• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
3 general anethesia
 

3 general anethesia

on

  • 5,714 views

 

Statistics

Views

Total Views
5,714
Views on SlideShare
5,515
Embed Views
199

Actions

Likes
7
Downloads
661
Comments
0

3 Embeds 199

http://www.webicina.com 191
http://www.slideshare.net 6
http://translate.googleusercontent.com 2

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    3 general anethesia 3 general anethesia Presentation Transcript

    • General Anesthetics Jieyu Fang The First Affiliated Hospital 房洁渝 中山大学附属第一医院
    • Principles of General Anesthesia
      • Minimizing the potentially harmful direct and indirect effects of anesthetic agents and techniques
      • Sustaining physiologic homeostasis during surgical procedures
      • Improving post-operative outcomes
    •  
    • What are General Anesthetics?
      • Drugs that bring about a reversible loss of consciousness.
      • These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.
    • Background
      • General anesthesia was absent until the mid-1800’s
      • William Morton administered ether to a patient having a neck tumor removed at the Massachusetts General Hospital, Boston, in October 1846 .
      • The discovery of the diethyl ether as general anesthesia was the result of a search for means of eliminating a patient’s pain perception and responses to painful stimuli.
    • Anesthetics divide into 2 classes:
      • Inhalation Anesthetics
        • Gasses or Vapors
        • Usually Halogenated
      • Intravenous Anesthetics
        • Injections
        • Anesthetics or induction agents
    • Hypotheses of General Anesthesia
      • Lipid Theory : based on the fact that anesthetic action is correlated with the oil/gas coefficients .
          • The higher the solubility of anesthetics is in oil, the greater is the anesthetic potency.
          • Meyer and Overton Correlations
          • Irrelevant
    • Other Theories included
      • 2. Protein (Receptor) Theory : based on the fact that anesthetic potency is correlated with the ability of anesthetics to inhibit enzymes activity of a protein. The GABA A receptor is a potential target of anesthetics action.
      • GABA: γ-aminobutyric acid synapse
      • NMDA receptor: N-methyl-D-aspartate
      • 3.Binding theory:
        • Anesthetics bind to hydrophobic portion of the ion channel
    • GABA receptors gamma- aminobutyric acid
      • The GABA receptors are a class of receptors that respond to the neurotransmitter gamma- aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the central nervous system .
      • two classes of GABA rec: GABA A and GABA B .
      • GABA A receptors are ligand -gated ion channels , Its endogenous ligand is γ- aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system .
      • GABA B receptors are G protein-coupled receptors .
    • GABA receptors
      • Upon activation, the GABA A receptor selectively conducts Cl - through its pore , resulting in hyperpolarization of the neuron . This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.
    • NMDA receptor
      • The NMDA ( N -methyl D -aspartate) receptor , is for controlling synaptic plasticity and memory function.
      • Activation of NMDA receptors results in the opening of an ion channel . NMDA receptor is voltage-dependent activation, a result of ion channel block by extracellular Mg 2+ ions. This allows voltage-dependent flow of Na + and small amounts of Ca 2+ ions into the cell and K + out of the cell.
      • Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity , a cellular mechanism for learning and memory .
      • The NMDA receptor is distinct in two ways: First, it is both ligand -gated and voltage-dependent; second, it requires co-activation by two ligands - glutamate and glycine .
    • Mechanism of Action
      • UNKNOWN!!
      • Most Recent Studies:
        • General Anesthetics acts on the CNS by modifying the electrical activity of neurons at a molecular level by modifying functions of ION CHANNELS.
        • This may occur by anesthetic molecules binding directly to ion channels or by their disrupting the functions of molecules that maintain ion channels.
    • Mechanism
      • Scientists have cloned forms of receptors in the past decades, adding greatly to knowledge of the proteins involved in neuronal excitability. These include:
        • Voltage-gated ion channels, such as sodium, potassium, and calcium channels
        • Ligand-gated ion channel superfamily and
        • G protein-coupled receptors superfamily.
    • Intravenous Anesthetics
        • Barbiturates –
          • thiopental (Pentothal) 硫喷妥钠
          • methohexital (Brevital)
          • thiamylal (Surital)
        • propofol (Diprivan) 丙泊酚
        • Ketamine 氯胺酮
        • Benzodiazepines
          • midazolam (Versed) 咪达唑仑
          • diazepam (Valium) 地西泮
          • lorazepam (Ativan)
        • etomidate (Amidate ) 依托咪酯
    • Pharmacology of intravenous (IV) anesthetics
      • IV anesthetics are commonly used for induction of general anesthesia, maintenance of GA, and sedation during local or regional anesthesia.
