Discuss the following:

(a)        Drug interactions which can potentiate the hypoglycaemic effect of the sulphonylureas.

(b)            Tripotassium dicitratobismuthate in the treatment of peptic ulcer.

(c)            Adverse effects of corticosteroids.

Suggested answers:

(a)       

Sulphonylureas are one of the two main classes of oral anti-diabetic drug most commonly used today, the other being biguanides. Sulphonylureas activate receptors on beta-cells of the pancreatic islets to release stored insulin in response to glucose.

Sulphonylureas appear to enhance insulin action on liver, muscle and adipose tissue by increasing insulin receptor number and by enhancing the post-receptor complex enzyme reactions mediated by insulin. The principal result is decreased hepatic glucose output and increased glucose uptake in muscle. They are ineffective in totally insulin-deficient patients and for successful therapy probably require about 30% of normal beta-cell function to be present. They cause hypoglycaemia in normal subjects as well as in diabetics.

Drug interactions which can potentiate the hypoglycaemic effects of sulphonylureas occur by three mechanisms: displacement from binding proteins, inhibition of metabolism of sulphonylureas and blocking the beta-adrenergic responses to hypoglycaemia.

Most sulphonlyureas like tolbutamide are highly protein bond and they can displace from their protein-binding sites by oral anticoagulants, hydantoins, salicylates and other nonsteroidal anti-inflammatory agents, and sulfonamides. This increase their free plasma concentration which potentiate the hypoglycaemic effects of a given dose of sulphonylurea.

Phenylbutazone or oxyphenbutazone may potentiate the hypoglycemic effects of tolbutamide and other sulfonylurea antidiabetic agents, possibly through competition for protein-binding sites or for urinary excretion. Phenylbutazone and oxyphenbutazonehave been shown to inhibit the metabolism of tolbutamide, possibly by stimulating a cytochrome P-450-like enzyme system that has a low metabolic activity for tolbutamide hydroxylation. If phenylbutazone or oxyphenbutazone is administered concomitantly with tolbutamide, the patient should be closely monitored for signs of hypoglycemia.

Azole antifungals such as fluconazole, ketoconazole and miconazole inhibit the metabolism of sulphonylureas and increase their effectiveness which may result in clinical symptoms of hypoglycaemia.

Beta-blockers such as propranolol potentiate the hypoglycaemic effects of sulphonylureas by blockade of a variety of beta-adrenergic responses to hypoglycaemia. Diminished response to sulphonylureas may occur. Frequency and severity of hypoglycaemic episodes may be increased, while symptoms of low blood sugar may be masked.

(b)

Tripotassium dicitratobismuthate, or bismuth chelate acts primarily by selectively chelating with protein material in the ulcer base, so forming a coating that protects it from the adverse influences of acid, pepsin and bile. Bismuth chelate is also active against Helicobacter pylori, especially when combined with an antimicrobial.

Bismuth chelate is used for benign gastric and duodenal ulcer and has a therapeutic efficacy approximately equivalent to histamine H₂-receptor antagonists.

Bismuth chelate, particularly as a liquid formulation, darkens the tongue, teeth and stool. Systemic absorption of bismuth from the chelated preparations appears to be well below the levels at which encephalopathy occurs but bismuth is eliminated by the kidney and it is prudent to avoid giving the drug to patients with impaired renal function. Elimination in the urine continues for months after bismuth is eliminated.

(c)

The chief use of corticosteroids in medicine is for their anti-inflammatory and immunosuppressive effects. These are only obtained when the drugs are given in doses far above those needed for physiological replacement.

Corticosteroids, being lipid soluble, enter inside their target cells, and combine with the glucocorticoid receptor in the cytoplasm. The unoccupied receptor is normally bound to a heat shock protein HSP90. After occupation by a glucocorticoid steroid, the HSP90 is induced to change conformation and dissociate from the occupied glucocorticoid receptor. The reason for the multiple actions of corticosteroids is the presence of glucocorticoid response elements (GRE) in the promoter region of several genes; some of these are switched off by binding of the receptor to their GRE, whereas others are activated. A transcription factor is stimulated by a variety of inflammatory mediators to turn on the production of cytokines.

Corticosteroids cause mobilization and redistribution of body fat, which together with loss of protein from peripheral tissues lead to a characteristic appearance: ‘moon-face’, ‘buffalo hump’, truncal obesity with relatively thin limbs. In addition to wasting due to catabolism of protein from skeletal muscle, patients also develop muscular weakness in the thighs and upper arms (proximal myopathy). Disturbed carbohydrate metabolism leads to hyperglycaemia and glycosuria and, rarely, may proceed to overt diabetes mellitus.

Osteoporosis and collapse of vertebrae occur due to reduced bone formation, increased calcium loss and bone protein mobilization. Avascular necrosis of femoral head may occur. Retardation of growth may be seen after long-term use in children due to inhibition of DNA synthesis and cell division.

Sodium and water retention due to the inherent mineralocorticoid activity leads to increased body weight, hypertension and edema. This may proceed to cardiac failure. Hypokalaemic alkalosis may be associated.

Suppression of all components of the inflammatory and immune responses lead to increased susceptibility to bacterial, viral and fungal infection. Latent tuberculosis foci may be reactivated. Psychotic reactions of all types may occur – euphoria, mania or depression.

Corticosteroids cause increased intraocular pressure in the eye which may lead to glaucoma and posterior subcapsular cataract, a rare complication, usually in children, reflecting prolonged high-dosage therapy.

Prolonged corticosteroid therapy leads to increased incidence of dyspepsia, peptic ulceration and upper GIT bleeding. Hirsutism and menstrual disturbances are disturbing effects commonly seen in women on long-term steroids.

The complications associated with topical application are worsening of local infections, local thinning of skin and formation of irreversible atrophic striae. The use of high doses of beclomethasone by aerosol inhalation can result in hoarseness or oral candidiasis.

The administration of exogenous corticosteroids results in negative feedback to the anterior pituitary hypothalamic-axis with inhibition of ACTH release and the consequent withdrawal of trophic stimulation to the adrenal cortex. Adrenal suppression leads to impairment of the patient’s response to stress as well as to symptoms and signs of adrenal insufficiency if the steroid is abruptly withdrawn. Hence, apart from short-term therapy, withdrawal must be undertaken cautiously and gradually.