Inhaled Anesthetics

Inhaled anesthetics are chemical compounds that can induce and maintain general anesthesia when delivered by inhalation. Inhaled anesthetics can be divided into 2 groups: volatile anesthetics and gases. Volatile anesthetics include halothane, isoflurane, desflurane, and sevoflurane. Nitrous oxide (N2O) is the most common of the anesthetic gases; cyclopropane and xenon are less commonly used. While the exact mechanism of action of the inhaled anesthetics is unknown, the drugs are believed to have variable effects on GABA, glycine, glutamate, and NMDA receptors in the CNS. Inhaled anesthetics have been used for medical purposes for the last 200 years.

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Chemistry and Pharmacodynamics

Table: Chemical characteristics of commonly used inhaled anesthetics
AgentCharacteristicsMinimum alveolar concentration (MAC)
Nitrous oxide (N2O)
  • Naturally occurring nonvolatile gas
  • Can be artificially synthesized
  • Nonflammable
104%
Halothane
  • Hydrocarbon
  • Nonflammable
  • Halogenated
  • Volatile liquid
  • No longer commercially available in the United States
0.75%
Desflurane
  • Fluorinated ether
  • Clear and volatile liquid
6.6%
Sevoflurane
  • Fluorinated isopropyl ether
  • Volatile liquid
1.8%
Isoflurane
  • Fluorinated ether
  • Volatile liquid
1.2%

Mechanism of action

  • A single site of action is not shared by all inhaled anesthetics.
  • The mechanism of action for most inhaled anesthetics is poorly understood.
  • Inhaled anesthetics work within the CNS:
    • Variable receptor interaction:
      • Acetylcholine (nicotinic and muscarinic)
      • GABA
      • NMDA
      • Glutamate
      • Glycine
      • Serotonin (also known as 5-hydroxytryptamine (5-HT))
    • Augment the physiology of receptor-related ion channels:
      • K
      • Cl
    • Depression of neurotransmission pathways

Physiologic effects

General class effects (individual agents may have unique properties):

  • Desired therapeutic targets:
    • Sedation (reversible loss of consciousness)
    • Analgesia
    • Amnesia
    • Skeletal muscle relaxation/immobility
  • Cardiovascular effects:
    • Myocardial depression
    • ↓ Arterial blood pressure 
  • Respiratory effects:
    • Respiratory depression
    • Tachypnea:
      • N2O
      • Desflurane
    • Bronchodilation:
      • Halothane
      • Sevoflurane
      • Isoflurane
    • Airway irritation:
      • Isoflurane
      • Desflurane
  • Cerebral effects:
    • ↓ Cerebral glucose utilization
    • ↑ Cerebral blood flow
    • ↑ Intracranial pressure (ICP)
  • Renal effects:
    • ↑ Renovascular resistance
    • ↓ Renal blood flow
    • ↓ Urine output

Pharmacokinetics

Administration of inhaled anesthetics

Administration by inhalation:

  • Face mask
  • Laryngeal mask airway
  • Endotracheal tube

Delivery by anesthesia machine:

  • The machine takes in fresh, pressurized gas.
  • The gas passes through a hypoxic trap where a mixture of gasses is determined by the operator (e.g., anesthesiologist or certified registered nurse anesthetist).
  • The gas is passed through a vaporizer where the anesthetic agent is mixed in with fresh gas, reaching the concentration determined by the anesthesiologist. 
  • The mixed gas flows into the common gas outlet and into the breathing circuit.

Inhaled anesthetic dosing:

  • Dosed in units of minimum alveolar concentration (MAC):
    • Gas concentration of 1 MAC is needed for 50% of recipients to not respond to noxious stimuli.
    • To achieve anesthetic goals, dose adjustments are made in increments of 1 standard deviation (equal to 0.1 MAC).
  • Anesthetic goals:
    • Induction: transition from an awake state to an anesthetized state 
    • Anesthesia: absence of pain perception
    • Immobility: absence of spontaneous movements and absence of movement in response to noxious stimuli
    • Amnesia: lack of recall for an event (i.e., surgery)
  • MAC of common agents at sea level:
    • Desflurane: 6.6%
    • Halothane: 0.75%
    • Isoflurane: 1.2%
    • Sevoflurane: 1.8%
    • Nitrous oxide: 104%
  • Factors affecting MAC:
    • Advancing age: ↓
    • Coadministration of other sedating drugs: ↓ 
    • Hypothermia: ↓
    • Hyperthermia: ↑
    • Chronic stimulant use: ↑
    • Chronic alcohol abuse: ↑
  • Agents with higher MAC need lower potency administration to achieve anesthetic goals.
  • Achieving and maintaining anesthetic goals requires monitoring and adjustment of respiratory parameters (usually performed with a mechanical ventilator):
    • End-tidal CO2
    • Tidal volume
    • Respiratory rate
Anesthesia machine

Anesthesia machine

Image: “Datex – Ohmeda” by Kitmondo Marketplace. License: CC BY 2.0

Pharmacokinetic principles of inhaled anesthetics

Partition coefficient (Ostwald coefficient):

  • The ratio of the anesthetic concentration in the blood to the concentration in the gas
  • The more soluble the anesthetic is in blood:
    • The more the anesthetic binds to proteins in the blood
    • ↑ Blood-gas partition coefficient
  • The blood-gas partition coefficient is inversely related to the induction rate.

