GeneralAnesthetics.ppt
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Transcript GeneralAnesthetics.ppt
General
Anesthetic
Agents
Anesthesia
Definition: “Reversible loss of consciousness,
reversible depression of CNS function resulting in
loss of response to and perception of all external
stimuli.”
Mechanism of Action
There are two types of hypotheses
concerning the mechanism of action of
general anesthetics
(1) Lipid theory
(2) Protein theory
Lipid Theory
Based on the fact that anesthetic action is correlated
with the oil/gas partition coefficients
(Meyer and Overton Correlations).
Meyer and Overton had discovered the correlation
between the physical properties of general anesthetic
molecules and their potency: the greater is the lipid
solubility of the compound in olive oil the greater is its
anesthetic potency
Good correlation between potency and lipid solubility,
not with chemical structure. The potency of an anesthetic
is associated with its lipid solubility which is measured by
its oil/gas partition coefficient.
Physically disturbing the structure of cell membranes
via dissolving (increase membrane fluidity and volume
expansion) of the lipid bilayer.
Bulky and hydrophobic anaesthetic molecules accumulate inside the
neuronal cell membrane causing its distortion and expansion
(thickening) due to volume displacement. Membrane thickening
reversibly alters function of membrane ion channels thus providing
anaesthetic effect. Actual chemical structure of the anaesthetic agent
per se was not important, but its molecular volume plays the major
role: the more space within membrane is occupied by anesthetic - the
greater is the anesthetic effect.
• Question: Why might lipid solubility be
related to potency of the volatile and
gaseous anesthetic agents?
• Answer: Because they must reach the
CNS to have their effect and this requires
them to cross the BBB. Only lipid soluble
drugs can gain access to the brain.
Minimum alveolar concentration (MAC)
• A measure of potency of inhalational general
anesthetics
• 1 MAC is the concentration necessary to prevent
responding in 50% of population.
• A lower MAC value represents a more potent
volatile anesthetic.
• The oil:gas coefficient is an index of potency
and is inversely related to MAC.
• Values of MAC are additive:
– Avoid cardiovascular depressive concentration of
potent agents.
Lipid Theory: The Meyer-Overton
correlation
Factors affecting MAC
Increase
MAO inhibitors
Cocaine
Amphetamines
Chronic alcoholism
Hyperthermia
Ephedrine
…etc
Decrease
Opioids
Barbiturates
Benzodiazepines
Hyponatremia
Hypothermia
Hypoxia
…etc
Validity of Lipid Theory
Volume can expand by non-anesthetic compounds.
Correlation between fluidity and anesthetic levels
only occurred at high concentrations.
Newer agents, enflurane and isoflurane, have same
oil/gas partition coefficient but different potency.
Stereoisomer of isoflurane have different potency
Protein (Receptor) Theory
Assumes that the mechanisms of action of general
anesthetics primarily involve specific molecular
interactions between anesthetic agents and their
target proteins such as GABAA receptor
General anesthetics bind to
hydrophobic/lipophilic sites of proteins
(membrane protein) to:
Induce/prevent conformational changes.
Alter kinetics of conformational changes.
Compete with ligands (competitive
antagonism).
Specific sites for anesthesia
• Enhancing the function of GABAA receptor
• Enhancing the function of Glycine receptor - Spinal level
(analgesia and mobility)
• Inhibiting the effect of glutamate on excitatory NMDA
receptors -Example, Ketamine, N2O and Xenon
• Alter K+ conductance
– Hyperpolarize cells
• Final outcome:
• GA will cause synaptic block:
– Decrease presynaptic Ca2+ entry --- decrease transmitter
release
– Increase postsynaptic Cl- entry and K+ outward leakage -- inhibition
Effects of General Anesthetics on Neurons
(Inhibition of synaptic transmission)
- General anesthetics
decrease presynaptic
transmitter release
- Affect postsynaptic
receptors
- Alter dendritic and
somatic integration
- Depress axonal
conductance of action
potentials.
Site of Action
Thalamic sensory relay nuclei and the deep layer of
the cortex. Anesthetics block the signal for pain.
