Synonyms: Antidiabéticos sulfonilureas; Sulfonylurea Antidiabetics; Sulphonylurea Antidiabetics

Adverse Effects

Gastrointestinal disturbances such as nausea, vomiting, heartburn, anorexia, diarrhoea, and a metallic taste may occur with sulfonylureas and are usually mild and dose-dependent increased appetite and weight gain may occur. Skin rashes and pruritus may occur and photosensitivity has been reported. Rashes are usually hyper sensitivity reactions and may progress to more serious disorders (see below). Facial flushing may develop in patients receiving sulfonylureas, particularly chlorpropamide, when alcohol is consumed (see under Interactions, below).

Mild hypoglycaemia may occur severe hypoglycaemia is usually an indication of overdosage and is relatively uncommon. Hypoglycaemia is more likely with long-acting sulfonylureas such as chlorpropamide and glibenclamide, which have been associated with severe, prolonged, and sometimes fatal hypoglycaemia. Other severe effects may be manifestations of a hypersensitivity reaction. They include altered liver enzyme values, hepatitis and cholestatic jaundice, leucopenia, thrombocytopenia, aplastic anaemia, agranulocytosis, haemolytic anaemia, erythema multiforme or the Stevens-Johnson syndrome, exfoliative dermatitis, and erythema nodosum.

The sulfonylureas, particularly chlorpropamide, occasionally induce a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) characterised by water retention, hyponatraemia, and CNS effects. However, some sulfonylureas, such as glibenclamide, glipizide, and tolazamide are also stated to have mild diuretic actions.

Work on tolbutamide has suggested that the sulfonylureas might be associated with an increase in cardiovascular mortality this has been the subject of considerable debate (see Effects on the Cardiovascular System, below).

Effects on the cardiovascular system. A multicentre study carried out under the University Group Diabetes Program (UGDP) reported an increased incidence in mortality from cardiovascular complications in diabetic patients given tolbutamide as compared with those treated with diet alone or insulin a similar increase was also noted in patients given phenformin. The reports from the UGDP aroused prolonged controversy which was not entirely settled by detailed reassessment of relevant studies. Eventually in 1984 the FDA made it a requirement that sulfonylurea oral antidiabetics be labelled with a specific warning about the possibility of increased cardiovascular mortality associated with the use of these drugs Subsequently the cardiovascular effects of the sulfonylureas were reviewed. It has been hypothesised that the action of the sulfonylureas in preventing the opening of ATP-sensitive potassium channels in the myocardium may abolish adaptive changes (ischaemic preconditioning) that protect the heart against ischaemic insult. A recent retrospective cohort study has also found that, among patients newly treated for type 2 diabetes, sulfonylurea monotherapy was associated with an increased mortality compared with metformin therapy. However, results from the UK Prospective Diabetes Study did not demonstrate any adverse cardiovascular effects associated with sulfonylurea therapy.

Effects on the eyes. When a diabetic patient who had experienced bilateral visual loss for several months and who had been taking chlorpropamide for one year stopped treatment, visual acuity improved and colour vision rapidly returned. A 5-day challenge with chlorpropamide resulted in a mild decrease in acuity followed by return to baseline values when treatment was again stopped. Drug-induced optic neuropathy was considered to have occurred. There is also a report of a patient with type 2 diabetes mellitus who developed myopia two days after starting treatment with glibenclamide 10 mg daily. Visual difficulties resolved a few days after stopping glibenclamide.

Effects on the kidneys. The nephrotic syndrome has been reported in a patient treated with chlorpropamide. Serological testing and renal biopsy showed that the glomerular lesions were of an immune-complex nature. Both the nephrotic syndrome and the glomerulonephritis resolved after treatment was stopped. The patient also developed a skin eruption, hepatitis, and eosino-philia.