Inspiratory concentration (FI):

  • Depends mainly on:
    • Flow rate of fresh gas
    • Volume of the breathing system
    • Absorption by the breathing system
  • Directly proportional to the concentration of fresh gas

Alveolar concentration (FA):

  • Reflects pulmonary capillary uptake of gas:
    • The concentration of a gas is directly proportional to the partial pressure of the gas.
    • ↑ Capillary uptake equates to ↓ alveolar concentration.
  • The FA:FI ratio describes the relationship of alveolar concentration to inspiratory concentration. 
  • Speed of induction: The rate at which the FA:FI ratio approaches 1.

Partial pressure:

  • Alveolar partial pressure determines the partial pressure of anesthetic in the blood. 
  • The partial pressure of anesthetic in the blood determines the concentration in the brain.

Effects of ventilation rate:

  • The speed of induction is directly proportional to the ventilation rate. 
  • ↑ Ventilation maintains the partial pressure of anesthetic within the alveoli. 

Effects of cardiac output:

  • At the level of the alveolus, uptake is directly proportional to cardiac output (CO): ↑ CO → ↑ alveolar blood flow → ↑ uptake from the lungs 
  • However, induction speed is inversely proportional to CO: ↑ uptake of gas → ↓ partial pressure of the anesthetic within the alveoli → induction delay

Effects of pulmonary circulation: 

  • Uptake is also affected by the partial pressure gradient of the anesthetic between the alveoli and venous blood.
  • ↑ Partial pressure of the anesthetic in venous blood → ↓ gradient between the blood and the alveoli → ↓ uptake 
  • Indirectly indicates uptake by the peripheral tissues

Effects of concentration:

  • Speed of induction is directly proportional to the alveolar concentration.
  • ↑ Uptake → ↓ alveolar concentration → slows down induction
  • ↑ Concentration of the inhaled anesthetic → ↑ alveolar concentration → quicker induction 
  • Capacity = tissue/blood solubility × tissue volume

Summary of determinants of induction speed:

  • Solubility of the anesthetic: ↑ solubility, the slower the induction
  • Inspired gas partial pressure: ↑ partial pressure, the faster the induction
  • Ventilation rate: ↑ ventilation rate, the faster the induction
  • Blood flow: ↑ blood flow, the slower the induction
  • Arteriovenous (AV) concentration gradient: ↑ AV gradient, the slower the induction
Table: Classification of tissues by solubility and blood flow
GroupOrgansDescription
Vessel-rich groupBrain, heart, liver, kidney, and endocrine organs
  • Moderate solubility and small volume → limited capacity
  • Reaches steady state quickly (i.e., equalized arterial and tissue partial pressures)
Muscle groupSkin and muscles
  • Larger volume → greater capacity → hours for uptake
Fat groupAdipose tissue
  • Similar perfusion to muscle group
  • Increased solubility of anesthetic → increased capacity
  • Days to reach a steady state
Vessel-poor groupBones, ligaments, teeth, hair, and cartilage
  • Insignificant uptake

Metabolism and excretion

  • < 5% of inhaled anesthetic is metabolized in the body.
  • Metabolism involves phase 1 and phase 2 reactions:
    • Phase 1 (catabolic reactions): hydrolysis and oxidation 
    • Phase 2 (anabolic reactions): the addition of a glucuronyl or methyl group to the metabolite
  • Excretion of the end product is through: 
    • Exhalation
    • Transcutaneous loss
    • Kidneys
    • Hepatobiliary system 

