General Anesthetics

• Objectives:
• List characteristics of an ideal general anesthetic
• Explain the concept of balanced anesthesia
• Describe the use of pre-anesthetic medications
• Explain induction and recovery times based on physical properties of general anesthetics
• Describe the factors controlling the passage of a volatile anesthetic from the anesthesia machine to the brain
• Explain what is meant by MAC
• Describe physiological indices for surgical anesthesia and anesthetic overdose
• Recognize malignant hyperthermia and how to treat it
• Compare and contrast the physical, pharmacological, kinetic, toxicological properties and uses of inhalation anesthetics
• Explain what is meant by "incomplete anesthetic"

Goals of General Anesthesia

• Preserve the life of the patient
• Provide the surgeon with an adequate surgical field
• Block pain

Characteristics of an Ideal General Anesthetic

• Provides a smooth and rapid induction of unconsciousness
• Produces amnesia
• Inhibits autonomic and sensory reflexes
• Produces skeletal muscle relaxation
• Produces analgesia
• Provides a smooth and rapid emergence and recovery without long lasting adverse effects

Balanced Anesthesia

• Combination of drugs used to take advantage of their best properties and minimize the undesirable side effects
• Rapid induction with IV anesthetics
• Maintenance with inhalation anesthetics

Preanesthetic Medications

• Decrease anxiety without producing excessive drowsiness
• Facilitate a rapid, smooth induction without prolonging emergence
• Provide amnesia for the perioperative period
• Relieve pre- and postoperative pain
• Minimize undesirable side effects of anesthetics

Preanesthetic Medications: Specifics

• Opioids, such as morphine and fentanyl, provide analgesia
• Benzodiazepines, such as diazepam reduce anxiety, provide sedation, and cause amnesia
• Barbiturates such as Phenobarbital and Secobarbital reduce anxiety, provide sedation, and induce rapid induction
• Phenothiazines, such as Promethazine provide sedation and act as an antiemetic
• Antimuscarinics, such as Atropine inhibit secretions and laryngospasms and act as an antiemetic
• Antihistamines, such as Hydroxyzine provide sedation, have antimuscarinic effects, and prevent hypotension and bronchospasm produced by d-Tubocurarine-induced histamine release

Inhaled Anesthetics

• Anesthetic gas: Nitrous oxide
• Volatile liquids include:
• Desflurane (Suprane)
• sevoflurane (Ultane)
• Isoflurane (Forane)
• Enflurane (Ethrane)
• Methoxyflurane (Penthrane)

Mechanism of Anesthetic Action

• Inhibit neuronal activity in many brain regions
• Meyer-Overton relationship: Potency correlates w/ lipid/gas partition coefficient
• Nonspecific interactions w/ lipid membranes that modify ionic currents
• Modification of ionic currents by specific interactions with hydrophobic portions of proteins
• GABA Receptor
• Major molecular target
• Enhance chloride influx even in absence of GABA
• works in the transmembrane domain to alter gating
• NMDA receptor: Inhibited by ketamine
• K+ channels: K2P, possibly KV, and KATP channels
• Nicotinic receptors are also inhibited

Potency

• Anesthetic gases are given as partial pressures (% of total gas)
• Relative potency of anesthetic gases is expressed as MAC
• Larger MAC = less potent
• 1 MAC is defined as the amount that will block movement of 50% of patients in response to incision, expressed as % of total gas (ED50 of quantal dose-response curve)
• Dosing in terms of MAC: 0.5-1.1 MAC
• MAC values are additive
• 0.5 MAC of N2O + 0.5 MAC of isoflurane = 1 MAC and will anesthetize 50% of the patients
• MAC values are not affected by height, weight, or sex
• Conditions that decrease MAC values
• Elderly
• Hypothermia
• Hypothyroidism
• Sedatives
• MAC inversely correlates with oil/gas partition coefficient

Stages of General Anesthesia

• Stage I: Analgesia
• Analgesia depends on agent
• Amnesia
• Euphoria
• Stage II: Excitement
• Excitement (Block Inhibitory Neurons)
• Delirium
• Combative behavior
• Stage III: Surgical Anesthesia
• Unconsciousness (Depressed RAS)
• Regular Respiration
• Decreasing eye movement
• Stage IV: Medullary Depression
• Respiratory Arrest
• Cardiac Depression and Arrest
• No eye movement

Efficacy

• Efficacy of inhalation anesthetics is related to potency
• Most can produce all stages of anesthesia at low concentrations allowing sufficient O₂ to the patient (complete anesthetics)
• Nitrous oxide is an incomplete anesthetic because it cannot produce all stages of anesthesia without producing hypoxia
• 1 MAC for nitrous oxide = 100% of inhaled air
• Nitrous oxide does produce analgesia and amnesia

