Inhaled Anesthetics

Chemistry and Pharmacodynamics

Mechanism of action

• A single site of action is not shared by all inhaled anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts.
• The mechanism of action for most inhaled anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts is poorly understood.
• Inhaled anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts work within the CNS:
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors interaction:
    • Acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS (nicotinic and muscarinic)
    • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS
    • NMDA
    • Glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids
    • Glycine Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids
    • Serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS (also known as 5-hydroxytryptamine 5-hydroxytryptamine A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS ( 5-HT 5-HT A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS))
  • Augment the physiology of receptor-related ion channels Channels The Cell: Cell Membrane:
    • K
    • Cl
  • Depression of neurotransmission Neurotransmission The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across electrical synapses. Synapses and Neurotransmission pathways

Physiologic effects

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

• Desired therapeutic targets:
  • Sedation (reversible loss of consciousness)
  • Analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts
  • Amnesia
  • Skeletal muscle relaxation/immobility
• Cardiovascular effects:
  • Myocardial depression
  • ↓ Arterial blood pressure 
• Respiratory effects:
  • Respiratory depression
  • Tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination:
    • N₂O
    • Desflurane
  • Bronchodilation:
    • Halothane
    • Sevoflurane
    • Isoflurane
  • Airway Airway ABCDE Assessment irritation:
    • Isoflurane
    • Desflurane
• Cerebral effects:
  • ↓ Cerebral glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance utilization
  • ↑ Cerebral blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure
  • ↑ Intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension ( ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP))
• Renal effects:
  • ↑ Renovascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
  • ↓ Renal blood flow Renal blood flow The amount of the renal blood flow that is going to the functional renal tissue, i.e., parts of the kidney that are involved in production of urine. Glomerular Filtration
  • ↓ Urine output

Pharmacokinetics

Administration of inhaled anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts

Administration by inhalation:

• Face mask
• Laryngeal mask airway Airway ABCDE Assessment
• Endotracheal tube

Delivery by anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts 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 Standard deviation The standard deviation (SD) is a measure of how far each observed value is from the mean in a data set. Measures of Central Tendency and Dispersion (equal to 0.1 MAC).
• Anesthetic goals:
  • Induction: transition from an awake state to an anesthetized state 
  • Anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts: absence of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways perception Perception The process by which the nature and meaning of sensory stimuli are recognized and interpreted. Psychiatric Assessment
  • 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 Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia: ↓
  • Hyperthermia: ↑
  • Chronic stimulant use: ↑
  • Chronic alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder: ↑
• 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 Tidal volume The volume of air inspired or expired during each normal, quiet respiratory cycle. Common abbreviations are tv or V with subscript t. Ventilation: Mechanics of Breathing
  • Respiratory rate Respiratory rate The number of times an organism breathes with the lungs (respiration) per unit time, usually per minute. Pulmonary Examination

Pharmacokinetic principles of inhaled anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts

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 Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 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 Flow rate maximum flow the ventilator will deliver a set tidal volume in liters per minute Invasive Mechanical Ventilation of fresh gas
  • Volume of the breathing system
  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange 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 Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange:

• Alveolar partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange determines the partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of anesthetic in the blood. 
• The partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of anesthetic in the blood determines the concentration in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification.

Effects of ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing rate:

• The speed of induction is directly proportional to the ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing rate. 
• ↑ Ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing maintains the partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of anesthetic within the alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS). 

Effects of cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics:

• At the level of the alveolus, uptake is directly proportional to cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics (CO): ↑ CO → ↑ alveolar blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure → ↑ uptake from the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy 
• However, induction speed is inversely proportional to CO: ↑ uptake of gas → ↓ partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of the anesthetic within the alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS) → induction delay

Effects of pulmonary circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment: 

• Uptake is also affected by the partial pressure gradient Pressure gradient Vascular Resistance, Flow, and Mean Arterial Pressure of the anesthetic between the alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS) and venous blood.
• ↑ Partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of the anesthetic in venous blood → ↓ gradient between the blood and the alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS) → ↓ 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 pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange: ↑ partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange, the faster the induction
• Ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing rate: ↑ ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing rate, the faster the induction
• Blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure: ↑ blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure, the slower the induction
• Arteriovenous (AV) concentration gradient: ↑ AV gradient AV gradient Gas Exchange, the slower the induction

Metabolism and excretion

• < 5% of inhaled anesthetic is metabolized in the body.
• Metabolism involves phase 1 Phase 1 Skin: Structure and Functions and phase 2 Phase 2 Skin: Structure and Functions reactions:
  • Phase 1 Phase 1 Skin: Structure and Functions (catabolic reactions): hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides and oxidation 
  • Phase 2 Phase 2 Skin: Structure and Functions (anabolic reactions): the addition of a glucuronyl or methyl group to the metabolite
• Excretion of the end product is through:
  • Exhalation
  • Transcutaneous loss
  • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy
  • Hepatobiliary system 

Indications

• Generally used in the operating room (FDA approved):
  • Induction of general anesthesia General anesthesia Procedure in which patients are induced into an unconscious state through use of various medications so that they do not feel pain during surgery. Anesthesiology: History and Basic Concepts (faster onset of action than IV anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts)
  • Maintenance of general anesthesia General anesthesia Procedure in which patients are induced into an unconscious state through use of various medications so that they do not feel pain during surgery. Anesthesiology: History and Basic Concepts
• Sometimes used in the ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus (not FDA approved):
  • Sedation (e.g., ventilated individual, combative individual, or a bedside procedure)
  • Refractory bronchospasm Bronchospasm Asthma Drugs
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures unresponsive to antiepileptics (i.e., status epilepticus Status Epilepticus A prolonged seizure or seizures repeated frequently enough to prevent recovery between episodes occurring over a period of 20-30 minutes. The most common subtype is generalized tonic-clonic status epilepticus, a potentially fatal condition associated with neuronal injury and respiratory and metabolic dysfunction. Nonconvulsive forms include petit mal status and complex partial status, which may manifest as behavioral disturbances. Simple partial status epilepticus consists of persistent motor, sensory, or autonomic seizures that do not impair cognition. Subclinical status epilepticus generally refers to seizures occurring in an unresponsive or comatose individual in the absence of overt signs of seizure activity. Seizures)
• Often used in conjunction with IV anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts:
  • Midazolam Midazolam A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at ph less than 4 and lipid-soluble at physiological pH. Benzodiazepines
  • Propofol Propofol An intravenous anesthetic agent which has the advantage of a very rapid onset after infusion or bolus injection plus a very short recovery period of a couple of minutes. Propofol has been used as anticonvulsants and antiemetics. Intravenous Anesthetics

Adverse Effects and Contraindications

Drug-drug interactions

• N₂O: ameliorates the circulatory and respiratory effects of other volatile anesthetics Anesthetics Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. Anesthesiology: History and Basic Concepts when used together
• Halothane:
  • Β-adrenergic blocking agents and calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blocking agents (myocardial depression)
  • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants and monoamine oxidase Oxidase Neisseria (blood pressure fluctuations and arrhythmias)
• Desflurane, sevoflurane, and isoflurane: potentiate neuromuscular blocking agents