02 General Anaesthetic Agents

Transcription

1 02 General Anaesthetic Agents

2 02 General Anaesthetic Agents (2 Hours) Hydrocarbons and halogenated hydrocarbons Ethers and alcohols Ultra-short acting barbiturates

3 General Anaesthetics General anesthetics depress the central nervous system to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures Not therapeutic or diagnostic General anesthesia may be defined as a state which includes 1. A reversible loss of consciousness 2. Inhibition of sensory and autonomic reflexes (including nociceptive reflexes) 3. Skeletal muscle relaxation 4. Anterograde amnesia (upon recovery) [the extent to which any individual anesthetic drug can exert these effects depend upon the drug, the dose, and the clinical circumstances}

4 General Anaesthetics General anesthetics are drugs that act in the CNS. They produce reversible loss of consciousness, thereby causing a generalized loss of sensation. The general anesthetic effect involves the following components: -loss of arousabilityin response to noxious stimuli sedation and loss of anxiety - loss of pain sensation (analgesia) in response to noxious stimuli - loss of mobility (immobility) in response to noxious stimuli skeletal muscle relaxation - loss of awareness and memory (amnesia) -attenuation of autonomic responses to noxious stimuli i.e. troublesome reflexes Not all anesthetics bring about all of these. Ex: barbiturates are not analgesics, but they will put you to sleep

5 SIGNS AND STAGES OF GENERAL ANESTHESIA (as described for diethyl ether anesthesia) 1. Stage of analgesia: Pain sensation is lost, Consciousness is still kept, unaltered pupils Minor operations (e.g., removal of pharyngeal tonsils) can be performed in this stage. 2. Stage of delirium consciousness is lost, however, there is: Disturbed consciousness: incoordinatemovements, incoherent talk Motor hyperactivity: muscle tone is increased, jaw becomes set, irregular breathing, vomiting, defecation Sympathetic hyperactivity: hypertension, tachycardia, dilation of pupils Hyperactivity is caused by blockade of small inhibitory neurons, such as the GABA-ergic Golgi II cells.

6 Stages of Anaesthesia 3. Stage of surgical anesthesia in which surgery can be performed It starts with return of regular breathing. This stage is divided into 4 planes. As the anesthesia deepens, 3 changes occur gradually: The intercostalventilation weakens, then ceases, and only the diaphragmatic ventilation remains. The pupil (constricted in plane 1) dilates gradually. Various reflexes disappear: -Corneal reflex: in plane 2 (no blinking upon stimulation of the cornea) -Peritoneal reflex: in plane 3 (no abdommuscle contrupon perit stimulation) - Pupillary reflex: in plane 4 (no pupillary constriction upon light) Loss of the pupillaryreflex is a warning sign; the sign of hypoxia!!! Other warning signs: -decreased BP, rapid pulse -shallow, irregular ventilation, cyanotic skin

7 4. Stage of medullary paralysis Respiration ceases (respiratory center paralysis) The heart stops (vasomotor center paralysis) Note: Inhalation anesthetics have a low therapeutic index, making these the most dangerous drugs in clinical use! To rescue the patient: Stop anesthetic administration, provide O 2, apply cardiopulmonary resuscitation! To prevent stage-4: Monitor cerebral function using indices of EEG activity These stages appear in diethyl ether anesthesia (no longer practiced). In modern anesthesia, the stage of delirium does not develop (i.e., "induction is smooth") because the anesthesia is induced rapidly with an: -i.v. anesthetic (e.g., thiopental, propofol), or with a -rapidly acting inhalation anesthetic (e.g., sevoflurane). Combination of i.v. and inhalation anesthetics is called balanced anesthesia: the favorable properties of each agent are exploited while the unfavorable ones are minimized.

8 Pre-anesthetics Preanesthetic medications drugs given generally prior to anesthesia (may be given during or after, as well) in order to: ❶ Decrease anxiety ❷ Sedation ❸ Provide amnesia ❹ Relieve pre-and post-operative pain ❺ Inhibit secretion ❻ Antiemetic

9 Preanesthetic Agents Drug Classification Generic Name Desired Effect Benzodiazepines Diazepam Midazolam Reduce anxiety, Sedation, Amnesia, Conscious sedation Antihistamines Hydroxyzine Sedation Opioid analgesics Morphine Meperidine Fentanyl Remifentanil Sedation to decrease tension, anxiety, and provide analgesia Phenothiazines Promethazine Sedation, antihistaminic, antiemetic, decreased motor activity Anticholinergics GI Drugs Atropine Glycopyrollate Ondansetron Ranitidine Metoclopramide Inhibit secretion, bradycardia, vomiting, and laryngospasms Antiemetic Decrease gastric acidity Decrease stomach contents

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12 Classification:

13 Minimum Alveolar Concentration The minimum alveolar concentration (MAC) is defined as the concentration at 1 atmosphere of anesthetic in the alveoli that is required to produce immobilityin 50% of adult patients subjected to a surgical incision. A further increase to 1.3 MAC frequently will cause immobility in 99% of patients. At equilibrium, the concentration (or partial pressure) of an anesthetic in the alveoli is equal to that in the brain, and it is this concentration in the brain that probably most closely reflects the concentration at the site responsible for the anesthetic actions. Thus, the MAC often is used as a measure of the potency of individual anesthetic agents