Pharmacokinetics of Anesthetic Gases

• Speed of induction and emergence (recovery) depend on the rate of change of the partial pressure (concentration) of the anesthetic in the brain, which is determined by the partial pressure of the gas in arterial blood
• The speed of induction is inversely correlated with the blood/gas partition coefficient
• Inhalation anesthetics with smaller blood/gas partition coefficients saturate blood faster and cross into the CNS faster

Factors Modifying Induction Rate of Soluble Gases

• Increasing ventilation rate enhances the rate of loss of consciousness more for soluble gases than insoluble gases
• Opioid analgesics
• Decreasing pulmonary blood flow (decreasing cardiac output) increases induction rate of soluble gases
• Hemorrhagic shock
• Increasing the concentration of soluble gases in inspired air increases their induction rate
• A high concentration of nitrous oxide will increases the induction rate of more soluble anesthetics (second gas effect)
• Distribution of anesthetic from blood to tissues:
• Brain and Viscera: High perfusion, small partition coefficient, rapid equilibration
• Lean tissues: Moderate perfusion, moderate partition coefficient, moderately rapid equilibration
• Fat: Low perfusion, large partition coefficient, slow equilibration

Emergence (Recovery)

• Determined by the same factors operating in the reverse direction
• Recovery slows with longer duration of anesthesia, especially with more lipid soluble anesthetics
• Diffusion Hypoxia
• Nitrous oxide
• Rapid release of N₂O from blood to lungs
• Give pure O₂ for a few minutes to counter this effect

General Pharmacological effects of Inhalation Anesthetics

• CNS: Dose-dependent depression of all portions of CNS
• Sensitivity order: spinothalamic (analgesia) → RAS and cortex (anesthesia) → spinal reflexes (muscle relaxation) → medulla
• Increased intracranial pressure; increase cerebral blood flow by vasodilation of cerebral vasculature secondary to inhibition of sympathetic nerves
• Cardiovascular Effects: Decrease Mean Arterial Pressure: Vasodilation from inhibition of sympathetic nerves (Isoflurane, desflurane, sevoflurane) → reflex tachycardia
• Respiratory Depression: Depresses medullary respiratory center
• Decreases response to hypoxia (increased PCO2)
• Halothane and sevoflurane particularly cause bronchodilation
• Desflurane causes airway irritation and coughing
• Miscellaneous effects:
• Kidney: Decrease renal blood flow
• Liver: Decrease hepatic blood flow
• Uterine smooth muscle: Relaxation via halogenated anesthetics but not N₂O, increased risk of abortion

Properties of Specific Inhaled Anesthetics

• Nitrous Oxide:
• Oil-gas ratio of 1.4
• MAC of >100
• Blood-gas ratio of 0.5
• Minimal CV effects
• No skeletal muscle relaxation
• Not metabolized
• Lowest potency, but often used in combo for rapid onset and recovery, potential for abuse
• Enflurane:
• Oil-gas ratio of 98
• MAC of 1.7
• Blood-gas ratio of 2
• Decreases CO
• Medium skeletal muscle relaxation
• 8% metabolism
• Tonic clonic muscle spasms
• Isoflurane:
• Oil-gas ratio of 98
• MAC of 1.3
• Blood-gas ratio of 1.4
• Vasodilation and tachycardia
• Medium skeletal muscle relaxation
• Slight metabolism
• Bronchiolar secretions and spasms
• Desflurane:
• Oil-gas ratio of 19
• MAC of 7
• Blood-gas ratio of 0.4
• Vasodilation and tachycardia
• Medium skeletal muscle relaxation
• Almost none metabolism
• Most rapid onset but airway irritation and coughing; rapid recovery
• Sevoflurane:
• Oil-gas ratio of 51
• MAC of 2.5
• Blood-gas ratio of 0.7
• Vasodilation
• Medium skeletal muscle relaxation
• 2-5% metabolized to fluoride
• Rapid onset and recovery
• Methoxyflurane:
• Oil-gas ratio of 0.2
• MAC of 2
• Blood-gas ratio of 2

• 70% metabolized to fluoride

• Generally not used due to risk of nephrotoxicity

Malignant Hyperthermia

• Autosomal dominant genetic disorder of skeletal muscle
• Abnormal Ca²+ channels (ryanodine receptors) in skeletal muscle
• Exposure to potent inhalation anesthetics and depolarizing muscle relaxants like succinylcholine cause abnormally large increase in Ca2+ within skeletal muscle
• Rapid onset of severe muscle rigidity, hyperthermia, hyperkalemia, tachycardia, hypertension, and acid-base imbalance with acidosis
• Rare but important cause of anesthetic morbidity and mortality
• Treatment:
• Dantrolene which blocks calcium release channels in sarcoplasmic reticulum
• Measures to control body temperature