1.         A 25 year-old man with a past history of drug addiction is now suffering from anxiety and insomnia. Discuss the pharmacology of drugs that may be used in the management of his anxiety and insomnia.

Outline:

·        Introduction: prevalence and causes of anxiety and insomnia.

·        Choice of anxiolytic / hypnotic.

·        Benzodiazepines: pharmacokinetics, adverse effects, drug intereactions.

·        Choice of benzodiazepine.

·        Clinical management.

Suggested answer:

The word anxiety comes from the latin word anxieta which means troubled in the mind about some uncertain event. Anxiety in moderation is a normal, appropriate and even useful response to life events and situations. But inappropriate or excessive or chronic anxiety is disabling, especially when the cause cannot be removed. In a community survey of 3,020 people aged 13 to 65 years in Singapore, the 12-month prevalence for any anxiety disorder was 9.3% (CSL Fones, EH Kua, TP Ng, SM Ko Singapore Medical Journal 1998; 39(6): 251-255). Benzodiazepines now dominate ant-anxiety medication.

When anxiety is present, it is accompanied by many signs of motor tension (e.g., trembling, twitching, shakiness, restlessness, easy fatigability), autonomic hyperactivity (e.g., shortness of breath, smothering sensation, tachycardia, palpitations, sweating, cold clammy hands, dry mouth, diarrhea, hot flushes), and vigilance. A beta-adrenoceptor blocker, e.g. propranolol, is used where there are somatic symptoms. A sedative antidepressant is used where there is depression with anxiety, e.g. amitriptyline.

Insomnia is the perception of disturbed or inadequate sleep and includes difficulty in falling asleep; frequent awakening and early morning waking. A survey of government and private clinics in Singapore showed that 8% of outpatients had insomnia (Tsoi WF & Kua EH, Family Physician 1986). Clinical types of insomnia are transient insomnia which is usually situational with a duration of less than a week; short-term insomnia which persists for 1-4 weeks and is often due to family or work stress and chronic insomnia which may continue for more than a month and is usually the consequence of medical and psychological problems. In the case of this patient, his insomnia may be due to drugs such as steroids, alcohol and hypnotic withdrawal. Benzodiazepines generally are preferred to most other hypnotics for the management of insomnia because of their established short- and intermediate-term efficacy and relative safety. Benzodiazepines shorten the time taken to go to sleep (sleep latency), decrease intermittent awakening and increase total sleep duration. Alternative drugs used are zopiclone, zolpidem, paraldehyde, chlormethiazole and the phenothiazines.

The benzodiazepines are most widely used as anxiolytics and hypnotics for the treatment of insomnia. Benzodiazepines have hypnotic, sedative, anxiolytic, anticonvulsant and muscle relaxant actions. They attach to a specific side on the GABA receptor/chloride channel complex, potentiating the effect of GABA by increasing the opening frequency of the chloride channel. Benzodiazepines act chiefly on the brain reticular activating system (reducing sensory input), the limbic system (affect), the median forebrain bundle (reward and punishment systems) and the hypothalamus.

Generally the benzodiazepines are rapidly and completely absorbed with oral administration. Some are absorbed within 0.5 to 1h (e.g. chlordiazepoxide and diazepam), while others may take longer than 6h. The absorption of benzodiazepines tends to be erratic after intramuscular injection.

Most benzodiazepines are extensively bound to serum albumin, e.g. 99% with diazepam. Binding correlates strongly with lipid solubility. Since the benzodiazepines are highly lipid soluble, penetration into the brain is very rapid except oxazepam which is relatively slow. Rapid uptake of benzodiazepines into the brain and other highly perfused organs is followed by a phase of redistribution into tissues like fat and muscle. Generally, benzodiazepines and their metabolites cross the placenta; the concentration of diazepam in the fetal circulation has been reported to be equal to or greater than maternal plasma drug concentrations. The drugs and their metabolites are distributed into milk.

Elimination half-lives of benzodiazepines and their metabolites exhibit wide inter-patient variation. Geriatric patients and patients with liver disease may have prolonged elimination of all benzodiazepines and their metabolites. Benzodiazepines are metabolized in the liver. Lorazepam, oxazepam, temazepam, and the hydroxylated metabolites of chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, midazolam, quazepam, and triazolam are conjugated with glucuronic and/or sulfuric acid; these inactive conjugates are excreted principally in urine. Glomerular filtration of unchanged benzodiazepines is low because of their extensive serum albumin binding.

