Drugs in anaesthesia

Clinical pharmacology has long been the basis of anaesthetic practice and we rely on a library of drugs with which we are familiar and whose deficiencies and unwanted effects we understand. In most, but not all, cases our practice is underpinned by understanding the mechanisms of drug action, distribution and elimination. The last 30 years have seen a flurry of anaesthetic drug discovery and development, giving us an effective portfolio of compounds which are mostly off-patent and therefore available as cheaper generic formulations. This article reviews the modern anaesthetist's therapeutic portfolio with emphasis on recent and future developments. The pharmaceutical industry is in rapid retreat from anaesthesia as evidenced by decreased numbers of drug-related trade stands at congresses, rare sightings of reps in anaesthetic department offices and a reduced flow of mugs, postit notes, free pens and food! This disengagement of industry reflects an anaesthesia market which is stable in total value, in contrast to other therapeutic areas including cancer, cardiovascular and neurological medicines, which are growing strongly. None of the UK's top 30 medicines (by sales value) is used in anaesthesia. Our practice is dominated by well understood safe and effective drugs provided at reduced cost by generic manufacturers. This makes anaesthetic drug development an unattractive target as new compounds must compete with relatively satisfactory established products sold at generic prices. On a positive note, development costs of anaesthetic drugs are (relatively) low in comparison with other therapeutic sectors. Clinical trials in anaesthesia can be completed, for each patient, within hours or days; contrast this to oncology where a patient's participation in a clinical trial may last for several years. Current targets for anaesthesia drug development are primarily in analgesia and critical care medicine, where our portfolio is weakest and the commercial opportunities therefore greatest. A final confounder is the impact of the human-genome project and related sequencing activities. An excellent example is analgesia, where there are close to 20 definable receptor targets that lend themselves to drug discovery projects. However, patenting activity by individual companies has already exerted a substantial inhibitory effect on drug development. A typical modern receptor based development project involves expressing cloned receptors in an experimental system such as Xenopus oocytes (the eggs of the clawed-toed toad) or stable cell lines in culture. Where a single company has patented the genetic sequences describing a human receptor, competitor companies can only experiment in that area by expressing the different animal variants of the same receptor in their cell systems. This forces them to conduct their research against a proxy target (the animal receptor) rather than the real thing (the cloned human receptor) and renders the entire project unattractive. It is hard to see how it is in mankind's interest that private companies that are willing to speculatively invest in research against a receptor target are driven away from the investment by a rival's genetic patents. Clearly, intellectual property is a cornerstone of the pharmaceutical industry as it allows speculative investment against potential future profits. Logically, such intellectual property should cover molecules, developmental processes and possibly laboratory techniques but it is hard to understand how patients are served by speculative patenting of genetic sequences that reduces developmental competition. Special groups of patients have frequently been ignored in drug development, with early studies sometimes focussing on young adult males. Typically, females of child-bearing age, and the elderly and frail were only included in the later stages of a trial programme and dosing recommendations frequently required revision. Recently, there has been a shift in regulatory position and manufacturers are more likely to design trials addressing the needs of subgroups but much remains to be done. Papers continue to describe meaningful differences between male and female patients yet as clinicians we seem strangely uninterested [1]. Development projects must be more inclusive and resist the temptation to develop a one-size-fits-all set of dosing recommendations. Worldwide, most anaesthetics involve an inhaled anaesthetic agent. Despite 20 years of intravenous anaesthesia and compelling evidence of reduced postoperative nausea and vomiting with IV techniques, it seems clear that anaesthetists will not give up their vaporisers in the foreseeable future. Faced with the capital and maintenance costs of a broad array of vaporisers and limited use, halothane seems destined for the history books, at least in the West. Many departments have already withdrawn the drug from service and most trainees have never used it. Halothane isn't necessary for any clinical scenario including remote ones and both the armed forces and the British Antarctic Survey now provide isoflurane for their doctors to give simple anaesthetics in remote situations. Nevertheless, halothane is cheap and is the mainstay of global anaesthesia. As its manufacturing process is significantly simpler (and therefore cheaper than that for isoflurane), it is likely that the latter will remain an expensive luxury in most Third World countries. I worked for ICI Pharmaceuticals in the late 1980s when trichloroethylene (Trilene) was withdrawn and was tasked to answer frustrated and, in some cases, angry letters from around the world where clinicians resented the disappearance of a drug with which they felt comfortable and whose use was part of their daily practice. Any formal withdrawal of halothane would undoubtedly lead to similar protests so I predict that it will stay on the UK formulary as a ghostly presence even though nobody uses it! Of the other vapours, enflurane has almost disappeared except for some cardiothoracic enthusiasts and we are left with a three-way battle between generic isoflurane and more expensive sevoflurane and desflurane. Against the protestations of Professor Eger and others [2–4], sevoflurane has been a tremendous clinical and commercial success despite compounds A−F and some hotly contested animal data describing renal injury. Vast clinical experience now suggests sevoflurane to be a safe and useful agent. Desflurane, whose metabolic profile is superior, has been much less