Week 2 - Volatile Anesthetics Flashcards
What are the sites of desired anesthetic actions in the nervous system?
Cortex/Thalamus/Brainstem = Unconsciousness (Glutamate Blockade)
Spinothalamic Tract = Analgesia (NMDA, K channel, AMPA)
Spinal Cord Central Pattern Generators = Immobility (Glycine Receptors)
Amygdala/Hippocampus = Amnesia (GABA) (nACHr -may cause hyperalgesia)
What is the Meyer-Overton Correlation?
Lipid-Based Theory related to Inhaled Anesthesia
- Chemically indifferent substances that are soluble in fat are anesthetics
- Relative potency dependent on their affinity for water and fat (Fat/Water Partition coefficient)
- Potency is proportional to lipid solubility as measured by oil-gas partition coefficient
What is the Unitary Theory related to inhaled anesthesia?
Cell membranes were mostly lipid therefore the majority of anesthetic effects must come from the effects on the cell membranes
What is the concept of MAC?
It is analogous to plasma EC50
Universal measure for inhaled anesthetic potency (was developed to compare agents)
Product of an anesthetics oil gas partition coefficient and MAC is a Konstant
What is the protein centered theory related to inhaled anesthetics?
Signaling proteins (ion channels/receptors) are the molecular site of action
If we interrupt a protein channel we can get the desired effect
What are the molecular targets of inhaled anesthetics?
Ligand Gated Ion Channels (potentiation of GABA/Glycine)
Voltage Gated Ion Channels (Na, Ca, K)
Intracellular Signaling Mechanisms (G-protein coupled, protein phosphorylation, gene expression)
How do Iso, Sevo, and N2O affect GABAa receptors?
ISO = sig. potentiation
SEVO = sig. potentiation
N2O = no effect at clinically relevant concentrations
How do Iso, Sevo, and N2O affect Glycine receptors?
ISO = sig. potentiation
SEVO = sig. potentiation
N2O = no effect at clinically relevant concentrations
How do Iso, Sevo, and N2O affect nACH receptors?
ISO = some inhibition
SEVO = some inhibition
N2O = no effect at clinically relevant concentrations
How do Iso, Sevo, and N2O affect 5-HT3 receptors?
ISO = sig. inhibition
SEVO = sig. inhibition
N2O = sig. inhibition
How do Iso, Sevo, and N2O affect AMPA receptors?
ISO = sig potentiation
SEVO = sig inhibition
N2O = sig inhibition
How do Iso, Sevo, and N2O affect NMDA receptors?
ISO = sig. inhibition
SEVO = sig. inhibition
N2O = sig. inhibition
How do Iso, Sevo, and N2O affect Na channels?
ISO = sig. inhibition
SEVO = sig. inhibition
N2O = no effect at clinically relevant concentrations
How do Iso, Sevo, and N2O affect Ca channles?
ISO = sig. inhibition
SEVO = sig. inhibition
N2O = no effect at clinically relevant concentrations
How do inhalation agents affect neuronal excitability?
they hyperpolarize neurons
neuronal excitability is determined by resting membrane potential, threshold potential, and in put resistance
What are the presynaptic and postsynaptic effects of inhalation agents
Presynaptic = alter transmitter release
Postsynaptic = alter neurotransmitter responses
What are the desired effects of inhalation agents?