Anesthetics block the signal for pain.
• In the nervous system a general anesthetic changes the
nerve cells so that normal communication among
many of them is closed off for a time. Anesthetics can
achieve this is by altering the chemistry of the synapses,
the gaps between the nerve cells.
• Therefore, sensations of all kinds are temporarily
blocked from reaching the brain. At the same time, the
person under anesthesia cannot move parts of the body.
The muscles are completely relaxed, making surgery
easier.
• At any point along this branching nerve system, the pain
message can be blocked. Ultimately, what all
anesthetics do is block the signal for pain.
Signs and Stages of Anesthesia
Stage
Signs
I. Analgesia
Conscious but drowsy.
Responses to painful stimuli are reduced.
Normal response to verbal stimuli.
II. Excitement
Excited but amnesic.
Loss of consciousness.
Protective reflexes such as cough and gagging
reflexes.
Irregular respiration.
III. Surgical
Anesthesia
IV. Medullary
Depression
Regular respiration and extends to complete cessation
of spontaneous respiration.
Cessation of spontaneous respiration and vasomotor,
and death occurs within a few minutes.
What is meant by narrow therapeutic index?
The Ideal Anesthetic
Produce reversible “sleep”
Produce analgesia
Suppress reflexes
Produce muscle relaxation
Induce smooth onset and recovery
Induce anterograde amnesia
Do not suppress respiratory and cardiovascular function
Cause no systemic toxicity
Present no hazard to others
Inexpensive and easy to administer
Balanced Anesthesia
Ideal general anesthetic does not exist.
Combinations of anesthetic drugs to accomplish
what one anesthetic can not do alone.
Agents used for balanced anesthesia are:
Hypnotics
Neuromuscular blocking agents
Analgesics
Combination of drugs can lower doses of each
drug to produce the same or greater effect on
patient.
Effects on the CV system
All anesthetics decrease the contractility of isolated
heart preparations.
Effect on cardiac output and blood pressure in
humans vary:
Nitrous oxide increases sympathetic discharge and
increases plasma NE and tend to increase blood
pressure
Ketamine increases blood pressure, COP as well
Other halogenated anesthetics (e.g. halothane)
have the opposite.
Cardiac dysrhythmias (esp. halogenated agents) due
to sensitization to adrenaline.
Effects on the respiratory system
With the exception of nitrous oxide and
ketamine, all anesthetics:
Depress respiration markedly
Increase arterial partial pressure of carbon
dioxide
Pathway for Inhalation General
Anesthetics
• These drugs are small lipid-soluble molecules that
cross the alveolar membrane easily. Move into and
out of the blood based on the partial pressure
gradient.
• Partial Pressure in brain quickly equilibrates with
partial pressure in arterial blood which has
equilibrated with partial pressure perfused alveoli.
• Furthermore, the DEPTH of anesthesia induced by
an inhaled anesthetic depends primarily on the
PARTIAL PRESSURE Of the anesthetics in the brain,
and the rate of induction and recovery from
anesthesia depends on the rate of change of partial
pressure in the brain.
Factors that determine the speed
of induction and recovery
Properties of the anesthetic
Blood: gas partition coefficient (solubility
in blood)
Oil: gas partition coefficient (solubility in
fat); Determine the potency of an
anesthetic
Physiological factors
Alveolar ventilation rate
Cardiac output
Oil:gas partition coefficient
Determine the potency of an anesthetic
High lipid soluble tends to delay recovery
from the effects of anesthesia
Blood:gas partition coefficient
The main factor that determines the
rate of induction and recovery of
inhalation anesthetics.
The lower the blood: gas partition ( low
solubility in blood) coefficient, the
faster the induction and the recovery.
Rate of Entry into the Brain:
Influence of Blood id Solubility
LOW solubility in blood= fast induction and
recovery
HIGH solubility in blood= slower induction
and recovery.
