Anesthesia

• General anesthetics consist of monitored anesthesia care, which involves local anesthetics and sedatives, allowing the patient to respond to verbal commands.
• Balanced anesthesia combines intravenous and inhaled anesthetics.

Intravenous Anesthetics

• Barbiturates like thiopental and methohexital are administered intravenously.
• Benzodiazepines such as midazolam and diazepam are administered intravenously.
• Propofol is administered intravenously.
• Ketamine is administered intravenously.
• Opioid analgesics like morphine, fentanyl, sufentanil, alfentanil, and remifentanil are administered intravenously.
• Miscellaneous sedative hypnotics, including etomidate and dexmedetomidine, are administered intravenously.

Inhaled Anesthetics

• Volatile anesthetics like halothane, enflurane, isoflurane, desflurane, and sevoflurane are liquids at room temperature.
• Gaseous anesthetics such as nitrous oxide and xenon are gases at room temperature.

Balanced Anesthesia

• Anesthesia can be induced intravenously.
• Anesthesia can be maintained with inhaled anesthetics.

Stages of Anesthesia

• Stage I (Analgesia) involves initial analgesia without amnesia.
• Stage II (Excitement) includes delirium, vocalization, and amnesia.
• Stage III (Surgical Anesthesia) involves using pupil size to determine the plane of this stage.
• Stage IV (Medullary Depression) leads to CNS depression and potential death.
• The most reliable indication of Stage III Surgical Anesthesia is the loss of response to noxious stimuli and reestablishment of a regular respiratory pattern.

Inhaled Anesthetics: Pharmacokinetics

• Major factors controlling the rate of entry of gas into the CNS include:
• Concentration, proportional to partial pressure (tension).
• Factors controlling gas movement into the CNS (time to induction).
• Solubility:
  • The blood:gas partition coefficient is a key factor.
  • Nitrous oxide has low solubility in blood, causing a rapid onset of action.
• Inspired Air Concentration:
  • Enflurane, isoflurane, and halothane have moderate blood solubility.
  • Increasing inspired air concentration to 1.5% raises blood levels for brain entry, then reduces to 0.7% for maintenance.
• Pulmonary Ventilation:
  • Minute ventilation equals the rate and depth of ventilation.
  • A fourfold increase in ventilation rate almost doubles the arterial tension of halothane.
  • Hyperventilation increases anesthesia induction speed.
  • Opioid analgesics depress respiration, slowing anesthesia onset.
• Pulmonary Blood Flow:
  • Increased blood flow through the lung exposes the anesthetic to larger blood volumes in the alveoli, reducing its effect.
  • Increased exposure and solubility in blood decreases transfer into the brain.
• Arteriovenous Concentration Gradient:
  • Creates an arterial to venous blood gradient.
  • Venous blood returning to the lung has less anesthetic due to tissue uptake, reducing drug entry into the brain.

Elimination

• The most important factor is the blood:gas partition coefficient.
• Gas must leave the brain, enter the blood, and then be exhaled.
• Gases insoluble in blood (low blood:gas partition coefficient) are eliminated faster than more soluble ones.
• Halothane is twice as soluble in the brain compared to nitrous oxide and takes longer to be eliminated.
• The major elimination route for inhaled anesthetics is clearance via the lungs.
• Liver biotransformation contributes to the elimination of some inhaled anesthetics: halothane is 40% biotransformed, compared to <10% for enflurane.
• Liver biotransformation of fluoride-containing inhaled anesthetics can lead to chlorotrifluoroethyl free radicals, causing halothane hepatitis.
• Liver biotransformation of enflurane and sevoflurane may produce fluoride ions, potentially causing kidney damage, especially with methoxyflurane.
• Sevoflurane is degraded by carbon dioxide absorbent in anesthesia machines, producing a vinyl ether that can cause kidney damage.

