Inhalational Anaesthetic Agents

History

• Horace Wells administered N₂O for dental extraction in 1844.
• William Green Morton demonstrated the use of ether for surgical anesthesia on October 16, 1846, at MGH (Massachusetts General Hospital).
• A famous quote honoring the contributions of these pioneers:

  "Inventor and revealer of anesthetic inhalation before whom, in all time, surgery was agony, by whom pain in surgery was averted and annulled, since whom science has control of pain."

Volatile anaesthetic agents are substances whose vapours are administered by the inhalational route to produce anaesthesia.

Thus, nitrous oxide (N₂O), cyclopropane, being gases (and not vapours) are not considered as volatile anaesthetics. They are, however, inhalational anaesthetics.

Nitrous oxide, diethyl ether, and chloroform were almost simultaneously introduced into clinical practice.

N₂O was not potent enough, ether was flammable and highly soluble in blood and tissues, chloroform was toxic and soluble in blood and tissues.

Nitrous oxide and volatile anaesthetic agents are inhalational agents.

Ether, Chloroform, and Trichloroethylene are the early agents used but have been discontinued for various unfavorable effects.

Ether is explosive, chloroform damages the liver, and trichloroethylene is neurotoxic. Methoxyflurane has been discontinued because of nephrotoxicity.

Inhalational agents currently in use are halothane, enflurane, isoflurane, sevoflurane, and desflurane.

1. Causes rapid, smooth, pleasant induction, amnesia, and anaesthesia readily
2. Adequate muscular relaxation
3. Safe, potent, easily reversible. Absence of flammability, nonexplosive
4. Readily acceptable by the patient
5. Cheap, readily available
6. Easy to administer
7. Nontoxic, no side effects/complications
8. Safe for the vital organs like brain, heart, lungs, liver, and kidneys
9. Does not undergo metabolism in the body
10. Not toxic to theatre staff in low concentrations
11. Have some analgesia
12. No interaction with other drugs
13. Reversible non-stimulant CNS effect
14. Stable molecule
15. Non-sensitizing the heart to catecholamines

Desirable Features of Inhaled Anaesthetic Agents

1. Low blood-gas solubility. Insolubility causes quicker induction of anaesthesia and faster recovery from anaesthesia.
2. High potency and volatility.
3. Resistance to biotransformation.
4. Ether structure conveys cardiac stability.
5. Halogenation reduces flammability.
6. Compatible with adrenaline.

True Anaesthetic Gases

True anaesthetic gases, such as Nitrous oxide and Cyclopropane:

• Their saturated vapour pressure is above ambient pressure and exists as a liquid under pressure.

Other agents are volatile liquids with SVP below ambient pressure and these need special calibrated vaporisers.

The rate of uptake of inhalational anaesthetic agents in the brain depends on several factors:

• The alveolar partial pressure, which determines the partial pressure of anaesthetic in the blood and ultimately in the brain.
• The partial pressure of the anaesthetic in the brain is directly proportional to its brain tissue concentration, which determines the clinical effects.

The uptake of anaesthetics depends on:

1. Solubility in the blood: The higher the blood/gas coefficient, the greater the solubility, and the greater the uptake by the pulmonary circulation. Alveolar partial pressure rises more slowly, leading to slow induction.
2. Alveolar blood flow, which is essentially equal to cardiac output.
3. Increased fresh gas flow.
4. Tissue/blood partition coefficient: The partial pressure difference between alveoli gas and venous blood is dependent on tissue uptake.
5. Inspired concentration.
6. Second gas effect: When nitrous oxide is administered with a volatile anaesthetic agent, rapid uptake of nitrous oxide increases the effective minute ventilation during induction. Uptake of N2O from the alveoli decreases the volume of gas remaining in the alveoli and increases the concentration of remaining gases within the alveoli, enhancing induction.

