INSOMNIA CASE STUDY “Sleeplessness”
Case study- Mr AB, a 21-year-old, white European, pharmacy student came to the local pharmacy last week with a 7-day prescription for diazepam 10 mg tablets, one to be taken at night.The drug was prescribed to him by his GP because some five weeks ago Mr AB started suffering from insomnia.
In fact, although he is typically supposed to wake up at 7.00am to attend his lectures, at 4.00am he is already fully awake.He does not find it difficult to fall asleep, nor does he wake up too frequently during the night.During the day, he feels very tired, anxious and tearful.It is now 3 days since you dispensed his prescription and the patient has returned to you because he claims he is still not able to sleep properly.
1. How is insomnia defined?
2a. What are the risk factors for its development?
2b. Does Mr AB have any of the risk factors for developing insomnia?
3a. What group of drugs does diazepam belong to? What are the main pharmacokinetic differences between the components of this class of drugs?
3b. What is the mechanism of action of diazepam in the treatment of insomnia?
3c.What are the side-effects of diazepam?
4a. What formulations are available for diazepam?
4b. What alternative preparation(s) could you recommend for Mr AB?
5. What counselling could you give Mr AB to help try and resolve the issue?
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1.How is insomnia defined?
Insomnia is characterised by the incapacity to sleep and/or to remain asleep for a reasonable period, which may vary from individual to individual.The sleep disturbance is observed at least three times per week and for at least one month.
2a.What are the risk factors for its development?
2bDoes Mr AB have any of the risk factors for developing insomnia?
Some of the most common risk factors for development of insomnia are asfollows:
Depression; typically, depressed individuals wake up earlier than usual, e.g.atleast 2 hours before the scheduled time.For this reason, in the case presented one might suspect the existence of an underlying dession.
Excessive use of alcohol; excessive use of caffeine: Mr AB might have recently increased his alcohol intake.A possible recent increase in caffeine intake might be associated with the need to cope with his pending academic commitments.
Stress, pain: Mr AB may be suffering from a short-term, exam-related,stressful situation.
Hypomanic/manic episodes: in people with bipolar disorder.
Circadian rhythm sleep disorders: jet lag; insomnia experienced by shiftworkers; and delayed sleep phase syndrome (sometimes seen in students who are enjoying their first experiences outside the family environment and whogo to bed too late).This is something that should be discussed with the present client.
Nocturnal polyuria, sometimes observed in conditions such as: diabetes,kidney diseases, prostate enlargement, hormonal imbalances, use of diuretics.
Sleep apnoea: interrupts the normal breathing stimulus of the central nervous system and the person must actually wake up to resume breathing.
3a.What group of drugs does diazepam belong to? What are the mainpharmacokinetic differences between the components of this class of drugs?
Diazepam is a benzodiazepine.
Diazepam is more reliably absorbed following oral rather than intramuscular admininstration.This may be due to precipita-tion in the muscle.Diazepam appears to undergo enterohepatic recirculation with a second plasma peak occurring 4–6 hours after initial administration.This may be associated with re-sedation.Diazepam is oxidised in the liver to active metabolites including desmethyldiazepam (nordiazepam), which has a half-life of over 100 hours.Benzodiazepine oxidation may be impaired in patients with liver disease and in some elderly patients.Metabolism of benzodiazepines suchas oxazepam and lorazepam is not impaired in the elderly and in those with liver dysfunction.Benzodiazepines have five major clinical indications:
1.as anti-anxiety agents
2.as sedative hypnotics
4.as muscle relaxants
5.as amnestic agents.
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This fivefold clinical activity is possessed, to a greater or lesser extent, by all benzodiazepines in current clinical use.The properties of benzodiazepines make them ideally useful for managing anxiety (e.g.diazepam, chlordiazepoxide,lorazepam); insomnia (e.g.diazepam, temazepam, nitrazepam, loprazolam,flurazepam, lormetazepam); epilepsy (e.g.clobazam, diazepam, lorazepam);sports injuries where muscle relaxation is required (e.g.diazepam) and as pre-medications prior to surgery (e.g.midazolam, lorazepam).The benzodiazepines have a number of other uses, including management of alcohol withdrawal syndrome (chlordiazepoxide, diazepam) and restless legs (clonazepam).
Short duration of action may be useful (e.g.for falling asleep), although longerduration of action may be desired (e.g.in treatment of sleep-maintenance dis-turbances or for seizure control).Among the different benzodiazepines large variation exists in respect totheir pharmacokinetic properties.Those benzodiazepines that have the long-acting metabolite N-desmethyldiazepam in common (diazepam, prazepam,clorazepate) are eliminated relatively slowly, others are metabolised rather rapidly (e.g.oxazepam, temazepam, triazolam).Pharmacokinetic parameters constitute the basis for a rational dosage regimen.In anticonvulsant and anti-anxiety treatment stable blood levels of the drug are pursued, so that com-pounds with long elimination half-lives of parent drug or active metabolites areof advantage.Conversely, if a benzodiazepine is taken as an hypnotic, the dura-tion of action should be restricted to the night, hence a compound with a short elimination half-life is to be preferred.
