21 Pharmacology of Therapeutic Gases and Inhalational Aneshtetics Flashcards Preview

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Flashcards in 21 Pharmacology of Therapeutic Gases and Inhalational Aneshtetics Deck (27)
1

Therapeutic gases:
Oxygen

  • Oxygen is administered to prevent or treat...which results from...
  • Administration of high amounts of oxygen for prolonged periods of time may lead to adverse effects
  • Any oxygen-enriched atmosphere also constitutes...
  • Oxygen toxicity 
    • In part a consequence of...
    • Primarily results in...

  • Oxygen is administered to prevent or treat...
    • Tissue hypoxia, which results from...
      • A failure of the lungs to normally oxygenate the blood
      • Inadequate delivery of oxygen to the tissues
      • Impaired oxygen utilization
  • Administration of high amounts of oxygen for prolonged periods of time may lead to adverse effects
    • Promote absorption atelectasis
    • Dry and irritate mucosal surfaces of the airway and the eyes
    • Decrease mucociliary transport and clearance of secretions
  • Any oxygen-enriched atmosphere also constitutes...
    • A fire hazard
  • Oxygen toxicity
    • In part a consequence of excess generation of free radicals
    • Primarily results in alterations in pulmonary structure and function

2

Therapeutic gases:
Oxygen:
Administration

  • Low-flow systems
  • The FIO2 of these systems 
  • Examples of these systems 
  • High-flow systems
  • For precise delivery of defined FIO2, closed systems require...

  • Low-flow systems
    • Oxygen flow is lower than the inspiratory flow rate
    • Have a limited ability to raise the FIO2 because they depend on entrained room air to make up the balance of the inspired gas
  • The FIO2 of these systems
    • Extremely sensitive to small changes in the ventilatory pattern
  • Examples of these systems
    • Nasal cannulae
    • Simple face masks, with or without reservoir bags
  • High-flow systems
    • Deliver oxygen at flows that exceed the patient's minute ventilation by three to four times
    • Provide a relatively constant FIO2 at high flow rates
  • For precise delivery of defined FIO2, closed systems require...
    • Employing an endotracheal tube (or sealed mask) with an oxygen blender

3

Therapeutic gases:
Oxygen:
Monitoring

  • Monitoring and titration are required to...
  • Cyanosis 
  • Invasive approaches for monitoring oxygenation 
  • Noninvasive monitoring of arterial oxygen saturation
    • Now widely available with...
    • Useful for...

  • Monitoring and titration are required to...
    • Meet the therapeutic goal of oxygen therapy
    • Avoid complications and side effects
  • Cyanosis
    • A physical finding of substantial clinical importance
    • Not an early, sensitive, or reliable index of oxygenation
  • Invasive approaches for monitoring oxygenation
    • Intermittent laboratory analysis of arterial or mixed venous blood gases
    • Placement of intravascular cannulae capable of continuous measurement of oxygen tension
  • Noninvasive monitoring of arterial oxygen saturation
    • Now widely available with...
      • Pulse oximetry, in which oxygen saturation is measured from the differential absorption of light by oxyhemoglobin and deoxyhemoglobin and the arterial saturation determined from the pulsatile component of this signal
    • Useful for...
      • The rapid evaluation and monitoring of potentially compromised patients
      • Titrating oxygen therapy in situations where toxicity from oxygen or side effects of excess oxygen are of concern

4

Therapeutic gases:
Nitric oxide

  • Nitric oxide (NO)
  • Inhaled NO 
  • This improvement in ventilation-perfusion matching leads to...

  • Nitric oxide (NO)
    • Important cell signaling molecule
    • Acts primarily through the activation of soluble guanylate cyclase (sGC) and generation of cGMP
  • Inhaled NO 
    • Preferentially dilates the pulmonary vasculature
    • Limits effects on the systemic vasculature
    • Delivered to areas of the lung that are well-ventilated, leading to...
      • Increased pulmonary vasodilation in those areas
      • Increased perfusion to well-ventilated areas of the lung
  • This improvement in ventilation-perfusion matching leads to...
    • A significant improvement in oxygenation

5

Therapeutic gases:
Nitric oxide

  • Therapeutically, NO is administered to newborns to treat...
  • Administration of high levels of NO for extended periods of time can lead to...

