General and Inhalation Anesthetics

General Anesthetics and Inhalation Anesthetics

• General anesthetics ensure patient safety and comfort during surgical procedures.
• The primary goals of general anesthesia are to preserve the patient's life, provide satisfactory surgical conditions, and block pain.

Characteristics of Ideal General Anesthetic

• Smooth and rapid induction of unconsciousness is desired.
• An ideal anesthetic produces amnesia.
• Autonomic and sensory reflexes are ideally inhibited.
• Skeletal muscle relaxation is a desired effect.
• Analgesia is a key component.
• A smooth and rapid emergence and recovery without lasting adverse effects is essential

Balanced Anesthesia

• A drug combination is used to maximize beneficial effects and minimize unwanted side effects, as a single agent will not meet all requirements.
• Intravenous (IV) anesthetics are used for rapid induction.
• Inhalation anesthetics are used for maintenance.

Preanesthetic Medications

• Given before, during, or after anesthesia.
• They aim to decrease anxiety without causing excessive drowsiness.
• These medications facilitate rapid, smooth induction and prevent prolonged emergence.
• They provide amnesia during the perioperative period.
• Additional goals are to relieve pre- and postoperative pain.
• It is important to minimize undesirable anesthetic side effects.

Specific Preanesthetic Medications

• Opioids like morphine and fentanyl provide analgesia.
• Benzodiazepines like diazepam reduce anxiety, cause sedation, and induce amnesia.
• Barbiturates such as phenobarbital and secobarbital reduce anxiety and cause sedation; secobarbital also induces rapid induction.
• Phenothiazines like promethazine induce sedation and act as an antiemetic.
• Antimuscarinics such as atropine inhibit secretions and laryngospasms, also working as an antiemetic.
• Antihistamines like hydroxyzine have antimuscarinic and sedative properties, preventing hypotension and bronchospasm which are caused by d-Tubocurarine-induced histamine release.

Inhaled Anesthetics

• Anesthetic gases include nitrous oxide.
• Volatile liquids include desflurane (Suprane), sevoflurane (Ultane), isoflurane (Forane), enflurane (Ethrane), and methoxyflurane (Penthrane).

Mechanism of Action

• Neuronal activity is inhibited in many brain regions.

Meyer-Overton Relationship

• Anesthetic potency correlates with the lipid/gas partition coefficient.
• Nonspecific interactions with lipid membranes modify ionic currents.
• Ionic currents are modified via specific interactions with hydrophobic protein portions.

GABAA Receptor

• Targeted due to being a major molecular target.
• It enhances chloride influx even without GABA.
• Anesthetics alter gating by working in the transmembrane domain.

NMDA Receptor

• NMDA Receptor is inhibited by ketamine.

Potassium (K+) Channels

• K2P, KV, and KATP channels are affected.

Nictonic Receptors

• Nicotinic receptors are inhibited

Potency

• Anesthetic gases are administered in partial pressures (% of total gas).
• Relative potency is expressed as MAC (Minimum Alveolar Concentration).
• A larger MAC indicates lower potency.
• 1 MAC refers to the alveolar concentration at which movement is blocked in 50% of patients responding to incision, or the ED50.

MAC Dosing

• Dosing is 0.5-1.1 MAC.
• MAC values are additive, meaning 0.5 MAC of N2O + 0.5 MAC of isoflurane = 1 MAC in 50% of patients

Factors Affecting MAC

• MAC values are not affected by height, weight, or sex.
• MAC values can be decreased by:
  • Elderly age
  • Hypothermia
  • Hypothyroidism
  • Sedatives

MAC and Oil/Gas Partition Coefficient

• MAC is inversely correlated with the oil/gas partition coefficient.
• Anesthetics with large oil/gas partition coefficients are more potent and reach surgical anesthesia at lower partial pressures.

Safety and Therapeutic Index

• The therapeutic indices for most general anesthetics is low (2-4).

Stages of General Anesthesia

• Stage I (Analgesia):
  • Analgesia is agent-dependent.
  • Amnesia and euphoria are present.
• Stage II (Excitement):
  • Excitement occurs (inhibitory neurons are blocked).
  • Delirium.
  • Combative behavior.
• Stage III (Surgical Anesthesia):
  • Unconsciousness achieved (RAS depressed).
  • Respiration becomes regular.
  • Eye movement decreases.
• Stage IV (Medullary Depression):
  • Respiratory arrest.
  • Cardiac depression and arrest.
  • No eye movement.

Efficacy of Anesthetics

• The efficacy of inhalation anesthetics is related to potency.
• Most agents effectively induce all anesthesia stages at low concentrations and allow sufficient oxygen to the patient; these are considered complete anesthetics.
• Nitrous oxide is an incomplete anesthetic, because it will not produce all stages of anaesthesia without hypoxia.
  • At 1 MAC = 100% inhaled air, nitrous oxide produces analgesia and amnesia.

