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By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 5

GENERAL ANAESTHETICS I

Requirements for general anesthetics


• The patient must be unconscious the whole time
• The rate of induction and rate of recovery must be rapid
• Recovery must be prompt and not unpleasant
• The level of anesthesia should be able to be adjusted as required (it must be controllable)
• The patient must not move unexpectedly - reflex responses are abolished or diminished
• Gross physiological disturbances must be avoided

General anaesthesia
• General anesthesia often involves more than one drug to get different, favourable effects.
• Premedication is often used to:
1. Treat anxiety
• Benzodiazapenes
2. Reduce pain
• Opiod anaglesics such as morphine
3. Produce muscle paralysis
• E.g. Tubocurare
4. Reduce secretions
• Induction of anesthesia is often done via intravenous anesthetics, which are quick and easy to administer.
• Maintenance of anesthesia involves inhalation agents.

Some examples of inhalation anesthetics


• Used clinically today:
• Nitrous oxide (N2O)
• N2O is not potent enough to be used as a anesthetic on its own. It is often used as a carrier
gas. It has analgesic effects.
• Halothane (metabolised)
• Isoflurane
These are not broken down in the body, and are highly stable. Hence, if they
• Sevoflurane
get into the atmosphere, they represent a pollution hazard.
• Enflurane
• Older ones (obsolete)
• Cyclopropane
• Methoxyflurane The reason these drugs are no longer used is because of their
• Chloroform potential toxicity to tissues and also they are highly flammable gases.
• Diethylether

• All drugs have the ability to cause unconsciousness, but at very high levels. Agents which are used as general
anesthetics have a primary action to make people drowsy and unconscious at low levels.
• At high levels, most of the general anesthetics have the potential to depress respiration and cause death.

Stages of anesthesia
• Stage I
• Analgesia
• Still conscious but drowsy
• Stage II
• Excitement stage
• Loss of consciousness, however, irregular ventilation may be present which affects absorption of
inhalation agents.
• Reflexes may be exaggerated.
• This is a very dangerous stage
• Stage III
• Surgical anesthesia
• Loss of spontaneous movement
• Regular, shallow respiration
• Relaxation of muscles
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 5

• Stage IV
• Medullary paralysis
• Death

• These 4 stages are no longer evident with the newer anesthetics. They were particularly evident with agents
such as ether.

How general anesthetics work?


• We do not know how general anesthetics work because we do not know what consciousness is, so we don’t
know what causes the loss of it.
• We do know that there is a strong relationship between the lipid solubility of the drug (the oil:gas partition
coefficient) and its potency.
• The MAC (minimum alveolar concentration) is a measure of the potency of a drug, and it is
inversely related to the lipid solubility of a drug.
• This means that the more lipid soluble a drug is, the lower the MAC value and the more potent it is.

MAC

Oil:gas partition coefficient

• A theory on how the drugs act is as follows:


• The drugs do not act on a receptor because there is no structural requirement. Only need to be lipid
soluble.
• Since lipid solubility is a prerequisite for potency, it means that the drug must be interacting with
lipid components in the body.
• Cell membranes are rich lipid components
• The drug gets into the lipid bilayer and physically prevents the expansion of certain ion channels

Drug molecule in
lipid bilayer prevents
channel opening

Where does this occur?


• The reticular activating system of the brain stem seems to be the most important area regulating
consciousness.
• At the cellular level, anesthetics may inhibit the conduction of the action potential and inhibit the
transmission at synapses. Higher concentrations are needed to inhibit action potential conduction, and so the
transmission at synapses seems to be more important.
• Theories as to the site of action:
1. Act at the synapse
• Interfere with Ca2+ conductances
• Reduction in transmitter
• Reduction in the sensitivity of the post synaptic cell
2. Afferent blockage
• Reduction in the response to noxious stimuli
• Thalamic depression (so signals cannot go to the cortex)
3. Depression of RAS
• The RAS modulates cortical activity
4. Intercellular communications
• All neurons are connected by gap junctions
• The drug may interfere with the gap junctions, thus interfering with the occilating fields
which maintain our consciousness.
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 5

Pharmacokinetics
• Ideally, inhalation anesthetics have a very rapid rate of induction.
• The rate of induction is dependent on various factors:
1. Concentration of the gas in inspired air
2. The solubility of the gas in blood (blood:gas coefficient)
• The higher the coefficient (the more soluble the gas is in the blood), the longer it takes for
the gas to reach equilibrium with the concentration in the lung.
• What we want is for the tension (concentration) of the gas in the blood to reach
equilibrium (become equal to) the concentration of the gas in the lungs (we want Fa/Fi =
1).
• If the gas is very soluble in the blood (essentially, the gas is being removed), then it will
take longer for the gas to reach equilibrium.
3. The solubility of the gas in tissues
• Initially, there is a steep rise in gas tension but as the blood containing the gas starts to
circulate, the gas gets redistributed to tissues.
• Tissues which are normally highly perfused, will get the drug first. These tissues are the
brain, heart, liver, kidney and gut.
• The lipid:gas coefficient (lipid solubility) is a measure of the solubility of the gas in tissues
and gives an indication of the potency. The higher the value, the more readily the gas will
dissolve into the brain (our target organ).
• However, there is a tradeoff. The more the gas is removed from the blood and into the
tissues, the longer it will take for the drug to reach equilibrium. The leveling off of the
graph is due to the redistribution of the drug into the tissues. If the drug did not
redistribute, equilibrium will be reached much quicker.
4. Rate of delivery of the gas into the lungs (respiratory rate)
• The faster you breathe, the quicker the gas reaches the lung and the quicker it takes for the
gas to enter the blood (hence a faster rise in tension)
5. Rate of removal of the gas from the lungs (heart rate)
• The faster the heart rate, the quicker the drug is removed from the blood as a result of the
increased delivery to tissues.
• Therefore, an increased heart rate leads to a prolonged time to equilibrium.

