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.
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:
Gasses or Vapors
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
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
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 .
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.
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
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.
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.
thiopental (Pentothal) 硫喷妥钠
propofol (Diprivan) 丙泊酚
midazolam (Versed) 咪达唑仑
diazepam (Valium) 地西泮
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 (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.
Mode of action: Increases activity at inhibitory GABA synapses. Inhibition of glutamate ( N -methyl-D-aspartate [NMDA]) receptors may play a role.
Hepatic (and some extrahepatic) metabolism to inactive metabolites.
The CSHT of propofol (see Fig. 11.1) is 15 min after a 2-hour infusion.
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 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
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
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.
Venous irritation ： Injection pain during IV administration
reduced by adding lidocaine
antiemetic effects ： Less postoperative
nausea and vomiting
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 .
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.
Mode of action: Enhance the inhibitory tone of GABA receptors.
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.
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
Reduce cerebral blood flow and metabolic rate.
a mild systemic vasodilation and reduction in cardiac output. Heart rate unchanged.
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.
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.
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 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 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.
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.
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.
↑ HR ， ↑ BP ， centrally mediated release of endogenous catecholamines.
Often used to induce general anesthesia in hemodynamically compromised patients.
depresses RR and tidal volume mildly
Alleviates bronchospasm by a sympathomimetic effect.
Laryngeal protective reflexes are relatively well-maintained .
Dosage and administration: See Table 11.1.
IM / IV, IM in whom IV access is not available (e.g., children).
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.
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 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.
clearance in the liver and by circulating esterases to inactive metabolites.
Times to loss of consciousness and awakening similar to propofol.
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.
Dosage and administration: IV, See Table 11.1.
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 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).
Mode of action: Opioids bind at specific receptors in the brain, spinal cord, and on peripheral neurons. The opioids are selective for μopioid receptors .
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..
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.
minimal changes in cardiac contractility ， except meperidine.
reduce SVR ， meperidine or morphine （ histamine release ）
bradycardia. Meperidine has a weak atropine-like effect.
◆ 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 .
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.
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.
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.
Dosage and administration.
IV, either by bolus or infusion.
Larger doses may be required in patients chronically receiving opioids.
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.
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 .
Reverses opioids CNS and respiratory depression .
Crosses the placenta .
Dosage and administration: 0.04 mg IV every 2 to 3 min as needed.
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
Mode of action
interaction with cellular membranes of the CNS
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.
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
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.
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.
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.
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.
Conc greater than 60% may produce amnesia, not reliable.
high MAC (104%), usually combined with other anesthetics to attain surgical anesthesia.
Mild myocardial depressant and a mild sympathetic nervous system stimulant.
Respiratory system . a mild respiratory depressant
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).
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.
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 .
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
Problems related to specific agents
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.
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 , 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 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 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 can produce electroencephalographic epilepti-form activity at high inspired concentrations (>2%).
Inhalation Anesthetic Agents
Anesthetic gases – only one is Nitrous Oxide
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
propofol ： cvs depress
Ketamine : analgesic, ↑HR ， BP ， CBF, Emotional disturbance ， im
Long t1/2 , anticonvulsion , mild m . relax
Etomidate- Less CVS depress, aged group , Adrenocortical suppress , 1 dose