      • The rapid onset and offset of these drugs are due to their physical translocation in and out of the brain. After a bolus IV injection, fat-soluble drugs like propofol, thiopental, and etomidate rapidly distribute into highly perfused tissues like brain and heart, causing an extremely rapid onset of effect.
    • Pharmacology of intravenous (IV) anesthetics
      • Plasma conc ↓ rapidly as the drugs continue to be distributed into muscle and fat. When plasma conc have decreased sufficiently, these drugs rapidly redistribute out of the brain, and their effects are terminated.
    • Pharmacology of intravenous (IV) anesthetics
      • Active drug remains in the body, so clearance still needs to occur, typically by hepatic metabolism and renal elimination.
      • Elimination half-time is defined as the time required for the plasma concentration of drug to decrease by 50% during the terminal (elimination) phase of clearance
      • Context-sensitive half-time (CSHT) is defined as the time for a 50% decrease in the central compartment drug concentration after an infusion of specified duration.
    • Propofol
      • Propofol (2,6-diisopropylphenol) is used for induction or maintenance of general anesthesia as well as for conscious sedation. It is prepared as a 1% isotonic oil-in-water emulsion, which contains egg lecithin, glycerol, and soybean oil.
    •  
    • propofol
      • Mode of action: Increases activity at inhibitory GABA synapses. Inhibition of glutamate ( N -methyl-D-aspartate [NMDA]) receptors may play a role.
        • Pharmacokinetics
          • Hepatic (and some extrahepatic) metabolism to inactive metabolites.
          • The CSHT of propofol (see Fig. 11.1) is 15 min after a 2-hour infusion.
    • propofol
        • Pharmacodynamics
          • Central nervous system (CNS)
      • Induction doses produce unconscious (30 to 45 seconds), followed by rapid reawakening due to redistribution
      • Low doses produce sedation . Weak analgesic effects
            • Raises seizure threshold.
            • Decreases intracranial pressure (ICP) but also cerebral perfusion pressure..
    • Properties of Intravenous Anesthetic Agents-propofol
          • Cardiovascular system
            • Cardiovascular depressant Dose-dependent decrease in preload and afterload and depression of heart contractility leading to decreases in arterial pressure and cardiac output.
            • Heart rate is minimally affected, and baroreceptor reflex is blunted .
            • #
    • Dosages of commonly used IV anesthetics
          • Respiratory system
            • Produces a dose-dependent decrease in respiratory rate and tidal volume.
            • Ventilatory response to hypercarbia is diminished.#
        • Dosage and administration: Table 11.1.
      • Induction dose: 2~2.5 mg/kg
      • Maintenance infusion
          • Titrate with reduced doses in elderly or hemodynamically compromised patients
      • Discard propofol opened more than 6 hours : Propofol emulsion supports bacterial growth; prevent bacterial contamination.
    •  
    • propofol
        • Other effects
          • Venous irritation : Injection pain during IV administration
            • reduced by adding lidocaine
          • antiemetic effects : Less postoperative
      • nausea and vomiting
          • Lipid disorders
          • Myoclonus
          • Propofol infusion syndrome :a rare and fatal disorder that occurs in critically ill patients (usually children) subjected to prolonged, high-dose propofol infusions. Typical features include rhabdomyolysis, metabolic acidosis, cardiac failure, and renal failure
          • Some abuse potential .
    • Benzodiazepines
      • midazolam
      • Diazepam
      • lorazepam
      • They are often used for sedation and amnesia or as adjuncts to general anesthesia.
      • Midazolam is prepared in a water-soluble form at pH 3.5, while diazepam and lorazepam are dissolved in propylene glycol and polyethylene glycol, respectively.
    • Benzodiazepines
        • Mode of action: Enhance the inhibitory tone of GABA receptors.
        • Pharmacokinetics
          • IV , the onset of CNS effects occurs in 2 to 3 minutes for midazolam and diazepam.
          • metabolized in the liver. Elimination half-lives for midazolam, lorazepam, and diazepam are approximately 2, 11, and 20 hours. The active metabolites of diazepam last longer than the parent drug.
          • Diazepam clearance is reduced in the elderly, but this is less of a problem with midazolam and lorazepam.