- Sedation
- Learning and Memory
- Unconsciousness
- Neuroprotection (prevent apoptosis, decrease CMRO)
- Dose dependent myocardial depression and HoTN; decreases Ca availability/sensitivity
- Significant respiratory depression via central depression
- Immobility (requires 2.5-4x MAC needed to produce amnesia/unconsciousness)
GABA-ergic effects of volatile anesthetics
- Decrease CMRO
- Loss of consciousness
- Postop N/V
- Resp Depression, Spinal analgesia, Immobility
- Myocardial Depression, Cardiac Dysrhythmias, Anesthetic Preconditioning
- Skeletal Muscle Relaxation, Malignant Hyperthermia
- Hepatic Toxicity
- Vasodilation
- Supraspinal analgesia
State whether volatile anesthetic activate or inhibit the following:
1) Inhibitory GABAa receptors
2) Inhibitory Glycine receptors
3) Excitatory NMDA-type glutamate receptors
4) Neuronal nACH receptors
5) K(2p) and K leak channels
6) Voltage gated Na channels
- Activate inhibitory GABAa receptors
- Activate inhibitory Glycine receptors
- Inhibit excitatory NMDA-type glutamate receptors
- Inhibit neuronal nACH receptors
- Activate K2p and K+ leak channels
- Inhibit multiple voltage gated Na+ channels
Why are volatile anesthetics fluorinated?
Reduce or eliminate toxicity (metabolism)
Reduce or eliminate anesthetic flammability
Allow increased speed of induction and recovery from anesthesia
Rank Halothane, Desflurane, Sevoflurane, and Isoflurane based on number of Fluorine molecules
- Halothane (3)
- Isoflurane (5)
- Desflurane (6)
- Sevoflurane (7)
What are the boiling points (*C) of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 50.2 ISO = 48.5 DES = 23.5 (room temp, thus needs special vaporizer) SEVO = 58.5
What are the saturated vapor pressures (mmHg) of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 243 ISO = 239.5 DES = 669.2 SEVO = 157
What are the MACs (Vd %) of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 0.74% ISO = 1.15% DES = 6% SEVO = 2%
What are the Blood/Gas coefficients of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 2.3 ISO = 1.4 DES = 0.42 SEVO = 0.69
What are the Brain/Blood coefficients of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 2.9 ISO = 2.6 DES = 1.3 SEVO = 1.7
What are the Muscle/Blood coefficients of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 3.5 ISO = 4 DES = 2 SEVO = 3.1
What are the Fat/Blood coefficients of Halothane, Isoflurane, Desflurane, and Sevoflurane?
HAL = 60 ISO = 45 DES = 27 SEVO = 48
Define ____/Blood coefficients
the amount of molecules attached for every one free molecule
the lower the coefficient the faster moving drug (more free molecules)
What are the pulmonary effects of inhaled anesthetics?
Dose dependent decrease in title volume
Less than adequate increase in RR
Increased resting ETCO2
Increase activity of laryngeal irritant receptors
Decrease activity of pulmonary irritant receptors
Decrease in FRC (Functional Residual Capacity)
Why is there a decrease in FRC with inhaled anesthetics? How do you overcome it?
Loss of intercostals
Altered respiratory pattern
Cephalad movement of diaphragm
Altered thoracic blood volume
Leads to a drop in O2 levels, overcome this effect by preoxygenating prior to admin (Obese/Pregnant have even lower FRC)
How do inhaled anesthetics cause bronchodilation?
- Directly depressing smooth muscle contractility
- Direct effects on bronchial epithelium/airway smooth muscle cells
- Indirect inhibition of reflex neural pathways
- Block voltage gated Ca channels
- Depletion of Ca stores in sarcoplasmic reticulum
- Possible potentiation of GABAergic mechanisms
(not noticeable under normal conditions, great for bronchospastic conditions, less evident with DES)
When is pulmonary vascular resistance the lowest?
at a lung volume equivalent to FRC
What increases pulmonary vascular resistance? What does an increase in pulmonary vascular resistance cause?
PVR is increased by:
-PEEP, Alveolar hypoxia/hypercapnia, and Critical closing pressure
It causes an increase in pulmonary arterial pressure (promotes interstitial fluid transudation)
How do inhaled anesthetics affect pulmonary vascular resistance?
Indirectly by reducing lung volume
What do regional alterations in pulmonary vascular resistance affect?
The regional distribution of blood flow within the lung, produce changes in ventilation-perfusion matching, and simultaneously affect gas exchange
How does pulmonary circulation react to hypoxia? How does anesthetics interfere with this?