14 Minimum Alveolar Concentration Properties of the Inhaled Anesthetics

15 Minimum Alveolar Concentration When used in combinations, the MACs for inhaled anesthetics are additive. For instance, the anesthetic depth achieved with 0.5 MAC of enfluraneplus 0.5 MAC of nitrous oxide is equivalent to that produced by 1.0 MAC of either agent alone. The combination of two anesthetics is a very common practice, because this technique allows a reduction in the patient exposure to any one of the individual agents, thereby decreasing the likelihood of adverse reactions. Many factors can influence the MAC via a number of different mechanisms

16 Factors that may affect MAC:

17 Theories of Anaesthetic Action Anesthetics are a mainstay of modern medicine, but their molecular mechanism of action is still not precisely known No single theory adequately explains how anesthetics exert their pharmacological effects Our understanding on the mechanism of action of general anesthetics has developed in stages: 1. Early 1900s: Meyer-Overton Theory: Physico-chemical theory In the early 1900s Hans Meyer and Charles Overton suggested that the potency of a substance as an anesthetic was directly related to its lipid solubility, or oil/gas partition coefficient. This has commonly been referred to as the unitary theory of anesthesia. They used olive oil, octanol and other membrane-like lipids to determine the lipid solubility of the agents available at the time. Compounds with high lipid solubility required lower concentrations ( i.e., lower MAC) to produce anesthesia.

18 Theories of Anaesthetic Action This correlation is accurate for a broad range of general anesthetics: alkanols, volatile agents, and barbiturates Also, volatile anesthetics are generally additive in their effects: a mixture of a half dose of two different volatile anesthetics was in fact equal to a full dose of either drug in isolation However, it does not explain the drugs mechanism of action. i.e. General anesthetics act by being dissolved in the lipid membranes of the CNS neuronesand anesthesia develops when the anesthetic reaches a critical concentration in the neuronal cell membrane However, it was unclear what GAs did in the membrane of CNS neurons to cause anesthesia.

19 Theories of Anaesthetic Action Speculations: GAs cause physicochemical alterations. For example, they expand the membrane s lipid layer upon being dissolved in it; increase the membrane fluidity by disturbing the ordered lipid structure; induce formation of water crystals (called clathrates) in the membrane; interact with the hydrophobic domains of integral membrane proteins, e.g. ion channels In support of this theory, it was found that at high pressures ( atmospheres), the anesthetic actions of many of these agents could be partially reversed, presumably by compressing membranes back to their original conformation

20 Anomalies with unitary theories the unitary theory of anesthesia cannot adequately explain the mechanism of action of the inhaled anesthetic drugs for a number of reasons: i) Some compounds do not obey the Meyer and Overton rule. For example, not all highly lipid-soluble substances are capable of producing anesthesia e.g. some halogenated alkanespredicted to be potent anaestheticsbased on their lipid solubility fail to suppress movement in response to noxious stimulation at appropriate concentrations. These compounds are therefore termed non-immobilizers The inhaled anesthetics do disrupt the lipid bilayer but it is unclear if they make enough changes to effect cell signaling

21 Anomalies with unitary theories (ii) The ability of general anaestheticsto perturb lipid membranes in vitro can be reproduced by a temperature increase of less than 1 o C, a change well within the physiological range and clearly not sufficient to induce loss of consciousness per se. (iii) Enantiomers have identical physicochemical effects in an achiral environment (e.g. the lipid bilayer). However, in vitro and in vivo studies demonstrate that enantiomersof many general anaestheticsdo not produce identical clinical effects. For example, the R isomer of etomidateis 10 times more potent than its S isomer at potentiating GABA-A receptor activity. These differential effects suggest that the primary site of action of such anaestheticsis not the lipid bilayer and provide compelling evidence for specific interactions with stereoselective binding sites (i.e. within proteins).

22 Anomalies with unitary theories (iv) According to Meyer and Overton, the addition of methylenegroups to a homologous series of long chain alcohols, or alkanes, should increase their lipid solubility and thereby produce a corresponding increase in anaesthetic potency. However, at a certain chain length (n = 10) addition of further methylenegroups does not produce the expected increase in anaestheticpotency, i.e. there appears to be a cut off effect above a certain molecular volume which is indicative of anaestheticagents interacting with binding site(s) of finite dimensions.

23 Receptor Theories of General Anaesthesia: In a landmark series of experiments in the early 1980s, Franks and Liebdemonstrated that the relationship reported by Meyer and Overton could be reproduced using a soluble protein. They demonstrated that a range of general anaestheticsacted as competitive antagonists of the protein firefly luciferase. Remarkably, inhibition of luciferasewas directly correlated with anaestheticpotency providing persuasive evidence that general anaestheticdrugs could selectively interact with proteins. Of course, the next major hurdle involved identifying which proteins within the mammalian CNS were responsible for mediating the dramatic behaviouraleffects of general anaesthetic drugs

24 Ion Channel and Protein Receptor Hypotheses More recently, investigators have determined the effects of anesthetics on a number of protein receptors within the central nervous system. Features that support the likelihood of an interaction with a protein include: 1) the steep dose response curves observed, 2) the stereochemical requirements of various anesthetics, 3) the finding that increasing the molecular weight and corresponding lipid solubility of an anesthetic may actually decrease or abolish anaestheticactivity, and 4) the finding that specific ion channels and neurotransmitter receptor systems are required for most of the observed effects of the anesthetics. What appears to be emerging as a central theme for the mechanism of action of general anesthetics involves the interact ion of the anesthetics with receptors that allostericallymodulate the activity of ion channels (e.g., chloride and potassium) or with the ion channel directly (e.g., sodium). Many other mechanisms also are emerging to help explain the mechanisms of act ion of the general anesthetics.

