The "ideal" sedative or anaesthetic agent

This chapter is relevant to the aims of Section K2(i) from the 2023 CICM Primary Syllabus, which expects the exam candidate to demonstrate an understanding of the pharmacology of sedating drugs". Specifically, this brief entry explores the properties of the "ideal" anaesthetic/sedative agent, as explored by the college in Question 10 from the second paper of 2008 and in Question 24 from the first paper of 2016. There, the candidates had been asked to compare this mythical agent to propofol and midazolam. Interestingly, 60% of them passed this question; and the majority knew this imaginary anaesthetic in such detail that their knowledge of midazolam itself was actually less precise by comparison. 

In summary:

Chemistry Ideal anaesthetic agent
Pharmaceutics Should be water soluble
Should be stable chemically
Should be chemically inert and non-interactive with circuits or giving sets
Routes of administration Multiple routes of administration should be available
Absorption Should be well absorbed orally, or from the lung (if inhaled)
Solubility Should be soluble in water, so that it may present as an aqueous solution without excipients
Distribution Should not be protein-bound (as this decreases availability).
Should not accumulate with sustained use (eg. through compartment distribution)
Target receptor Molecular targets should be specific to produce sedation and anaesthesia with no other effects
Metabolism Should undergo no metabolism, or be metabolised without reliance on any specific organ system.
There should be no active metabolites.
Elimination Should be cleared without delay 
Time course of action Should have a rapid onset of effect, as well as offset of effect. 
Should have minimal half-life.
Mechanism of action Propofol binds to the β-subunit of the postsynaptic GABAA receptor, where it causes an inward directed chloride current that hyperpolarizes the postsynaptic membrane and inhibits neuronal depolarisation.
Clinical effects There should be ONLY an anaesthetic effect, and no other effects.
The drug should not produce any change in the patient's cardiovascular or respiratory performance.
There should be no withdrawal or rebound effects.
There should be minimal interindividual variation in dose requirements.
 
Single best reference for further information Dundee (1980)

So, where does this concept come from, and why do we need it? Other medical disciplines don't seem to have a lot of literature dedicated to the properties of substances that don't actually exist. For example, you don't see cardiology journals lamenting an unfavourable comparison between available drugs and the ideal statin or the ideal antiplatelet agent. Clearly there is something about anaesthesia that calls for this sort of thing. The history of it spans decades, perhaps even centuries- for example, in 1935 (back when anaesthetic was spelled with an æ ), William N. Kemp was writing this for the BJA:

"Almost from the time when the anaesthetic properties of "sulphuric ether" were first put to such humanitarian and practical use by Dr. Long in Kentucky, physicians and surgeons have looked forward to the discovery or creation of the ideal general anesthetic....  The general opinion seems to be that in the future some super-chemist will create or discover some substance which will with entire satisfaction meet all of the postulated demands of our ideal anaesthetic." 

This wish probably stemmed from the fact that,  in Kemp's day, the routinely used anaesthetic agents were far from ideal, and would in fact be viewed as toxic and uncontrollable by today's standards. The standards may have shifted over the years (they were much lower- Kemp's paper goes on to extoll the virtues of ether as a nearly ideal agent), but the list of desirable characteristics has only increased in size. Other similar papers discuss the "idealness" of xenon (Bein et al, 2007) and propofol (Dundee, 1980). Panani et al (2018) brings this up in a broader sense, like "don't you wish our agents had some of these desirable characteristics". In short, this trope has longevity, and it has made its way into the CICM exams, which means there's a pragmatic reason to learn about it. In the interest of simplifying a chapter which was supposed to be just a list of criteria, the properties of the ideal intravenous agent are the main focus (because ICU), with a few gas properties randomly thrown in. 

