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