  • Therapeutically, NO is administered to newborns to treat...
    • Persistent pulmonary hypertension
    • Diseases associated with increased pulmonary vascular resistance
      • Pulmonary hypertension
      • Pulmonary embolism
      • Acute chest syndrome in sickle-cell patients
  • Administration of high levels of NO for extended periods of time can lead to...
    • Toxicity
    • This may be related to oxidation of NO to nitrogen dioxide (NO2) in the presence of high concentrations of oxygen
    • The development of methemoglobinemia can be a significant complication of inhaled NO at higher concentrations, particularly in infants

6

Therapeutic gases:
Helium

  • Helium
  • A primary use of helium
  • The low density of helium makes it useful to...
  • Helium has high thermal conductivity, which makes it useful during...
  • Helium has also been used as...

  • Helium
    • Inert gas with low density, low solubility, and high thermal conductivity
  • A primary use of helium: pulmonary function testing
    • Determinations of residual lung volume, functional residual capacity, and related lung volumes require a highly diffusible gas that is insoluble (and thus does not leave the lung via the bloodstream) so that, by dilution, the lung volume can be measured
  • The low density of helium makes it useful to...
    • Decrease work of breathing, particularly in patients with elevated airway resistance
  • Helium has high thermal conductivity, which makes it useful during...
    • Laser surgery on the airway, where it can prolong time to ignition of flammable materials (including oxygen)
  • Helium has also been used as...
    • An inhalational contrast agent for pulmonary magnetic resonance imaging

7

Therapeutic gases:
Carbon monoxide (CO)

  • CO production
  • Both the toxic and potentially therapeutic effects of CO are a result of...
  • CO and hemoglobin

  • CO production
    • As a result of the incomplete combustion of all carbon containing fuels or endogenously
    • Humans generate ~ 10 ml of CO daily, as a by-product of conversion of heme to biliverdin by heme oxygenase (HO)
  • Both the toxic and potentially therapeutic effects of CO are a result of...
    • Its affinity for heme-containing compounds
  • CO and hemoglobin
    • CO reversibly binds to hemoglobin, to form carboxyhemoglobin (CO-Hb)
    • The affinity of CO for the hemoglobin heme iron is 240 times that of O2
    • The partial occupation of these binding sites by two CO molecules (half-saturation) inhibits the release of O2 from the remaining heme groups, leading to a leftward shift of the oxyhemoglobin dissociation curve
    • This property of CO reduces the O2-carrying capacity of the blood to deliver O2, causing the asphyxiating properties of CO

8

Therapeutic gases:
Carbon monoxide (CO)

  • CO and other metalloproteins
  • The physiological effects of CO have been related to...
  • The exogenous application of non-toxic CO doses produces...
  • The known physiological signaling effects of CO involve...
  • Inhalation of CO has been demonstrated to be effective in animal models of...

  • CO and other metalloproteins
    • CO can also form complexes with reduced forms of other metalloproteins including myoglobin, sGC, inducible NO synthase, cytochrome P-450, NADPH oxidases and cytochrome C oxidase
  • The physiological effects of CO have been related to...
    • Its endogenous production from basal and inducible HO activity
  • The exogenous application of non-toxic CO doses produces...
    • Effects similar to those seen with up-regulation of HO-1.
  • The known physiological signaling effects of CO involve...
    • Relatively few defined mechanisms
    • The modulation of sGC activity and subsequent stimulation of cGMP production is the most commonly observed
    • Other mechanisms include the modulation of MAPK activation and the stimulation of Ca2+-dependent K+ channel activity
  • Inhalation of CO has been demonstrated to be effective in animal models of...
    • Inflammation, hypertension, organ transplantation, vascular injury, and ventilator-induced lung injury

9

Therapeutic gases:
Hydrogen sulfide

  • Primarily known for its ability to...
  • When delivered in a dose-controlled manner, H2S has been shown experimentally to...
  • Its signaling actions are mediated through...

