Clasificación de las lagunas

at least some forms o f depression and disturbances o f the sleep/wake cycle (Czeisler 1980, Moore-Ede 1982). The clock involved in the generation o f many o f the circadian rhythms is located in the hypothalamic suprachiasmatic nucleus (SCN). A number o f afferent inputs to the SCN have been identified and a variety o f neurotransmitters have been localised within it (Card 1984). Thus it should be possible to alter the circadian clock in the SCN with pharmacological agents that alter the activity o f neural inputs to, or neural activity within, the SCN. Indeed, a variety o f endogenous and exogenous substances have now been identified which can directly or indirectly speed up, slow down or induce a phase shift in circadian rhythms that are under the control o f the SCN (Turek 1987).

As our knowledge of the nature o f sleep disturbances increases, the appropriate role for hypnotics in the management o f insomnia becomes clearer. It is well known that hypnotics may reduce the time required to fall asleep, but their place in the management o f those who are unable to stay asleep is less certain. Hypnotics are most appropriately used to treat temporary sleep difficulties such as those which may occur with transmeridian travel (Nicholson 1990), but, before prescribing a drug it is important to weigh up the benefits against possible adverse effects. Particularly important amongst these is the impairment o f skills such as driving and decision-making or the carrying out o f certain tasks.

In the past, it has been considered that the habitual use o f any drug which impairs performance should preclude "employment from certain occupations". However, with the greater knowledge now available in therapeutics, this view is less concrete and provided that the drug is free

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from residual effects, then it may be made available to most occupational groups. The duration o f action o f a drug depends on its absorption, distribution and elimination. To assist an individual to fall asleep, the absorption rate o f a hypnotic drug must be rapid enough to ensure that the plasma levels peak soon after ingestion. Following absorption, the drug is distributed around the body and a hypnotic generally produces an effect for as long as the plasma concentration remains above a certain level. The duration o f action will be short if this level is related to the distribution phase, but may be much longer if it is related to the elimination phase (Nicholson 1990).

Many hypnotics have a pharmacokinetic profile in which the parts played by distribution and elimination in the decline in plasma concentration are clear although it must be borne in mind that the continued daily ingestion o f such drugs may lead to accumulation if elimination is relatively slow. However, Temazepam, which is a derivative o f Diazepam, has a distribution phase similar to its parent compound, but it is more rapidly eliminated, does not have a slowly eliminated metabolite, and therefore does not lead to accumulation (Nicholson 1990).

Significant interest has in the past centred on even more rapidly eliminated drugs, some with half-lives o f two to three hours, such as Triazolam, although such rapid elimination is less likely to result in sustained sleep. It would appear that achieving sustained sleep without residual effects the next day, using drugs in which the elimination phase is predominant, requires a pharmacokinetic profile with a mean elimination half-life o f approximately five hours (Nicholson 1990).

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The benzodiazepines are at present the drug treatment o f choice for the management o f insomnia (Office o f Medical Applications o f Research, Consensus Conference 1984) and are thought to act by potentiating the action o f the neurotransmitter gamma-aminobutyric acid (GABA), which is widely distributed in the central nervous system (Muller 1982). It would also appear that both cell bodies and axons containing GABA are present within the bilaterally-paired suprachiasmatic nuclei (Card 1984, Van den Pol

1985). These findings raise the possibility that the benzodiazepines may have a fundamental effect on the central circadian pacemaker. Indeed, it has been found that the acute administration o f Triazolam can induce a phase shift in the circadian rhythm o f locomotor activity (Turek 1986, Turek 1988a, Turek 1989) and pituitary luteinising hormone release (Turek 1988a, Turek 1989) in hamsters. In addition, following a shift in the light/dark cycle, a single injection o f Triazolam can facilitate the time it takes for the activity rhythm to be resynchronised to the new lighting schedule (Turek 1988a, Turek 1989, Turek 1988b). More than this, it is also important to bear in mind that the phase shifting effect on the biological clock is dependent on the circadian time o f administration. Hence, any attempt to design an appropriate drug regime that will enhance sleep, as well as shorten the time needed for re-entrainment o f the circadian system following a shift in the sleep/wake cycle, must take into account both the direction o f the phase shift and the circadian time o f drug administration (Turek 1986). Indeed, preliminary studies indicate that the administration o f Triazolam at appropriate times may facilitate the adaptation o f human endocrine rhythms to an eight-hour delay shift o f the sleep/wake cycle (Van Cauter 1987).

Sleep may be disturbed and alertness impaired for several days after a transmeridian flight and re-aligns slowly according to the local pattern of

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rest and activity. Resynchronisation may take as long as six days after westward flights and as many as eleven days after eastward flights. This difference in time required to adapt to a new time zone after eastward and westward flights is related to the fact that the period o f innate circadian rhythmicity is longer than that o f the normal light/dark cycle.

Any hypnotic that is to be used during a flight should be tested beforehand to ensure that the patient's response is appropriate. This is important to consider as a recognised side effect o f benzodiazepines is anterograde amnesia (Harvey 1985), although this is usually seen only after intravenous administration. However, cases have been documented after oral doses o f Triazolam in the therapeutic range have been taken together with alcohol (Morris 1987).

As outlined above, sleep difficulties following transmeridian flights vary according to the direction o f the flight. Those that occur following eastward flights appear to be relatively persistent, whereas those that occur after westward flights are much less marked and usually persist for no more than one or two days. The inability to stay asleep may be overcome if a hypnotic is taken the first night or two after flying westward and for several nights after flying eastward. The type o f hypnotic needed will be the one that is likely to sustain sleep without residual sequelae and that is free from accumulation on daily ingestion. The hypnotic most likely to meet these requirements is rapidly rather than ultra-rapidly eliminated and for this reason, the benzodiazepine Temazepam has been used successfully for many years in the management o f sleep disturbances in civil aircrews (Nicholson

1.14 THE EFFECT OF SLEEP DISTURBANCE ON TRAVEL