The pulmonary circulation vasoconstricts in response to hypoxia
Anesthetics vasodilate the pulmonary vascular bed and cause dose dependent myocardial depression (this adversely affects gas exchange)
Location of central chemical control of respiration and what it responds to
located near the ventrolateral medulla and other brainstem sites
Responds to changes in H+ concentration in CSF, NOT arterial CO2 tension or pH
More profoundly affected by respiratory than by metabolic alterations in arterial CO2 tension
Location of peripheral chemical control of respiration and what it responds to
located in the carotid bodies
sensitive to changes in arterial CO2 tension, pH, and arterial O2 tension
How do volatile anesthetics affect the CO2 response curve?
Shifts curve to the right
Volatile anesthetics cause dose dependent depression in ventilatory response to hypercapnia
<1 MAC sig reduce or entirely eliminate hypercapnia-induced increases in ventilatory drive
<0.2 MAC may depress peripheral chemoreflex loop and inhibit ventilatory response to hypercapnia
Takes a much more sig increase in CO2 to increase RR
How do volatile anesthetics and N2O affect the hypoxemia response?
They reduce the ventilatory response to hypoxia in a dose dependent manner
At concentrations as low as 0.1 MAC
(can remain depressed for hours after GA)
What are the pulmonary effects of Isoflurane?
- Causes respiratory depression
- Less tachypnea than is seen with halothane
- Causes the most depression of the ventilatory response to hypoxemia and hypercapnia (Shifts curve furthest to the right)
- Similar impairment of hypoxic pulmonary vasoconstrictor response
What are the pulmonary effects of Desflurane?
- Effects are similar to Enflurane and slightly less than Isoflurane
- It is an extremely noxious pulmonary irritant (NOT recommended for inhalation induction and probs poor choice for pts with reactive airway disease)
- Respiratory depressant and causes slight tachypnea
What are the pulmonary effects of Sevoflurane?
- Causes resp depression with very slight tachypnea
- Decreased tidal volume causes decreased minute ventilation and CO2 retention
- Causes bronchodilation and inhibits bronchoconstriction
- Least airway irritation of all inhalation agents (Great for inhalation induction)
What are the pulmonary effects of Halothane?
- Causes resp depression
- Dose-dependent alveolar hypoventilation (results in arterial hypercapnia) - typical RR is rapid/shallow
- Profoundly blunts ventilatory response to hypercapnia
- Subanesthetic concentrations abolish ventilatory response to hypoxemia
- Increases the A-a gradient as result of atelectasis in dependent regions of the lungs and blunting of hypoxic pulm vasoconstrictor response
What are the CV effects of inhaled anesthetics?
Dose- dependent depression of myocardial contractility (alteration of Ca homeostasis)
Dose-dependent decrease in SBP (HAL/ENF - reduced contractility and CO; ISO/SEVO/DES - reduction in LV afterload)
Dose-dependent decrease in SVR
Direct negative chronotropic effects (depress SA node)
Arrhythmogenicity of inhaled anesthetics
Halothane, Enflurane, Isoflurane - cardioprotective against V-fib produced by coronary artery occlusion and reperfusion
Halothane - sensitize myocardium to the arrhythmogenic effects of epinephrine
Des, Iso, and Sevo do not sensitize heart to ventricular extrasystoles
What are the CV effects of Isoflurane?
- Dose-dependent decrease in BP due to decreased peripheral vascular resistance
- Mild myocardial depressant (enhanced in pts on Ca channel blockers)
- Mild direct negative chronotropic effects on SA node (Despite this, increase HR will likely result due to indirect activation of SympNS/activation of ANS/baroreceptor response to hypotension)
- Cause vasodilatation and decrease coronary vascular resistance
- Does NOT cause coronary steal
What are the CV effects of Desflurane?
- Similar amounts of myocardial depression and arterial vasodilatation as ISO when ANS responses are blocked (less than ISO when ANS responses are left intact)
- Autonomic tone is important
- Abrupt increase in admin concentration leads to increase in BP (30mmHg), HR (30bpm), doubling of SympNS activity, and increased plasma epi
- Does NOT cause coronary steal
What are the CV effects of Sevoflurane?
