Discuss the mode(s) of action, therapeutic use(s) and adverse effects of:

(a)            propylthiouracil.

(b)            selective serotonin re-uptake inhibitors.

(c)            cimetidine.

Suggested Answers:

(a)

Propylthiouracil is a thiourea-derivative antithyroid agent. Propylthiouracil occurs as a white, powdery, crystalline substance with a bitter taste and a starch-like appearance and texture.

Propylthiouracil reduces formation of thyroid hormone by inhibiting the organification of iodine, and by inhibiting the coupling of iodotyrosines to form T3 and T4. It also inhibits the peripheral conversion of T4 to T3.

Propylthiouracil is rapidly and readily absorbed from the GI tract following oral administration. It appears to be concentrated in the thyroid gland. The elimination half-life of propylthiouracil has generally been reported to be about 1—2 hours. The drug is rapidly metabolized to its glucuronide conjugate and other minor metabolites and requires frequent administration to maintain its antithyroid effect. The drug and its metabolites are excreted in urine, with about 35% of a dose excreted within 24 hours.

Propylthiouracil is used for the palliative treatment of hyperthyroidism, as an adjunct to ameliorate hyperthyroidism in preparation for surgical treatment or radioactive iodine therapy, and when thyroidectomy is contraindicated or not advisable.

Adverse reactions to propylthiouracil reportedly occur in less than 1% of patients receiving the drug. Minor adverse effects of propylthiouracil include rash, urticaria, pruritus, abnormal hair loss, skin pigmentation, edema, nausea, vomiting, epigastric distress, loss of taste, arthralgia, myalgia, paresthesia, and headache. Drowsiness, neuritis, vertigo, sialadenopathy, lymphadenopathy, jaundice, and nephritis have also occurred in patients receiving the drug. Although reported much less frequently, severe adverse effects, including inhibition of myelopoiesis with resultant agranulocytosis, granulocytopenia, and thrombocytopenia; aplastic anemia; drug fever; lupus-like syndrome (including splenomegaly); severe hepatic reactions (including encephalopathy, fulminant hepatic necrosis, and death); periarteritis; and hypoprothrombinemia and bleeding, have been reported to occur in some patients receiving propylthiouracil. Agranulocytosis is potentially the most serious adverse effect of propylthiouracil, and most cases of agranulocytosis appear to occur within the first 2 months of therapy, but rarely may occur after 4 months of therapy. The risk of propylthiouracil-induced agranulocytosis appears to be substantially increased in patients older than 40 years of age compared with younger patients. Propylthiouracil-induced hepatotoxicity, which appears to occur rarely, usually has manifested as predominately hepatocellular hepatitis.

(b)

Selective Serotonin Re-uptake inhibitors (SSRIs) are anti-depressants. According to the amine hypothesis of depression, it is believed that decreased amine (serotonin and noradrenalin) neurotransmission is associated with depression. By selectively inhibiting the re-uptake of serotonin, SSRIs have mood-elevating effects clinically and less adverse effects as compared to the non-selective anti-depressants such as the tricyclic antidepressants.

Fluoxetine (Prozac) was the first SSRI to reach general clinical use. Paroxetine and sertraline differ mainly in having shorter half-lives. While they have not been shown to be more effective overall than prior drugs, they lack many of the toxicities of the tricyclics and other antidepressants. Thus, patient acceptance has been high despite new adverse effects such as headache, nausea and restlessness.

Fluoxetine hydrochloride appears to be well absorbed from the GI tract following oral administration. The onset of antidepressant activity following oral administration of fluoxetine hydrochloride usually occurs within the first 1—3 weeks of therapy, but optimum therapeutic effect usually requires 4 weeks or more of therapy with the drug. Fluoxetine and norfluoxetine, the principal metabolite, are eliminated slowly. Following a single oral dose of fluoxetine in healthy adults, the elimination half-life of fluoxetine reportedly averages approximately 2—3 days (range: 1—9 days) and that of norfluoxetine averages about 7—9 days.

