Transcript anesthetics
MCMP 407 General Anesthesia Sleep induction Loss of pain responses Amnesia Skeletal muscle relaxation Loss of reflexes MCMP 407 General Anesthesia Stages of Anesthesia Stage I Analgesia Stage II Disinhibition Stage III Surgical anesthesia Stage IV 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 CH3CH2 O CH2CH3 Ether (diethyl ether) Spontaneously explosive Irritant to respiratory tract High incidence of nausea and vomiting during induction and post-surgical emergence MCMP 407 I. Inhalation anesthetics O Nitrous Oxide N N Rapid onset Good analgesia Used for short procedures and in combination with other anesthetics Supplied in blue cylinders MCMP 407 I. Inhalation anesthetics Halothane (Fluothane) F F Br C CH Volatile liquid Narrow margin of safety F Cl Less analgesia and muscle relaxation Hepatotoxic Reduced cardiac output leads to decrease in mean arterial pressure Increased sensitization of myocardium to catecholamines MCMP 407 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 H F F F C C F O CH Cl F F F H F C C F Cl O CH F 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 Alveoli Nitrous oxide (low solubility) Halothane (high solubility) Blood Brain MCMP 407 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 MCMP 407 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 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 Cl HN CH3 O MCMP 407 II. Intravenous anesthetics Etomidate (Amidate) Non-barbiturate Rapid onset Minimal cardiovascular and respiratory toxicities High incidence of nausea and vomiting N O C2H5 O C N CHCH3 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) CH(CH3)2 OH CH(CH3)2 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 a1adrenergic receptor agonist (exception….cocaine) O H 2N C C2H5 O CH2 CH2 N C2H5 Procaine MCMP 407 III. Local anesthetics Structure-Activity Relationships Benzoic acid derivatives (Esters) Aniline derivatives (Amides) R Ester/Amide X NH R MCMP 407 III. Local anesthetics Structure-Activity Relationships O H 2N C C2H5 O CH2 CH2 N C2H5 Procaine (Novocain) CH3 NH O C C2H5 CH2 N C2H5 CH3 Lidocaine (Xylocaine, etc.) MCMP 407 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? MCMP 407 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 MCMP 407 III. Local anesthetics Drug Esters Cocaine Procaine (Novocain) Tetracaine (Pontocaine) Benzocaine Amides Lidocaine (Xylocaine) Mepivacaine (Carbocaine, Isocaine) Bupivacaine (Marcaine) Duration of Action Medium Short Long Topical use only Medium Medium Long MCMP 407 III. Local anesthetics Techniques of administration Topical: benzocaine, lidocaine, tetracaine Infiltration: lidocaine, procaine, bupivacaine Nerve block: lidocaine, mepivacaine Spinal: Epidural: Caudal: lidocaine, bupivacaine bupivacaine, tetracaine bupivacaine MCMP 407 III. Local anesthetics Toxicities: CNS-sedation, restlessness, nystagmus, convulsions Cardiovascular- cardiac block, arrhythmias, vasodilation (except cocaine) Allergic reactions-more common with esters