Pharmaceutical properties of the ideal anaesthetic agent

  • It should be water soluble.  Because it is inconvenient to solubilise it by presenting it with eggy emulsions or weird pH buffers, and in any case to add excipients would be to deviate from "idealness" because any extra chemicals in the ampoule add further risk of adverse reactions like anaphylaxis. Ergo, the ideal anaesthetic would ideally require no additional carrier, and would dissolve happily in water. Which means this ideal characteristic directly contradicts one of its ideal pharmacokinetic properties (that it should be sufficiently lipid-soluble to cross the blood-brain barrier). There are some sedating substances that are amphoteric (relatively good water and lipid solubility), but those are their only ideal qualities - we are really mainly talking about ethyl alcohol.
  • It should be chemically stable. The discussion of this desirable property probably does not need to be overcooked, as it seems like a basic requirement for any substance you plan to use routinely in the hospital setting. At minimum, the ideal anaesthetic should at least last the duration of a single dose being given as an infusion, eg. for 24 hours hanging up on a drip stand at room temperature.  However, this criterion does not appear essential, and we do have a history of using anaesthetics like ether and cyclopropane which would just explode randomly in the operating theatre, which did nothing to diminish their popularity for many years. 
  • It should be available in the concentration required for both induction and infusion, which minimises drug errors in dilution
  • It should be chemically inert, in the sense that it should not react violently with the administration set, the anaesthetic vapouriser, the patient's mucous membranes or the insides of their veins. Strict reading of this requirement would only qualify xenon as an ideal agent, but in reality most modern anaesthetics are capable of remaining civil under normal operating temperature and pressure, which is good, because modern polyvinyl or polyethylene circuit components are rather more fragile than their old hardcore rubber counterparts. Ether and chloroform are potent organic solvents and would rapidly dissolve their way out of a modern ventilator tube. 

Pharmacokinetic properties of the ideal anaesthetic agent

  • It should be available by a variety of routes. Ketamine and midazolam are famously available through a variety of routes, making their use much more convenient. With propofol and the volatile anaesthetics, you are really limited in how you can deliver them. Though this characteristic appears in many lists of "ideal" anaesthetic properties, the convenience of administering your anaesthetic in a million different ways is probably not very important, as any environment properly designed for the safe administration of sedation will come equipped with plentiful facilities for IV access and artificial ventilation.
  • It should have a rapid onset. There are a large number of drugs which do this, mainly ones with high lipid solubility. For example, propofol and thiopentone feature onset within a single arm-brain circulation time.
  • It should have a rapid offset. The fat solubility of most modern agents makes them "ideal" in this sense, as they rapidly distribute into the fatty tissues and virtually disappear from the circulating compartment, leaving their effect site. 
  • It should not accumulate with sustained use. Apart from anaesthetic gases, there are few agents which can claim this as a property. Remifentanil and remimazolam are probably the only IV agents currently which can genuinely claim to have no context-sensitive half time with prolonged infusion. 
  • It should not have active metabolites. For the majority of anaesthetic and sedative agents, the drug either undergoes no metabolism (eg. nitrous oxide) or is metabolised into harmless breakdown products (propofol). Midazolam and other benzodiazepines tend to have long-lived and fully or partially active metabolites, making them less ideal.
  • It should be cleared without delay and without reliance on any specific organ system. The clearance of an anaesthetic agent should be independent of organ function in order for it to be attractive to the intensivist, as many of our patients have very marginal organ function. Volatile agents are probably the best examples of this, as they are cleared rapidly through the respiratory tract. 

Pharmacodynamic properties of the ideal anaesthetic agent

  • It should only have an anaesthetic effect.  All agents fail this test, as all agents have some circulatory effects, even if they are exerted by means of depressing sympathetic activity in the course of generalised neurological depression. 
  • There should be minimal interindividual variation in dose. You should have some predictability in the per-kilogram dosing of your agent. This is probably most true for ketamine, and least true for benzodiazepines, though the author has no scientific evidence to support those statements beyond personal anecdote. 
  • It should not have a withdrawal or rebound phenomenon. Upon ceasing the drug, there should be no adverse consequence. This characteristic may actually contradict some of the pharmacokinetic characteristics listed above. A sustained infusion of the agent may result in some pharmacodynamic remodelling, such as the reduction or increase in receptors which is seen in drug tolerance. For an agent which rapidly and completely disappears from the circulation when the infusion is turned off, the sudden loss of effect could be disastrous. The long washout of drugs like midazolam and morphine may actually be protective against withdrawal when the drug is abruptly ceased.

References

Kemp, W. N. "The Ideal General Anaesthetic." BJA: British Journal of Anaesthesia 12.3 (1935): 99-105.

Bein, Berthold, Jan Höcker, and Jens Scholz. "Xenon--the ideal anaesthetic agent?." Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie: AINS 42.11 (2007): 784-791.

Dundee, John. "THE IDEAL INTRAVENOUS ANAESTHETIC.г CLINICAL EVALUATION OF PROPOFOL (1980): 3.

Panahi, Yunes, et al. "Analgesic and sedative agents used in the intensive care unit: A review." Journal of cellular biochemistry 119.11 (2018): 8684-8693.

Keenan, Richard L. "The hazard of cyclopropane explosion." Archives of Surgery 105.5 (1972): 802-802.