MCMP 407 General Anesthesia  Sleep induction  Loss of pain responses  Amnesia  Skeletal muscle relaxation  Loss of reflexes

MCMP 407 General Anesthesia Stages of Anesthesia vStage I l Analgesia vStage II l Disinhibition vStage III l Surgical anesthesia vStage IV l Medullary depression

MCMP 407 Types of anesthetics I. Inhalation anesthetics II. Intravenous anesthetics III. Local anesthetics

MCMP 407 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.

MCMP 407 I. Inhalation anesthetics Ether (diethyl ether) l Spontaneously explosive l Irritant to respiratory tract l High incidence of nausea and vomiting during induction and post-surgical emergence

MCMP 407 I. Inhalation anesthetics Nitrous Oxide l Rapid onset l Good analgesia l Used for short procedures and in combination with other anesthetics l Supplied in blue cylinders

MCMP 407 I. Inhalation anesthetics Halothane (Fluothane) l Volatile liquid l Narrow margin of safety l Less analgesia and muscle relaxation l Hepatotoxic l Reduced cardiac output leads to decrease in mean arterial pressure l Increased sensitization of myocardium to catecholamines

MCMP 407 I. Inhalation anesthetics Enflurane (Ethrane) l Similar to Halothane l Less toxicities Isoflurane (Forane) l Volatile liquid l Decrease mean arterial pressure resulting from a decrease in systemic vascular resistance

MCMP 407 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) AlveoliBloodBrain Halothane (high solubility)

MCMP 407 I. Inhalation anesthetics Pharmacokinetics u Increase in inspired anesthetic concentration will increase rate of induction u Direct relationship between ventilation rate and induction rate u Inverse relationship between blood flow to lungs and rate of onset u MAC=minimum concentration in alveoli needed to eliminate pain response in 50% of patients Elimination l Redistribution from brain to blood to air l Anesthetics that are relatively insoluble in blood and brain are eliminated faster

MCMP 407 I. Inhalation anesthetics Side Effects l Reduce metabolic rate of the brain l Decrease cerebral vascular resistance thus increasing cerebral blood flow = increase in intracranial pressure l Malignant Hyperthermia u Rare, genetically susceptible u Tachycardia, hypertension, hyperkalemia, muscle rigidity, and hyperthermia u Due to massive release of Ca ++ u Treat with dantrolene (Dantrium), lower elevated temperature, and restore electrolyte imbalance

MCMP 407 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

MCMP 407 II. Intravenous anesthetics Etomidate (Amidate) ] Non-barbiturate ] Rapid onset ] Minimal cardiovascular and respiratory toxicities ] High incidence of nausea and vomiting

MCMP 407 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)

MCMP 407 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  1 - adrenergic receptor agonist (exception….cocaine) Procaine H 2 NCO O CH 2 CH 2 N C 2 H 5 C 2 H 5

MCMP 407 III. Local anesthetics Structure-Activity Relationships  Benzoic acid derivatives (Esters)  Aniline derivatives (Amides)

MCMP 407 III. Local anesthetics Structure-Activity Relationships H 2 NCO O CH 2 CH 2 N C 2 H 5 C 2 H 5 Procaine (Novocain) Lidocaine (Xylocaine, etc.)

MCMP 407 III. Local anesthetics Structure-Activity Relationships u Direct correlation between lipid solubility AND potency as well as rate of onset u Local anesthetics are weak bases (pKa’s ~ ) Why are local anesthetics less effective in infected tissues?

MCMP 407 vActivation gate (m gate) is voltage-dependent vOpen channel allows access to drug binding site (R) from cytoplasm vInactivation gate (h gate) causes channel to be refractory vWith inactivaton gate closed, drug can access channel through the membrane vClosing of the channel (m gate) is distinct from inactivation and blocks access to drug binding site vThus, local anesthetics bind preferentially to the open/inactivated state See Katzung, Page 220

MCMP 407 III. Local anesthetics DrugDuration of Action Esters CocaineMedium Procaine (Novocain)Short Tetracaine (Pontocaine)Long BenzocaineTopical use only Amides Lidocaine (Xylocaine)Medium Mepivacaine (Carbocaine, Isocaine)Medium Bupivacaine (Marcaine)Long

MCMP 407 III. Local anesthetics Techniques of administration u Topical: benzocaine, lidocaine, tetracaine u Infiltration: lidocaine, procaine, bupivacaine u Nerve block: lidocaine, mepivacaine u Spinal: bupivacaine, tetracaine u Epidural: bupivacaine u Caudal: lidocaine, bupivacaine

MCMP 407 III. Local anesthetics Toxicities: v CNS-sedation, restlessness, nystagmus, convulsions v Cardiovascular- cardiac block, arrhythmias, vasodilation (except cocaine) v Allergic reactions-more common with esters