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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Gastrointestinal and Endocrinal Drugs

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Sulfonylureas - Oral Hypoglycaemics

Sulfonylureas are antidiabetic agents that lower blood glucose in non-insulin dependant diabetics by directly stimulating the acute release of insulin from functioning beta cells of pancre-atic islet tissue.

Sulfonylureas

Sulfonylureas are antidiabetic agents that lower blood glucose in non-insulin dependant diabetics by directly stimulating the acute release of insulin from functioning beta cells of pancre-atic islet tissue.

Uses

·              Treatment of NIDDM patients who cannot achieve appro- priate control with changes in diet alone.

·              Sulfonylureas are contraindicated in IDDM, pregnancy, lactation, and liver and kidney disease.

Toxicokinetics

Sulfonylureas are rapidly absorbed on oral administration, are highly protein-bound, and are subjected to extensive hepatic metabolism

Adverse Effects

■■   Severe hypoglycaemia, especially in elderly patients and those with hepatic or renal impairment.

■■   Cholestatic jaundice.

■■   Agranulocytosis, thrombocytopenic purpura, aplastic anaemia, haemolytic anaemia.

■■   Vomiting, epigastric pain.

■■   Sensitivity reactions.

Drug Interactions

■■   Hypoglycaemic effect of sulfonylureas is increased by salicylates, coumarin anticoagulants, phenylbutazone, sulfonamides, MAOIs, chloramphenicol, cimetidine, and beta blockers.

■■   Hypoglycaemic effect is reduced by barbiturates, phenytoin, rifampicin, oestrogens, corticosteroids, furose-mide, thiazides, and sympathomimetic drugs.

■■   Alcohol can cause a disulfiram -like reaction with first generation sulfonylureas. Some investigators claim that such a reaction can also occur with second generation drugs such as glipizide and glibenclamide.

■■ There are indications that long-term use of tolbutamide may be associated with increased susceptibility to myocardial infarction.

Clinical (Toxic) Features

·              CNS: Confusion, lethargy, slurred speech, restlessness, dizziness, delirium, convulsions, opisthotonus. The following have been reported —monoplegia, hemiplegia, ataxia, extensor plantar response, absent deep tendon reflexes, and athetoid movements. Decerebrate posture, coma, and death may supervene.

·              Eye: Normal or dilated.

·              Skin: Hot, sweaty, sensitivity reactions.

·              GIT: Vomiting, abdominal pain.

·              RS: Dyspnoea, pulmonary oedema, apnoea.

·              CVS: Tachycardia, hypotension.

·              Renal: Proteinuria, oliguria.

·              Hepatic: Cholestatic jaundice.

·              Blood: Agranulocytosis, pancytopenia, aplastic anaemia,thrombocytopenia.

·              Though sulfonylureas are generally not recommended to be given in pregnancy, some reports indicate that drugs such as glyburide may be relatively safe.

Diagnosis

·              Blood levels of sulfonylureas do not correlate well with Blood levels of sulfonylureas do not correlate well with Frequent measurement of blood sugar levels is important.

·              Arterial blood gases and serum potassium levels may reveal a hypokalaemic metabolic acidosis.

·              Leukocytosis is often present.

·              ECG: may show sinus tachycardia, T-wave inversion or ST elevation.

Treatment

·              Stabilisation: Endotracheal intubation and assisted ventila- tion may be required.

·              Treatment of hypoglycaemia: Hypoglycaemic episodes may last for several days; prolonged treatment may be required.

o     Glucose: 50 ml, 50% glucose as IV bolus, followed by IV infusion of 10% glucose in water (for upto 24 to 48 hours).

o     Glucagon: 1 to 2 mg, IM (or SC or IV), can help in raising blood sugar. It may have to be repeated every few hours.

o     Diazoxide: It is an inhibitor of insulin secretion, and can be given orally (200 mg every 4 hours), for several days.

o     Dexamethasone: Some reports suggest beneficial effects with dexamethasone when administered early.

·              Alkaline diuresis: Sodium bicarbonate has been shown to enhance elimination of chlorpropamide.

·              Decontamination: Emesis can be induced in the alert patient if seen within 4 to 8 hours. In the convulsive or comatose patient, gastric lavage can be done (after endotracheal intubation). Activated charcoal is beneficial.

·              Treatment of hypotension: Trendelenberg position, IV fluids, pressor amines.

·              Treatment of convulsions: Benzodiazepines or phenytoin.

·     Treatment of cerebral oedema: Mannitol and dexametha-sone.

·     Other measures: Octreotide has been shown to be beneficialin suppressing plasma insulin. Dose – 50 mcg, every 12 hours, subcutaneously.

 

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