    • Benzodiazepines
        • Pharmacodynamics
          • CNS
            • Produce amnestic, anticonvulsant, anxiolytic, muscle-relaxant, and sedative-hypnotic effects in a dose-dependent manner. Amnesia may last only 1 hour after a single premedicant dose of midazolam. Sedation may sometimes be prolonged.# anterograde amnesia
            • no analgesia.#
            • Reduce cerebral blood flow and metabolic rate.
    • Benzodiazepines
          • Cardiovascular system
            • a mild systemic vasodilation and reduction in cardiac output. Heart rate unchanged.
          • Respiratory system
            • Produce a mild dose-dependent decrease in respiratory rate and tidal volume.
            • Respiratory depression may be pronounced if administered with an opioid, in patients with pulmonary disease, or in debilitated patients.
    • Benzodiazepines
        • Dosage and administration: See Table 11.1
        • midalozam iv 0.1-0.4mg/kg
          • IV diazepam 2.5 mg
          • IV lorazepam 0.25 mg for sedation.
          • orally diazepam 5 to 10 mg
          • orally lorazepam 2 to 4 mg of.
    • Benzodiazepines
        • Adverse effects
          • Drug interactions. a benzodiazepine to anticonvulsant valproate may precipitate a psychotic episode.
          • Pregnancy and labor
            • associated with birth defects (cleft lip and palate) when administered during the first trimester.
            • Cross the placenta and may lead to a depressed neonate.
          • Superficial thrombophlebitis and injection pain diazepam and lorazepam.
    • Flumazenil
        • Flumazenil is a competitive antagonist for benzodiazepine receptors in the CNS.
          • Reversal of benzodiazepine -induced sedative effects occurs within 2 min.
          • Flumazenil is shorter acting than the benzodiazepines. Repeated administration may be necessary.
          • Metabolized in the liver.
          • Flumazenil is contraindicated in patients with tricyclic antidepressant overdose and in those receiving benzodiazepines for control of seizures or elevated intracranial pressure .
    • Ketamine
      • Ketamine is a sedative-hypnotic agent with powerful analgesic properties. Usually used as an induction agent.
        • Mode of action: Not well defined, antagonism at the NMDA receptor.
        • Pharmacokinetics
          • unconsciousness in 30 to 60 s after an IV dose. Effects are terminated by redistribution in 15 to 20 min. After intramuscular (IM) administration, the onset of CNS effects is 5 min, with peak effect at approximately 15 min.
          • Metabolized rapidly in the liver. Elimination half-life = 2 to 3 hours.
      • Repeated bolus doses or an infusion results in accumulation.
    • Ketamine
        • Pharmacodynamics
          • CNS
            • Produces a “ dissociative ” state accompanied by amnesia and analgesia. Analgesic effects persist after awakening.
            • Increases cerebral blood flow (CBF), metabolic rate, and intracranial pressure . #CBF response to hyperventilation is not blocked.
            • #
    • Ketamine
          • Cardiovascular system
            • ↑ HR , ↑ BP , centrally mediated release of endogenous catecholamines.
            • Often used to induce general anesthesia in hemodynamically compromised patients.
          • Respiratory system
            • depresses RR and tidal volume mildly
            • Alleviates bronchospasm by a sympathomimetic effect.
            • Laryngeal protective reflexes are relatively well-maintained .
    • Ketamine
        • Dosage and administration: See Table 11.1.
          • IM / IV, IM in whom IV access is not available (e.g., children).
        • Adverse effects
          • Oral secretions stimulated
          • antisialagogue (glycopyrrolate,atropine) be helpful.
          • Emotional disturbance. #
          • 1)cause restlessness and agitation ; hallucinations and unpleasant dreams .
          • 2) Risk factors :age, female gender, and dosage.
          • 3) reduced with benzodiazepine (e.g., midazolam) or propofol. Children seem to be less troubled. Alternatives to ketamine should be considered in patients with psychiatric disorders.
    • Ketamine
          • Muscle tone ↑. random myoclonic movements.
          • Increases intracranial pressure and is relatively contraindicated in patients with head trauma or intracranial hypertension.
          • Ocular effects. May lead to mydriasis, nystagmus, diplopia, blepharospasm, and increased intraocular pressure ; alternatives should be considered during ophthalmologic surgery.
          • Anesthetic depth may be difficult to assess. .
    • Etomidate
      • Etomidate is an imidazole-containing hypnotic unrelated to other anesthetics.
      • It is most commonly used as an IV induction agent for general anesthesia.
        • Mode of action: Augments the inhibitory tone of GABA in the CNS.