• Recovery from anaesthesia depends on lowering anaesthetic concentration in brain tissue.
• Anaesthetic agents are eliminated via the lungs, and only a very small percentage is metabolized.
• Recovery is slower with inhalational anaesthetic agents as fatty tissues of the body get saturated.
• Nitrous oxide elimination is so rapid that it dilutes alveolar oxygen and CO2, producing diffusion hypoxia. This can be prevented by giving 100% oxygen 3-5 minutes after discontinuing N2O.

Factors that increase the rate of recovery:

1. Increase in fresh gas flow.
2. Increased alveolar ventilation.
3. Lower blood-gas solubility.
4. Low tissue gas solubility.
5. Decreased anaesthetic duration.

MAC is a standard measure of the potency of inhaled anaesthetics. It represents the partial pressure of an inhaled anaesthetic at 1 atmosphere that prevents movement in 50% of subjects in response to a painful stimulus like surgical incision.

The agent with the minimum MAC will be the most potent and is used as a measure of potency for inhaled anaesthetics.

MAC values for inhaled anaesthetics are additive; for example, 1% N2O decreases MAC by 1%.

	MAC	BP(°C)	VP(20°C)
Halothane	0.77	50.2	241 mmHg
Enflurane	1.7	56.2	175 mmHg
Isoflurane	1.15	48.5	238 mmHg
Desflurane	6.0	23	664 mmHg
N20	104
Xenon	71

Factors Affecting Minimum Alveolar Concentration (MAC)

Factors that increase MAC:

1. Young age
2. Hyperpyrexia
3. Alcoholics
4. Infants
5. Hypernatraemia
6. CNS stimulants e.g., cocaine

Factors that decrease MAC:

1. Hypothermia
2. IV anaesthetics
3. Premedicants
4. Neonates
5. Elderly
6. Pregnancy
7. Lithium
8. CNS depressants e.g., benzodiazepines

Factors that do not affect MAC:

1. Sex
2. Duration of anaesthesia
3. Metabolism of anaesthetics
4. Hyper/hypokalemia
5. Thyroid dysfunction

• Non irritant sweet smelling gas supplied in blue color coded cylinders.
• First anaesthetic use in 1844.
• Low blood gas solubility.
• Smooth and rapid induction of anaesthesia.
• Weak anaesthetic agent.
• Excellent analgesia.
• Nitrous oxide 50% in oxygen is used for painless labour.
• Causes mild depression of CVS (Cardiovascular System).
• May cause megaloblastic changes in the bone marrow in prolonged use.
• Prolonged use may cause diffusion into the body cavity.
• Diffusion hypoxia.

Entonox

1. A mixture of 50% nitrous oxide in oxygen.
2. Stored in gas cylinders whose body is blue and shoulder in white.
3. Under pressure, some parts of the mixture may remain in gaseous phase at temperature and pressure which N2O is normally in liquid phase.
4. It is stored horizontally at 10 degrees C.
5. It liquefies at -7 degrees C.
6. In cold climate, there may be liquefaction and separation of components. This may lead to uneven delivery of gases.
7. Uses: for pain relief in labour, burn dressing.

• Volatile anaesthetic agents are mostly divided into two groups:
• Halogenated hydrocarbons:
  • Halothene
  • Triclorethylene
  • Chloroform
• Ethers:
  • Enflurane
  • Isoflurane
  • Methoxyflurane
  • Diethyl ether
  • And more

NOTE:

1. Hepatotoxic volatile anaesthetics: halothane, chloroform
2. Nephrotoxic volatile anaesthetics: methoxyflurane, sevoflurane
3. Epileptogenic: enflurane
4. Inflammable: diethyl ether, cyclopropane