25 Ion Channel and Protein Receptor Hypotheses In the 1980s, Benzodiazepines (BZD) and barbiturates were discovered to produce hypnotic effect by activating the GABA-A receptors. GABA-A receptor (GABA-gated Cl - channel) activation causes Cl- influx, neuronal hyperpolarization and is inhibitory. GAs bind to GABA-A receptor in a hydrophobic pocket located in the tran-smembranedomain and stabilize the open form of the Cl - channel May this be a major mechanism underlying the 78-yr-old lipid theory? In the 1990s,it was discovered that it was not only BZD and barbiturates that activate GABA-A receptor, but most general anesthetics as well! Moreover, GAs were also discovered to affect other ligandgated ion-channels, thereby causing neuronal hyperpolarization In the Early 2000s, it was discovered that GAs also activate TREK-1, a two-pore-domain background K + channel, causing K + efflux and neuronal hyperpolarization. TREK-1 knock-out mice exhibit resistance to several volatile anesthetics

26 Ion Channel and Protein Receptor Hypotheses

27 Ion Channel and Protein Receptor Hypotheses The concept today: By acting on ligand-gated ion channels and certain K + channels, general anesthetics hyperpolarize neurons and thereby inhibit synaptic transmission in the CNS. Unlike local anesthetics, general anesthetics do not inhibit axonal conductance, as they do not affect the voltage-gated Na + channels at anesthetic concentrations Inhibition of synaptic transmission in specific brain areas by GAs is responsible for the 4 components of the general anesthetic effect:

28 Ion Channel and Protein Receptor Hypotheses

29 INHALATION ANESTHETICS GENERAL PROPERTIES: 1. Chemical properties: More or less lipid soluble hydrophobic chemicals. Lipid solubility determines both their potency and pharmacokinetics 2. Potency: The more lipophilic, the more potent they are (= the lower is their MAC value). Nitrous oxide never used alone low potency anaesthetic Lipid solubilty oil:gas part. Coeff. PotencyMAC value, % conc Methoxyflurane Halothane Isoflurane Enflurane Sevoflurane Desflurane Nitrous Oxide * 0.5 Blood:gaspart. Coeff.

30 3. Pharmacokinetics INHALATION ANESTHETICS Absorption: -Mechanism: diffusion across the alveolar membrane (driven by the concentration gradient); Speed: rapid (due to large alveolar surface, short diffusion distance, and large blood flow) Distribution from the blood to tissues (including the brain): Mechanism: diffusion (an equilibrativeprocess); Speed:depends on the degree of lipid solubility of the anesthetic: -Less lipophilicdrugs (e.g., desflurane) are less dissolved in blood lipids less retained in the blood equilibrate rapidly between the blood and ssues, including the brain the anesthe c concentra on in the brain is rapidly reached rapid induction of anesthesia (at 1.3 MAC!) -More lipophilicdrugs (e.g., halothane) are more dissolved in blood lipids more retained in the blood equilibrate slowly between the blood and ssues, including the brain the anesthe c concentra on in the brain is slowly reached slow induction of anesthesia (at 1.3 MAC!) However, one may facilitate induction by: -transiently increasing the inhaled conc. of the anesthetic -increasing the minute ventilation (by hyperventilation)

31 INHALATION ANESTHETICS Elimination: - Mechanism: > largely by exhalation > halothane is also eliminated by biotransformation (20-40%; forms a reactive metabolite) -Speed of elimination determines the speed of recovery from anesthesia after GA inhalation is stopped: > slow for highly lipophilicanesthetics, as they are retained the brain and adipose tissue > rapid for less lipophilicanesthetics, as they are less retained the brain and adipose tissue

32 Specific Inhalational Agents: 1. Volatile liquids: a). Ethers b). Halogenated hydrocarbons: halothane (Br-, Cl-and F-substituted) highly lipid sol. c). Halogenated ethers: -Cl-and F-substituted (more lipid sol.): enflurane, isoflurane-only F-substituted (less lipid soluble): desflurane, sevoflurane a. Ethers: No longer used! i) Diethyl ether: CH3-CH2-O-CH2-CH3 Diethyl ether is not used nowadays mainly because of the flammability and explosiveness of its vapor. Yet, it is still instructive to learn, through the example of diethyl ether, about what type of favorable and unfavorable properties the inhalation anesthetics may have.

33 Ether Other undesirable properties: -Light sensitive: light induces peroxidationof ether; ether peroxides are toxic (prevent by keeping in cans). - Causes strong excitation during the stage of delirium. -Irritates the airways induces hypersecretion(like isofluraneand desflurane; prevented by atropine). -Excites the vomi ng center postopera ve vomi ng. Advantages: - Ether produces good muscle relaxation. -Ether is a safe anesthetic. It does not have severe toxic effects (e.g., hepato-and nephrotoxicity), and it does not depress cardiac contractility and respiration markedly (mechanical ventilation is not required). In contrast, all halogenated inhalation anesthethics(as well as barbiturates and propofol) have respiratory depressive effect, necessitating mechanical ventilation. Halothane and enflurane(as well as barbiturates and propofol) also produce cardiodepressive (negative inotropic) effects.

