3. THEORIES OF ANESTHETIC
ACTION
S Lipid Solubility (Meyer-Overton Rule)
S Alterations to lipid bilayer
S Alteration to protein inhibition
4.
5. MINIMUM ALVEOLAR
CONCENTRATION
S Produces immobility in 50% of subjects exposed to
standard noxious stimuli (surgical incision)
S Analogous to ED50
S MAC awake
S MAC intubation
S MAC bar
20. XENON
ADVANTAGES
S Inert (probably nontoxic with no
metabolism)
S Minimal cardiovascular effects
S Low blood solubility
S Rapid induction and recovery
S Does not trigger malignant hyperthermia
S Environmentally friendly
S Nonexplosive
DISADVANTAGES
S High cost
S Low potency (MAC = 70%)
Editor's Notes
GENERAL ANESTHESIA- reversible state of unconsciousness with loss of sensation of pain
Intravenous- induce anesthesia
Inhalational- maintain anesthesia
- MOA: despite widespread use current understanding of molecular basis for the action is poorly understood.
-
Molecular mechanism of GA:
1. Ligand gated - GABA –a, glycine receptor (enhanced by volatile)--- inhibitory postsynaptic channels
NMDA (blocked by volatile)--- excitatory channels
2. Voltage gated- blocked
Sites of action
Anesthesia induced amnesia- hippocampus
Anesthesia induced sedation- hypothalamus
Stages of anesthesia
1 analgesia- beg of administration until LOC,
2 excitement, combative behavior, spasm, heart rate BP rises,
3 surgical anesthesia- regular deep breathing, loss of corneal reflex
phase1- light surgical anesthesia: roving of eyeballs then becomes fixed
phase 2- moderate surgical anesthesia: loss of corneal and laryngeal reflex
phase 3- deep: fixed pupils, light reflex lost
phase 4- very deep—apnea: intercostal paralysis
4 medullary paralysis-shallow irregular breathing, non reactive dilated pupils, thready pulse
Guedel’s criteria based on:
Respiration
Eyeball movement
Presence or absence of various reflex
Gillespie added:
Secretion of tears
Response to skin incision
Evaluation of pharyngeal and laryngeal reflexes
Hallmarks of anesthesia:
amnesia/uncosciousness
Anlagesia
Muscle relaxation
1.Lipid Solubility - Overton & Meyer
2. Alterations to Lipid Bilayers
- lipidperturbation-dimensionalchange lipid phase transition - "lateral phase separation"
lipid-proteininteractions
3. Alteration to Protein Function - luciferase inhibition
Best correlation with anesthetic potency was nited to be the oil:gas partition coefficient by meyer-overton
Potency and speed of induction of inhaled agents correlate with their lipid solubility
Greater lipid solubility, greater potency
-Best estimate for potency of inhalational anesthetics
The alveolar concentration, at equilibrium, at 1 atm pressure
Animals: clamping of tail or passing electric current through subcutaneous electrodes
Mac values are remarkably consistent across species and are roughly additive
1.3 MAC would prevent 95% subjects from moving and is equivalent to ED95
MAC awake: a value that would allow response to verbal/tactile stimulation (0.3-0.4)
MAC intubation: necessary to prevent laryngeal response to endotracheal intubation (1.3)
MAC bar: necessary to blunt the autonomic response to a noxious stimulus (1.5)
DECREASE IN MAC: hypercarbia PaCo2 >95mmhg, ketamine,barbiturates, bzd, verapamil,amphetamine, hgb <5
INCREASE: cocaine,ephedrine, MAO inhibitors, levodopa
NO CHANGES: gender, hypo/hyperthyroidism,hypercalcemia, metabolic alkalosis, duration of inhaled anesthetics
Vapor pressure- pressure exerted by the molecules
-measures the agents ablity to evaporate (volatlity)
- greater vp, greater concentration delivered
greater temp, greater vp
Blood- determines the rate of induction and recovery from inhalational anesthetics (inversely proportional)
Fat/ lipid- potency of the agent (directly proportional)
BLOOD FLOW
Vessel rich group-brain, heart, kidney, liver
Muscle group-
Fat group- large capcity, minimal flow
Vessel poor group-bone, cartilage
Redistribution- as long as an arterial to tissue partial pressure exists, muscle and fat will absorb anesthetic, even after discontinuation of anesthesia, it continues until blood/alveolar anesthetic partial pressure falls below tissue partial pressure
Recovery- low solubility= fastser recovery, des>sevo>iso
greater solubility= greater absorption
Increased ventilation help recovery
Inc CBF (time dependent and dose dependent)=inc ICP (especially halothane) and impair autoregulation of vascular tone=vasodilate