The Kinetics of Transfer of Anesthetic
Gases from Alveolar Space to Blood
Less
soluble
More
soluble
Classification of GA
Route
Intravenous
Characteristics
Inhalation
agents
Volatile liquids
Gases
Rapid onset (<1 min)
duration depending on
redistribution (in a single bolus
dose)
Mostly used to:
–Induce anesthesia
–Short procedures
–Supplemental
Slow onset (>4 min)
Duration depends on tissue
solubility
Used mostly to maintain anesthesia
Rapid recovery
Easy titration
Inhalation route readily accessible
Respiration controlled while
delivering gases
Examples
Thiopental
Benzodiazepines
Etomidate
Ketamine
Propofol
halothane, enflurane:
Older agents: chloroform, ether
isoflurane, desflurane,
sevoflurane,
Nitrous oxide.
Older: cyclopropane, ethylene
Structural Comparison
Ether
No longer used
Analgesic and muscle relaxant
properties
Slow onset of recovery
Postoperative nausea and vomiting
Highly explosive
Irritant to respiratory tract
Nitrous oxide (N2O)
Advantages
Good analgesic, reduce pain during
childbirth.
Relatively safe (minimal effect on
cardiovascular and respiratory systems).
Rapid induction and recovery (low blood
solubility)
Nitrous oxide (N2O)
Disadvantages
Weak anesthetic properties
Low potency (combined with other agents)
Inhibits methionine synthesis (precursor to
DNA synthesis) resulting on bone marrow
depression (prolonged use).
Hypoxia
Inhibits vitamin B-12 metabolism
Poor muscle relaxant
Halothane
Widely used agent
Potent, non-explosive, non-irritant
Has relaxant effect on the uterus
Hypotensive; may cause dysrhythmias
Hangover likely (high lipid solubility)
Risk of liver damage (repeated dose)
Malignant hyperthermia (excessive metabolic
heat production in skeletal muscles)
Enflurane
Similar to halothane.
Less hepatotoxicity.
Faster induction and recovery than
halothane.
Less accumulation in fat.
Epilepsy-like seizures.
Isoflurane
Similar to enflurane
It lacks epileptogenic property.
Precipitates myocardial ischemia in
patients with coronary disease.
Irritant to respiratory tract.
Desflurane and sevoflurane
Similar to isoflurane but have faster onset
and recovery.
Only sevoflurane lacks respiratory tract
irritation.
Intravenous Anesthetic Agents
Most commonly used for induction of
anesthesia, followed by inhalation
agent.
Thiopental, etomidate and propofol are
most commonly used (act within 20-30
second if given IV).
Thiopental
Barbiturate (CNS depressant) with very high
lipid solubility.
Rapid action (rapid transfer across BBB)
Short duration (5-10 minutes) due to
redistribution.
Slowly metabolized (accumulates in the body),
may cause prolonged effect .
No analgesic effect.
Narrow margin (between therapeutic and
cardiovascular depression doses)
Severe vasospasm if injected into artery (give
procaine).
Etomidate
Similar to thiopental but quickly
metabolized (less hangover).
Less risk of cardiovascular depression
(large margin of safety).
May cause involuntary movement
during induction.
Adrenocortical suppression (suppress
adrenal cortex).
Propofol
Similar to thiopental.
Rapidly metabolized.
Very rapid recovery (no hangover).
No cumulative effect.
Useful for day-case surgery.
Ketamine
Analogue of phencyclidine.
Block NMDA receptors.
Relatively slow onset (2-5 minutes).
Cause dissociative anesthesia
(conscious, though amnesic and
insensitive to pain).
High incidence of dysphoria and
hallucinations during recovery.
Used mainly for minor procedures in
children.
Midazolam
Benzodiazepine.
Slower than the other agents.
Little respiratory or cardiovascular
depression.
Neuroleptanalgesia
Combination of opiate analgesic and
tranquilizer/sedative. ???
Produces state of deep sedation and
analgesia (light anesthesia).
Patient remains responsive to simple
commands and questions but does not
respond to painful stimuli.
Used for minor surgical procedures
(e.g. endoscopy).
Example of combination
This combination would allow the use of less of each drug;
this will
1. Lower toxicity of halogenated drugs
2. Preserve good anesthesia (from halogenated drug) and
3. Preserve good analgesia (From N2O)