General Anesthetics I-II Flashcards
In the broad sense, what is the target for general anesthetics?
GABAa receptors
More potent GAs are _____ in olive oil
more soluble
MAC and potency
MAC: minimum alveolar concentration of a GA that produces insensibility to pain in 50% of subjects
Potency: 1/MAC
Evidence for GA “receptor site”
- size cut off (of related compounds, only those below a specific size have anesthetic effects)–molecs must fit into pockets of specific size w/in membrane proteins (like ion channels)
- electron spin resonance show volatile anesthetic is immobilized in nerve membrane (binds to immobilized memb prot)
- ESR shows that volatile anesthetic solvation in protein containing membranes exhibits saturable component
- Stereoselectivity
Ion channels affected by clinically relevant levels of GA
- potentiation of glycine receptors in brainstem and spinal cord=neuronal inhibition (increase inhibitory transmission)
- inhibition of brain nicotinic ACh receptors (decrease excitatory transmission)
- potentiation of TASK-1 K+ channels that set resting potential (decrease excitability)
Ion channels affected by clinically relevant levels of GA
- potentiation of glycine receptors (increase inhibitory transmission)
- inhibition of brain nicotinic ACh receptors (decrease excitatory transmission)
- potentiation of TASK-1 K+ channels that set resting potential (decrease excitability)
Actions of GAs that occur above clinical range
- impaired AP conduction (but conduction block doesn’t underlie anesthesia in normal range)
- Inhalational anesthetics act on voltage gated Na, Ca, and K channels but only at high levels
Summary of protein theory of GA action
- Volatile GAs partition into membrane and enter hydrophobic pockets in various memb prot like GABAa recep, ion channels, etc
- Volatile GA occupancy of hydrophobic pockets depresses CNS func–>gen anesthesia
- ***Volatile and IV anesthetics potentiate GABAergic IPSPs in CNS (key)
- not specific binding sites involved but size cut offs exist
- So: clinically relevant effect only at concentrations much higher (1-100mM) than those needed for drugs w/ specific binding sites
Summary of protein theory of GA action
- Volatile GAs partition into membrane and enter hydrophobic pockets in various memb prot like GABAa recep, ion channels, etc
- Volatile GA occupancy of hydrophobic pockets depresses CNS func–>gen anesthesia
- Volatile and IV anesthetics potentiate GABAergic IPSPs in CNS (key)
- not specific binding sites involved but size cut offs exist
- So: clinically relevant effect only at concentrations much higher (1-100mM) than those needed for drugs w/ specific binding sites
GA effects
-analgesia, amnesia and loss of consciousness
- sensory and autonomic reflexes are suppressed
during surgical anesthesia, and skeletal muscle relaxation is generally present
-actions at CNS
Volatile (inhalational) GA structure
- high oil:water partition coefficient (higher=more potent)
- uncharged, nonpolar molecules with structures seemingly unrelated to one another
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
IV GAs
Barbiturates: Thiopental, Benzodiazepines: Diazepam, Opioid analgesics: Morphine, Fentanyl Glutamate receptor agent: Ketamine Miscellaneous agents: Propofol, Etomidate
Descending depression
-progressive loss of function from higher (cognition/consciousness) to lower (resp control) levels within the CNS. Progression: -loss of fine motor func/impaired coord -alteration of consciousness and often analgesia -loss of temp regulation -unconsciousness -effects on eye motion, pupil size, and light reflex -loss of muscle tone ------- -respiratory failure -CV failure -coma, death
Guedel’s Stages & Planes of anesthesia
Stage I – analgesia
Stage II – excitement, delirium
Stage III – surgical anesthesia (this stage is not reached by N2O)
-Plane 1 regular, metronomic respirations
-Plane 2 onset of muscular relaxation, fixed pupils
-Plane 3 good muscular relaxation, depressed excursion of intercostal muscles during respiration
-Plane 4 diaphragmatic breathing only, dilated pupils
• Stage IV – medullary paralysis
-Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes
*pt can be resuscitated following accidental overdose if circulation preserved (use artificial respiration)
Guedel’s Stages & Planes of anesthesia
Stage I – analgesia
Stage II – excitement, delirium
Stage III – surgical anesthesia (this stage is not reached by N2O)
-Plane 1 regular, metronomic respirations
-Plane 2 onset of muscular relaxation, fixed pupils
-Plane 3 good muscular relaxation, depressed excursion of intercostal muscles during respiration
-Plane 4 diaphragmatic breathing only, dilated pupils
• Stage IV – medullary paralysis
-Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes
Time course of surgical anesthesia
• Induction: time between initiation of administration of anesthetic and attainment of surgical anesthesia,
that is, 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
Factors impacting rate of approach to steady state anesthesia: Phase I
I. lung factors: the rate of increase in the partial pressure of anesthetic gas in alveoli and pulmonary capillary blood is proportional to the rate of ventilation (rate of induction increased by overventilation, but depth unaffected by vent rate).
Factors impacting rate of approach to steady state anesthesia
I. lung factors
II. uptake of anesthetic by blood from alveoli
III. uptake from blood to body tissues
IV. tissue distribution
Is induction of anesthesia slower or faster for more soluble anesthetic gases?
SLOWER**
-Higher GA solubility in blood means that MORE anesthetic must be dissolved in blood in order to reach stage III, surgical anesthesia. (ie compartment size is “larger” for more soluble anesthetic gas)
-rate of rise in partial pressure of anesthetic in blood is faster for a gas with low solubility (small lambda) like Nitrous oxide, and slower for a gas with higher solubility (larger lambda) like halothane.
Factors impacting rate of approach to steady state anesthesia: Phase II
II. uptake of anesthetic by blood from alveoli (rate determined by: solubility in blood of anesthetic gas–measured by lambda (blood:gas partition coefficient–or conc of anesthetic in blood divided by conc in inspired gas mixture); and pulmonary blood flow (CO) (faster pulmonary flow thru lungs, less time for anesthetic to diffuse into blood–blood eventually becomes loaded over time)
*the rate of transfer of anesthetic from alveoli to blood is inversely related to both pulmonary blood flow and solubility of anesthetic gas in blood.
Factors impacting rate of approach to steady state anesthesia: Phase IV
IV. tissue distribution
- vessel rich group: highly vascularized tissues (brain, heart, kidney, liver, endocrine glands). Uptake is rapid–well perfused
- muscle group: muscle and skin (2-4 hrs)
- fat group: very slow GA uptake because: large amounts of anesthetic can be dissolved in fatty tissue; and low perfusion (fat group dominates rate of uptake)
- ->longer duration of anesthesia, greater loading of fatty tissue, leading to longer recovery time (unloading from fatty tissue is slow)
Factors impacting rate of approach to steady state anesthesia: Phase IV
IV. tissue distribution
oil: gas partition coefficient is an index of
GA potency
blood: gas partition coeff is related to
kinetics of GA uptake and elimination