34 Specific Inhalational Agents: ii) Divinyl ether (Vinydan): CH2=CH-O-CH=CH2 It is also rarely used due to its flammability. Differences from diethyl ether: it is more potent than diethyl ether, and is less irritativeto the airways. May be used for short anesthesia to reach the stage of analgesia for a short surgical intervention, e.g., for removal of pharyngeal tonsils. b. Halogenated hydrocarbons: i) Chloroform, CHCl3: Introduced in 1847 by James Simpson, a Scottish obstetrician. Queen Victoria delivered her 8th child in chloroform anesthesia (after which JS was knighted). Its sweetish odor made chloroform popular, but it is no longer used because of its hepato-and cardiotoxicity. Its hepatotoxicmetabolite is phosgene (once a suffocating chemical warfare agent), an electrophilicacylchloride, formed by oxidative dehalogenation:

35 Halothane ii) Halothane (Narcotan) It is the only inhalational anaesthetic agent containing a bromine atom. Its use has been drastically curtailed due to its idiosyncratic hepatotoxicity Advantages:-It is non-flammable (just like any other alogenated hydrocarbon and halogenated ether). -It causes smooth induction with virtually no stage of delirium. - It rarely induces postoperative nausea and vomiting. -It has bronchodilatoryeffect, like all halog. inhal. anesthetics last resort in st. asthmaticus. Disadvantages:-Insufficient decrease of muscle tone (easily overcome by muscle relaxants). -Adverse effects: 2 common (predictable) and 2 rare (unpredictable).

36 Halothane Common and predictable adverse effects of halothane: (1) Cardiac adverse effects: cardiodepressiveeffect + arrythmogeniceffect Cardio-depressive effect is manifested in decreased heart rate and decreased contractility halothane decreases cardiac output by 20-50%, Hypotension (can be beneficial because of decreased bleeding); Decreased splanchnic(visceral; renal, hepatic) blood flow However, cerebral blood flow (CBF) is increased due to dilata on of cerebral vessels intracranial pressure (ICP);* halothane (and other halog. inhal. anest., except isoflurane) is NOT suitable for brain surgery. Slightly sensi zes the heart to catecholamines exogenous catecholamine may provoke arrhythmias (this is uncommon in children).

37 Halothane (2) Respiratory adverse effects: respiratory depressive effect + depression of mucociliaryfunction: Halothane reduces the respir. minute volume by inducing rapid shallow respira on pco 2, po2; This necessitates assisted ventilation (i.e., use of anesthesia machine which also contains a ventilator). Halothane impairs the mucociliaryclearance mucus reten on, post-operative respiratory infections. Rare and unpredictable adverse effects of halothane: (1) Halothane hepatitis an immunologically determined reaction: An idiosyncratic reaction = rare (1 in cases; higher after repeated use), unpredictable reaction Symptoms start 2-5 days after anesthesia: fever, nausea; elevation of ALT, eosinophilia Hepatic failure rate may be as high as 50%.

38 Halothane Mechanism: oxidative debromination(20% of dose) by CYP2El to reactive trifluoro-acetylchloride(a reactive electrophilicacylchloride) covalent binding to hepatic proteins = neoantigeneforma on immune hepatitis On theoretical basis, disulfirampretreatment has been recommended before halothane anesthesia to prevent hepatitis. Disulfiramis a potent inhibitor of CYP2E1 (not only of aldehydedehydrogenase) and thus decreases formation of trifluoro-acetylchloride.

39 Halothane (2) Malignant hyperthermia (MHT) a genetically determined reaction: MHT may be caused by any halogenated inhalation anesthetic and also by succinylcholine. Symptoms: Hyperthermia Muscle rigidity rhabdomyolysis hyperkalemia, CK, myoglobinuria renal failure Metabolic acidosis (caused by lac c acid produced in the hyperactive muscles) Pathomechanism: inherited myopathy; caused by mutation of ryanodinereceptor (RYR1), or of the dihydropyridine-sensitive L-type Ca2 + -channels in the skeletal muscle, or by other unknown cause.

40 Halothane RYR1 is a Ca 2+ -release channel in the sarcoplasmicreticulum; RYR1 opens in response to -Ca 2+ in the sarcoplasm. Halothane sensitizes the mutant RYR1 to Ca 2+, thus triggering RYR1 opening and release of Ca 2+ from the sarcoplasmicreticulum into the sarcoplasm muscle contrac on - heat produc on, etc. Therapy: -Stop delivery of the inhalation anesthetic, continue with N 2O + an i.v. anesthetic.; -Infuse NaHCO 3 to correct acidosis and prevent myoglobin precipitation in renal tubules. -Decrease body temperature (with ice, or by gastric lavagewith cold water). - Inject dantrolene(blocks RYR1) to relax the skeletal muscle.

