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