HINDU COLLEGE PG COURSE

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

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

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

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

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

I. Inhalation anesthetics 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 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 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 Nitrous oxide (low solubility) Alveoli Blood Brain Halothane (high solubility)

I. Inhalation anesthetics 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 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

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

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

III. Local anesthetics 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) O C H 2 5 H N C O C H C H N 2 2 2 C H 2 5 Procaine

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

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

Structure-Activity Relationships III. Local anesthetics Structure-Activity Relationships 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?

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

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

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

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