Discuss the following:

(a)            benzodiazepine dependence.

(b)            mechanisms of antithyroid drugs.

(c)            pharmacodynamic drug interactions.

Suggested Answer:

(a)

Benzodiazepines are the most are most widely used as anxiolytics and hypnotics for the treatment of insomnia. Chronic use leads to physical and psychological dependence.

Dependence, as shown by occurrence of withdrawal symptoms, is usual with therapeutic doses used beyond a few weeks, though it is commonly mild. Dependence occurs earlier with the short half-life members but rebound or withdrawal symptoms are not so well correlated with half-life. Withdrawal symptoms begin after 2-3 days with alprazolam and lorazepam but may be delayed for 2-3 weeks with diazepam. They pass off over 2 – 4 weeks and are greatly affected by expectations and personality. It may be difficult to distinguish between withdrawal symptoms and those that are manifestations of illness return or rebound, although their management may differ. Because some benzodiazepines and their metabolites have long elimination half-lives, withdrawal symptoms may not occur until several days after the drugs have been discontinued.

Withdrawal symptoms include anxiety, agitation, irritability, confusion, delirium, depersonalization, sleep disturbance, tremor, headache, muscle twitching or aches, sweating and diarrhoea. After prolonged high doses abrupt withdrawal may cause confusion, delirium, psychosis and convulsions.

Withdrawal of benzodiazepines should be gradual after as little as 3 weeks’ use, but for long-term users it should be very slow, e.g. about 1/8 of the dose every 2 weeks, aiming to complete it in 6 – 12 weeks. 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. Abandonment of the final dose may be particularly distressing. In difficult cases withdrawal may be assisted by concomitant use of a sedative anti-depressant.

(b)

Anti-thyroid drugs are used in the treatment of hyperthyroidism and they include thionamides, iodide and radioactive iodine.

The thioamides are carbimazole, methimazole and propylthiouracil. They reduce the formation of thyroid hormone by inhibiting the organification of iodine, and by inhibiting the coupling of iodotyrosines to form T₄ and T₃. Maximum effect is delayed until existing hormone stores are exhausted. The drugs are used in hyperthyroidism as principal therapy, adjuvant to radioiodine to control the disease and to prepare patients for surgery.

Iodide effects are complex and related to dose and to thyroid status of the subject. In hyperthyroid subjects an excess of iodide inhibits hormone release and promotes storage of hormone and involution of the gland, making it firmer and less vascular so that surgery is easier. The effect is transient and its mechanism uncertain.

Radioiodine (¹³¹I) is concentrated in the thyroid gland when swallowed. It emits mainly b radiation, which penetrates only 0.5mm of tissue and thus allows therapeutic effect on the thyroid without damage to the surrounding structures. It is increasingly used as treatment of choice in hyperthyroidism at all ages, and in combination with surgery in some cases of thyroid carcinoma.

(c)

In pharmacodynamic interactions, both drugs act on the target site of clinical effect, the result is altered drug action.

Action on receptors provides numerous examples. Beneficial interactions are sought in overdose, as with the use of naloxone for morphine overdose, or atropine for anticholinesterase. Unwanted interactions include the loss of anti-hypertensive effect of beta-blockers when common cold remedies containing ephedrine or phenylephrine are taken, their alpha-adrenoceptor agonist action is unrestrained in the beta-blocked patient.

Actions on body systems provide scope for a variety of interactions. Diuretics lose efficacy if administered with NSAIDs; the mechanism may involve inhibition of prostaglandin synthesis. Digoxin is more effective, but also more toxic in the presence of hypokalaemia, which may be caused by thiazide or loop diuretics. Verapamil given i.v. with a beta-blocker may cause dangerous bradycardia since both drugs delay AV conduction.