Effects on the liver. Chlorpropamide was implicated in 8 of 53 cases of drug-induced acute liver disease admitted to a hospital in Jamaica over the years 1973 to 1988. Hepatocanalicular cholestasis occurred in 5 cases and diffuse necrosis in 3. One patient with massive hepatic necrosis died. Intrahepatic cholestasis, an acute hepatitis-like syndrome, and a combination of both have been described in patients receiving glibenclamide.

Effects on the thyroid. See under Precautions, below.

Hypoglycaemia. Severe hypoglycaemia may occur in any patient treated with any sulfonylurea this potentially life-threatening complication requires prolonged and energetic treatment.Sulfonylureas with a prolonged duration of action such as chlorpropamide and glibenclamide appear to cause severe hypoglycaemia more often than shorteracting drugs such as tolbutamide. Experience with newer drugs is limited.

A review of 1418 cases of drug-induced hypoglycaemia reported since 1940 showed that sulfonylureas (especially chlorpropamide and glibenclamide), either alone or with a second antidiabetic or potentiating agent, accounted for 63% of all cases. A study of sulfonylurea use in nearly 14,000 patients aged 65 years or older confirmed that chlorpropamide and glibenclamide were associated with hypoglycaemia. However, glipizide caused significantly fewer cases than glibenclamide.

An analysis, of 185 children reported to 10 regional poison centres in the USA after ingesting sulfonylureas found that hypoglycaemia developed only in 56. A lack of hypoglycaemia during the first 8 hours after ingestion was predictive of a benign outcome, and it was recommended that suspected cases be observed for 8 hours with frequent blood glucose monitoring. Children who developed signs of hypoglycaemia, or in whom blood glucose fell below 3.3 mmol/litre could be given intravenous glucose if necessary.

Treatment of Adverse Effects

In acute poisoning with sulfonylureas, if the patient is conscious and presents within 1 hour of ingestion, the stomach should be emptied and/or activated charcoal given. Hypoglycaemia should be treated with urgency the general management of hypoglycaemia is described under insulin. The patient should be observed over several days in case hypoglycaemia recurs. Octreotide has been used in the treatment of severe refractory cases of sulfonylurea-induced hypoglycaemia.

Precautions

Sulfonylureas should not be used in type 1 diabetes mellitus. Use in type 2 diabetes mellitus is contra-indicated in patients with ketoacidosis and in those with severe infection, trauma, or other severe conditions where the sulfonylurea is unlikely to control the hyperglycaemia insulin should be used in such situations.

Insulin is also preferred for therapy during pregnancy.

Sulfonylureas with a long half-life such as chlorpropamide or glibenclamide are associated with an increased risk of hypoglycaemia. They should therefore be avoided in patients with impairment of renal or hepatic function, and a similar precaution would tend to apply in other groups with an increased susceptibility to this effect, such as the elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency. Irregular mealtimes, missed meals, changes in diet, or prolonged exercise may also provoke hypoglycaemia. Where a sulfonylurea needs to be used in patients at increased risk of hypoglycaemia, a short-acting drug such as tolbutamide or gliclazide may be preferred these 2 sulfonylureas, being principally inactivated in the liver, are perhaps particularly suitable in renal impairment, although careful monitoring of blood-glucose concentration is essential.

Abuse. Severe hypoglycaemia, at first thought to be due to insulinoma but later found to be due to nesidioblastosis [proliferation of the islet cells], was reported in a woman covertly taking chlorpropamide.

Administration. It has been suggested that continuously high plasma concentrations of sulfonylureas may lead to the development of tolerance, and that therefore the maximum recommended doses should be reduced.

Breast feeding. Some sulfonylureas are distributed into breast milk and the class of drugs should be avoided during breast feeding.

Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemics are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses. References.

Fasting. For the suggestion that sulfonylureas should be used with caution in fasting Muslim patients during Ramadan, and that chlorpropamide is contra-indicated in this group, see under Precautions of Insulin.