Indications

  • Generally used in the operating room (FDA approved):
    • Induction of general anesthesia (faster onset of action than IV anesthetics)
    • Maintenance of general anesthesia
  • Sometimes used in the ICU (not FDA approved):
    • Sedation (e.g., ventilated individual, combative individual, or a bedside procedure)
    • Refractory bronchospasm
    • Seizures unresponsive to antiepileptics (i.e., status epilepticus)
  • Often used in conjunction with IV anesthetics:
    • Midazolam
    • Propofol
Table: Advantages and disadvantages of inhaled anesthetics
AgentAdvantagesDisadvantages
Nitrous oxide (N2O)
  • Odorless
  • No taste or pungency
  • Fast uptake and excretion
  • Minimal cardiovascular depression
  • Minimal biotransformation
  • Inexpensive
  • Rarely used as a solo agent (low potency)
  • Airspace expansion
  • Increased nausea and vomiting
  • Inhibition of methionine synthase
  • Greenhouse gas
  • Supports combustion
Isoflurane
  • Good muscle relaxation
  • Bronchodilation
  • Stable heart rate
  • Inexpensive
  • Slower uptake and elimination
  • Strong odor → may cause airway irritation → poor choice for induction
Sevoflurane
  • The most common inhaled anesthetic
  • Fast uptake and excretion → rapid induction and recovery time
  • Bronchodilation
  • No pungency → no airway irritation → appropriate choice for induction
More expensive than isoflurane
Desflurane
  • Fast uptake and excretion
  • Minimal biotransformation
  • Strong odor → may cause airway irritation → poor choice for induction
  • Expensive

Adverse Effects and Contraindications

Table: Adverse effects
AgentAdverse effects
Nitrous oxide (N2O)
  • Hypotension
  • Confusion
  • Dizziness
  • Headache
  • Nausea and vomiting
  • Apnea
  • Potential neurotoxicity
Halothane
  • Fulminant hepatic necrosis
  • Arrhythmia (increased sensitivity to catecholamines)
  • Malignant hyperthermia
  • Potential neurotoxicity
Desflurane
  • Arrhythmia
  • Bradycardia or tachycardia
  • Hypertension
  • Laryngospasm
  • Malignant hyperthermia
  • Potential neurotoxicity
Sevoflurane
  • Hypotension
  • Agitation
  • Nausea and vomiting
  • Sialorrhea
  • Malignant hyperthermia
  • Potential neurotoxicity
Isoflurane
  • Laryngospasm
  • Malignant hyperthermia
  • Severe acute liver injury
  • Potential neurotoxicity

Drug-drug interactions

  • N2O: ameliorates the circulatory and respiratory effects of other volatile anesthetics when used together
  • Halothane:
    • Β-adrenergic blocking agents and calcium channel blocking agents (myocardial depression)
    • Tricyclic antidepressants and monoamine oxidase (blood pressure fluctuations and arrhythmias)
  • Desflurane, sevoflurane, and isoflurane: potentiate neuromuscular blocking agents
Table: Contraindications of commonly used inhaled anesthetics
AgentContraindications
Nitrous oxide (N2O)
  • Air embolism
  • Pneumothorax
  • Bowel obstruction
  • Pneumocephalus
  • Pulmonary air cysts
  • Intraocular air bubbles
  • Tympanic membrane grafting
HalothaneUnexplained liver dysfunction after exposure in a previous procedure
Desflurane
  • Severe hypovolemia
  • Malignant hyperthermia
  • Intracranial hypertension
Sevoflurane
IsofluraneSevere hypovolemia

References

  1. McKay, R. E. (2018). Inhaled Anesthetics. Pardo, M. C., & R. D. Miller, R. D. (Eds.) Basics of Anesthesia, 7e (pp. 83–103). https://www.elsevier.com/books/basics-ofanesthesia/pardo/978-0-323-40115-9
  2. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 948, Nitrous oxide. Retrieved June 11, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Nitrous-oxide 
  3. Butterworth IV, J. F., Mackey, D. C., & Wasnick, J. D. (2018). Inhalation Anesthetics. In Morgan &amp; Mikhail’s Clinical Anesthesiology, 6e. McGraw-Hill Education. http://accessmedicine.mhmedical.com/content.aspx?aid=1161426360 
  4. Nizamuddin, J., & O’Connor, M. (2019). Anesthesia for surgical patients. Brunicardi F., & Andersen D. K., & Billiar T. R., & Dunn D. L., & Kao L. S., & Hunter J. G., & Matthews J. B., & Pollock R. E. (Eds.), Schwartz’s Principles of Surgery, 11e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2576&sectionid=216218112
  5. Miller, A. L., Theodore, D., & Widrich, J. (2021). Inhalational anesthetic. StatPearls (). Treasure Island (FL): StatPearls Publishing. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK554540/ 
  6. Clar, D. T., Patel, S., & Richards, J. R. (2021). Anesthetic gases. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK537013/ 
  7. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 3562, Halothane. Retrieved June 18, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Halothane 
  8. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 4116, Methoxyflurane. Retrieved June 18, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Methoxyflurane 
  9. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 3226, Enflurane. Retrieved June 18, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Enflurane
  10. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 3763, Isoflurane. Retrieved June 18, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Isoflurane
  11. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 42113, Desflurane. Retrieved June 20, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Desflurane

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