41 c). Halogenated ethers

42 Enflurane Halogenation was used to prevent inflammation in ethers Enflurane(Ethrane) Its use has been diminished. It combines some of the properties of diethyl ether and some of the properties of halothane. Advantages: Like ether - Enflurane has a good muscle relaxant effect. - Enflurane does not sensibilize the heart toward catecholamines. Like halothane - Enflurane is not flammable. - Enflurane smoothly induces anesthesia. Disadvantages: Like ether - Enflurane mildly stimulates the tracheobronchial secretions. - Enflurane may cause postoperative nausea and vomiting (10%). Like halothane -Enfluranedecreases cardiac contractility (but not the heart rate) it causes a moderate decrease in cardiac output and blood pressure. -Enfluranedepresses the respira on pco2; assisted ven la on is needed.

43 Enflurane Rare adverse effect: tonic-clonicseizures (specific for enflurane); sometimes only EEG signs appear. Characteristic EEG: high voltage-high frequency activity, spike and dome complexes. The seizures are of short duration, self-limiting and of no special concern. CAUTION: Hyperventilation should be avoided, because it causes hypocarbia( pco2) which sensi zes the CNS to enflurane-induced seizures. NOTE: CO 2 in the brain causes two effects: -Anticonvulsive effect (remember the carbonic anhydraseinhibitor acetazolamidealso CO 2 and is used as an adjuvant to antiepipleptics); therefore, CO 2 is pro-convulsive. -Vasodilatoryeffect; therefore, CO 2 causes vasoconstriction desirable in brain surgery. Biotransformation of enflurane: 2-5% of dose undergoes dehalogenation(much less than halothane).

44 Isoflurane (Forane; an isomer of enflurane) The most commonly used volatile anesthetic today Its properties are very similar to those of enflurane, except for 5 main differences: (1) Isoflurane sdehalogenationin the body is only 0.2% there is no reason to fear toxic metabolite(s). (2) Isofluranedoes not cause cardiac depression cardiac output is well maintained. Nevertheless, it -decreases BP because it reduces peripheral vascular resistance (including the coronary) - increases the heart rate, but arrhythmias are not precipitated. (3) Isoflurane does not induce seizures. (4) Isoflurane is a preferred anesthetic for BRAIN SURGERY for 2 reasons: -It decreases O 2 demand/utilization by the brain. -Although isofluraneslightly the cerebral blood flow (CBF), the CBF and ICP can be by inducing hypocarbia(low pco 2 ) with hyperventilation. (Hypocarbia causes cerebral vasoconstriction.) (5) An unfavorable property: isofluranehas pungent odor and irritates airways. This necessitates induction with an i.v. anesthetic.

45 Methoxyflurane(Penthrane) used for inducing the stage of analgesia, but not for general anesthesia. It is the most lipid-soluble (oil:gaspart. coeff. = 970) and the most potent inhal. anesthetic (MAC = 0.2%). However, its use as a GA has been discontinued due mainly to its NEPHROTOXIC effect: -Clinical presentation: "High-output renal failure", a concentrating defect (ADH-refractory polyuria). - Mortality rate: 20%, survivors slowly recover (it may take years). -Increased susceptibility: after long anesthesia, in patients with existing renal disease, in older patents, and after treatment with CYP inducers. - Mechanism: 50-70% of methoxyflurane(mf) undergoes biotransformation via CYP-catalyzed O-demethylationand subsequent oxidative dehalogenations. Its extensive biotransformation is mainly due to large accumulation of methoxyfluranein fat prolonged release of MF from the fat prolonged delivery of MF to the liver for biotransformation.

46 Methoxyflurane Nephrotoxicmethoxyfluranemetabolites: Methoxyfluoroaceticacid, dichloroaceticacid, oxalic acid, and fluoride ion. Note: Oxalic acid is also one of the nephrotoxic metabolites of ethylene glycol. Methoxyfluraneis used extensively in the Australian DefenceForce and Australian ambulance services as an emergency analgesic in sub-anesthetic dose (given by a pipe-like inhaler) nephrotoxicity does not occur.

47 Desflurane and Sevoflurane Common properties: -Ethers containing only fluorine substitutions -They have lower lipid solubility and blood solubility than halothane, enfluraneand isoflurane(see table); consequently: > they induce anesthesia more rapidly > recovery from anesthesia is also more rapid -They do not cause cardiac depression (like isoflurane), but they cause: > hypotension (due to vasodilatation) > respiratory depression -Dehalogenation: is negligible for desflurane(0.02%) and is little for sevoflurane(3%) Differences: -Desfluraneinduces anesthesia most rapidly out of all volatile liquid anesthetics (as it is the least lipophilic), yet it is not used for anesthesia induction because it irritates the airways and causes coughing, breath holding, secretions and laryngospasm. (It is also expensive, precluding its use in poor countries.) In contrast, sevoflurane has a pleasant odor and can be used for induction.

