General Anesthetics Flashcards
General anesthesia as a condition includes what?
- Analgesia
- Anmnesia
- Loss of consciousness
- Also a loss of sensory and autonomic reflexes and general skeletal muscle relaxation
Most modern inhalational general anesthetics are based on what molecule that entered surgical anesthesia use in 1956?
• Halothane
Is the mechanism of action for inhaled general anesthetics easy to track?
• Nope. They have no single receptor
• Uncharged, nonpolar molecules with structures seemingly unrelated to one another
• Also, no specific antagonists of volatile anesthetics are known
○ Anticonvulsants and proconvulsants can decrease the duration of anesthesia
• CONTRAST - the IV general anesthetics are much better characterized
What are the important inhalational general anesthetics to know?
• Inorganic gases ○ Xenon, Nitrous oxide, nitrogen • Ethers ○ Diethyl ether • Hydrocarbons ○ Cyclopropane, ethylene • Chlorinated hydrocarbons ○ Chloroform, trichloroethylene • Fluorinated hydrocarbon ○ halothane • Fluorinated ethers ○ Enflurane, isoflurane, desflurane, sevoflurane
What are the IV general anesthetics that are important to know?
• Barbiturates ○ Thiopental • Benzodiazepines ○ Diazepam • Opioid analgesics ○ Morphine, fentanyl • Glutamate receptor agent ○ ketamine • Miscellaneous agents ○ Propofol, etomidate
What is the lipid theory of general volatile anesthetic mechanism of action?
• Behave as ideal gases thus their solubility in different media can be described by partition coefficients
○ Oil:water or Blood:gas
• The higher the oil:water partition coefficient, the more potent the general anesthetic
• Thus, evidence that they interact with lipids
• Also, MAC (minimum alveolar concentration to produce analgesia) is correlated with lipid solubility
What is the protein theory of general anesthetic mechanism of action?
- Instead of the lipid solubility truly meaning the gases mess with the neurons themselves, this theory suggests that the gasses actually mess with the proteins on the neuronal membrane
- The hydrophobic pockets of the proteins take up the anesthetic gasses, messing essentially with neuronal receptors and NT systems
- Evidence comes from in vitro experiemnts where anesthetic gases mess with protein properties without lipid bilayer
- Other evidence is the size cut-off for efficacy of these drugs, suggesting only certain sizes fit into the hydrphobic pockets of the membrane proteins
ESR evidence supports the protein theory over the lipid theory. What is ESR?
- Electron spin resonance
* Shows halothane trapped in protein, not lipid bilayer
Which neurons in the CNS are affected by general anesthetics?
- GABA systems. They are all CNS depressants
* Potentiation of GABA-a receptor activity by volatile and IV anesthetics
Though there are many documented mechanisms of action for general anesthetics, what is NOT believed to happen?
- Full conduction block
- Conduction block happens at concentrations above that used in clinical use
- Also, peripheral AP conduction is fine in anesthetized patients
What brain regions seem to be very sensitive to general anesthetics?
• Hypothalamic nuclei that produce sleep are probably the most sensitive
• Reticular formation of the brainstem b/c this is involved in control of pain sensation, alertness and sleep
○ Also, damage to this region can cause unconsciousness
• Hippocampus is also implicated b/c of amnesia
What is meant by “progression” in General Anesthetic Action
• It works by descending depression (progressive loss of function from higher (cognition) to lower (respiratory control) within the CNS
• Nobody knows why but the dose-dependence is from cognition and memory low to respiratory depression high doses
• List of progression
○ Fine motor and coordination
○ Alteration of consciousness and analgesia
○ Temp regulation
○ Consciousness
○ Eye motion, pupil size and light reflex
○ Loss of muscle tone
○ Respiratory failure
○ Cardiovascular failure
○ Coma and death
What are the 4 planes of surgical anesthesia?
• These are all in stage III of general anesthesia progression
• 1 - Regular metronomic respirations
• 2 - onset of muscular relaxation, fixed pupils
• 3 - good muscular relaxation, depressed excursion of intercostal muscles during
• 4 - diaphragmatic breathing only, dilated pupils
Why do you not want to overdose patients into stage IV of general anesthesia?
• Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes
What are the three periods of the time course of surgical anesthesia
• Induction
○ Time between initiation of admin and attainment of surgical anesthesia, until stage III is reached
• Maintenance
○ Time during which surgical anesthesia is in effect (surgery carried out during this period)
• Recovery
○ Time following termination of administration of anesthetic until complete recovery of patient from anesthesia
The volatile anesthetics behave like noble gases. What does this mean for determining concentration?
• The total pressure exerted by a mixture of non-reacting gases is equal to the sum of the partial pressures of the individual gases
○ Dalton’s law
• The amount of a gas dissolved in a liquid solution is proportional to the partial pressure of the gas to which the solution is exposed
○ Henry’s law
How could you predict between two drugs which one would cause CNS depression faster (or with less total drug administered)?
- Rate of rise of partial pressure of inhalational anesthetic agents in arterial blood is determined by anesthetic solubility (blood:gas partition coefficient)
- The solubility of anesthetic gas in blood determines the rate of rise in its concentration in blood
- The more soluble the gas, the longer it takes for the partial pressure to rise and the lower the “knee”
What is the result of combining the two principles of the 2nd phase of approaching anesthesia steady state?
• The rate of approach to stage 3 anesthesia for a volatile anesthetic is inversely related to pulmonary blood flow and the solubility of the anesthetic gas in blood
Phase III of approaching anesthetic steady state has three subparts. What are they?
• Solubility in body tissues
○ Brain and blood are about the same
○ Fatty tissues end up being a large reservoir for volatile anesthetic drugs
• Tissue blood flow
○ How fast the drugs are even delivered to the tissues
• Partial pressures of anesthetic in blood and in tissues
When thinking about phase IV of approaching anesthetic steady state, you think about tissue distribution in three basic groups. Explain.
• Three different “watery” groups that allow for the volatile gases to “sink” into
○ Vessel-rich group
§ Highly vascularized tissues like brain, heart, kidney and liver and endocrine glands
§ Uptake into these tissues is high (within minutes) because these tissues are so well perfused
○ Muscle group
§ Includes muscle and skin
§ Uptake here is about 2-4 hours since the perfusion is less
○ Fat group
§ Inhaled anesthetic uptake occurs very slowly in fatty tissue owing to the enormous amount of anesthetic that can be dissolved in fatty tissue and the low perfusion of that tissue
§ High lipid solubility accoutns for the huge anesthetic storage capacity of fatty tissue
After a pretty dang long surgery, that patient will be feeling the recovery from anesthesia for a long time. Why?
- They loaded up the fat compartment and that takes a super long time to unload
- Fatty tissue is a large reservoir for volatile gas anesthetic
What is meant by the MAC in anesthesia?
• Minimum anesthetic concentration
○ Alveolar concentration that prevents gross skelatal muscle response to a standard painful stimulus (skin incision) in 50% of patients
○ The inverse of the MAC value is generally an accepted estimate of it’s potency
Blood:gas partition and oil:gas partitions speak of two different properties. What are they?
- Potency is determined by the oil:gas partition
* Uptake and elimination kinetics are estimated by the blood:gas partition coefficient
How can you estimate the potency of a general volatile gas anesthetic?
• The inverse of the MAC value is generally an accepted estimate of it’s potency
Describe the elimination component of inhalational general anesthetics
- Essentially the reverse of the uptake
- The major clearance of inhaled anesthetics is through the lungs
- Determined by cardiac output and respiration rate of patient, so doc has little control over it
- NOTE - the liver isn’t important for metabolism and elimination, but some metabolites of inhalational gases can cause the adverse side effects
Describe the main important points about N2O use as a general anesthetic
• Can never reach stage III (which is surgical level) on its own
• However, it’s often used as an adjunct because it’s a great analgesic and a great anxiolytic
• It has a rapid onset and recovery
• It has a couple funky admin dynamics to be aware of
○ Tends to get sucked into lungs faster than expected
○ On recovery, it gets out of blood into lungs so fast it can push out O2 and cause diffusion hypoxia
○ It can help any co-administered drug get sucked into the blood faster (second gas effect)
What are the contraindications for use of N2O?
- Be careful if they have a head injury
- Respiratory obstruction, especially COPD
- pregnancy
What are the important points of Halothane use?
• It is a fluorinated hydrocarbon, and fluorination reduces flammability of alkyl hydrocarbons
• WATCH OUT FOR DAMAGE!