3b.What is the mechanism of action of diazepam in the treatment of insomnia?
Benzodiazepine agonists and other agonist ligands at the benzodiazepine site achieve their therapeutic effects by enhancing the actions of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at its receptor.Benzo-diazepines have a binding site on the GABA-A receptor, which forms a channelthrough the membrane and opens and closes to control chloride flow into the cell.When benzodiazepine agonists act on their receptor site, GABA produces amore frequent opening of the channel, so that the fl ow of chloride is increased.As a result, the neuron will be less likely to go through depolarisation, which ultimately results in neuronal inhibition.For this reason, all GABAergic drugs produce sedation.Type I and type II GABA receptors have been identif i ed;benzodiazepines bind with relative non-selectivity to both types.There are sev-eral other drugs which are also ligands of the GABA–chloride ion receptor com-plex, notably barbiturates, chloral hydrate and the newer non-benzodiazepine hypnotics, zopiclone, zolpidem and zaleplon (‘Z’-drugs).The Z-drugs are likelyto possess smaller residual next day sequelae than clinically equivalent doses ofmost benzodiazepines.
3c.What are the side-effects of diazepam?
Any prescription for benzodiazepines must be preceded by a careful risk–benefit analysis considering the issues of an individual’s particular life situation,personality style and psychiatric diagnosis.Risks of both abuse and cognitive/psychomotor impairments have to be balanced against therapeutic benefits.The most common side-effects of benzodiazepines in routine clinical use are drowsiness, muscle weakness, lightheadedness, dizziness, ataxia, dysarthria,blurring of vision, confusion and apathy.Because of pharmacokinetic changes of pro-nordiazepam molecules (e.g.diazepam) associated with ageing, the elderly may be at increased risk.There may be an association between benzo-diazepine use and the risk of falls and/or hip fractures in the elderly.For thosebenzodiazepines given at bedtime for sleep induction and/or sleep maintenance in patients with insomnia, the problem arises when the clinically desired effectof nocturnal sedation carries over into the early part of the next day.Patients who work in any high accident risk environment (e.g.with heavy machinery) as well as those where cognitive failure could cause accident to themselves orothers should be warned about possible interactions of benzodiazepines with alcohol. Finally, increased hostility and aggression (‘paradoxical effects’) cansometimes be observed following ingestion of these drugs, especially in border-line personality disorders and in the elderly.Both benzodiazepines and newernon-benzodiazepine molecules possess a signif i cant addiction liability; typical rebound and withdrawal symptoms may be observed if the drug is not carefully titrated down.
4a.What formulations are available for diazepam?
Diazepam formulations include: tablets: 2 mg; 5 mg; 10 mg.Oral solution:2 mg/5 mL.Strong oral solution: 5 mg/5 mL.Injection (solution): diazepam5 mg/mL.Formulation for intravenous injection or infusion (emulsion):5 mg/mL.Rectal solution: 2 mg/mL; 1.25 mL (2.5 mg); 2.5 mL (5 mg) tube;4 mg/mL, 2.5 mL (10 mg).Suppositories: 10 mg.Dental prescribing on NHS:tablets or oral solution 2 mg/5 mL.
4b.What alternative preparation(s) could you recommend for Mr AB?
Diazepam is better indicated if insomnia is associated with daytime anxiety.Other benzodiazepines prescribed for insomnia include: nitrazepam, flur-azepam, loprazolam, lormetazepam and temazepam.The non-benzodiazepinehypnotics zaleplon, zolpidem and zopiclone are not licensed for long-term use.The sedative antipsychotic promethazine hydrochloride is sometimes used to facilitate sleep, with a 25–50 mg recommended dose.Melatonin has proved effective for some clients, mostly in regulating the sleep/waking cycle.Although evidence of efficacy is limited, some clients use herbs such as valerian andchamomile.If Mr AB will finally be diagnosed with depression, a trial with anantidepressant will be indicated.
5.What counselling could you give Mr AB to help try and resolve the issue?
Relevant sleep hygiene issues may be discussed with the client.Some traditional remedies for insomnia have included drinking warm milk before bedtime, tak-ing a warm bath in the evening; exercising vigorously for half an hour in the afternoon, having only a light evening meal, avoiding mentally stimulating activities in the evening hours, and making sure to get up early in the morningand to go to bed at a reasonable hour.Mr AB should seriously consider the possibility of tapering down gradually his caffeine intake and might want to avoid any excessive intake of alcohol.Distractions in the bedroom, including excessive light and noise (e.g.from television) should be avoided.Finally, Mr AB should be informed that with a continuous, long-term (e.g.more than 3–12weeks), prescription of benzodiazepines both tolerance and dependence have been described.