Diethyl Ether

• It is cheap and safe.
• It is colorless, has a strong smell, and is a very volatile liquid.
• Boiling point: 35.5 degrees C
• Saturated vapor pressure: 442 mmHg at 20 degrees C
• Large concentrations can be delivered.
• Heavier than air with a specific gravity of 2.6.
• MAC (Minimum Alveolar Concentration): 3%
• It is inflammable and explosive in the presence of oxygen and should be avoided when diathermy is in use.
• Unstable and decomposes with exposure to light and heat. Decomposition products include ester peroxides and aldehydes, which reduce its potency.
• Induction with ether is slow and can be turbulent. Patients may cough, hold their breath, or go into laryngeal spasm.
• Deep ether anesthesia depresses the fetus and causes uterine relaxation.
• Depletes liver glycogen, raises blood sugar, and may result in ketone bodies in the urine, so it should be avoided in diabetics.
• Diethyl ether may be used in various methods: open-drop method, EMO machine, semi-closed, and closed systems.

Halothane

• Introduced into medical practice in 1957.
• A halogenated hydrocarbon (not an ether as it lacks an etheric bond).
• Heavy, colorless, volatile liquid with a sweet smell. Requires thymol for stability.
• Potent and nonflammable.
• Boiling point: 50 degrees C.
• Saturated vapor pressure (STP): 242 mmHg at 20 degrees C.
• Well-tolerated and provides rapid and smooth induction of anesthesia.
• Causes a dose-related fall in blood pressure, myocardial depression, and sensitizes the heart to circulating catecholamines, leading to arrhythmias.
• Has the capacity to provide muscle relaxation in clinical concentrations.
• Potentiates competitive muscle relaxants.
• May lead to post-operative shivering.
• Causes bronchodilation.
• May cause hypotension.
• May trigger malignant hyperthermia.
• May be associated with nonspecific hepatotoxic damage.
• May cause uterine relaxation, leading to postpartum hemorrhage.

Enflurane

• Potent volatile anaesthetic liquid.
• Clear, colorless, and has a pleasant smell.
• Noninflammable, nonexplosive, and noncorrosive.
• Produces rapid and smooth induction of anesthesia.
• Depresses cardiovascular (CVS) and respiratory systems.
• Depresses the central nervous system (CNS), increases intracranial pressure (ICP), and cerebral blood flow.
• Only about 2% undergoes biotransformation in the liver, and metabolites are excreted in urine.
• Little risk of teratogenesis.

Isoflurane

• An isomer of enflurane, clear colorless volatile liquid.
• Nonflammable.
• Low blood gas coefficient. Induction and recovery mostly rapid.
• Somewhat pungent and irritant, causes coughing.
• Depresses cardiovascular (CVS) and respiratory systems.
• Decreases cerebral metabolism and increases cerebral blood flow. Intracranial pressure (ICP) may rise. Does not cause seizure activity.
• Only 0.2% is metabolized in the liver, no significant toxic metabolites are formed.
• Potentiates muscle relaxation.

Desflurane

• Fluorinated ether, potent volatile anaesthetic liquid.
• Induction is rapid, recovery is prompt.
• Pungent and irritant to the airway; breath-holding and laryngospasm can occur.
• Dose-dependent fall in blood pressure, respiratory depression.
• Metabolism to trifluoroacetic acid and inorganic fluoride is about 10 times less than that of isoflurane.
• It has a boiling point of 23.5 degrees C.
• This low boiling point precludes delivery by a standard vaporizer. The vaporizers are electrically heated and pressurized.
• Major drawback is that a special handling vaporizer makes it expensive.

Sevoflurane

• Fluorinated methyl ether.
• Potent anaesthetic.
• Nonirritant to the airway.
• Causes CVS and respiratory system depression.
• Induction is rapid, and recovery is prompt.
• Does not sensitize the myocardium to catecholamines.
• Instability in soda (compound A).
• It undergoes oxidative metabolism in the liver, producing fluoride ions.

The role of inhalational anaesthetic drugs in current anaesthetic practice is changing.

The introduction of potent intravenous agents and infusion techniques have decreased the need for high doses of inhalational agents.

There has been some approximations towards an ideal agent.

The ideal volatile anaesthetic agent is still elusive.

The search still continues.