  • Primarily known for its ability to...
    • Limit mitochondrial respiration by inhibition of cytochrome C oxidase
  • When delivered in a dose-controlled manner, H2S has been shown experimentally to...
    • Limit some forms of cellular injury
  • Its signaling actions are mediated through...
    • Chelation of metallo-proteins
    • Direct covalent modification of proteins
    • Redox reactions such as reduction of disulfide bonds and reaction with free radical molecules

10

Pharmacology of general anesthetics:
Anesthesia

  • Anesthesia
  • An ideal inhaled anesthetic

  • Anesthesia
    • A generalized reversible depression of the central nervous system such that perception of all senses is ablated
    • No single drug is available that satisfies all of the characteristics of an ideal anesthetic
    • Typically, multiple drugs are used to achieve surgical anesthesia
  • An ideal inhaled anesthetic
    • Pleasant to inhale
    • Potent
    • Easy to administer and regulate
    • Inexpensive
    • Stable and safe
    • Acts at specific sites in the CNS
    • Devoid of side effects
    • Provides postoperative pain relief

11

Pharmacology of general anesthetics:
History of anesthesia

  • Ether
  • Better inhaled anesthetic agents
  • Newer agents
  • Currently used agents

  • Ether
    • The ideal "first" anesthetic
    • Easily synthesized and purified
    • Relatively nontoxic to vital organs
    • A liquid at room temperature
    • Readily vaporizes
    • Easy to administer
    • Unlike less potent nitrous oxide (N2O), ether induces anesthesia without diluting the oxygen in room air to hypoxic levels
    • Generally sustains respiration and circulation, important when assisted respiration and circulation was technically limiting
  • Better inhaled anesthetic agents
    • Chloroform
    • Cyclopropane
    • Other highly flammable and explosive agents
    • Halothane, a nonflammable fluorinated hydrocarbon
  • Newer agents
    • Halogenated alkanes and ethers modeled after halothane
  • Currently used agents
    • Isoflurane
    • Sevoflurane
    • Desflurane

12

Pharmacology of general anesthetics:
Principles of anesthesia

  • The components of the anesthetic state
  • Unlike the practice of every other branch of medicine, induction of surgical anesthesia is usually...
  • Administration of general anesthesia has been driven by three general objectives

  • The components of the anesthetic state
    • Amnesia
    • Immobility in response to noxious stimulation
    • Attenuation of autonomic responses to noxious stimulation
    • Analgesia
    • Unconsciousness
  • Unlike the practice of every other branch of medicine, induction of surgical anesthesia is usually...
    • Neither therapeutic nor diagnostic
  • Administration of general anesthesia has been driven by three general objectives
    • Minimizing the potentially deleterious direct and indirect effects of anesthetic agents and techniques
    • Sustaining physiologic homeostasis during surgical procedures that may involve major blood loss, tissue ischemia, reperfusion of ischemic tissue, fluid shifts, exposure to a cold environment, and impaired coagulation
    • Improving postoperative outcome

13

Pharmacology of general anesthetics:
Measures of anesthetic potency

  • The potency of inhaled general anesthetics is usually defined as...
  • MAC
  • MAC values are useful because they...
  • MAC values

  • The potency of inhaled general anesthetics is usually defined as...
    • The minimum alveolar concentration (MAC)
  • MAC
    • That prevents movement in 50% of patients in response to a surgical incision
    • Represents the ED50 for inhaled anesthetics: the lower the MAC value, the more potent the anesthetic
  • MAC values are useful because they...
    • (a) allow easy comparison of different anesthetics
    • (b) are easily measured by sampling end tidal gas concentration
    • (c) represent important clinical endpoints
  • MAC values
    • Consistent and reproducible measures within a patient population
    • Decrease with age and body temperature and during pregnancy

14

Pharmacology of general anesthetics:
Measures of anesthetic potency

  • General anesthetics
  • Therapeutic index
  • Anesthetics...
  • For general anesthetics, the difference in dose between no effect, surgical anesthesia, and severe cardiac/respiratory depression...