SSRIs are used in the clinical management of major depressive disorder, obsessive-compulsive disorder, panic disorder, social phobia, bulimia nervosa, premature ejaculation, alcohol dependence and depression associated with bipolar disorder.

Headache, nervousness, anxiety, insomnia, drowsiness and fatigue are the most common side effects of SSRIs. The common GI effects are nausea, vomiting and diarrhea. Maculopapular rashes, urticaria and purpura have been reported. Weight loss frequently occurs during therapy with SSRIs and is reversible after discontinuation of the drug. Sexual dysfunction occurs in a small percentage of patients on SSRIs, the most common of which is ejaculatory delay.

The concurrent administration of tramadol and a selective serotonin reuptake inhibitor (SSRI) may result in an additive blockage of serotonin reuptake, resulting in central serotonergic hyperstimulation and serotonin syndrome. The SSRIs may inhibit the metabolism of tramadol at the cytochrome P450-2D6 isoenzyme and may lower the seizure threshold.  Symptoms of serotonin syndrome may include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death. The concurrent administration of tramadol with a SSRI may also increase the risk of seizures. SSRIs may displace warfarin from its plasma protein binding sites or inhibit its hepatic metabolism leading to an increase in the clinical effects and toxicities of warfarin. It also inhibit the metabolism of benzodiazepines, TCAs and clozapine resulting in an increase in their clinical effects.

(c)

Cimetidine is a histamine H₂-receptor antagonist. Cimetidine contains an imidazole ring and is structurally similar to histamine. Cimetidine competitively inhibits the action of histamine on the H₂ receptors of parietal cells, reducing gastric acid output and concentration under basal conditions and also when stimulated by food, insulin, betazole, histamine, pentagastrin, and caffeine. Although the concentration of pepsin is not reduced, the total amount secreted falls because the volume of gastric juice is less. Cimetidine does not affect gastric emptying.

Cimetidine is readily absorbed from the upper small intestine. The half-life is 2h and 60% of an oral dose is recovered as unchanged drug in the urine, the remainder appearing as metabolites. Cimetidine is widely distributed throughout the body and is 15-20% bound to plasma proteins.

Cimetidine is used for conditions in which reduction of gastric acid secretion is beneficial. These are duodenal ulcer, benign gastric ulcer and reflux esophagitis. When treating a gastric ulcer, it is desirable to confirm that it is benign by endoscopy and biopsy every 6-8 weeks until it is healed, for the symptoms of gastric carcinoma can be relieved by cimetidine so that apparently successful treatment may fatally delay the correct diagnosis. Cimetidine is also used for the prophylaxis of gastrointestinal bleeding due to gastric erosions complicating the stress of burns, fulminant hepatic failure, renal failure or trauma. Cimetidine is given before anaesthesia for emergency surgery and before labor to lessen the risk of pulmonary aspiration of gastric acid; it is also used to prevent peptic ulcer induced by NSAIDs in high-risk patients, e.g. elderly women and those with a previous history of ulceration.

Cimetidine 400 mg  x 2/day, with breakfast and at bedtime is usually satisfactory for peptic ulcer. Most patients become symptom-free in about 8 days but treatment should continue for 6-8 weeks, after which 85-90% of duodenal and 60% of gastric ulcers can be expected to heal.

Adverse effects and interactions are few in short-term use. Minor complaints include headache, dizziness, constipation, diarrhea, tiredness and muscular pain. Bradycardia and cardiac conduction defects may also occur. Cimetidine is a weak anti-androgen and may cause gynaecomastia and sexual dysfunction in males. In the elderly particularly, it may cause CNS disturbances including lethargy, confusion and hallucinations. Cimetidine is an inhibitor of hepatic drug-oxidizing enzymes; raised plasma concentrations with enhanced activity of warfarin, phenytoin, lignocaine, propranolol and theophylline result when these drugs are administered with it.