1. General principles of General principles of anesthesia anesthesia

5. 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. Ether

12. 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. N 2 O is not lipophilic, has low solubility, and therefore has fast induction and recovery. The low solubility of N 2 O 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. Inhaled and exhaled gases Aveoli Blood Tissues, including Brain Induction and Recovery

17. Properties

20. Lipid vs Protein

23. Inhalation Anesthetic Structures

27. Analgesic Anesthetics - Fentanyls

28. 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 duration Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000 Sufentanil - 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. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears. Fentanyls

31. Barbiturates (thiopental, methohexital), benzodiazepines (diazepam, lorazepam, midazolam); Etimodate; neuroleptic butyrophenones (droperidol); muscle relaxers” – neuromuscular blocking agents, i.e. nicotinic antagonists could be either depolarizing or non-depolarizing (succinylcholine or tubocurarine); ketamine, propofol. Other Important anesthetic and pre-anesthetic compounds. How do analgesics potentiate anesthetic action? I.e. lower the MAC value of volatile anesthetics.

33. 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

34. Molecular and Neuronal Substrates for General Anesthetics Nature 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  4  3  and  6  3  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. Wallner MHanchar HJOlsen RW What is the Evidence that They Work This Way? How Do General Anesthetics Work

35. 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 GABA A (  - aminobutyric acid) and glycine receptors. a, GABA A 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)

37. The GABA A 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 didn’t necessarily prove that these were the binding sites, one would need to do pharmacological experiments for that. Ion channel mutations in vivo would prove that these were the channels involved in anesthesia. An experiment similar to the  opioid receptor that we learned about. Could also be good for looking at anticonvulsants. Summary of 1997 Nature Article on Anesthetics.

39. gamma-Aminobutyric acid type A receptors (GABARs) have long been implicated in mediating ethanol (EtOH) actions, but so far most of the reported recombinant GABAR combinations have shown EtOH responses only at fairly high concentrations (> or = 60 mM). We show that GABARs containing the delta-subunit, which are highly sensitive to gamma-aminobutyric acid, slowly inactivating, and thought to be located outside of synapses, are enhanced by EtOH at concentrations that are reached with moderate, social EtOH consumption. Ethanol enhances  4  3  and  6  3  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.Wallner MHanchar HJOlsen RW Ethanol Binding ot GABA-A Receptors

40. Copyright ©2003 by the National Academy of Sciences Wallner, M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 15218-15223 Synaptic versus extrasynaptic receptors

44. Membrane fluidity seems to be unsupported except in non-physiological model systems. Temperature dependence: Increasing temperature decreases anesthetic potency, but increases fluidity. Age correlations of anesthetic potency are the reverse of fluidity. Differential sensitivity of different types of neurons argues against a generic fluid model. You would think the membranes would be similar. Mutational experiments show specific amino acids are involved in the receptors. Many general anesthetics have a stereochemical preference, even though physical properties are the same. Some lipid soluble, halogenated compounds do not have anesthetic activity. Summary of Anesthetic mechanisms.

45. Another View