General Anesthesia

1. Sleep induction Loss of pain responses Amnesia Skeletal muscle relaxation Loss of reflexes General Anesthesia

2. Stages of Anesthesia Stage I Analgesia Stage II Disinhibition Stage III Surgical anesthesia Stage IV Medullary depression General Anesthesia

3. I. Inhalation anesthetics II. Intravenous anesthetics III. Local anesthetics Types of anesthetics

4. Mechanisms of Action Activate K+ channels Block Na+ channels Disrupt membrane lipids In general, all general anesthetics increase the cellular threshold for firing, thus decreasing neuronal activity. I. Inhalation anesthetics

5. Ether (diethyl ether) Spontaneously explosive Irritant to respiratory tract High incidence of nausea and vomiting during induction and post-surgical emergence I. Inhalation anesthetics

6. Nitrous Oxide Rapid onset Good analgesia Used for short procedures and in combination with other anesthetics Supplied in blue cylinders I. Inhalation anesthetics

7. Halothane (Fluothane) Volatile liquid Narrow margin of safety Less analgesia and muscle relaxation Hepatotoxic Reduced cardiac output leads to decrease in mean arterial pressure Increased sensitization of myocardium to catecholamines I. Inhalation anesthetics

8. Enflurane (Ethrane) Similar to Halothane Less toxicities Isoflurane (Forane) Volatile liquid Decrease mean arterial pressure resulting from a decrease in systemic vascular resistance I. Inhalation anesthetics

9. Pharmacokinetics The concentration of a gas in a mixture of gases is proportional to the partial pressure Inverse relationship between blood:gas solubility and rate of induction Alveoli Blood Brain Nitrous oxide (low solubility) Halothane (high solubility) I. Inhalation anesthetics

10. Pharmacokinetics Increase in inspired anesthetic concentration will increase rate of induction Direct relationship between ventilation rate and induction rate Inverse relationship between blood flow to lungs and rate of onset MAC=minimum concentration in alveoli needed to eliminate pain response in 50% of patients Elimination Redistribution from brain to blood to air Anesthetics that are relatively insoluble in blood and brain are eliminated faster I. Inhalation anesthetics

11. Side Effects Reduce metabolic rate of the brain Decrease cerebral vascular resistance thus increasing cerebral blood flow = increase in intracranial pressure Malignant Hyperthermia Rare, genetically susceptible Tachycardia, hypertension, hyperkalemia, muscle rigidity, and hyperthermia Due to massive release of Ca++ Treat with dantrolene (Dantrium), lower elevated temperature, and restore electrolyte imbalance I. Inhalation anesthetics

12. Ketamine (Ketaject, Ketalar) Block glutamate receptors Dissociative anesthesia: Catatonia, analgesia, and amnesia without loss of consciousness Post-op emergence phenomena: disorientation, sensory and perceptual illusions, vivid dreams Cardiac stimulant II. Intravenous anesthetics

13. Etomidate (Amidate) Non-barbiturate Rapid onset Minimal cardiovascular and respiratory toxicities High incidence of nausea and vomiting II. Intravenous anesthetics

14. Propofol (Diprivan) Mechanism similar to ethanol Rapid onset and recovery Mild hypotension Antiemetic activity Short-acting barbiturates Thiopental (Pentothal) Benzodiazepines Midazolam (Versed) II. Intravenous anesthetics

15. Blockade of sensory transmission to brain from a localized area Blockade of voltage-sensitive Na+ channels Use-dependent block Administer to site of action Decrease spread and metabolism by co-administering with a1-adrenergic receptor agonist (exception….cocaine) III. Local anesthetics O C H 2 5 H N C O C H C H N 2 2 2 C H 2 5 Procaine

16. Structure-Activity Relationships Benzoic acid derivatives (Esters) Aniline derivatives (Amides) III. Local anesthetics

17. Structure-Activity Relationships O C H 2 5 H N C O C H C H N 2 2 2 C H 2 5 III. Local anesthetics Procaine (Novocain) Lidocaine (Xylocaine, etc.)

18. Structure-Activity Relationships III. Local anesthetics • Direct correlation between lipid solubility AND potency as well as rate of onset • Local anesthetics are weak bases (pKa’s ~8.0-9.0) Why are local anesthetics less effective in infected tissues?

19. See Katzung, Page 220 • Activation gate (m gate) is voltage-dependent • Open channel allows access to drug binding site (R) from cytoplasm • Inactivation gate (h gate) causes channel to be refractory • With inactivaton gate closed, drug can access channel through the membrane • Closing of the channel (m gate) is distinct from inactivation and blocks access to drug binding site • Thus, local anesthetics bind preferentially to the open/inactivated state

20. III. Local anesthetics Drug Duration of Action Esters Cocaine Medium Procaine (Novocain) Short Tetracaine (Pontocaine) Long Benzocaine Topical use only Amides Lidocaine (Xylocaine) Medium Mepivacaine (Carbocaine, Isocaine) Medium Bupivacaine (Marcaine) Long

21. Techniques of administration Topical: benzocaine, lidocaine, tetracaine Infiltration: lidocaine, procaine, bupivacaine Nerve block: lidocaine, mepivacaine Spinal: bupivacaine, tetracaine Epidural: bupivacaine Caudal: lidocaine, bupivacaine III. Local anesthetics

22. Toxicities: CNS-sedation, restlessness, nystagmus, convulsions Cardiovascular- cardiac block, arrhythmias, vasodilation (except cocaine) Allergic reactions-more common with esters III. Local anesthetics