Pharmacology Chapter 16: Anesthetic Agents

History of Anesthesia

• Horace Wells used nitrous oxide as a general anesthetic for surgery in 1844
• Samuel Cooley, a pharmacy clerk, injured his leg while under the influence of nitrous oxide and appeared to experience no pain
• Wells then began using nitrous oxide for dental procedures in his own practice

Types of Anesthetics

• General anesthetics:
  • Inhalation general anesthetics
  • Intravenous general anesthetics
• Local anesthetics

General Anesthesia

• Stages of anesthesia:
  • Stage I: Analgesia
  • Stage II: Delirium
  • Stage III: Surgical anesthesia
  • Stage IV: Medullary depression/Respiratory paralysis
• Characteristics of general anesthesia:
  • Sleep induction
  • Loss of pain responses
  • Amnesia
  • Skeletal muscle relaxation
  • Loss of reflexes

Guedel's Stages and Planes of General Anesthesia

• Stage I: Analgesia
  • Development of analgesia or reduced sensation to pain
  • Suitable for minor surgical procedures
• Stage II: Delirium
  • Unconsciousness and involuntary movement
  • Depression of inhibitory neurons in the CNS
• Stage III: Surgical anesthesia
  • Increasing CNS depression
  • Divided into 4 planes based on eye movement, depth of respiration, and muscle relaxation
    • Plane 1: Loss of spinal reflexes
    • Plane 2: Decrease in skeletal muscle reflexes (loss of blink reflex, regular respiration)
    • Plane 3: Paralysis of intercostal muscles (deep anesthesia, shallow breathing, assisted ventilation needed)
    • Plane 4: Loss of most muscle tone (diaphragmatic respiration only, assisted ventilation required)

Administration of Gaseous/Volatile Anesthetics

• Sophisticated devices used for administration
• Anesthesiologist controls the amount of anesthetic delivered to the patient
• Early systems used a gauzed pad in a mask placed over the nose and mouth of the patient

Risk Factors and MAC

• Risk factors:
  • No control over the amount of anesthetic and oxygen delivered to the patient
  • Anesthetic agent evaporates into the surrounding area, posing a risk to surgical personnel
• MAC (Minimum Alveolar Concentration):
  • Rough measure of potency
  • Concentration of anesthetic in the alveoli required to produce immobility in 50% of adult patients
  • Often used as a measure of the concentration at which anesthetic response occurs at the site of action in the brain

Factors Influencing MAC

• Factors that increase MAC:
  • Elevated or increased catecholamine levels in the CNS
  • Hyperthermia
  • Hypernatremia
• Factors that decrease MAC:
  • Decreased catecholamine levels in the CNS
  • Alcohol ingestion
  • Clonidine
  • Lithium
  • Lidocaine
  • Centrally administered opioids
  • Hyponatremia
  • Hypothermia
  • Hypoxia
  • Increase in age
  • Pregnancy

Theories of Anesthesia

• Meyer-Overton theory:
  • Potency of an anesthetic is directly related to its lipid solubility
• Ion channel and protein receptor hypothesis:
  • The interaction of anesthetics with protein receptors
  • Stereochemical requirements of various anesthetics
  • Increase in molecular weight and lipid solubility of an anesthetic can decrease or destroy anesthetic action

Inhalational Agents

• Gas: Nitrous oxide
• Volatile agents:
  • Halothane
  • Isoflurane
  • Enflurane
  • Desflurane

Halogenated Hydrocarbons and Ethers

• Fluorinated hydrocarbons:
  • Halothane
  • Enflurane
  • Isoflurane
  • Desflurane
  • Sevoflurane
  • Methoxyflurane### Inhalation Anesthetic Agents
• Desflurane:
  • Pungent, so patients are induced with an IV anesthetic agent and then maintained with desflurane
  • Not metabolized to a great extent, so it is not associated with hepatotoxicity or nephrotoxicity
  • Metabolites mostly trifluoroacetic acid, account for less than 0.02% of the administered dose
• Sevoflurane:
  • Nonflammable, nonirritating, and pleasant-smelling
  • Low blood solubility (blood/gas partition coefficient = 0.60)
  • Undergoes more metabolism than desflurane, with 3% of the administered dose being recovered as hexafluoroisopropanol
  • Can react with soda lime or baralyme to form a toxic product called "compound A"
• Methoxyflurane:
  • Seldom used due to renal toxicity
  • High solubility in blood (blood/gas partition coefficient = 12)
  • Induction and recovery are expected to be slow
  • Chemically unstable, with 50% of the dose being metabolized
• Nitrous Oxide (N2O):
  • Commonly called laughing gas
  • Least potent of the inhalation anesthetics used today
  • Poor blood solubility (blood/gas partition coefficient = 0.47)
  • Has an MAC value in excess of 105% and 140%

Intravenous General Anesthetic Agents

• Propofol:
  • One of the most commonly used parenteral anesthetics
  • Act by enhancing GABAergic neurotransmission within the CNS
  • Formulated as a 1% or 2% emulsion with soybean oil, egg lecithin, and glycerol
  • Administered intravenously, with a state of hypnosis achieved within 30 to 60 seconds, lasting for approximately 5 to 10 minutes
  • Blood pressure and heart rate usually decrease following administration
  • Highly bound to plasma proteins (approximately 98%)
  • Metabolism proceeds rapidly via hepatic conversion to its glucuronide and sulfate conjugates
• Fospropofol:
  • Phosphate ester prodrug of propofol
  • Water-soluble, with a dose of 6.5 mg/kg and supplemental doses of 1.6 mg/kg as needed
  • Pharmacodynamic effects are attributed to propofol, which is liberated following hydrolytic metabolism
• Ketamine:
  • Very potent, rapidly acting anesthetic agent
  • Does not relax skeletal muscles, so can only be used alone in procedures of short duration that do not require muscle relaxation
  • Blood pressure and heart rate usually increase following administration
  • Recovery from anesthesia can be accompanied by "emergence delirium" and disturbing dreams and hallucinations
  • Metabolism occurs through the liver by glucuronide conjugate and forms various metabolites, including norketamine
• Etomidate:
  • Ester of a carboxylated imidazole, available as the R-(+)-isomer solubilized in 35% propylene glycol for intravenous injection
  • Potent, short-acting hypnotic agent
  • Partition coefficient of 2,000 and a weak base pKa of 4.5
• Ultrashort-Acting Barbiturates:
  • Thiopental, an ultra-short-acting barbiturate (partition coefficient ∼390), is used intravenously to produce a rapid unconsciousness for surgical and basal anesthesia
  • Used initially to induce anesthesia, which can then be maintained during the surgical procedure with a general anesthetic agent