  • General anesthetics
    • Among the most dangerous drugs administered to patients
  • Therapeutic index
    • The LD50/MAC
  • Anesthetics...
    • have very steep dose-response relationships
    • Have low therapeutic indices (2-4)
    • No antagonists exist
  • For general anesthetics, the difference in dose between no effect, surgical anesthesia, and severe cardiac/respiratory depression...
    • Is small

15

Pharmacology of general anesthetics:
Mechanism of action of inhaled anesthetics

  • Dominant theory: single site of action
  • Lipid solubility hypothesis

  • Dominant theory: single site of action
    • i.e., all anesthetics exert all their effects via the same mechanism
    • Based largely on the observations that...
      • A wide variety of structurally diverse chemical compounds produce anesthesia
      • Anesthetic potency of a gas correlated with its solubility in olive oil
      • Stereoisomers of inhaled drugs generally have equal potencies
      • No specific anesthetic antagonists have been identified
      • All of these points argued for a single, nonspecific mechanism of action
  • Lipid solubility hypothesis
    • Meyer-Overton correlation
      • Powerful correlation between anesthetic potency and lipid solubility
    • Predicted that the site of action was the lipid bilayer of neurons
    • Anesthesia resulted from the accumulation of anesthetic molecules in the lipid bilayer and thus perturbed neuronal function

16

Pharmacology of general anesthetics:
Mechanism of action of inhaled anesthetics

  • Enantiomers with identical physical properties
  • An anesthetic agent produces...
  • Different anesthetic agents produce...

  • Enantiomers with identical physical properties
    • Have unique molecular actions, indicating that properties other than bulk solubility are important in determining anesthetic action
    • This has led to a search for identification of specific protein sites where anesthetics may bind, such as ligand-gated ion channels 
  • An anesthetic agent produces...
    • Different components of the anesthetic state via actions at different anatomic loci in the nervous system and may produce these component effects via different cellular and molecular actions
  • Different anesthetic agents produce...
    • Specific components of anesthesia via actions at different molecular targets

17

Pharmacology of general anesthetics:
Mechanism of action of inhaled anesthetics

  • General anesthetics act by...
  • The Meyer-Overton correlation was initially interpreted as evidence that...
  • General anesthetic potencies correlate equally well with...

  • General anesthetics act by...
    • Binding directly to proteins
  • The Meyer-Overton correlation was initially interpreted as evidence that...
    • Lipids of nerve membranes were the principal anesthetic target sites based on the correlation between anesthetic potency and lipid-water partition coefficient
  • General anesthetic potencies correlate equally well with...
    • Their ability to inhibit activity of the soluble firefly enzyme luciferase
    • The crystal structure of luciferase is shown in the inset with bound anesthetic in red

18

Pharmacology of general anesthetics:
Anatomic sites of action

  • Anesthetics exert their effects on pain and immobility (i.e., MAC) via...
  • Structure that plays a role in amnestic effects
  • Structure that plays a role in sedative/anxiolytic effects
  • A common attribute of general anesthetics
  • Major locus for transmission of peripheral sensation to the cortex
  • Inhibition of this function may result in...

  • Anesthetics exert their effects on pain and immobility (i.e., MAC) via...
    • The spinal cord, with possible modulatory input from supraspinal sites
  • Structure that plays a role in amnestic effects
    • The hippocampus
  • Structure that plays a role in sedative/anxiolytic effects
    • The tuberomammillary nucleus of the hypothalamus
  • A common attribute of general anesthetics
    • Suppression of thalamic excitability
  • Major locus for transmission of peripheral sensation to the cortex
    • Thalamus
  • Inhibition of thalamic function may result in...
    • The transition from the awake to the anesthetized state

19

Pharmacology of general anesthetics:
Molecular targets

  • Direct effect of anesthetics on...
  • Chloride channels gated by the inhibitory GABAA receptor 
  • By increasing the sensitivity of the GABAA receptor to GABA, anesthetics...
  • Point mutations at various sites on the GABAA receptor that abrogate the effects of specific anesthetic agents suggest that...
  • The GABA binding site itself...