Pharmacodynamics

• The primary target of anesthetics is the GABAĀ chloride channel.
• Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol enhance GABA-mediated inhibition.
• Ketamine, a dissociative anesthetic, acts as an antagonist at NMDA glutamic acid excitatory channels.
• Inhaled anesthetics may activate potassium channels to hyperpolarize neurons. -Inhaled anesthetics may block acetylcholine's excitatory actions at nicotinic receptors and their cation channels.

Dose-Response Characteristics: MAC

• Dose-response relationships for inhaled anesthetics are unique with ethical considerations.
• Low doses allow pain, higher doses stop pain, and even higher doses can induce death.
• At steady state, the concentration (partial pressure) of the inhaled anesthetic is the same in the brain and the lung.
• Anesthetic levels can be measured in alveolar air (lung air), not the brain.
• Alveolar air concentration is reported as the % of 760 mm Hg (atmospheric pressure at sea level).
• MAC (minimum alveolar anesthetic) is the concentration that results in immobility in 50% of patients when exposed to noxious stimulus (surgical anesthesia).
• MAC serves as a surrogate measure of anesthetic requirement and potency among different gases.
• Nitrous oxide has a MAC > 100%, making it the least potent.
• Enflurane has a MAC of 1.7%, making it more potent.
• 1 MAC produces surgical anesthesia in 50% of patients.
• MAC is decreased with coadministered drugs, opioids, sympatholytics, and sedative-hypnotics.
• Potency measures how low a dose can produce the desired clinical effect.

Additional Information on MAC Values

• Nitrous oxide has very poor potency.
• Sevoflurane and isoflurane have similar potencies but are not very different from each other.
• Examiners only want students to know the difference between 95 and 0.5.

Factors that Control the Time to Induction

• Gas Solubility in Blood:
  • Solubility is determined by the blood:gas partition ratio, which is determined by the blood:gas partition ratio
  • Highly blood-soluble gases take longer to enter the brain, while less blood-soluble drugs enter the brain faster.
  • Gases with a low blood:gas partition ratio induce rapidly, e.g., nitrous oxide.

The Minimal Alveolar Concentration (MAC)

• MAC measures the potency of an anesthetic gas.
• Nitrous oxide is low potency. It requires a high concentration to block pain from a surgical incision; halothane is a potent alternative.

Organ System Effects of Anesthetics: Cardiovascular System

• Generally decrease arterial blood pressure in direct proportion to their alveolar concentration which include halothane, desflurane, enflurane, sevoflurane, isoflurane.
• Halothane and enflurane decrease cardiac output via varying mechanisms.
• Isoflurane, desflurane, and sevoflurane decrease peripheral vascular resistance.
• Halothane causes bradycardia through direct vagal stimulation while enflurane and sevoflurane have no HR effect; desflurane and isoflurane increase heart rate.
• Beta-blockers are used to treat increased catecholamine stimulated increase in blood pressure.

Organ System Effects of Anesthetics: Respiratory System

• All anesthetics (except nitrous oxide) reduce tidal volume and increase respiratory rate.
• All volatile anesthetics are respiratory depressants that increase pACO2.
• All volatile anesthetics depress mucociliary function (leading to mucus pooling, atelectasis, and postoperative lung infection).
• Halothane and sevoflurane have bronchodilating actions, useful for patients with asthma, bronchitis, or COPD.

Effects on Other Organs

• Brain:
  • All decrease the metabolic rate of the brain and increase cerebral blood flow, which is not desired in patients with increased intracranial brain pressure due to tumor or head injury.
  • Nitrous oxide is less likely to increase cerebral blood flow.
• Kidney:
  • Decrease glomerular filtration.
• Liver:
  • Decrease hepatic blood flow (15-45%).