        • Pharmacokinetics
          • clearance in the liver and by circulating esterases to inactive metabolites.
          • Times to loss of consciousness and awakening similar to propofol.
    • Etomidate
        • Pharmacodynamics
          • CNS
            • No analgesic
            • Cerebral blood flow, metabolism, and ICP decrease while cerebral perfusion pressure is usually maintained.
          • Cardiovascular system. minimal changes in HR, BP, CO. Does not affect sympathetic tone or baroreceptor function, not suppress hemodynamic responses to pain. often chosen to induce general anesthesia in hemodynamically compromised patients.
          • Respiratory system. decrease in RR, tidal volume; transient apnea may occur.
    • Etomidate
        • Dosage and administration: IV, See Table 11.1.
        • Adverse effects
          • Myoclonus after administration
          • Nausea and vomiting more frequently than other anesthetics
          • Venous irritation and superficial thrombophlebitis
          • Adrenal suppression. A single dose suppresses adrenal steroid synthesis for up to 24 hours (probably an effect of little clinical significance). Repeated doses or infusions are not recommended because of the risk of significant adrenal suppression.
    • Properties of Intravenous Anesthetic Agents Drug Induction and Recovery Main Unwanted Effects Notes thiopental Fast onset (accumulation occurs, giving slow recovery) Hangover Cardiovascular and respiratory depression Used as induction agent declining. ↓ CBF and O2 consumption Injection pain etomidate Fast onset, fairly fast recovery Excitatory effects during induction Adrenocortical suppression Less cvs and resp depression than with thiopental, Injection site pain propofol Fast onset, very fast recovery cvs and resp depression Pain at injection site. Most common induction agent. Rapidly metabolized; possible to use as continuous infusion. Injection pain. Antiemetic ketamine Slow onset, after-effects common during recovery Psychotomimetic effects following recovery, Postop nausea, vomiting , salivation Produces good analgesia and amnesia. No injection site pain midazolam Slower onset than other agents Minimal CV and resp effects. Little resp or cvs depression. No pain. Good amnesia.
    • Non-barbiturate induction drugs effects on BP and HR Drug Systemic BP Heart Rate propofol ↓ ↓ etomidate No change or slight ↓ No change ketamine ↑ ↑
    •  
    • Opioids
      • Morphine
      • meperidine
      • hydromorphone
      • fentanyl
      • sufentanil
      • alfentanil
      • remifentanil
      • opioids used in GA.
      • ★ primary effect : analgesia
      • ★ to supplement other agents during induction or maintenance of GA.
      • In high doses, opioids are used as the sole anesthetic (e.g., cardiac surgery).
    • Opioids
        • Mode of action: Opioids bind at specific receptors in the brain, spinal cord, and on peripheral neurons. The opioids are selective for μopioid receptors .
        • Pharmacokinetics
          • The CSHTs for alfentanil, sufentanil, and remifentanil are shown in p19
          • Elimination is primarily by the liver. Remifentanil is metabolized by circulating and skeletal muscle esterases . Morphine and meperidine have important active metabolites; hydromorphone and the fentanyl derivatives do not. The metabolites are primarily excreted in the urine.
          • IV, onset of action is within minutes for the fentanyl derivatives; hydromorphone and morphine may take 20 to 30 minutes for peak effect..
    • Opioids
        • Pharmacodynamics
          • CNS
            • Produce sedation and analgesia in a dose-dependent manner; euphoria is common , not reliable hypnotics.
            • Reduce the minimum alveolar concentration (MAC) of volatile and gaseous anesthetic agents, and reduce the requirements for IV sedative-hypnotic drugs.
            • Decrease CBF and metabolic rate.
    • Opioids
          • Cardiovascular system
            • minimal changes in cardiac contractility , except meperidine.
            • reduce SVR , meperidine or morphine ( histamine release )
            • bradycardia. Meperidine has a weak atropine-like effect.
            • Hemodynamic stable
    • Opioids
          • Respiratory system
          • ◆ Produce respiratory depression in a dose-dependent manner. accentuated sedatives, other respiratory depressants, pulmonary disease.
          • ◆ Decrease ventilatory response to hypercapnia and hypoxia.
          • ◆ Decrease the cough reflex , endotracheal tubes are better tolerated.
          • Pupil size is decreased (miosis) by stimulation of the Edinger-Westphal nucleus of the oculomotor nerve .
    • Opioids
          • Muscle rigidity in the chest, abdomen, and upper airway, inability to ventilate.