48 Desflurane and Sevoflurane -Sevofluranecan react with the CO 2 absorber Ba(OH) 2 (Baralyme) in the anesthesia machine. This may have two adverse outcomes: (1) Sevofluranecauses an exothermic reaction with the CO 2 absorber, which is overheated, if desiccated airway burns, igni on, and explosion may occur. Therefore, the CO 2 absorber should not run dry! (2) In the basic CO 2 absorber, sevofluraneis dehydrofluorinatedto form compound A, which is nephrotoxicin rodents, but is much less toxic in humans. Nevertheless, 2 L/min fresh gas flow rate is prescribed during sevofluraneanesthesia in order to dilute the exhaled compound A in the inhaled gas. Rats convert Compound A into a reactive nephrotoxic metabolite. However, humans form this harmful metabolite at a low rate

49 2. Anaesthetic gases Cyclopropane an obsolete agent. Not used because - it is flammable and explosive, -it sensitizes the heart to catecholamines, and can induce arrhythmias, including ventricular fibrillation. Nitrous oxide (N 2 O) called"laughing gas, as it causes euphoria. It is the least lipid soluble and least potent inhalation anesthetic (MAC = 105%). As a sole anesthetic, it could be used reliably only under hyperbaric conditions. Advantages: -N 2 O is nonflammable, not explosive. - It lacks harmful effects under proper use. - It does not induce malignant hyperthermia. -Of the inhalation anesthetics, N 2 O is least likely to increase cerebral blood flow and intracranial pressure. - It promotes induction and recovery when combined with halothane. Disadvantages: -N 2 O is very weak used only in combina on with other general anesthetics. -It has no muscle relaxant ac vity use muscle relaxant.

50 Nitrous oxide (N 2 O) -It may cause 3 adverse effects: (1) Diffusionalhypoxia" occurs when N 2 O inhalation is discontinued and air inhalation is started. Reason: N 2 O is rapidly released from the blood into the alveolar space it dilutes O 2 there alveolar po 2 arterial po 2. Easily prevented by O 2 inhalation. (2) Expansion of closed air pockets in the body by replacing the N 2 in these closed air spaces. Reason: Large amounts of N 2O moves into the pocket readily, while N 2 moves out from the pocket into the blood slowly, due to the much lower blood/gas partition coefficient for N 2 (0.01) than for N 2 O (0.5). Air pockets: occluded middle air, cyst in the lung or kidney, pneumothorax, and formed during pneumoencephalography. Avoid N 2 O in these conditions! (3) N 2 O oxidizes Co(I) to Co(III) in methylcobalamin(= methyl-vitamin B12) inac vates methylcobalaminfor use by methioninesynthase (methylateshomocysto methionine) This may be harmful only after extremely prolonged or repeated use of N 2 O. Consequence: symptoms of vit. B12 deficiency - megaloblastic anemia - neuropathy (demyelinization = funicular myelosis)

51 Nitrous oxide (N 2 O) Clinical use (and abuse) of nitrous oxide: (N 2 O is supplied in gas tanks containing 70% nitrous oxide; NITRALGIN gas): -For anesthesia, in combination with other inhalation anesthetics (e.g., halothane, enflurane, isoflurane) The MAC value of the anesthetic is reduced by 60% when 70% N 2 O is added unwanted effects of the combined anesthetic (e.g., circulatory respiratory depression) are also reduced. -For inducing euphoria in order to relieve chronic pain (<50% N 2 O is used): > in patients with tetanus (for days), > in cancer patients with pain. Abuse of nitrous oxide in medical personnel: as N 2 O (laughing gas) induces euphoria; addiction may occur.

52 Part C. INTRAVENOUS ANESTHETICS I. GENERAL PROPERTIES OF I.V. ANESTHETICS 1. Chemical properties I.v. anesthetics are relatively hydrophobic and lipophilic compounds. Chemical classes: - Barbiturates: thiopental, methohexital - Others: propofol, etomidate, ketamine 2. Mechanism of action All (except ketamine) activate the GABA-A receptor. Barbiturates also inhibit the neuronal N-type acetylcholine receptor. Ketamine inhibits the NMDA-type glutamate receptor. 3. Pharmacokinetics only two phases, i.e. distribution and elimination a). Tissue distribution and redistribution of i.v. anesthetics: IMMEDIATELY AFTER I.V. INJECTION, they distribute rapidly to the wellperfused ssues, including the brain general anesthesia occurs rapidly (within ~ 1 min) LATER, they redistribute to the less well-perfusedtissues, such as the muscle, skin and adipose ssue. These have large mass remove the anesthe c from the brain the pa ent wakes up in a few minutes. The anesthetic action of i.v. anesthetics is terminated by redistribution, not by elimination. The rate of redistribution is quite similar for all i.v. anesthetics; therefore, after a single anesthetic dose, their duration of action is also similar (i.e., 5-10 min).

53 Part C. INTRAVENOUS ANESTHETICS The rate of redistribution of i.v. anesthetics may decrease in patients with: - decreased tissue perfusion (e.g., in cardiac failure and septic shock) -decreased muscle and adipose tissue mass (e.g., in elderly or malnourished patient). In such conditions, the dose of i.v. anesthetic should be lowered lest the anesthesia should be too long. b). Elimination of i.v. anesthetics: All i.v. anesthetics are eliminated by biotransformation, e.g., by CYPcatalyzed oxidation (barbiturates, ketamine), glucuronidation (propofol), and hydrolysis (etomidate). There are significant differences in the rate of elimination of i.v. anesthetics; this is reflected in their elimination half-lives (T 1/2β ): -Thiopental is eliminated very slowly: T 1/2β = 12 hrs! (Thiopental is biotransformed slowly.) -The others are eliminated relatively rapidly: T 1/2 = 1-4 hrs. Propofolis eliminated most rapidly (by glucuronidation); T 1/2β = 1-2 hrs.