Dec ceb met- may increase nitrous oxide
Desflurane and isoflurane <1 MAC= suppress status epilepticus
Inc sevo= epileptiform waves in EEG
Dec SVR, CO
Isoflurane best maintains CO==ok in cardiac patients
Halothane= dec MAP = dec CO, unchaged SVR
Nephrotoxic-due to fluoride
Most: methoxyflurane
Bronchodilates=most is sevo safe for asthmatics
Not halothane because of increased arryhthmias with beta agonist
All vasodilators except nitrous oxide (constrictor)
Dec mucociliary function--- smokers have impaired mucociliary function== inadequate clearing of secretions
Sequence of respiratory depression: en>des>iso>sevo
Hepatotoxic – halothane, chloroform, methoxyflurane
Ether based (iso, sevo,des)maintain or inc hepatic artery BF while dec portal vein BF
Halothane dec portal vein and hepatic artery blood flow=Inadequate hepatocyte oxygenation
Centrilobular area- prone to hypoxia
Muscle relaxant except n2o, potentiate action of nmb
All are potential to cause MH
PROVIDE ALL 3 CHARACTERISTICS OF GA: unconsciousness, analgesia, muscle relaxation
Ideal inhalational anesthetic gas:
Rapid, pleasant induction and emergence
Rapid and easily identified changes in depth of anesthesia
Adequate relaxation of skeletal muscle
Wide margin of safety
Absence of toxic adverse effectsat normal dose
High degree in specificity in action
Easy to administer
Useful for all ages
Physical property, laughing gas, gas at RT, liquid under pressure
Pharmacology: low potency, relatively insoluble in blood, does not produce muscle relaxation, but have analgesic effects
Side effects
inc cerbral oxygen consumption
diffusion hypoxia: dec in p02 usually observed in emergence which displaces the oxygen in alveoli
megaloblastic anemia: bone marrow depression
oxidizes Co in vit B12=inactivates methionine synthetase
affects myelin formation=neurotoxic
inhibits thymidylate synthetase= teratogenic
second gas effect: the inc in partial pressure of of other gases in alveolar mixture resulting from the rapid uotake of high conc of nitrous oxide during induction
the ability the large volume uptake of one gas (first gas) to acclerate the rate of rise of alveolar pressure of a concurrent gas (second gas)
Closed spaces: 35 times m0re soluble in blood than nitrogen – fills and expands aany air containing spaces= air embolism, pneumothorax, tension pneumocephalus
Weakest anesthetic but good analgesic
Cylinder: blue
Synthesized in 1951, halogenated alkene
Colorless, pleasant odor, non irritant, non flammable, light sensitive
Corrosive- rubber and plastic tubing
Rapid induction faster recovery
Amber colored bottle with Thymol preservative to prevent spontanoeus oxidative decomposition
CV: dec BP, CO, slow conduction=bradycardia
Sensitizes the heart to catecholamines
Resp: inc RR, dec TV, potent bronchodilator
Elimination: liver oxidation= trifluoroacetic acid (TFA)
Other meatbolites: bromin, chlorine,
Halothane isnot hepatotoxic in children,
Potent bronchodilator (asthmatics), used in ob for uterine relaxation only
Cauttion in renal failure due to fluorine
Contraindicated in epileptics: decrease threshold for seizures
Sweet, ethereal odor
Steal:isoflurane induced vasodilation leads to redistribution of Coronoary BF from diseased (maximally dilated ) to normal repsonsive arteries
inc in cbf, froom inadeq perf to adeq perf
Airway irrittant: spasm, increase in secretions
Agent of choice for neuroanesthesia: high conc:inc BF by vasodilattion f cerebral arteries= cns depression,
Agent of choice for cardaic anesthesia: maintains baroreceptor reflex == refelex tachy in response to dec BP
Substitution with fluoride results in greater stability
Ether linkage: dec incidence of cardiac arrhythmias
1995, Rapid induction and recovery
Agent of choice for pediatric anesthesia
2nd choice for neuro, cardiac, asthmatics
Does not sensitize myocardium to catecholamines
Metabolites:
Inorganic fluoride, hexafluoroisopropanol
Compound A- nephrotoxic:
1993
Differs from isoflurane: by substitution of fluorine atom to chlorine atom
Which increases vapor pressure, enhances molecular stability, decreases potency
Produces the highest carbon monoxide next is enflurane and isoflurane
Fastest induction, Rapid emergence
Fastest induction and fastest recovery
Mac 70%
Most ideal inhalational anesthetic
Blood gas coefficient 0.14
Least side effects
Expensive