The adverse effects of benzodiazepines are mainly due to an extension of their pharmacological effects on the CNS. Benzodiazepines are potent amnesics. Memory disturbances (anterograde) are particularly profound after i.v. sedation. CNS toxicity includes drowsiness, lethargy, retardation, depression, ataxia, confusion, disorientation and in the elderly, dementia. Benzodiazepines may cause paradoxical effects such as garrulousness, irritability, hallucinations and hypomanic behaviour.

During long-term administration, development of tolerance is common and rapid. Physical dependence may develop in patients taking large amounts. The short-acting compounds usually produce withdrawal symptoms – anorexia, headache, restlessness, anxiety, irritability, tremor, insomnia, confusions and dizziness soon after withdrawal. For the long-acting compounds, symptoms may be delayed for several days or more after stopping therapy.

Withdrawal of benzodiazepines should be gradual after as little as 3 weeks’ use, but for long-term users, it should be very slow. Withdrawal should be slowed if marked symptoms occur. Towards the end of the withdrawal of a short half-life drug, it may be useful to substitute a long half-life drug to minimize rapid fluctuations in plasma concentrations.

CNS adverse effects become a serious problem when benzodiazepines are taken with many psychoactive drugs such as opioid analgesics, anti-histamines, phenothiazines and tricyclic antidepressants. Interactions with alcohol may be especially serious. Metabolism of some benzodiazepines (e.g., alprazolam, midazolam, triazolam) is mediated by the cytochrome P-450 (CYP) microsomal enzyme system, and concomitant use with drugs that inhibit this enzyme system (e.g., cimetidine, azole antifungals, macrolide antibiotics, HIV protease inhibitors, calcium-channel blocking agents, fluvoxamine, nefazodone) may result in increased plasma concentrations of these benzodiazepines and, possibly, increased and prolonged sedation in some (e.g., midazolam). Concomitant use of some macrolide antibiotics (e.g. erythromycin), some azole antifungals (e.g., fluconazole, itraconazole, ketoconazole), nefazodone, fluvoxamine, diltiazem, or verapamil and these benzodiazepines may result in clinically important increases in the plasma concentrations.

As use of benzodiazepines is associated with the danger of dependence with withdrawal symptoms of anxiety and insomnia, use should be limited to 2-4 weeks. The occurrence of dependence will be minimized by critical prescribing using low doses for short periods or intermittently. Only in exceptional cases should use exceed a few weeks. A prescription for a hypnotic is justified for a few nights or up to 4 weeks to combat insomnia due to anxiety. The choice of benzodiazepine depends on the nature of the anxiety and insomnia, the occupation of the patient and the possibility of drug addiction. As this patient has a history of drug abuse and addiction, additional care must be taken in prescribing benzodiazepines for his anxiety and insomnia.

Rational choice is often made according to their duration of action. For a patient with a persisting high level of anxiety, a long-acting benzodiazepine such as diazepam or clorazepate is appropriate. Patients with fluctuating, acute anxiety may prefer to take a short-acting drug such as oxazepam, lorazepam or alprazolam. Benzodiazepines with a long half-life are preferred for smooth effect: either a single nocturnal dose, which will give anxiolytic effect the next day, or small divided doses during the day. The less lipid-soluble oxazepam and lorazepam give particularly smooth effect (slower absorption and slower entry into the CNS). Where there are somatic symptoms, a b-adrenoceptor blocker may be effective alone or in combination with a benzodiazepine.

In selecting a hypnotic, it is important to take note of the nature of sleep disturbance, i.e. is there difficulty in initiating sleep, frequent awakening or early morning awakening? and whether a person’s work or domestic situation  requires alertness early in the morning. Because of its long duration of action, diazepam is useful for patients whose insomnia is associated with daytime anxiety. The slow elimination and accumulation of its metabolites are responsible for the prolonged action of more than 12 hours. Temazepam has a shorter half-life than diazepam and an extremely slow rate of absorption. Peak concentration is not reached unfit 2-3 hours after administration. It is useful for those who have frequent awakening and produces minimal morning drowsiness. Triazolam has a very short half-life of about 3 hours and is without long-acting metabolites. The duration of sedative effect is about 3-4 hours. It is recommended for transient insomnia and especially insomnia associated with difficulty in falling asleep.

Zolpidem and zopiclone are two non-benzodiazepine hypnotics currently available in the market. Zolpidem is an imidazopyridine that has similar hypnotic property like the benzodiazepines. It appears to act by binding to the GABA receptor complex but with selective affinity for the subtype of benzodiazepine receptors in the cerebellum. It is used as a hypnotic (rapid onset and short duration of action) in the short-term management of insomnia. Zopiclone is a cyclopyrrolone that has similar sedative, anxiolytic, muscle relaxant, amnesic properties to those of the benzodiazepines. It is used as a hypnotic in the management of insomnia in human.