Porphyria. Sulfonylureas have been associated with acute attacks of porphyria and are considered unsafe in porphyric patients.

Thyroid disorders. There are conflicting reports concerning the effects of sulfonylureas on thyroid function, with some studies suggesting an increased incidence of thyroid dysfunction in patients treated with tolbutamide or chlorpropamide, while other suggest no antithyroid action. Some licensed product information consequently recommends that chlorpropamide should be avoided in patients with impaired thyroid function. Changes in thyroid function may conversely affect glycaemic control — for mention of the possible effects of thyroid hormones on anti-diabetic drug requirements see under Interactions, below.

Interactions

Many interactions have been reported with the sulfonylureas, largely representing either pharmacokinetic interactions (due to the displacement of the antidiabetic from plasma proteins or alteration in its metabolism or excretion) or pharmacological interactions with drugs having an independent effect on blood glucose. In the former class most reports concern older sulfonylureas such as chlorpropamide and tolbutamide, although the possibility of such reactions with newer drugs should be borne in mind.

A diminished hypoglycaemic effect, possibly requiring an increased dose of sulfonylurea, has been seen or might be expected on theoretical grounds with adrenaline, aminoglutethimide, chlorpromazine, corticosteroids, diazoxide, oral contraceptives, rifamycins, thiazide diuretics, and thyroid hormones.

An increased hypoglycaemic effect has occurred or might be expected with ACE inhibitors, alcohol, allopurinol, some analgesics (notably azapropazone, phenylbutazone, and the salicylates), azole antifungals (fluconazole, ketoconazole, and miconazole), chloramphenicol, cimetidine, clofibrate and related compounds, coumarin anticoagulants, fluoroquinolones, heparin, MAOIs, octreotide (although this may also produce hyperglycaemia), ranitidine, sulfinpyrazone, sulfonamides (including cotrimoxazole), tetracyclines, and tricyclic antidepressants.

Beta blockers have been reported both to increase hypoglycaemia and to mask the typical sympathetic warning signs. There are sporadic and conflicting reports of a possible interaction with calcium-channel blockers, but overall any effect seems to be of little clinical significance.

In addition to producing hypoglycaemia alcohol can interact with chlorpropamide to produce an unpleasant flushing reaction. Such an effect is rare with other sulfonylureas and alcohol.

ACE inhibitors. There are sporadic reports of marked hypoglycaemia developing in patients taking a sulfonylurea who are given an ACE inhibitor (mainly captopril or enalapril) and 2 case-control studies have indicated that the combination is associated with an increased risk of developing severe hypoglycaemia. However, other studies have failed to find much evidence of a problem.

Alcohol. Sulfonylurea-induced alcohol intolerance is seen mainly but not exclusively with chlorpropamide this is similar to the disulfiram-alcohol interaction, although it is not clear whether the mechanism is the same. Since the main symptom of the reaction (facial flushing) appears to occur more commonly in diabetic than non-diabetic subj ects, it has been proposed that this symptom could be used as a diagnostic test for a certain subset of patients with type 2 diabetes mellitus. However, some have not considered the test to be sufficiently specific and despite a great deal having been published on the chlorpropamide-alcohol flushing test (CPAF), its value remains poorly defined. Alcohol, as well as provoking a flushing reaction with chlorpropamide, has been reported both to increase and to decrease the half-life of tolbutamide depending on whether the alcohol administration was acute or chronic. Alcohol may also have a variable effect of its own on blood-glucose concentrations there is a general tendency to increased hypoglycaemia when alcohol and sulfonylureas are taken concurrently.

Analgesics. Phenylbutazone and related drugs such as azapropazone have been associated with acute hypoglycaemic episodes when given to patients receiving sulfonylureas (in most reports, tolbutamide). Other analgesics may enhance the hypoglycaemic effect of sulfonylureas, including indobufen fenclofenac and the salicylates. Although a study in healthy subjects found no interaction, there has been a report of hypoglycaemia with ibuprofen in a diabetic patient who had been stabilised on glibenclamide.