- Dose-dependent decrease in myocardial contractility, CO, and SVR
- Causes less arterial vasodilatation and less reduction in SVR than ISO
- Causes more of decrease in CO than ISO
- Causes similar decrease in myocardial contractility to ISO when decreases MVO2/Coronary vascular resistance
- Doesn’t increase SympNS activity like DES
- Does NOT cause coronary steal
What are the CV effects of Halothane?
- Does dependent arterial HoTN
- SVR remains relatively intact, Decreased BP with dose dependent increase in CVP
- Dose dependent decrease in CO (Greater depressant on myocardial contractility than vasomotor tone)
- Greatest negative inotropic effect (no indirect activation of SympNS)
- Decreases coronary blood flow and coronary vascular resistance
- Directly depresses the SA node and conduction (treat with atropine)
- Decreases threshold at which catecholamines cause ventricular ectopy (response is worse with hypercapnia.. kids less sensitive to this response)
How do inhalations anesthetics affect CBF and CMRO2?
Increase CBF (direct cerebrovascular vasodilation) - leads to increased ICP -HAL > ENF >/= ISO = Des = SEVO
Decrease CMRO2 (ISO has slight cerebral protective properties)
What inhalation agents causes EEG burst suppression and what level MAC?
Isoflurane: 1.5 MAC = burst suppression; 2 MAC = electrical silence
Halothane: 3.5 MAC = burst suppression
What effect do inhalation agents have SSEP response?
Somatosensory evoked potential
all agents depress the response to SSEP
Agent + N2O = minimal response
What effect do inhalation agents have on MEP monitoring?
Motor evoked potential
Sevo depresses MEP monitoring
Des has no effect
Iso is up in the air (sources say different things)
What are neuromuscular effects of inhalation agents?
Centrally mediated dose-dependent muscle relaxant properties
Potentiate BOTH depolarizing and non-depolarizing muscle relaxants
Elimination of volatile agent will facilitate recovery from neuromuscular blockade
What is the MAC level to cause Amnesia, Unconsciousness, and Immobility?
Amnesia = 0.25 MAC Unconsciousness = 0.5 MAC Immobility = 1 MAC
(for average pt)
What are hepatic effects of inhalation agents?
- Decreases hepatic blood flow (HAL>ISO>DES/SEVO)
- Iso, Des, Hal, Enf, all metabolize to a trifluoroacetylated protein that may produce liver injury in “susceptible” pts
- Bromide metabolism of HAL can cause somnolence and confusion if >6mEq/L
- Halothane hepatitis is secondary to reductive metabolism of halothane in presence of hepatocyte hypoxia
What percent of each inhalation agent is metabolized by the liver?
HAL = 20% ENF = 2.5% ISO = 0.2% DES = 0.2% SEVO 0.2% N2O is not metabolized in humans
What are the renal effects on inhalation agents?
- Decreases renal blood flow, GFR, and urine output
- Sevo metabolism results in free Fluoride (concentrations of 40-50 are nephrotoxic) - however Sevo DOES NOT cause renal failure
What are the obstetrical effects of inhalation agents?
Decrease uterine blood flow and uterine contractility (HAL more than the rest)
N2O decreases the activity of methionine synthetase and thymidylate synthetase which is important in RNA/DNA replication patterns (ok to use after 3rd trimester)
What are immune system effects of inhalation agents?
Inhibit inflammatory cytokines
Reversibly inhibit voltage gated Ca channels
Inhibit human neutrophil bacterial killing (Reduction of reactive oxygen species)
Effects of Nitrous Oxide by organ/organ system
NMDA blocking:
- Decreased CMRO
- Loss of consciousness
- Spinal analgesia, immobility
- No myocardial depression
- Decreased RR, increased total volume
- No vasodilation
- Supraspinal analgesia
What are the following properties of Nitrous Oxide?
