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| The UK Society for Intravenous Anaesthesia |
| Based in the UK - as a resource for Anaesthesia Worldwide |
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Annual Scientific Meeting, Belfast; November 2000. Developing new intravenous anaesthetic agents J R Sneyd Derriford Hospital, Plymouth, PL6 8DHPropofol was developed to address limitations in existing agents. Methohexitone had short onset and offset but caused excitation and thiopentone is cumulative, insoluble in water and can cause serious problems when injected out with a vessel. Propofol is now the "gold standard" for intravenous induction and maintenance of anaesthesia but scope exists for further improvements (Table 1).
Table 1. Limitations of propofol, and opportunities for improvement?
Etomidate Etomidate has found support because of haemodynamic stability and its suitability for maintenance of anaesthesia by infusion but it causes excitation and when used for longer periods, profoundly depresses adreno-cortical function causing excess deaths when used as an intensive care sedative.
Althesin Althesin was a satisfactory agent but limitations of its solvent were never resolved and successive results to identify an alternative solvent have been fruitless.
Eltanolone Eltanolone (formerly pregnanolone) underwent a lengthy development period and seemed an attractive agent but was eventually withdrawn because of cutaneous reactions. PK/PD studies were only carried out at a late stage filament and these eventually revealed that slow onset/offset and a tendency to accumulation would have made eltanenolone an unsuitable agent for IV maintenance of anaesthesia.
How are we to identify and select new candidate IV agents? One approach is to determine the ability of novel agents to modify the activity of extrinsically applied GABA to GABA activated chloride channels. This approach has been extensively developed by Lambert in Dundee where human GABA receptors are expressed on the surface of frog eggs and the activity of extrinsically applied agents can be determined using patch-clamping.
Animal Studies Traditionally, new agents are first tested in a small number of mice (6 - 8) and if hypnotic/anaesthetic activity is found then additional investigations determine the ED50. LD50 determinations are no longer required by regulatory bodies. Subsequent experiments take place in rats and this extends the dose range as well as confirming activity in a second mammalian species.
Relating Effects in Animals to Those in Man There is no simple scale whereby anaesthetic effects in animals can readily be extrapolated to humans. Glen developed a useful small animal model by repeatedly dosing mice with an anaesthetic dose of thiopentone or propofol and re-dosing each animal shortly after recovery from the previous one. This clearly demonstrated the strongly cumulative effects of thiopentone whilst illustrating the suitability of propofol for maintenance by infusion. Historically, the CNS effect of IV agents in animals is measured by sleep time and this, whilst satisfactory, is an inadequate measure for the graded response to which clinicians are accustomed. We developed a chronic rat model in which implanted extradural electrodes are implanted at craniotomy and are subsequently available by an external connector for experimental recordings. EEG effect is quantified as burst suppression ratio determined in real time on-line by custom software. When bolus injections of an hypnotic agent are given, their effect can be quantified as onset time, peak burst suppression ratio and various recovery times. Subsequently, we reported prolonged maintenance of IV anaesthesia using a closed-loop feedback algorithm to maintain a fixed burst suppression ratio in rats for 1hr periods. Changes in infusion rate required to maintain the burst suppression ratio indicate possible accumulation of the candidate agent. Recovery was quantified by the disappearance of burst suppression after the IV infusion was stopped. Prior to human administration, toxicology experiments are mandatory. Whilst some toxicology protocols are common to all new drugs, others must be specially developed to reflect the compound being tested. IV anaesthetic agents and opioids are problematic for long-term toxicology experiments as chronic or repeated high-dose illustration might cause adverse effects unrelated to the basic pharmacology of the drug.
Testing New Drugs in Humans We evaluated ORG21465 in man by short (1 minute) infusions. Historically, such initial experiments would be followed by a fixed rate infusion or by repeated bolus injections. We chose to establish a preliminary PK model from the bolus experiments and used this to design and evaluate a 45minute target controlled infusion scheme as the second human study. This early use of TCI allowed efficient exploration of a therapeutic range of a particular compound whilst limiting the number of subjects required and the dose of drug to which they are exposed. TCI potentially offers stable conditions for evaluating pharmacodynamic effects of the drug at different blood concentrations. In practice, infusion kinetics can only be modelled to a limited extent from a model derived from bolus experiments and the ability to maintain a constant blood concentration is less than well evaluated from a kinetic set derived from infusion experiments, or indeed from TCI itself. When we used TCI in the second study of ORG21465 we were unable to maintain stable blood concentrations but nevertheless did usefully evaluate the compound in sedation as well as light and deep anaesthesia. Clinical development of this compound was limited by excitation, a tendency to accumulation and a propensity to cause pain on injection. ORG25435 is a new IV compound whose characteristics in animal studies have recently been aborted and reports of human studies are awaited.
References
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