54 Part C. INTRAVENOUS ANESTHETICS What is the implication of the differences in elimination rate? -Thiopental should not be given in continuous infusion to maintain anesthesia, because it would accumulate in muscle and fat, forming a depot in these tissues. After termination of the infusion, thiopental release from the depot tissues would maintain high blood and brain levels and therefore recovery would be extremely delayed. For this reason, thiopental is not useful for TIVA (Total IntraVenousAnaesthesia) For the same reason, delayed recovery also follows repeated administration of thiopental in single i.v. doses. -The others (especially propofol) can be given in continuous infusion to maintain anesthesia, because they do not have a propensity to accumulate in the body, therefore their duration of action is only slightly prolonged after longlasting infusion. For example, the patient wakes up in 10 minutes even if propofolis infused for 3 hours.

55 Part C. INTRAVENOUS ANESTHETICS 4. Clinical use All may be given as a single dose for: -induction of anesthesia before inhalation anesthesia, if the inhal. anesthetic slowly induces anesthesia (e.g., halothane), or has unpleasant odor or airway irritating property (e.g., isoflurane, desflurane); - short anesthesia for short surgery or painful intervention (e.g., reposition of a dislocated joint). - Some (especially propofol) may be given in continuous infusion to produce long-lasting anesthesia. After discontinuation of the infusion, the patient wakes up in 10 minutes even if propofolwas infused for 3 hours. Propofolis the preferred i.v. anesthetic for TIVA (total intravenous anesthesia). At a lower dose rate, propofolis also used for continuous sedation of patients in ICUs.

56 II. SPECIFIC PROPERTIES OF I.V. ANESTHETICS 1. Barbiturates: thiopental (a thiobarbiturate) and methohexital (an oxobarbiturate) a. Dose for methohexital: mg/kg iv, for thiopental: 3-5 mg/kg i.v. b. Onset of action: ~20 sec; induction is rapid and smooth; Duration of action: ~5-10 min, for both

57 1. Barbiturates c. Elimination: by CYP: -Thiopental: Oxidative desulfuration(the product is pentobarbital, a hypnotic) - Methohexital: N-demethylation -Both: Hydroxylation on the aliphatic chains linked to C5 of the barb. ring at different speed: -Thiopental: very slow, T 1/2β = 12 hrs not used for TIVA -Methohexital: faster, T 1/2= 4 hrs may be given in infusion ( mg/kg/min) to maintain anesthesia. d. Advantages of barbiturates: Barbiturates (unlike most halogenated inhalation anesthetics, except isoflurane) the cerebral metabolic rate and O 2 utilization by the brain the cerebral blood flow intracranial pressure (an advantage in brain surgery) intraocular pressure Barbiturates exert an convulsive effect thiopental is valuable in the treatment of status epilepticus

58 1. Barbiturates e). Disadvantages: Incompatibility: The injectablesolution is basic (ph 10-11) as barbiturates are dissolved as Na-salts; if mixed with acidic solutions (e.g., a muscle relaxant, such as pancuronium bromide) the barbiturate precipitates out as a free acid! Barbiturates exert vascular irritative effect: -if the i.v. injected thiopental conc. is >2.5%, it may induce pain and thrombophlebitis - if injected intra-arterially, it induces endarteritis and gangrene! (The pain resulting from the veno-irritativeeffect can be prevented by prior injection of lidocaine.) Barbiturates induce respiratory depression (low minute volume) and apnea at high dose. In asthmatics, they may induce ehistaminerelease and wheezing.

59 1. Barbiturates Barbiturates induce hypotension by causing both: -vasodilatation, and -veinotropiceffect. Therefore, barbiturates should not be injected -too rapidly excessive decrease in cardiac contrac lity, and -to a pa ent who can not compensate for blood pressure, e.g. those with hypovolemia, -cardiomyopathy, -coronary artery disease, - β-receptor blockade Barbiturates induce ALA synthetase, the first enzyme in heme synthesis. This in turn will cause accumulation of porphyrins (neurotoxicbyproducts of hemesynthesis) in patients deficient in some downstream enzymes of the hemesynthetic pathway. Thus barbiturates may precipitate widespread demyelinizationin patients with: Acute intermi ent porphyria(deficiency in porphobilinogen deaminase), and Variegate porphyria(deficiency in protoporphyrinogen oxidase). In these inherited porphyriasbarbiturates are ABSOLUTELY CONTRAINDICATED!

60 2. Propofol(DIPRIVAN) = 2,6-diisopropylphenol a. Dose: mg/kg b. b. Onset and duration of anesthesia: -after a bolus dose, anesthesia develops in ~20 sec, like for barbiturates -recovery is > within 10 min after a 3-hr infusion; > within 40 min after an 8-hr infusion c. Elimination: -by glucuronidation(mainly) and sulfationat the hydroxyl group -rapid: T 1/2β = 2 hrs or less (However, it is longer in neonates because of the low quantity of UGT in the newborn liver. Therefore, recovery may be prolonged in neonates.)

