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General Anesthetics

Jieyu FangThe First Affiliated Hospital

房洁渝

中山大学附属第一医院

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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

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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.

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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.

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Anesthetics divide into 2 classes:

Inhalation Anesthetics

Gasses or Vapors Usually

Halogenated

Intravenous Anesthetics

InjectionsAnesthetics or induction agents

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Hypotheses of General Anesthesia

1. 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

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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 GABAA receptor is a potential target of anesthetics action.

GABA: γ-aminobutyric acid synapseNMDA receptor: N-methyl-D-aspartate

3.Binding theory: Anesthetics bind to hydrophobic portion of the ion

channel

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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: GABAA and GABAB.

GABAA receptors are ligand-gated ion channels, Its

endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.

GABAB receptors are G protein-coupled receptors.

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GABA receptors

Upon activation, the GABAA 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.

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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 Mg2+ ions. This allows voltage-dependent flow of Na+ and small amounts of Ca2+ 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.

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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.

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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.

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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

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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.

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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.

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Pharmacology of intravenous (IV) anesthetics

Active drug remains in the body, so clearance still needs to occur, typically by hepatic metabolism and renal elimination.

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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.

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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.

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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.

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propofol

Pharmacodynamics Central nervous system (CNS)

Induction doses produce unconscious Induction doses produce unconscious (30 to 45 seconds), followed by rapid reawakening due to redistribution

Low doses produce sedationLow doses produce sedation. Weak analgesic effects

Raises seizure threshold. Decreases intracranial pressure (ICP) but also

cerebral perfusion pressure..

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Properties of Intravenous Anesthetic Agents-propofol

Cardiovascular system Cardiovascular depressantCardiovascular 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.

#

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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.

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Monitor.jpg

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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.

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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.

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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.

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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.

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Benzodiazepines

Cardiovascular systema mild systemic vasodilation and reduction

in cardiac output. Heart rate unchanged.

Respiratory systemProduce 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.

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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.

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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.

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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.

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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.

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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.

#

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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.

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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.

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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..

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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.

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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.

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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.

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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.

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Non-barbiturate induction drugs effects on BP and HR

Drug Systemic BP

Heart Rate

propofol ↓ ↓

etomidate No change or slight ↓

No change

ketamine ↑ ↑

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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).

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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..

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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.

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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

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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.

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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.

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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.

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Opioids

Dosage and administration.

IV, either by bolus or infusion.

Larger doses may be required in patients chronically receiving opioids.

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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.

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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.

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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.

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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

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MAC and Lipid Solubility

Agent Lipid/Gas Coefficient

MAC

halothane 224 0.76

enflurane 98 1.68

ether 65 1.90

sevoflurane 53 1.85

nitrous oxide 1.4 105

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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.

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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.

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Uptake, Distribution and Elimination of Anesthetic Gases, p29

Agent Blood/Gas (λ) MAC Rapidity of Onset

N2O 0.47 104 1

sevoflurane 0.69 2.05 2

Isoflurane 1.4 1.15 3

enflurane 1.9 1.68 4

halothane 2.3 0.74 5

ethyl ether 12.1 6

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inhalation anesthetics

Volatile anesthetics Determinants of speed of onset and offset. FA : alveolar anesthetic concentrationFI: 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.

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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.

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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.

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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.

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Figure 11.2. Ratio of alveolar to inspired gas concentration (FA/FI)

as a function of time at constant cardiac output and minute ventilation.

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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

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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

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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.

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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.

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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

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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.

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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.

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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

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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.

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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. There has been no evidence of consistent renal toxicity with sevoflurane usage in humans.

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Enflurane

Enflurane can produce electroencephalographic epilepti-form activity at high inspired concentrations (>2%).

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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!!

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Halothane Isoflurane Desflurane sevoflurane

Alveolar equilibration

Slow Moderate Fast Fast

Recovery Slow Moderate Very fast Fast

Hepatotoxic Yes No No No

Metabolism 12 – 25% 0.2% 0.02% 3 – 6%

Muscle relax Moderate Significant Significant Significant

Heart rate Reduced Increased Increased Stable

Cardiac output

Reduced Slightly reduced

Stable Slightly reduced

Respir irritation

No Significant Significant No

Respir depression

Yes Yes Marked yes

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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 Less CVS depress, CVS depress, aged group, Adrenocortical suppress, 1 dose

OPIOID- Naloxone

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Elimination half-time Context-sensitive half-time (CSHT) ：

infusion 时 - 量相关半衰期

MAC

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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: GABAA Receptor Mechanism of Propofol (Diprivan®)

Metabolism and Toxicity Adverse Affects of Propofol Remaining Questions Concerning the GABAA Receptor Latest Discoveries and Current Events

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Historical Perspective

Original discoverer of general anesthetics Crawford Long: 1842,

ether anesthesia

Chloroform introduced James Simpson: 1847

Nitrous oxide Horace Wells

19th Century physician administering chloroform

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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

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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

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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

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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

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Structures

Intravenous

Inhalational

Propofol Etomidate Ketamine

Halothane Isoflurane Sevoflurane

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Molecular Actions: GABAA Receptor

Ligand-gated ion channels Chloride channels gated by

the inhibitory GABAA receptor GABAA receptor mediates

the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain

GABAA receptor found throughout the CNS

Most abundant, fast inhibitory, ligand-gated ion channel in the mammalian brain

Located in the post-synaptic membrane

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Molecular Actions: GABAA Receptor

GABAA 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

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Molecular Action: GABAA Receptor

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Molecular Action: GABAA 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

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Mechanism of Propofol

Action of anesthetics on the GABAA 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

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Mechanism of Propofol

Inhibits the response to painful stimuli by interacting with beta3 subunit of GABAA

receptor Sedative effects of Propofol mediated by the

same GABAA receptor on the beta2 subunit Indicates that two components of anesthesia

can be mediated by GABAA receptor Action of Propofol

Positive modulation of inhibitory function of GABA through GABAA receptors

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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

104

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

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Adverse Effects of Propofol

Hypotension Arrhythmia Myocardial ischemia

Restriction of blood supply

Confusion Rash Hyper-salivation Apnea

106

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Latest Discoveries: Implications for the Medicinal Chemist

Explosion of new information on the structure and function of GABAA receptors Cloning and sequencing multiple subunits

Advantageous: large number of different subunits (16) allows for a great variety of different types of GABAA receptors that will likely differ in drug sensitivity

Propofol delivery technology Mechanically driven pumps Computer-controlled infusion systems

“target controlled infusion” (TCI)

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Inhaled Anesthetics

Halothane Enflurane Isoflurane Desflurane

Halogenated compounds:

Contain Fluorine and/or bromide

Simple, small molecules