Download 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