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MCMP 407
General AnesthesiaGeneral Anesthesia
Sleep induction Loss of pain responses Amnesia Skeletal muscle relaxation Loss of reflexes
MCMP 407
General AnesthesiaGeneral Anesthesia
Stages of Anesthesia Stage I
Analgesia Stage II
Disinhibition Stage III
Surgical anesthesia Stage IV
Medullary depression
MCMP 407
Types of anestheticsTypes of anesthetics
I. Inhalation anesthetics
II. Intravenous anesthetics
III. Local anesthetics
MCMP 407
I. Inhalation anestheticsI. 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 anestheticsI. Inhalation anesthetics
Ether (diethyl ether) Spontaneously explosive Irritant to respiratory tract High incidence of nausea and vomiting during induction
and post-surgical emergence
CH3CH2 O CH2CH3
MCMP 407
I. Inhalation anestheticsI. Inhalation anesthetics
Nitrous Oxide Rapid onset Good analgesia Used for short procedures and in combination
with other anesthetics Supplied in blue cylinders
N
O
N
MCMP 407
I. Inhalation anestheticsI. 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
F C CH
BrF
F Cl
MCMP 407
I. Inhalation anestheticsI. 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 C C
FF
Cl F
O CH
F
F
F C C
HF
F Cl
O CH
F
F
MCMP 407
I. Inhalation anestheticsI. 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)
MCMP 407
I. Inhalation anestheticsI. 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 anestheticsI. 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 anestheticsII. 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
OHN
CH3
MCMP 407
II. Intravenous anestheticsII. Intravenous anesthetics
Etomidate (Amidate) Non-barbiturate Rapid onset Minimal cardiovascular and respiratory toxicities High incidence of nausea and vomiting
N
NC
O
OC2H5
CHCH3
MCMP 407
II. Intravenous anestheticsII. 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
CH(CH3)2
OH
MCMP 407
III. Local anestheticsIII. 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
H2N C O
O
CH2 CH2 NC2H5
C2H5
MCMP 407
III. Local anestheticsIII. Local anesthetics
Structure-Activity Relationships Benzoic acid derivatives (Esters) Aniline derivatives (Amides)
R
Ester/Amide X NH R
MCMP 407
III. Local anestheticsIII. Local anesthetics
Structure-Activity Relationships
CH3
CH3
NH C
O
CH2 N
C2H5
C2H5
H2N C O
O
CH2 CH2 NC2H5
C2H5
Procaine (Novocain)
Lidocaine (Xylocaine, etc.)
MCMP 407
III. Local anestheticsIII. 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
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
See Katzung, Page 220
MCMP 407
III. Local anestheticsIII. Local anesthetics
Drug Duration of Action
EstersCocaine MediumProcaine (Novocain) ShortTetracaine (Pontocaine) LongBenzocaine Topical use only
AmidesLidocaine (Xylocaine) MediumMepivacaine (Carbocaine, Isocaine) MediumBupivacaine (Marcaine) Long
MCMP 407
III. Local anestheticsIII. 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
MCMP 407
III. Local anestheticsIII. Local anesthetics
Toxicities: CNS-sedation, restlessness, nystagmus, convulsions Cardiovascular- cardiac block, arrhythmias, vasodilation
(except cocaine) Allergic reactions-more common with esters