          • * may be reversed by neuromuscular relaxants or opioid antagonists.
          • * pretreatment with benzodiazepine or propofol.
          • Gastrointestinal system
            • decrease in gastric emptying. Colonic tone and sphincter tone increase, and propulsive contractions decrease
            • Increase biliary pressure and may produce biliary colic
            • Nausea and vomiting can occur because of direct stimulation of the chemoreceptor trigger zone.
    • Opioids
          • Urinary retention
          • Allergic reactions are rare, although anaphylactoid (histamine) reactions are seen with morphine and meperidine.
          • Drug interactions. Administration of meperidine to a patient who has received a monoamine oxidase inhibitor may result in delirium or hyperthermia and may be fatal.
    • Opioids
      • Dosage and administration.
      • IV, either by bolus or infusion.
      • Larger doses may be required in patients chronically receiving opioids.
    • Naloxone
        • Naloxone is a pure opioid antagonist used to reverse unanticipated or undesired opioid-induced effects such as respiratory or CNS depression.
          • Mode of action. a competitive antagonist at opioid receptors in the brain and spinal cord.
          • Pharmacokinetics
            • Peak effects within 1 to 2 min; a decrease in its clinical effects occurs after 30 min because of redistribution. repeated
            • Metabolized in the liver .
          • Pharmacodynamics
            • Reverses opioids CNS and respiratory depression .
            • Crosses the placenta .
    • Naloxone
          • Dosage and administration: 0.04 mg IV every 2 to 3 min as needed.
          • Adverse effects
            • Pain. abrupt pain as opioid analgesia is reversed. ( hypertension, tachycardia).
            • Cardiac arrest. in rare cases, pulmonary edema and cardiac arrest.
            • Repeated administration may be necessary because of its short duration of action.
    • Pharmacology of inhalation anesthetics
      • Inhalation anesthetics are usually administered for maintenance of general anesthesia but also can be used for induction, especially in pediatric patients.
    • minimum alveolar concentration
      • MAC , minimum alveolar concentration at one atmosphere at which 50% of patients do not move in response to a surgical stimulus.
        • MAC best correlates inversely with lipid/gas partition coefficient ( the greater the lipid solubility the lower the MAC )
        • 最低肺泡有效浓度 ( MAC )
        • 1atm 下同时吸入麻醉药和氧, 50% 病人在切皮时无体动的最低肺泡浓度;
        • MAC 愈小,麻醉效能愈强 ,1.3MAC
    • MAC and Lipid Solubility 1.85 53 sevoflurane 105 1.4 nitrous oxide 1.90 65 ether 1.68 98 enflurane 0.76 224 halothane MAC Lipid/Gas Coefficient Agent
    • inhalation anesthetics
      • Mode of action
        • Nitrous oxide.
        • not clear
        • interaction with cellular membranes of the CNS
        • Volatile anesthetics.
        • unknown
        • Various ion channels in the CNS (including GABA, glycine, and NMDA receptors) have been shown to be sensitive to inhalation anesthetics and may play a role.
    • inhalation anesthetics
      • Pharmacokinetics
        • Nitrous oxide
          • Uptake and elimination of nitrous oxide are rapid compared with other inhaled anesthetics, low blood-gas partition coefficient (0.47).
          • Nitrous oxide is eliminated via exhalation.
    • Uptake, Distribution and Elimination of Anesthetic Gases, p29 0.74 1.68 1.15 2.05 104 MAC 3 1.4 Isoflurane 4 1.9 enflurane 6 12.1 ethyl ether 5 2.3 halothane 2 0.69 sevoflurane 1 0.47 N 2 O Rapidity of Onset Blood/Gas ( λ ) Agent
    • inhalation anesthetics
        • Volatile anesthetics
          • Determinants of speed of onset and offset.
          • FA : alveolar anesthetic concentration
          • FI: inspired anesthetic concentration . The rate of rise of the ratio of these two concentrations (FA/FI) determines the speed of induction of general anesthesia
          • Blood-gas partition coefficient. A lower solubility in blood will lead to lower uptake of anesthetic into the bloodstream, thereby increasing the rate of rise of FA/FI.
          • Inspired anesthetic concentration , which is influenced by circuit size, fresh gas inflow rate, and absorption of volatile anesthetic by circuit components.
            • Alveolar ventilation. Increased minute ventilation.
            • Concentration effect.
    • inhalation anesthetics
            • The second gas effect. When nitrous oxide and a potent inhalation anesthetic are administered together, the uptake of nitrous oxide concentrates the “second” gas (e.g., isoflurane) and increases the input of additional second gas into alveoli via augmentation of inspired volume.