MAC, B:G, B:B, B:M, B:F coefficients
MAC = 105% Blood:Gas = 0.47 Blood:Brain = 1.1 Blood:Muscle = 1.2 Blood:Fat = 2.3
Used as an adjunct to other agents (1 Vol% N2O added = 1 Vol% less of potent inhalation agent)
What is the concentration effect and second gas effect of nitrous oxide?
As the N2O is taken up it leaves space in the FRC for fresh gas inflow to occur. As fresh gas saturated with anesthetic flows in, the concentration of anesthesia in the FRC increases faster
The second gas (usually potent inhalation agent) also rises to a higher concentration more quickly because of the above principles.
Effects are less pronouned with Sevo/Des than Hal/Iso
Diffusion Hypoxia related to Nitrous Oxide
- Due to low B:__ coefficients N2O washes out fast
- The properties that result in the rapid uptake of inhalation agents cause a rapid reduction or washout of these agents at the end of the case
- As N2O rushes into the lungs, it drags other gases with it and displaces O2 which can result in diffusion hypoxia
What are CV effects of nitrous oxide?
- Increases SympNS tone (counteracts HoTN effects of ALL inhalation agents)
- Increases circulating norepi levels
- Increases arterial vasomotor tone
- Slight reduction in CO
What are respiratory effects of nitrous oxide?
- Decreases tidal volume and increases RR (minimal compared to potent agents)
- Reduces ventilatory response to hypoxia and hypercapnia
- Respiratory depressant effects are ADDITIVE to respiratory depressant effects of other agents being used
What are CNS effects of nitrous oxide?
- Inconsistent data about it
- Probably increase CBF, therefore increase ICP and CMRO (effects are probably attenuated by hypocapnia or balanced anesthetic technique)
- Decreases seizure activity
What are renal effects of nitrous oxide?
Decreases renal blood flow, GFR, and urinary output
What are complications related to nitrous oxide?
- it is 30x more soluble in blood than nitrogen and will rapidly move into air spaces filled with nitrogen before the nitrogen can move out (particular problem with closed air spaces)
- Impairs synthesis of DNA by inhibiting methionine synthetase (causes miscarriages)
Nitrous oxide is contraindicated in what type of patients?
- Tympanic membrane and ear surgeries
- Pneumothoraces (could double in size in 10 min)
- Small Bowel Obstruction
- Pneumocephalus
- Concerns about air emboli
NIOSH standards state _______ N2O in ambient OR air.
less than 25ppm
Define Time Constants
A way of describing the amount of change that is occurring in a dynamic system
-The amount of change that occurs per unit of time
TC = Capacity of System / Flow into System
What is the percent changed for 1, 2, 3, and 4 time constants?
Each time constant = 63% change in the system
1 TC = 63% changed
2 TC = 85% changed
3 TC = 95% changed
4 TC = 98% changed
Time constants related to anesthesia machines
Anesthesia Circuit = 7 L capacity
Flow = Flow meter flow volume
Induction/Emergence Flows = 8-10 L/min
Maintenance Flows = 0.5-1 L/min
10L/min Flow: TC= 7L/10L/min = 0.7 min for 1 TC
1L/min Flow: TC = 7L/1L/min = 7 min for 1 TC
Rank N2O, Hal, Iso, Des, and Sevo from lowest to highest Blood:Gas coefficient
Des (0.42) N2O (0.47) Sevo (0.69) Iso (1.4) Hal (2.3)
Rank N2O, Hal, Iso, Des, and Sevo from lowest to highest Blood:Brain coefficient
N20 (1.1) Des (1.3) Sevo (1.7) Iso (2.6) Hal (2.9)
Rank N2O, Hal, Iso, Des, and Sevo from lowest to highest Blood:Muscle coefficient
N20 (1.2) Des (2.0) Sevo (3.1) Hal (3.5) Iso (4.0)
Rank N2O, Hal, Iso, Des, and Sevo from lowest to highest Blood:Fat coefficient
N2O (2.3) Des (27) Iso (45) Sevo (48) Hal (60)