  • Direct effect of anesthetics on...
    • GABAA and NMDA receptors
    • Two-pore K+ channels
  • Chloride channels gated by the inhibitory GABAA receptor 
    • Responsive to a wide variety of anesthetics, including the halogenated inhalational agents
  • By increasing the sensitivity of the GABAA receptor to GABA, anesthetics...
    • Enhance inhibitory neurotransmission and depress nervous system activity
  • Point mutations at various sites on the GABAA receptor that abrogate the effects of specific anesthetic agents suggest that...
    • There may be specific binding sites for several anesthetic classes
  • The GABA binding site itself...
    • Does not appear to bind anesthetics

20

Pharmacology of general anesthetics:
Molecular targets

  • Structurally closely related to the GABAA receptors
  • Inhalational anesthetics...
  • While anesthetic gases can also inhibit neuronal nicotinic acetylcholine receptors,...
  • The NMDA receptor

  • Structurally closely related to the GABAA receptors
    • Other ligand-gated ion channels including glycine receptors
    • Neuronal nicotinic acetylcholine receptors
  • Inhalational anesthetics...
    • Enhance the capacity of glycine to activate glycine-gated chloride channels, modulating responses to noxious stimuli in the spinal cord and brainstem
  • While anesthetic gases can also inhibit neuronal nicotinic acetylcholine receptors,...
    • The consequences of these effects are unclear, as this inhibition does not mediate immobilization
  • The NMDA receptor
    • A glutamate-gated cation channel
    • Inhibited by nitrous oxide and xenon, as well as the intravenous anesthetic agent, ketamine

21

Pharmacology of general anesthetics:
Molecular targets

  • Halogenated gases activate...
  • Pre- vs. post-synaptic channel stimulation
  • Other potential targets of inhaled anesthetics
  • Receptors for excitatory vs. inhibitory neurotransmitters

  • Halogenated gases activate...
    • Two-pore domain channels, K+ channels that are present both pre-and post-synaptically
  • Pre- vs. post-synaptic channel stimulation
    • Stimulation of pre-synaptic channels results in hyperpolarization of the pre-synaptic terminal and a reduction in neurotransmitter release
    • Post-synaptic channels regulate the resting membrane potential, so that activation may also result in hyperpolarization of these neurons as well
  • Other potential targets of inhaled anesthetics
    • Channels that are gated by acetylcholine, serotonin, glutamate, and others
  • Receptors for excitatory vs. inhibitory neurotransmitters
    • Receptors for excitatory neurotransmitters are inhibited by anesthetics
    • Receptors for inhibitory transmitters are potentiated

22

Pharmacology of general anesthetics:
Pharmacokinetics of inhaled anesthetics

  • Anesthetics distribute...
  • At equilibrium, the partial pressure of a gas that is dissolved in a liquid or tissue, such as blood or brain, is equal to...
  • However, the amount of gas that is dissolved in the liquid or tissue (concentration) depends on both...
  • Thus, at equilibrium,...
    • The partial pressures of a gas will...
    • The concentrations will...
  • Anesthetic partition coefficients
  • Anesthetic gases tend to be more soluble in some tissues, such as...

  • Anesthetics distribute...
    • Between tissues (or between blood and gas) along partial pressure gradients
  • At equilibrium, the partial pressure of a gas that is dissolved in a liquid or tissue, such as blood or brain, is equal to...
    • The partial pressure of the free gas
  • However, the amount of gas that is dissolved in the liquid or tissue (concentration) depends on both...
    • The partial pressure and the solubility of the gas in that particular liquid or tissue
  • Thus, at equilibrium,...
    • The partial pressures of a gas will be the same in different compartments of the body
    • The concentrations will not
  • Anesthetic partition coefficients
    • The ratio of anesthetic concentration in two tissues when the partial pressures of anesthetic are equal
  • Anesthetic gases tend to be more soluble in some tissues, such as...
    • Tat compared with blood
    • However, there is a wide range of solubility between the anesthetics

23

Pharmacology of general anesthetics:
Pharmacokinetics of inhaled anesthetics

  • Equilibrium is achieved when...
  • At this point, there is...
  • For inhalational agents that are poorly soluble in blood and tissues, such as nitrous oxide, equilibrium...
  • If an anesthetic gas is more soluble, equilibrium...
  • The rise in end-tidal alveolar (FA) anesthetic concentration toward the inspired (FI) concentration 
    • Most rapid with...
    • Slower with...