Pharmacokinetics

• Induction and emergence (recovery) speed depends on the rate of change of the partial pressure/concentration of anesthetic in the brain
• This is determined by the partial pressure of gas in arterial blood.
• Induction speed is inversely correlated with the blood/gas partition coefficient.

Induction Rate

• Increasing the ventilation rate enhances the loss of consciousness with soluble, but not insoluble, gases.
• Opioid analgesics increase ventilation rate.
• Decreasing pulmonary blood flow (cardiac output) increases induction rates of soluble gases.
• Hemorrhagic shock reduces pulmonary blood flow.
• Increasing the concentration of soluble gases in inspired air increases induction rate.

Second Gas Effect

• A high concentration of nitrous oxide increases the induction rate of more soluble anesthetics.
• Rapid nitrous oxide uptake effectively increases the partial pressure of a second gas, causing it to dissolve more rapidly.

Anesthetic Distribution

• 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.

Recovery

• Defined by same factors in reverse.
• Recovery slows with lipid-soluble anesthetics and longer anesthesia.
• Diffusion Hypoxia.
  • Nitrous oxide.
  • Rapid release of N₂O from blood to lungs.
  • Give pure O₂ for a few minutes to counter effects.

General Pharmacological Effects - CNS

• Dose-dependent depression of all CNS regions.
• Order of Sensitivity (most to least):
  • Spinothalamic (analgesia)
  • RAS and cortex (anesthesia)
  • Spinal reflexes (muscle relaxation)
  • Medulla
• Increased intracranial pressure.
  • Increased cerebral blood flow by vasodilation of cerebral vasculature secondary to inhibition of sympathetic nerves.

General Pharmacological Effects - Cardiovascular

• Mean arterial pressure decreases.
  • Vasodilation via sympathetic nerve inhibition (Isoflurane, desflurane, sevoflurane) can create reflex tachycardia.

General Pharmacological Effects - Respiratory

• The medullary respiratory center is depressed
• Response to hypoxia is depressed (increased PCO₂).
• Halothane and sevoflurane particularly cause bronchodilation.
• Desflurane causes airway irritation and coughing.

General Pharmacological Effects - Miscellaneous

• Kidney: decreased renal blood flow
• Liver: decreased hepatic blood flow
• Uterine smooth muscle: relaxation via halogenated anesthetics (not N₂O), with an increased risk of abortion

Inhaled Anesthetics Properties

• Nitrous Oxide:
  • Oil-gas ratio: 1.4
  • MAC (% total gas): >100
  • Blood-gas ratio: 0.5
  • CV Effects: Minimal
  • Muscle Relaxation: None
  • Metabolism: None
  • Characteristics: Lowest potency, often used in combo for rapid onset/recovery; potential for abuse
• Enflurane:
  • Oil-gas ratio: 98
  • MAC (% total gas): 1.7
  • Blood-gas ratio: 2
  • CV Effects: Decreased CO
  • Muscle Relaxation: Medium
  • Metabolism: 8%
  • Characteristics: Tonic-clonic muscle spasms
• Isoflurane:
  • Oil-gas ratio: 98
  • MAC (% total gas): 1.3
  • Blood-gas ratio: 1.4
  • CV Effects: Vasodilation; tachycardia
  • Muscle Relaxation: Medium
  • Metabolism: Slight
  • Characteristics: Bronchiolar secretions and spasms
• Desflurane:
  • Oil-gas ratio: 19
  • MAC (% total gas): 7
  • Blood-gas ratio: 0.4
  • CV Effects: Vasodilation; tachycardia
  • Muscle Relaxation: Medium
  • Metabolism: Almost none
  • Characteristics: Most rapid onset, but airway irritation and coughing, rapid recovery
• Sevoflurane:
  • Oil-gas ratio: 51
  • MAC (% total gas): 2.5
  • Blood-gas ratio: 0.7
  • CV Effects: Vasodilation
  • Muscle Relaxation: Medium
  • Metabolism: 2-5% Fluoride
  • Characteristics: Rapid onset and recovery
• Methoxyflurane:
  • Oil-gas ratio: 0.2
  • MAC (% total gas): 2
  • Blood-gas ratio: N/A
  • CV Effects: N/A
  • Muscle Relaxation: N/A
  • Metabolism: >70% Fluoride
  • Characteristics: Generally not used due to nephrotoxicity

Malignant Hyperthermia

• Genetic disorder of skeletal muscle.
• Abnormal Ca2+ channels (ryanodine receptors) in skeletal muscle.
• Can be triggered with potent inhaled anesthetics and depolarizing muscle relaxants like succinylcholine which leads to drastically increased Ca2+ levels in cells.
• Rapid onset of severe muscle rigidity, hyperthermia, hyperkalemia, tachycardia, hypertension, and acid-base imbalance with acidosis
• Dantrolene: Blocks calcium release channels in sarcoplasmic reticulum.
• Measures to control body temperature.