            • Cardiac output. An increase in cardiac output will increase anesthetic uptake
            • Gradient between alveolar and venous blood.
    • inhalation anesthetics
          • Distribution in tissues. The rate of equilibration of anesthetic partial pressure between blood and a particular organ system depends on the following factors:
            • Tissue blood flow. Equilibration occurs more rapidly in tissues receiving increased perfusion. The most highly perfused organ include the brain , kidney , heart , liver, and endocrine glands .
            • Tissue solubility . anesthetic agents with high tissue solubility are slower to equilibrate. Blood-brain partition coefficients of inhalation agents are shown in Table 11.3.
            • Gradient between arterial blood and tissue.
    • inhalation anesthetics
          • Elimination
            • Exhalation. This is the predominant route of elimination.
            • Metabolism. Volatile anesthetics may undergo different degrees of hepatic metabolism, the effect is not clinically significant.
            • Anesthetic loss. Inhalation anesthetics may be lost both percutaneously and through visceral membranes, negligible.
    • Figure 11.2. Ratio of alveolar to inspired gas concentration (FA/FI)
      • as a function of time at constant cardiac output and minute ventilation.
    • Nitrous oxide
      • Pharmacodynamics
        • Nitrous oxide
          • CNS
            • Produces analgesia.
            • Conc greater than 60% may produce amnesia, not reliable.
            • high MAC (104%), usually combined with other anesthetics to attain surgical anesthesia.
          • Cardiovascular system
            • Mild myocardial depressant and a mild sympathetic nervous system stimulant.
            • HR,BP unchanged
            • Respiratory system . a mild respiratory depressant
    • Volatile anesthetics
          • CNS
            • Produce unconsciousness and amnesia at low inspired concentrations (25% MAC).
            • Produce a dose-dependent generalized CNS depression
            • Produce decreased somatosensory evoked potentials.
            • Increase CBF (halothane > enflurane > isoflurane, desflurane, or sevoflurane).
            • Decrease cerebral metabolic rate (isoflurane, desflurane, or sevoflurane > enflurane > halothane).
            • Uncouple autoregulation of CBF
    • Volatile anesthetics
          • Cardiovascular system
            • Produce dose-dependent myocardial depression
            • and systemic vasodilation
            • Heart rate unchanged.
            • Sensitize the myocardium to the arrhythmogenic effects of catecholamines (halothane > enflurane > isoflurane or desflurane > sevoflurane), particularly during infiltration of epinephrine-containing solutions or administration of sympathomimetic agents.
            • patients with coronary artery disease, isoflurane may redirect coronary flow away from ischemic areas.
    • Volatile anesthetics
          • Respiratory system
            • Produce dose-dependent respiratory depression.
            • Produce airway irritation (desflurane > isoflurane > enflurane > halothane > sevoflurane ) and, during light levels of anesthesia, may precipitate coughing, laryngospasm, or bronchospasm.#
            • volatile agents possess similar bronchodilator effects, with the exception of desflurane, which has mild bronchoconstricting activity .
    • Volatile anesthetics
          • Muscular system
            • decrease in muscle tone, enhancing surgical conditions.
            • May precipitate malignant hyperthermia
          • Liver. May cause a decrease in hepatic perfusion (halothane > enflurane > isoflurane, desflurane, or sevoflurane). “halothane hepatitis”
          • Renal system. Decrease renal blood flow
    • Volatile anesthetics
      • Problems related to specific agents
        • Nitrous oxide
          • Expansion of closed gas spaces . Spaces containing air such as a pneumothorax, occluded middle ear, bowel lumen , or pneumocephalus will markedly enlarge if nitrous oxide is administered. Nitrous oxide will diffuse into the cuff of an endotracheal tube and may increase pressure within the cuff.
    • Nitrous oxide
          • Diffusion hypoxia . After discontinuation of nitrous oxide, its rapid diffusion from the blood into the lung may lead to a low partial pressure of oxygen in the alveoli, resulting in hypoxia and hypoxemia if supplemental oxygen is not administered. Continue supply O2 after discontinuation of N2O for 10 min.
          • Inhibition of tetrahydrofolate synthesis. Nitrous oxide should be used with caution in pregnant patients and those deficient in vitamin B12.
