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
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 .
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.
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.
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.
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
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
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.
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.
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 ↑ ↑
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..
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
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.
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