General principles of anesthesia
Historical information People always wanted to overcome the sufferings caused by pain. The history of civilization left numerous documented evidences of permanent search for ways and methods of anaesthesia. The first written mention of the pain relieving medicines was found in Egypt (described in Ebers papyrus 4 - 5 thousand years ago). Much attention was paid to this problem by the doctors of ancient Greece and Rome. They used wine, mandrake root, opium, Indian hemp, henbane and thorn-apple. In the East, in the mountains of Tibet, acupuncture and massage were widely used with anaesthetic aim.
However, until the eighteenth century there was no radical ways of pain relieving. At this time, because of the fundamental discoveries in natural sciences the preconditions of new medical possibilities appeared. In 1776 chemist Priestley synthesized nitrous oxide - an anaesthetic, which is still widely used in anaesthesiology. Another chemist, Davy, on April 9, 1779 for the first time tested the effect of nitrous oxide on himself. Later he wrote: Nitrous oxide, along with other properties, has the ability to relieve pain and thus can be successfully used in surgical operations. And only 25 years later, an English surgeon Hickman began to use the "laughing gas" in medical practice. However, this method of anaesthesia had not received adequate acceptance in Europe. At the same time in America dentist Wells began to apply nitrous oxide anaesthesia. In April 1842 his compatriot surgeon Long first used ether anaesthesia in practice. (It should be noted, that diethyl ether was synthesized by well-known chemist Paracelsus a few centuries before). With ether anaesthesia Long performed eight operations, and his observations were never published.
However, priority in the use of ether narcosis belongs to another American researcher - Morton. On October 16, 1846 at Boston University clinic he successfully administered ether narcosis during surgical removing of hemangioma in public. The operation was performed by surgeon Warren. A special Mortons contribution was a preliminary study of ether narcosis effect on animals, which was the beginning of the experimental study of general anaesthesia techniques.Therefore, the 16th of October, 1846 is considered to be the birthday of anaesthesiology.
In few months enthusiastic followers of ether narcosis appeared in all civilized countries. At the beginning of February 1847 this type of narcosis was performed by professor F.I. Inozemtsev in Moscow clinic, two weeks later it was performed in St. Petersburg by our compatriot, surgeon Mykola Ivanovych Pirogov. This outstanding surgeon and the first anaesthesiologist played prominent role in the history of ether narcosis. He was the first to argument theoretical basis for the action mechanism of ether on the central nervous system; he proposed alternative ways of administration of ether (into the trachea, in the blood, into the gastrointestinal tract). Invaluable experience of ether narcosis M. I. Pirogov described in his monograph On the application of sulphuric ether vapours in operational medicine published in 1847.
In the Crimean-Turkish war (1853 1856) our compatriot performed hundreds of successful ether anaesthesias during surgeries on gunshot injuries.In 1937 Guedel determined the clinical stages of ether narcosis, which are still considered to be classic.In 1847 a prominent scientist Simpson introduced into clinical practice another preparation for narcosis - chloroform.Since that time anaesthesiology has begun its scientific development.For 150 years of anaesthesiology history scientists proposed and implemented in clinical practice dozens of anaesthetic preparations, both inhalation and non-inhalation, as long as various types and methods of pain relief. This stimulated development of operative surgery and allowed various range of surgical interventions in all organs and systems of the body.
Anaesthesiology is a science that studies how to protect the organism from operating injuries. It improves the well-known and develops new methods of preparing patients for surgeries, providing anaesthesia, controlling the body functions during the operation and in postoperative period.
Single agents like ether produce the 4 distinct stages. The volatile anesthetics may produce a similar response. Non-anesthetic agents may be used to individually produce analgesia, muscle relaxation, amnesia, and loss of consciousness.
Is ether the perfect anesthetic?
The depth of anesthesia that can be achieved is dependent on the potency relative to the amount that can be vaporized. That is the MAC % relative to the maximum vapor concentration. The common inhalation anesthetics have a much greater potential vapor concentration than is required for effect anesthesia. Therefore they are all sufficiently potent. The issue of flammability has been addressed with the halocarbon agents, and most of these also cause little airway irritation which can be another concern.