    • Nitrous oxide
      • Nitrous oxide , known as happy gas or laughing gas , due to the euphoric effects
      • Nitrous oxide is a weak anesthetic, not used alone in GA. It is used as a carrier gas in a 2:1 ratio with oxygen for more powerful general anesthetic agents such as sevoflurane or desflurane .
      • never receives 100% nitrous. Instead you breath a mix of nitrous and oxygen -- generally 70% N2O to 30% oxygen . This is equivalent to the amount of oxygen in room air -- but the nitrogen has been replaced by nitrous oxide. #
      • unless administered with at least 20 percent oxygen, hypoxia can be induced.
      • Nitrous oxide does not kill brain cells, but lack of oxygen does
    • Desflurane
      • Desflurane can be degraded to carbon monoxide in carbon dioxide absorbents (especially Baralyme).
      • a few cases of clinically significant carbon monoxide poisoning have been reported.
    • Sevoflurane
      • Sevoflurane can be degraded in CO2 absorbents (especially Baralyme) to fluoromethyl-2,2,-difluoro-1-vinyl ether (Compound A ), which has been shown to produce renal toxicity in animal models.
      • Compound A concentrations increase at low fresh gas rates. T here has been no evidence of consistent renal toxicity with sevoflurane usage in humans.
    • Enflurane
      • Enflurane can produce electroencephalographic epilepti-form activity at high inspired concentrations (>2%).
    • Inhalation Anesthetic Agents
      • Anesthetic gases – only one is Nitrous Oxide
      • Volatile liquids
        • halothane (Fluothane) – inexpensive, good bronchodilator
        • isoflurane (Forane) – commonly for adults, inexpensive
        • enflurane (Ethrane) – like isoflurane, except increased risk of seizures. Rarely used
        • desflurane (Suprane) – similar to isoflurane except for more rapid emergence, and more irritating to airway
        • sevoflurane (Ultane) – similar to desflurane except not irritating to airway, one of the best !!
    • yes Marked Yes Yes Respir depression No Significant Significant No Respir irritation Slightly reduced Stable Slightly reduced Reduced Cardiac output Stable Increased Increased Reduced Heart rate Significant Significant Significant Moderate Muscle relax 3 – 6% 0.02% 0.2% 12 – 25% Metabolism No No No Yes Hepatotoxic Fast Very fast Moderate Slow Recovery Fast Fast Moderate Slow Alveolar equilibration sevoflurane Desflurane Isoflurane Halothane
    • Summary
        • propofol : cvs depress
        • thiopental
        • Ketamine : analgesic, ↑HR , BP , CBF, Emotional disturbance , im
        • Benzodiazepines- Flumazenil
        • Long t1/2 , anticonvulsion , mild m . relax
          • midazolam
          • diazepam
          • lorazepam
        • Etomidate- Less CVS depress, aged group , Adrenocortical suppress , 1 dose
        • OPIOID- Naloxone
      • Elimination half-time
      • Context-sensitive half-time (CSHT) : infusion 时 - 量相关半衰期
      • MAC
    •  
    •  
    •  
    •  
    •  
    •  
    • Thank you!
    •  
    •  
    • Overview of Discussion
      • Historical Perspective
      • What is General Anesthesia?
        • Definition
      • Principles of Surgical Anesthesia
        • Hemodynamic and Respiratory Effects
        • Hypothermia
        • Nausea and Vomiting
        • Emergence
      • Mechanisms of Anesthesia
        • Early Ideas
        • Cellular Mechanisms
        • Structures
      • Molecular Actions: GABA A Receptor
      • Mechanism of Propofol (Diprivan ® )
        • Metabolism and Toxicity
      • Adverse Affects of Propofol
      • Remaining Questions Concerning the GABA A Receptor
      • Latest Discoveries and Current Events
    • Historical Perspective
      • Original discoverer of general anesthetics
        • Crawford Long: 1842, ether anesthesia
      • Chloroform introduced
        • James Simpson: 1847
      • Nitrous oxide
        • Horace Wells
      19 th Century physician administering chloroform
    • Definition of General Anesthesia
      • Reversible, drug-induced loss of consciousness
        • Depresses the nervous system
      • Anesthetic state
        • Collection of component changes in behavior or perception
          • Amnesia, immobility in response to stimulation, attenuation of autonomic responses to painful stimuli, analgesia, and unconsciousness
    • The Body and General Anesthesia
      • Hemodynamic effects: decrease in systemic arterial blood pressure
      • Respiratory effects: reduce or eliminate both ventilatory drive and reflexes maintaining the airway unblocked
      • Hypothermia: body temperature < 36˚C
      • Nausea and Vomiting
        • Chemoreceptor trigger zone
      • Emergence
        • Physiological changes
    • Mechanism
      • Early Ideas
        • Unitary theory of anesthesia