Toxicity

• Liver:
  • Halothane hepatitis (prior exposure required); Incidence: 1 in 25,000 – 35,000 and may induce immune-mediate case.
• Kidney:
  • Methoxyflurane, enflurane, sevoflurane are biotransformed and release fluoride ions that can lead to toxicity.
  • Sevoflurane is degraded by carbon dioxide absorbents in anesthesia machines leads to a toxic compound which causes proximal tubular necrosis.
  • Methoxyflurane is no longer used due to potential for fluoride-induced renal toxicity.
• Malignant Hyperthermia:
  • Caused by a genetic disorder of skeletal muscle and induced by general anesthetics and succinylcholine (a skeletal muscle relaxant).
  • Presents with tachycardia, hypertension, muscle rigidity, hyperthermia, hyperkalemia, and acidosis.
  • Triggering agents include general anesthetics and succinylcholine and is due to uncontrolled release of calcium from the sarcoplasmic reticulum (SR) in muscle.
  • Treat with dantrolene, which blocks the release of Ca from SR.
  • Diagnosis requires skeletal muscle biopsy and caffeine-halothane contracture testing.

Chronic Toxicity

• Mutagenicity: no effect demonstrated.
• Carcinogenicity: no effect demonstrated.
• Reproductive Organs: higher incidence of miscarriages among OR personnel.

Intravenous Anesthetics: General

• It is often used with inhaled anesthetics or alone allow for a faster induction compared to inhaled agents

Barbiturates

• Thiopental and methohexital readily cross the blood-brain barrier (BBB), are lipid soluble, and rapidly induce anesthesia.

Benzodiazepines

• Diazepam, lorazepam, and midazolam are used for preanesthesia medication, providing sedative, anxiolytic, and amnestic effects.
• Midazolam is often the drug of choice for IV administration.

Opioids

• Used with benzodiazepines (midazolam) to induce anesthesia.
• Fentanyl and sufentanil are used as adjuncts to general anesthetics.

Propofol

• It's the most popular IV anesthetic and reduces incidence of nausea and vomiting with rapid recovery at termination of IV infusion.
• Used for both induction and maintenance of anesthesia.
• Fospropofol is a prodrug that reduces injection site pain.

Etomidate

• Causes minimal cardiovascular and respiratory depression but has no analgesic properties, thus requiring the use of opioids.

Ketamine

• Ketamine produces a dissociative anesthetic state, including catatonia, amnesia, analgesia (with or without loss of consciousness/hypnosis).
• This drug blocks excitatory neurotransmitter glutamic acid at NMDA receptors.
• Only IV anesthetic with both analgesic and anesthetic properties.
• Often induces emergence phenomena as an anesthetic (perceptual illusions, vivid dreams).
• Diazepam or midazolam can reduce the incidence of emergence phenomena.
• Useful in low doses due to lack of respiratory depression.

Anesthetic Drug Classes

Inhaled Gas Anesthetics:

• Acts on GABA receptors, glycine, and potassium channels, but the exact mechanisms are incompletely understood.
• Examples include desflurane, sevoflurane, isoflurane, and enflurane.
• Can cause malignant hyperthermia

Volatile Anesthetics

• Cause halothane hepatitis
• Examples include desflurane, sevoflurane, isoflurane, and enflurane
• Enflurane may release fluoride ions, causing kidney damage.

Gaseous Anesthetic

• Including nitrous oxide (in a blue cylinder) for gas at room temperature.

Intravenous Anesthetics: Barbiturates

• Names normally end with "tal" and include thiopental and methohexital

Intravenous Anesthetics: Benzodiazepines

• Midazolam and lorazepam are GABAA agonists.

Hypnotic but not Analgesic

• Etomidate is a hypnotic but not analgesic and a GABAA agonist.

Propofol and Fospropofol

• Fospropofol is a prodrug of propofol, it's conversion is facilitated by alkaline phosphatase, reduces injection site pain.

Dissociative Anesthetic: Ketamine

• Inhibits NMDA receptors and has dissociative effects

Alpha2 Receptor Agonist: Dexmedetomidine

• Has analgesic actions in the spinal cord and hypnosis in locus caeruleus actions.

Explore general anesthetic effects on cerebral physiology, volatile anesthetic risks in renal insufficiency, and causes of intraoperative complications like malignant hyperthermia. Also covers anesthetic degradation, halothane hepatitis, and nitrous oxide mechanisms.