Antibacterials. Chloramphenicol markedly inhibits the metabolism of tolbutamide and increases its half-life, which can result in hypoglycaemia. Sulfonamides, including cotrimoxazole may also enhance the hypoglycaemic effects of the sulfonylureas. There have been rare reports of elevated glibenclamide concentrations and hypoglycaemia when ciprofloxacin was given to patients who were on stable glibenclamide therapy. For reports of hypoglycaemia when gatifloxacin was given to patients already receiving a sulfonylurea (glimepiride in one case, and glibenclamide plus pioglitazone in another). There have also been a few cases of severe hypoglycaemia when clarithromycin was added to glibenclamide or glipizide renal impairment may have played a role in these cases. Rifampicin (and probably other rifamycins) can enhance the metabolism and decrease the effect of tolbutamide, chlorpropamide, and glibenclamide and dosage of the hypoglycaemic drug may need to be increased. The effects on glipizide and glimepirideappear to be less pronounced.

Anticoagulants. Dicoumarol increases serum concentrations and therefore the hypoglycaemic effects of tolbutamide, and possibly chlorpropamide. In addition, sulfonylureas may affect anticoagulant function.

Antiepileptics. For references to phenytoin toxicity when tolbutamide or tolazamide was given, see under Phenytoin.

Antifungals. Increased plasma concentrations of tolbutamide have been reported when fluconazole was given, but there was no evidence of hypoglycaemia, and no hypoglycaemic symptoms were seen in 29 women receiving gliclazide or glibenclamide who were given fluconazole or clotrimazole for vulvovaginitis. A study in healthy subjects found that fluconazole increased plasma concentrations of glimepiride, but again there was no significant effect on glucose concentrations. However, there are reports of hypoglycaemia in a patient who took fluconazole with glipizide, and another who took fluconazole and cotrimoxazole with gliclazide. Similar interactions have been reported for ketoconazole (with tolbutamide, in healthy subjects)and miconazole (with tolbutamide, in a diabetic), suggesting that such combinations should be regarded with caution.

Ciclosporin. For the effect of glibenclamide on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Metformin. Results apparently suggesting increased mortality in patients who received intensive drug therapy with metformin and a sulfonylurea were reported by the UK Prospective Diabetes Study. This was considered to be artefactual, since it was not confirmed by epidemiological analysis, and such combinations are widely used in practice, but some concern remains and further study is needed.

Thyroid hormones. It has been suggested that starting thyroid replacement therapy may increase the requirement for insulin or oral antidiabetic drugs in diabetic patients, which would not seem unreasonable given the stimulant effects of thyroid hormones on metabolic function. For a discussion of the mooted effects of sulfonylureas on thyroid function, see under Precautions, above.

Uses and Administration

The sulfonylurea antidiabetics are a class of oral antidiabetic drugs used in the treatment of type 2 diabetes mellitus. They are given to supplement treatment by diet modification when such modification has not proved effective on its own, although metformin is preferred in patients who are obese. Sulfonylureas appear to have several modes of action, apparently mediated by inhibition of ATP-sensitive potassium channels. Initially, secretion of insulin by functioning islet beta cells is increased. However, insulin secretion subsequently falls again but the hypoglycaemic effect persists and may be due to inhibition of hepatic glucose production and increased sensitivity to any available insulin this may explain the observed clinical improvement in glycaemic control. The duration of action of sulfonylureas is variable drugs such as tolbutamide are relatively short-acting (about 6 to 12 hours) while chlorpropamide has a prolonged action (over 24 hours).

Sulfonylurea therapy may be combined with metformin or other oral hypoglycaemics in patients who fail to respond to a single type of drug such combination therapy is usually tried (in the absence of contraindications) before considering the addition of, or transfer to, insulin therapy.