Effect of respiratory rate on arterial tension


Fa/Fi
1.0 8 L/min

4 L/min

2 L/min

Time

Effect of cardiac output on arterial tension


Fa/Fi
1.0 2 L/min

18 L/min

Time
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 5

• If a patient is struggling or anxious, their heart rate (and hence CO) will be increased and so they need a
higher concentration of inhalation anesthetic for a longer time to induce anesthesia.
• On the other hand, a person suffering from shock will have a reduced heart rate and increased ventilation.
This means they will get a faster equilibration and induction of drug. If this is not taken into account, and
the person is given normal concentrations, cardiac depression may occur, resulting in heart failure.
• People who have some underlying lung condition, (V/Q mismatch and pulmonary shunt), will take longer to
reach equilibrium because some blood going to the lungs will be bypassing alveoli containing the drug.

Properties of inhalation anesthetics

Drug Blood:gas coefficient Time constant


(time to reach equilibrium)
N2O 0.47 1.2 min
Isoflurane 1.4 1.8
Enflurane 1.80 2.0
Halothane 2.30 3.1
Methoxyflurane 10.0 8.6
Diethyl ether 12 7.2

• The lower the solubility, the faster the onset and the faster the recoverability.

How doses are worked out


• The tension of the gas in the blood comes to equilibrium all at the same time, irrespective of the size of the
person.
• The concentration effect relationship is used to determine the MAC (minimum alveolar concentration) for
anesthesia.
• It is defined as the concentration of inhalation agent needed to cause 50% of the people to go to sleep.

Response
(No. of people
going to
sleep)

Concentration
MAC
• Practically, we do not give the exact MAC value, because we preferably want a better guarantee than 50%
that the patients will be anesthetised. In practice, we use a concentration that will cause around 85% of
people to go to sleep (20 – 30% of the MAC)
• The MAC value is an indication of the potency of an agent.
• It is inversely related to the lipid solubility.
• The higher the lipid solubility, the lower the MAC
• Typical MAC values are:
• Halothane 0.7% of 760mmHg
• Enflurane 1.7
• Isoflurane 1.2
• Sevoflurane 1.7
• Desflurane 6.0

• If the concentration given is too low:


1. Movement may occur Premedication of analgesic drugs and muscle
2. Reflex activity present (laryngeal spasm) relaxants are designed to minimise these effects
3. Hypertension
4. Awareness
By Duy Thai, 1997 Pharmacology Semester 1 page 5 of 5

• If the concentration given is too high:


1. Myocardial depression
2. Respiratory depression
3. Delayed recovery

Cardiovascular effects of inhalation anesthetics

Agent Effect on BP Effect on contractillity


In isolated heart tissue In vivo
N2O 0 ↓↓ 0
Halothane ↓ ↓↓↓ ↓
Methoxyflurane ↓ ↓↓↓ ↓
Enflurane ↓ ↓↓↓ ↓

• If the heart is depressed, the vasomotor center of the brain will respond to maintain blood pressure.
• However, if a person has some sort of heart disease, the vasomotor center will already be active
(there will already be some amount of vasoconstriction). If anesthetics are given to a person with
heart conditions, compensation will not be available, and so there is a marked drop in blood
pressure.
• The same is true for a patient in shock, whose vasomotor center will be active as well.

Respiratory effects
• All anesthetics cause depression of respiration, leading to an increased PACO2 EXCEPT nitrous oxide!
• In a normal person, when PACO2 is increased, there is a corresponding increase in minute ventilation.
• Howeveer, a person breathing halothane will have an alveolar CO2 level of 60 – 65 (normal 40 –
45) and very little increase in minute ventilation.
• After a while, the brain no longer responds to CO2 levels as a stimulus for breathing (which it
normally does). It is now dependent on oxygen. If something happens and there is no O2 in the gas
mixture, the person will die because they cannot respond.

Side effects of some specific inhalation agents


• Halothane
• Causes dose dependent hypotension, myocardial depression
• May cause arrhythmias
• Liver toxicity in some people
• Raised intracranial pressure
• Pollution
• Enflurane
• Less chance of arrhythmias
• Also causes dose dependent hypotension
• May cause convulsions
• May cause renal dysfunction

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