61 2. Propofol d). Used for: TIVA in infusion ( mg/kg/min); for example, TIVA is used by orthopedic surgeons in SCOLIOSIS CORRECTION SURGERY, which - requires anesthesia for several hours, however, -the patient has to be wakened up (by stopping propofolinfusion) to test sensory and motor functions after reposition of the spinal column and before completing the surgery. Also used for continuous sedation in intensive care units (ICU) be aware of the possibility of PRIS - Propofol Infusion Syndrome! e). Advantages: Like barbiturates, propofol cerebral metabolic rate, O 2 consumption cerebral blood flow, intracranial and intraocular pressure Propofol has antiemetic effect f). Disadvantages: Like barbiturates, propofol: - has venoirritative effect pain; prevented by lidocaine i.v. - has respiratory depressive effect (stronger than barbiturates) -decreases blood pressure because of vasodilatation and negative inotropic effect

62 2. Propofol Two special disadvantages of propofol: (1) Propofolis a water immiscible oily substance. Its emulsion is used as an i.v. anesthetic. Its solvent contains soybean oil, egg phospholipids and glycerol, which supports bacterial growth. Serious infections have occurred with the use of propofolthat had been opened and contaminated. PROPOFOL SHOULD BE USED SHORTLY AFTER OPENING OR DISCARDED! To overcome this problem, the water soluble prodrugof propofol, fospropofolis now marketed as Lusedrain the USA. Fospropofolis the phosphate ester of propofol, which is hydrolyzed by alkaline phosphatase(ap) in the body, thus releasing propofol: Because of the need of metabolic activation, fospropofolinduces anesthesia only in 10 min time

63 2. Propofol (2) PropofolInfusion Syndrome (PRIS): A rare, but potentially lethal adverse effect that occurs with high dose (>4 mg/kg/hour) and long-lasting (>48 hrs) propofolinfusion. The incidence of PRIS in American ICUs was 1.1% in the The lethality of PRIS cases was 18%. Mechanism: PRIS is caused by toxic effect of propofolon mitochondria, mainly in skeletal and cardiac muscle. Propofolacts as a weak protonophoricuncoupler: it diffuses into mitochondria, dissociates its phenolicproton, thus dissipating the inwardly directed H + gradient that drives ATP synthase. In addition, propofol also inhibits mitochondrial electron transport. Consequences and signs of the mitochondrial toxicity of propofol: i. Cardiac failure: acute refractory bradycardia(may lead to asystole), hypotension, and ST elevation; ii. Rhabdomyolysis serum K +, serum CK, myoglobinuria renal failure; iii. Hepatomegalywith fatty liver (probably caused by inhibition of fatty acid oxidation); iv.-high serum triglyceride levels (may be an early marker; caused by inhibition of fatty acid oxidation?); v. Lactic acidosis (pyruvateuse by PDH complex is impaired pyruvate is reduced to lactate by LDH)

64 a. Dose: mg/kg 3. Etomidate(AMIDATE) b. Rapidly and ultra short acting (4-8 min) anesthetic used mainly for induction of anesthesia c. Elimination: - by ester hydrolysis in the liver -rapid; T 1/2β = 3 hrs Etomidatecould be given in infusion (10 mg/kg/min), yet prolonged infusion is contraindicated because it inhibits cortisol synthesis and blunts the stress response (may increase mortality). d. Other disadvantages: often induces nausea and vomiting causes pain on injection (like barbiturates and propofol; prevent it by prior injection of lidocaine) appears to have pro-convulsive effect (contraindicated in seizures)

65 3. Etomidate(AMIDATE) e). Advantages: Like barbiturates and propofol, etomidatecauses: cerebral metabolic rate, O 2 consumption cerebral blood flow, intracranial and intraocular pressure Unlike barbiturates and propofol(and the halogenated inhalation anesthetics), etomidate causes: - little respiratory depression -little or no decrease in blood pressure and may slightly increase the heart rate the CARDIOVASCULAR FUNCTION IS STABLE during etomidate anesthesia etomidateis usually reserved for patients at risk for hypotension and/or myocardial ischemia

66 4. Ketamine (KETALAR) an NMDA receptor antagonist a. Dose: mg/kg b. Onset of action: relatively slow (1-2 min) Duration of anesthesia: min (the anesthesia is longer than that induced by other i.v. anesthetics) c. Elimination: by CYP-catalyzed N-demethylation rapid: T 1/2β = 3 hrs can be infused ( mg/kg min)

67 d). Ketamine has 3 peculiar effects: 4. Ketamine (KETALAR) Ketaminehas analgesic effect that outlasts the anesthetic effect an advantage: Ketaminemay be used by ambulance services for sedation and pain suppression in patients. Ketaminemay induce disagreeable dreams and hallucinations, when emerging from the anesthesia. This occurs seldom in children ketamineis a preferred anesthetic in pediatric surgery (may be given in combination with a benzodiazepine). Ketaminehas indirect sympathomimeticeffect because it neuronal reuptake of catecholaminesboth peripherally and centrally (like cocaine); the resultant effects are: - blood pressure; - heart rate, cardiac output, myocardial O 2 consumption - cerebral blood flow, - intracranial pressure; -pupillarydilation, nystagmus, lacrimation; - bronchodilation Consequently, ketamineis Indicated for patients: -who are at risk for hypotension (like etomidate); -who are asthmatic - Contraindicated for patients: - who are at risk for myocardial ischemia - who have intracranial pressure