many decades of research, the precise molecular mechanisms by which anaesthetic agents induce controllable oblivion are as obscure as those that generate conscious mind. Anaesthetics act on the brain's reticular activating formation, essential to waking consciousness; and the hippocampus, critical to memory-formation; and especially on the thalamic sensory relay nuclei and the regions of the lower cortex to which they project: the thalamic sensory relay nuclei normally control sensory information by coordinating and dynamically filtering impulses signalling hearing, touch, and vision from the rest of the body. One interesting if speculative hypothesis about general anaesthesia supposes that (an)aesthesia depends on a single thalamocortical switch - a hyperpolarization block of thalamocortical neurons.
There is no obvious structure-activity relationship between different anaesthetic agents. Inert gases, simple organic and inorganic compounds, and more complex organic compounds like halogenated alkanes can all induce reversible unconsciousness. General anaesthetics lack specific antagonists. A positive linear correlation (the Meyer Overton rule) over several orders of magnitude exists between the potency of many different gaseous anaesthetic agents and their lipid solubility. However, this correlation may prove a false lead. Earlier theories that anaesthetics work via the volume expansion of neuronal membranes or increased membrane fluidity have fallen from favour. Most anaesthetics enhance the activity of subtypes of the inhibitory gamma-aminobutyric acid type A (GABA(A)) and glycine receptors; most anaesthetics also inhibit the activity of excitatory glutamate receptors; and no general anaesthetics are known that aren't either GABA-mimetics or NMDA antagonists.
Some philosopher-anaesthetists believe that a solution to the mysteries of consciousness itself lies in understanding the mechanism of general anaesthesia. All anaesthetic gases dissolve in the hydrophobic pockets of neuronal membranes via extremely weak and transient quantum mechanical van der Waals forces known as London dispersion forces - named after German physicist Fritz London rather than any localised departure from the Uniformity of Nature in the metropolis. London dispersion forces arise from the weak attractive force of the electrons on one molecule for the nuclei of another molecule. They are a manifestation of instantaneous couplings of electron clouds between two or more otherwise non-polar atoms or molecules. Anaesthetics disrupt this intermolecular force, sabotaging the normal protein conformational dynamics that underlies waking and dreaming sentience. The effect on consciousness of this subtle disruption is readily reversible, more-or-less controllable - and profound. Yet until we understand how something akin to unitary conscious mind is generated from a giant colony of neurons, it is hard to be sure how it can best be reversibly extinguished for the purposes of surgical medicine - or just sounder sleep.
Even the assumption that consciousness is extinguished rather than disrupted under anaesthesia is problematic; it rests on a dualist ontology of mind and matter. Possibly what's lost in anaesthesia is not consciousness but unitary consciousness: a loss of macroscopic quantum coherence in the cytoskeletal microtubules and consequent disruption of the ultrafast succession of coherent states that sustains one's egocentric virtual world and its illusory permanence. The effect of this drug-induced decoherence isn't unique to states of general anaesthesia. A loss of "binding" of spatially and temporally distributed brain activities into unitary visual objects, and a parallel loss of unitary self, occurs in dreamless sleep as well. Fortunately, binding/coherence is normally regenerated after a short interval: we either start dreaming again or wake up. On this analysis, when all appreciable quantum mechanical coherence is lost under general anaesthesia or for the duration of dreamless sleep, mind/brains decohere to mere quasi-classical cellular aggregates again, with no more collective awareness than an ant-colony or the enteric nervous system of the gut. This status is all that one might intuitively expect of a warm, wet, noisy bunch of cells in the first place. More disconcertingly, there are common molecular mechanisms of action between different anaesthetic agents used on animals and (experimentally) on plants. Presumably plants and animals without central nervous systems lack unitary awareness, whether drugged and anaesthetised or otherwise.
Such philosophical musings might seem academic for the patient undergoing surgery. Yet their clinical relevance can't be discounted altogether. "General" anaesthesia is sometimes incomplete; it varies in depth as well as duration. Tens of thousands of mid-operative awakenings occur in operating theatres every year, in spite of a battery of sophisticated monitoring equipment to aid the anaesthetist. Emergence reactions and out-of-the body experiences are especially common with the dissociative anaesthetic ketamine, a cousin of PCP ("angel dust") now used mainly by veterinarians and psychonauts rather than anaesthetists for that very reason.
Agents used as general anaesthetics induce amnesia too, mainly in consequence of their effects on the hippocampus. Historically, the amnesia induced by Seishu Hanaoka's powerfully anticholinergic herbal concoction tsusensan, an orally administered general anaesthetic, was presumably profound. But sometimes post-surgical amnesia is only partial. This is one reason patients are often given amnestic benzodiazepines as premeds. There is a voluminous literature of anaesthesia-induced mystical experiences. John Millington Synge (1871-1909), the Irish poet and playwright [Riders to the Sea etc], wrote of his experiences under ether anaesthesia: "I seemed to traverse whole epochs of desolation and bliss. All secrets were open before me...." [Interstate Medical Journal 23:45-49, 1916].
In a similar vein, the philosopher, writer and naturalist Henry David Thoreau (1817-1862) underwent a transcendental ether experience while several of his teeth were extracted: "If you have an inclination to travel take the ether - you go beyond the furthest star..." Yet the likelihood of extrastellar travel is now remote: patients preparing for surgery should not be unduly alarmed. The unitary consciousness of most contemporary subjects undergoing anaesthesia goes out like a light.
and further reading
The End of Suffering?
The Good Drug Guide
The Abolitionist Project
MDMA: Utopian Pharmacology
Critique of Huxley's Brave New World
Anaesthesia and Pain History Resources
Anestesia contemporânea e anestésicos (Br. Portuguese)