Inhalational Anaesthetics

General anaesthetics refer to the diverse group of drugs that are capable of producing total insensibility to external stimuli in a reversible manner.¹
A subgroup of these drugs is the inhaled anaesthetics, which broadly fall into two categories: volatile liquid anaesthetics and gaseous anaesthetics. Both of these can be used for induction and maintenance of anaesthesia but may also be used following induction with intravenous anaesthetics. Their potency is expressed in terms of the minimum alveolar concentration (MAC), which is the concentration required to abolish the response of 50% of subjects to a noxious stimulus (such as a skin incision); about 1.5 times the MAC generally has the same effect in 95% of subjects.² Although this is of limited clinical use, it acts as a baseline from which a number of other values are derived (such as the MAC-awake: the dose required to prevent response to a verbal command).³

MAC values are subject to change depending on a number of factors including age, body temperature, blood pressure, thyroid status, anaemia, pregnancy, blood sodium and carbon dioxide concentrations and the presence of CNS-influencing drugs (alcohol, opioids, lithium etc).⁴

Mode of action⁵

There is no single effect exerted by these drugs as they have no common chemical structure. They work at the level of the central nervous system in a number of different ways via direct action on the neuronal plasma membrane:

• Interfering with neurotransmitter release at the synapse
• Altering neurotransmitter uptake
• Changing the binding of neurotransmitter with receptors
• Influencing the ionic conduction changes following post-synaptic receptor activation

Uptake: induction⁶

Administration is via the lungs with the aim to achieve suitable tissue concentrations. The gas transfer from source in the vaporiser machine to tissue depends on it travelling down a series of concentration gradients. These can be influenced by any of the structures (external to the patient, such as dissolving in the rubber of certain breathing systems,¹ as well as within the patient) involved along this pathway, notably at the level of the rate of entry into the circulation and the blood supply of the tissue. (Interestingly, a higher cardiac output prolongs induction time as more anaesthetic is removed from the alveoli, so increasing the time it takes for the gas to reach equilibrium across the blood-brain barrier). The tissue affinity for the anaesthetic is the final rate-limiting step in this process.

Metabolism⁷

Most of the anaesthetic is exhaled although a small amount is metabolised in the liver and kidneys.

Excretion: recovery³

Recovery is not as clear-cut as induction. It is related to the mass of anaesthetic present in body tissues: different degrees of lipid solubility of different agents gives rise to greater or lesser residual stores of the agent which are dissipated according to the blood supplies of the tissue involved. This phenomenon accounts for the variety in recovery post general anaesthesia.

• CNS - paralysis commences at the cortical level and descends from there. The thalamus is the most affected structure. The safety margin of an anaesthetic is the difference between concentration required to cause medullary paralysis and that high enough to cause cardiac arrest.
• Autonomic system - there is stimulation then suppression of both sympathetic and parasympathetic functions. Different drugs suppress each system to different degrees. The nausea and vomiting associated with recovery relates more to autonomic function than to direct effect on the gastrointestinal system itself.
• Cardiovascular system - there is an initial increase in heart rate (accentuated by sympathetic overactivity) followed by depression and a decrease in cardiac output (can be down to 3 L/min or less). Blood pressure remains fairly even (hypotension is often a sign of hypovolaemia).
• Respiratory system - depression of medullary respiratory centre causes respiratory depression. Some degree of hypoxaemia may persist for hours or days after surgery.
• Metabolism - this is depressed.
• Temperature - hypothalamic regulation of body temperature is lost and therefore the body is subject to environmental changes.
• Renal function - there is a reduction in renal blood flow and glomerular filtration rates. The retention of water and sodium relates more to the pituitary and adrenocortical systems rather than the kidneys.
• Hepatic function - it is generally unaffected although hypoxia and hypotension exacerbate pre-existing liver disease.
• Voluntary muscle - relaxation occurs.

Halothane⁸

• Advantages - this is a potent drug providing smooth induction and is non-irritant with a pleasant smelling vapour.
• Drawbacks - hepatotoxicity in about 1:10,000 anaesthetics: mild (type 1) is a relatively common, benign self-limiting condition. Type 2 (fulminant) is severe and more likely to occur after repeated exposures (even years apart). The latter is thought to occur in genetically predisposed individuals but CSM guidance suggests avoidance in patients with a previous history of induction with halothane, repeated exposure within 3 months and a previous history of unexplained jaundice or pyrexia following general anaesthesia. Other side effects include cardiorespiratory depression, cardiac arrhythmias (especially with concurrent use of adrenaline) and it is a potent trigger for malignant hyperthermia which occurs in ~ 1:200,000 general anaesthetics without succinyl choline and 1:50,000 general anaesthetics with succinylcholine.⁹ Shivering and tremor are common post-operatively ('halothane shakes').²
• Cautions - hepatic impairment, renal impairment, pregnant and breast-feeding patients, children less than 18 years old.

Isoflurane¹⁰

• Advantages - there is less risk of arrhythmias and it allows good muscle relaxation.
• Drawbacks - it is less potent than halothane, very irritant to respiratory tract, can trigger malignant hyperthermia and there have been isolated reports of hepatotoxicity (especially in patients sensitised to halothane).
• Cautions - pregnancy; isoflurane is particularly prone to drug interactions.

Desflurane^11,12

• Advantages - it enables rapid induction. The risk of hepatotoxicity very low, even in patients with a previous history of this. Furthermore, it does not sensitise myocardium to circulating catecholamines. Rapidly eliminated. Safe to use in patients with renal impairment.
• Drawbacks - breath-holding, cough, laryngospasm and it can trigger malignant hyperthermia.
• Cautions - not to be used in children and in neurosurgical patients.

Sevoflurane¹³

• Advantages - it is a rapid-acting, non-irritant anaesthetic of pleasant odour, suitable for induction in adults and children.
• Drawbacks - emergence is also rapid and therefore patients need early pain relief. Can interact with CO₂ absorbents to form the nephrotoxic Compound A. Agitation frequently occurs in children and it is a trigger agent for malignant hyperthermia.
• Cautions - renal impairment and pregnancy.

Enflurane¹⁴

• Advantages - this is a sweet smelling, non-irritant induction agent.
• Drawbacks - it is unstable in the presence of light and a trigger agent for malignant hyperthermia. There are isolated reports of hepatotoxicity and a theoretical risk of fluoride ion toxicity in renal failure. May cause myocardial dysrhythmias.

Nitrous oxide¹⁵

• Use - widely used in all forms of surgery with more powerful volatile agents.¹ In sub-anaesthetic concentrations, mixed with an equal amount of oxygen (entonox) it is used for analgesia in minor procedures, changing painful dressings and in obstetric practice during uncomplicated labour.
• Advantages - allows reduction of dosage required of more potent agents when used in combination with these. The entonox mixture is easy to use and wears off rapidly.
• Drawbacks - hypoxia is the most common problem. When there are prolonged periods of exposure, megaloblastic anaemia and white cell synthesis are also hazards.
• Cautions - this gas can be dangerous in patients with pneumothorax, pneumopericardium and pneumoperitoneum, where the gases contained can expand so aggravating the pre-existing condition. A gas filled obstructed intestine will also expand.

Xenon¹⁶

This is one of the noble gases which appears to have all the hallmarks of the perfect anaesthetic gas: it is inert, non-toxic (although its compounds are highly toxic on account of their strong oxidising properties), it is more potent than nitrous oxide and it allows rapid induction into and emergence from anaesthesia. Furthermore, it does not undergo biotransformation and has markedly fewer adverse effects on the different body systems. It is also not a trigger for malignant hyperthermia. The rate-limiting factor in its everyday use is its price.