  • Equilibrium is achieved when...
    • The partial pressure in end-tidal (alveolar) gas (FA) is equal to the partial pressure in inspired gas (FI) i.e., when FA/FI is 1
  • At this point, there is...
    • No net movement of anesthetic from the alveoli into the circulation
  • For inhalational agents that are poorly soluble in blood and tissues, such as nitrous oxide, equilibrium...
    • Is achieved quickly
  • If an anesthetic gas is more soluble, equilibrium...
    • May take much longer, due to the large reservoir of body fat
  • The rise in end-tidal alveolar (FA) anesthetic concentration toward the inspired (FI) concentration
    • Most rapid with the least soluble anesthetics, nitrous oxide and desflurane
    • Slower with more soluble anesthetics, such as halothane

24

Pharmacology of general anesthetics:
Pharmacokinetics of inhaled anesthetics

  • An important parameter of anesthetic pharmacokinetics 
  • The anesthetic state occurs when...
  • Because the brain is well-perfused, the anesthetic partial pressure in brain...
  • Thus, anesthesia is achieved soon after...
  • Highly soluble anesthetics such as halothane
    • The rate of increase of FA will be...
    • The speed of induction can be increased by...
  • What influences the FA/FI ratio
  • The magnitude of this influence is usually governed by...

  • An important parameter of anesthetic pharmacokinetics
    • The speed of anesthetic induction
  • The anesthetic state occurs when...
    • The partial pressure of the anesthetic in brain is equal to or greater than MAC
  • Because the brain is well-perfused, the anesthetic partial pressure in brain...
    • Equalizes with the partial pressure in alveolar gas quickly
  • Thus, anesthesia is achieved soon after...
    • Alveolar partial pressure (FA) reaches MAC
  • Highly soluble anesthetics such as halothane
    • The rate of increase of FA will be slower 
    • The speed of induction can be increased by delivering higher inspired partial pressures; this is called the concentration effect
  • What influences the FA/FI ratio
    • Changes in physiologic variables (e.g., ventilation, circulation, distribution of circulation, ventilation-perfusion abnormalities)
  • The magnitude of this influence is usually governed by...
    • Solubility

25

Pharmacology of general anesthetics:
Effects on circulation

  • All inhalational anesthetics...
  • However, cardiac output is maintained with...
  • This suggests that...

  • All inhalational anesthetics...
    • Reduce systemic blood pressure in a dose-related manner
  • However, cardiac output is maintained with...
    • Isoflurane and desflurane
  • This suggests that...
    • The mechanisms for diminished blood pressure vary with the agent

26

Pharmacology of general anesthetics:
Effects on respiration

  • All halogenated inhalational anesthetics...
  • In patients whose ventilation is not controlled, this results in...

  • All halogenated inhalational anesthetics...
    • Reduce spontaneous minute ventilation in a dosedependent manner
  • In patients whose ventilation is not controlled, this results in...
    • An increase in arterial CO2 tension

27

Pharmacology of general anesthetics:
Xenon

  • Rare gas that can only be obtained by extracting it from air
    • Thus, only very limited quantities of xenon are available and the cost is high
    • If costs can be reduced in the future, it is probable that xenon will become a widely used inhaled anesthetic
  • Xenon is very close to being an ideal anesthetic
    • Has very low blood and tissue solubility (results in rapid induction and recovery)
    • Is potent
    • Is not metabolized in the body
    • Is nonflammable
    • Has minimal side effects

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