○ Easily produces respiratory and cardiovascular failure (arrhythmias)
○ Can cause liver damage
§ 2-5 days after anesthesia, fever, anorexia and nausea with vomiting develop
§ Incidence is low but of those who get it, 50% progress to liver failure
§ Thought to be tied to an immune response to halothane
○ Can trigger malignant hyperthermia and central core disease
§ Muscle rigidity and fever
§ Inherited ryanodine receptor mutation
§ Other halogenated volatile gases can cross-activate
§ Use IV anesthetic if family history indicates MH
Why is chloroform no longer used?
- Produces cardiac arrhythmias
* Real problems with hepatotoxicity
Enflurane has what important characteristics?
- It’s a similar drug to halothane, just less side effects
- Used most commonly for maintenance phase
- Can trigger seizures during induction or recovery
- Less CV effects, less hepatotoxicity
Isoflurane compares to enflurane and halothane how to make it the most widely used volatile gas anesthetic?
- These are all variations on a theme
- Isoflurane is super similar to enflurane but is more potent
- Less liver or kidney effects
- Doesn’t trigger seizures
- Can trigger coughing as it is more smelly, so smother coughing with an IV agent
- MOST WIDELY USED
Desflurane and sevoflurane are the newer volatile gas anesthetics on the market. What are they good for?
• They have better pharmacokinetics in general
• They also have less side effects
• Desflurane smells really bad and causes coughing, so despite it’s great kinetics can’t be used in induction
○ About as potent as N2O (high compared to other halogenated compounds)
• Sevoflurane smells GOOD and is used as induction
○ Super high potency
Compare thiopental and propofol for use as IV general anesthetics
- Both are barbiturates
- Both are rapid on and rapid off
- Both potentiate the GABA-a receptor, prolonging IPSP at GABAergic synapses
- Propofol is faster for recovery and doesn’t elicit any involuntary movements
- Propofol does not cause nausea
How is etomidate different than propofol and thiopental?
• It’s not a barbiturate
• It is a hypnotic that lacks analgesic properties
• Still potentiates GABA-a receptor
• Used primarily for induciton of general anesthesia and as adjunct
• Advantage - Causes minimal depression of CV and respiratory systems
○ Larger safety margin
○ Slight hypotension, no alteration in HR and low frequecy of apnea
• LOC in seconds
• Liver metabolized
• Disadvantage -
○ Can cause involuntary patient movements
○ High incidence of nausea, vomiting, pain on injection
Describe the pros and cons of ketamine use as an IV general anesthetic
• PCP derivative
• Produces dissociative anesthesia characterized by catatonia, amnesia and analgesia
• Problems with emergence phenomena of disorientation and hallucination
○ Can reduce by IV admin of diazepam 5 min prior to admin of ketamine
• Molecular action
○ Antagonism of NMDA-subtype glutamate receptor
○ Inhibits excitatory, glutamate synaptic transmission in CNS
○ No action at the GABA-a receptor
• Slower onset (minutes)
• Bronchodilator - use with asthmatic patients
Why is MAC such an accurate measure of concentration for anesthetic use?
- Does not vary with weight, gender nor duration of anesthesia
- Also, the values are linearly additive so that a dose of 1/2 MAC for one volatile plus 1/2 MAC of another means 1MAC total effect
Using MAC, show that the dos-response to volatile anesthetics is super steep and thus the therapeutic window is super tiny
- 50% of patients fail to respond to an incision at 1 MAC (defiinition)
- But 99% of patients are fully anesthetized at 1.3 MAC (which is the target for most surgeries)
For an IV anesthetic, which would have a faster onset: one with high lipid solubility or low?
- High lipid solubility means that sucker sucks into the brain super quick
- Faster onset for high lipid solubility
What muscle relaxants are used as adjuncts for general anesthesia?
• Idea is to keep movement from happening and help in surgery, moving all that crap around
○ Especially in abdominal surgery
• Do not cross BBB
• D-tobocurarine
○ Competitive antagonist of Ach at NMJ, an AP blocker
• Vecuronium
○ More common now
What adjuncts, in general, would you use to aid in general anesthesia?
• Anti-anxiety agents ○ BDZs and barbiturates • Anticholinergics ○ Atropine, scopolamine, glycopyrrolate • Analgesics ○ Opioids like morphine and fentanyl • Anti-emetics ○ Ondansetron (serotonin receptor antagonist)