Induction rate and recovery are important considerations. The more lipophilic compounds (higher blood:gas ratio) have slower induction and recovery, distribution into fat can also slow recovery. N2O is not lipophilic, has low solubility, and therefore has fast induction and recovery. The low solubility of N2O means that the equilibration with blood from gas is quite rapid.
Solubility in blood is somewhat counterintuitive! More lipophilic (greater oil:gas ratio) compounds also have a greater blood:gas ratios. The more lipophilic compounds are more potent as indicated by the lower MAC% values.
Induction of anesthesia involves a series of equilibration events. The anesthetic first equilibrates with the aveoli and may be slow, equilibration into the blood is rapid. The blood must become saturated for transfer to the tissues to occur, this can be slow.
Induction and Recovery
Lipid vs Protein
Inhalation Anesthetic Structures
Analgesic Anesthetics - Fentanyls
Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 g/h) Therapeutic index=400, morphine = 70 Alfentanil - Ultra-short acting, 5-10 minutes analgesic durationRemifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000Sufentanil - 5-10x Fentanyl, used for heart surgery.Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue Chechen hostage takers. Didnt turn out so well. 42 terrorists and 130 hostages died. Works well on bears.Fentanyls
Barbiturates (thiopental, methohexital),
benzodiazepines (diazepam, lorazepam, midazolam);
neuroleptic butyrophenones (droperidol);
muscle relaxers neuromuscular blocking agents, i.e. nicotinic antagonists could be either depolarizing or non-depolarizing (succinylcholine or tubocurarine);
Other Important anesthetic and pre-anesthetic compounds.How do analgesics potentiate anesthetic action?
I.e. lower the MAC value of volatile anesthetics.
Ketamine (Ketalar) Causes dissociative anesthesia. Patients feel dissociated from the environment. Similar to neuroleptic anesthesia, but caused by a single agent. Phencyclidine (PCP) has similar effects. Ketamine is injectable.Mechanism Blocks NMDA glutamate receptors
Etimodate (Amidate) is a ultrashort acting hypnotic without analgesic properties. Used only for induction because of the very short, 5 minute, duration.Mechanism GABA receptor. Similar to barbiturates
Propofol (Diprivan) Another IV anesthetic. Similar to thiopental in anesthetic effects and application, but has little renal or hepatic interaction and/or toxicity. Low incidence of side effects, little post-operative confusion.Mechanism Probably similar to the volatile anesthetics and ethanol. GABA, nACh Injectable anesthetics - Mechanisms
Molecular and Neuronal Substrates for General AnestheticsNature Reviews Neuroscience (2004) 5, 709-720. Rudolph, U. and Antkowiak, B.
Anesthetics and Ion Channels: Molecular Models and Sites of Action. Annu. Rev. Pharmacol. Toxicol. (2001) 41, 23-51. Yamakura, T., Bertaccini, E., Trudell, J.R., Harris, R.A.
Ethanol enhances 43 and 63 gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc. Natl. Acad. Sci. (2003) 100, 15218-15223. Wallner M, Hanchar HJ, Olsen RW.What is the Evidence that They Work This Way?How Do General Anesthetics Work
Figure 1 Mihic et al.5 have found that single amino-acid substitutions at two positions remove the potentiating effects of volatile anaesthetics and ethanol on GABAA (-aminobutyric acid) and glycine receptors. a, GABAA and glycine receptors bind the neurotransmitters that are released at inhibitory chemical synapses, and open to allow chloride ions to diffuse across the postsynaptic membrane. b, The main effect of volatile anaesthetics is to prolong channel opening and, hence, to increase postsynaptic inhibition. c, The receptor channels consist of pentamers of closely related subunits, and the structure of a single subunit is shown in d. The authors suggest that the two critical amino acids may form a binding site for general anesthetics and ethanol. Comment by Franks and Lieb on Mihic et al. (1997) Nature, 385-389 (1997)
The GABAA Cl- channel is structurally related to Na+, 5HT and nACh channels
Anesthetics inhibit nACh, but potentiate the others.A specific anesthetic binding site was mapped using mutational genetics.
Mutational experiments didnt nec