successful. Its high price and physical characteristics demanding a special vaporiser has confined it to a much smaller practice and, although it will remain with us, widespread adoption seems unlikely. Propofol remains the mainstay of anaesthetic induction and is successfully established for anaesthetic maintenance and sedation. The expiry of key patents leaves us with generic propofol (and a debate about preservatives and their possible side-effects [5]) and a small swarm of derivative projects. In addition to the original emulsion preparation (by original I am dismissing the original, original Cremofor formulation), we now have propofol in medium chain triglycerides [6], and the prospect of a water soluble pro-drug [7]. Currently, none of these appear to offer substantial benefits over the original. Novel water soluble intravenous agents have been developed and abandoned [8,9] and although such projects are neither intellectually nor pharmacology exhausted, they have become commercially unattractive given the presence of generic propofol. The fentanyl series appears maximally exploited. The most recent arrival, remifentanil, is currently expensive but has established itself in neuroanaesthesia and increasingly in other areas. Remifentanil ICU sedation was originally described as an off-licence clinical intervention performed without ethical approval, patient consent or a Doctors and Dentists Exemption Certificate (DDX) [10]. It has subsequently been developed and is now a licensed indication but remains extraordinarily expensive. Other compounds are in development for acute and neuropathic pain and this area is described in detail in a separate article by David Rowbotham in this edition of the journal. One therapeutic area that may see some development activity is that of sedation and analgesia. Anaesthetists have long been troubled by disasters typically caused by non-anaesthetists inadvertently inducing anaesthesia and then being unable to manage the consequences. Constructive engagements with colleagues in dentistry, radiology and surgery have substantially improved patient safety and provided various training schemes and guidelines. Nevertheless, the pharmacology of current compounds still works against us. Most procedures performed by interventional radiologists and many minor surgical procedures are intrinsically painful and sedation with incremental midalozam is clinically unsatisfactory. What is required is an analgesic and it is the potent opioid/benzodiazepine interaction which gets non-anaesthetists into trouble. We know that single compounds can provide both sedation and analgesia (think of ketamine) but none are currently right for the task. Some new analgesics appear to have sedative effects and may find application in this therapeutic area. The failure of rapacuronium has postponed the emergence of a succinylcholine alternative but development in this area is not exhausted. The Hungarian chemist, Laszlo Gyermek, described a new series of neuromuscular blockers with rapid onset [11]; however, their development has recently been discontinued as the compounds appeared to be toxic. A major innovation, the reversal of rocuronium neuromuscular block by chelation with a cyclodextrin, is in development and offers exciting clinical prospects [12]. If the drug works (and so far it seems that it does) and survives the development programme, then we could maintain intense paralysis throughout the procedure and completely reverse it after the last skin stitch. Other opportunities exist for new drugs to block neuromuscular transmission but their development remains shadowy and uncertain. Most doctors don't understand pharmaceutics. It isn't enough for a new drug to be discovered, it has to be manufactured at high purity in a reproducible manner for a manageable cost. In addition, the regulatory authorities now take a dim view of racemic mixtures, so any optical isomers must be presented separately, often at great additional cost. As clinicians, we require injectable drugs to be stable, preferably in aqueous solution at an acceptable pH. If they must be presented as a powder, then it has to dissolve quickly and conveniently. Regulators won't approve drugs with a shelf-life of less than 2 years and given the additional requirements of countries where drugs may be transported or stored at higher temperatures, a longer shelf-life is commercially attractive. Pharmaceutical considerations therefore influence all drug development programmes and it is surprising how often an attractive compound cannot be progressed because it is either unstable in solution or unaffordably expensive to manufacture. In anaesthesia we have seen pharmaceutical and engineering innovation combined in Target Controlled Infusion (TCI) of propofol which remains popular in Europe but has not been licensed in the United States. Hopes that TCI and prefilled syringes could extend to other drugs in other areas have not been realised. TCI remifentanil has seen some development, although clinicians (including myself) will need some convincing as the drug is simple to use by conventional bolus and infusion techniques. The technology exists to present intensivists with a comprehensive range of prefilled and chipped syringes which could be placed in an infusion pump by nursing staff. One could imagine a range of inotropes, opioids and other medicines for the critically ill presented in this way to the great advantage of ICU staff, whose time in drug preparation could be greatly reduced, and patients, who would benefit from an improved safety environment. In practice, this is never going to happen as the key drugs are almost entirely generic formulations and it is unclear how the development costs could be resourced. Hard pressed healthcare systems will be reluctant to pay a premium price for a prefilled syringe and the associated delivery system. In this way, innovation is sometimes stifled by market forces. This is another key area for therapeutic drug development and is described by Saxon Ridley in a separate article in this edition of the journal. Drug development in anaesthesia is not dead but it certainly isn't alive and well. The prospects for the future are only moderately enticing, with the bulk of development activity (and therefore money) directed towards chronic pain and critical care medicine. Technological innovations will be limited by the generic nature of most existing compounds and relatively high levels of satisfaction amongst existing users.