          • Anesthesia is produced by disturbance of the physical properties of cell membranes
          • Problematic: theory fails to explain how the proposed disturbance of the lipid bilayer would result in a dysfunctional membrane protein
            • Inhalational and intravenous anesthetics can be enantio-selective in their action
      • Focus on identifying specific protein binding sites for anesthetics
    • Cellular Mechanism
      • Intravenous Anesthetics
        • Substantial effect on synaptic transmission
        • Smaller effect on action-potential generation or propagation
        • Produce narrower range of physiological effects
      • Actions occur at the synapse
        • Effects the post-synaptic response to the released neurotransmitter
          • Enhances inhibitory neurotransmission
    • Structures
      • Intravenous
      • Inhalational
      Propofol Etomidate Ketamine Halothane Isoflurane Sevoflurane
    • Molecular Actions: GABA A Receptor
      • Ligand-gated ion channels
        • Chloride channels gated by the inhibitory GABA A receptor
          • GABA A receptor mediates the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain
            • GABA A receptor found throughout the CNS
              • Most abundant, fast inhibitory, ligand-gated ion channel in the mammalian brain
              • Located in the post-synaptic membrane
    • Molecular Actions: GABA A Receptor
      • GABA A receptor is a 4-transmembrane (4-TM) ion channel
        • 5 subunits arranged around a central pore: 2 alpha, 2 beta, 1 gamma
          • Each subunit has N-terminal extracellular chain which contains the ligand-binding site
          • 4 hydrophobic sections cross the membrane 4 times: one extracellular and two intracellular loops connecting these regions, plus an extracellular C-terminal chain
    • Molecular Action: GABA A Receptor
    • Molecular Action: GABA A Receptor
      • Receptor sits in the membrane of its neuron at the synapse
      • GABA , endogenous compound, causes GABA to open
      • Receptor capable of binding 2 GABA molecules, between an alpha and beta subunit
        • Binding of GABA causes a conformational change in receptor
          • Opens central pore
          • Chloride ions pass down electrochemical gradient
        • Net inhibitory effect, reducing activity of the neuron
    • Mechanism of Propofol
      • Action of anesthetics on the GABA A receptor
        • Binding of anesthetics to specific sites on the receptor protein
        • Proof of this mechanism is through point mutations
          • Can eliminate the effects of the anesthetic on ion channel function
        • General anesthetics do not compete with GABA for its binding on the receptor
    • Mechanism of Propofol
      • Inhibits the response to painful stimuli by interacting with beta 3 subunit of GABA A receptor
      • Sedative effects of Propofol mediated by the same GABA A receptor on the beta 2 subunit
        • Indicates that two components of anesthesia can be mediated by GABA A receptor
      • Action of Propofol
        • Positive modulation of inhibitory function of GABA through GABA A receptors
    • Mechanism of Propofol
      • Parenteral anesthetic
        • Small, hydrophobic, substituted aromatic or heterocyclic compound
      • Propofol partitions into lipophilic tissues of the brain and spinal cord
        • Produces anesthesia within a single circulation time
    • Metabolism and Toxicity
      • Recovery after doses/infusion of Propofol is fast
      • Half-life is “context-sensitive”
        • Based on its own hydrophobicity and metabolic clearance, Propofol’s half-life is 1.8 hours
        • Accounts for the quick 2-4 minute distribution to the entire body
          • Expected for a highly lipid-soluble drug
      • Anesthetic of choice
    • Adverse Effects of Propofol
      • Hypotension
      • Arrhythmia
      • Myocardial ischemia
        • Restriction of blood supply
      • Confusion
      • Rash
      • Hyper-salivation
      • Apnea
    •  
    • Latest Discoveries: Implications for the Medicinal Chemist
      • Explosion of new information on the structure and function of GABA A receptors
        • Cloning and sequencing multiple subunits
          • Advantageous: large number of different subunits (16) allows for a great variety of different types of GABA A receptors that will likely differ in drug sensitivity
        • Propofol delivery technology
          • Mechanically driven pumps
          • Computer-controlled infusion systems
            • “ target controlled infusion” (TCI)
    • Inhaled Anesthetics
      • Halothane
      • Enflurane
      • Isoflurane
      • Desflurane
        • Halogenated compounds:
        • Contain Fluorine and/or bromide
        • Simple, small molecules