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
Surgical anesthesia

Stage III

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
Ether (diethyl ether)

CH2CH3

Spontaneously explosive Irritant to respiratory tract High incidence of nausea and vomiting during induction and post-surgical emergence

MCMP 407
I. Inhalation anesthetics
Nitrous Oxide

O 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
F
Halothane (Fluothane)

Br 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)

F H C

F C O

F CH F

Similar to Halothane Less toxicities

Cl F

Isoflurane (Forane)

F F C F

H C Cl O

F CH F

Volatile liquid 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
Alveoli Blood Brain

Nitrous oxide (low solubility)

Halothane (high solubility)

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)

Cl

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

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

O C2H5 O C N

CHCH3

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II. Intravenous anesthetics
Propofol (Diprivan)

CH(CH3)2 OH CH(CH3)2

Mechanism similar to ethanol Rapid onset and recovery Mild hypotension Antiemetic activity

Short-acting barbiturates

Thiopental (Pentothal)

Benzodiazepines

Midazolam (Versed)

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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 O CH2 CH2 N

C2H5

C2H5

Procaine

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III. Local anesthetics Structure-Activity Relationships

Benzoic acid derivatives (Esters) Aniline derivatives (Amides)

R Ester/Amide X NH R

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III. Local anesthetics Structure-Activity Relationships
O H 2N C O CH2 CH2 N C2H5 C2H5

Procaine (Novocain)

CH3 NH CH3

O C CH2 N

C2H5 C2H5

Lidocaine (Xylocaine, etc.)

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III. Local anesthetics Structure-Activity Relationships

Direct correlation between lipid solubility AND potency as well as rate of onset Local anesthetics are weak bases (pKas ~8.0-9.0)

Why are local anesthetics less effective in infected tissues?

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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

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III. Local anesthetics
Techniques of administration

Topical: benzocaine, lidocaine, tetracaine

Infiltration: lidocaine, procaine, bupivacaine Nerve block: lidocaine, mepivacaine Spinal:
bupivacaine, tetracaine bupivacaine

Epidural:

Caudal: lidocaine, bupivacaine

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