Sulfonylurea toxicity

Hypoglycaemia can occur at therapeutic doses especially in those who develop renal impairment. In overdose these drugs cause a profound and prolonged hypoglycaemia, usually apparent within 8 hours post ingestion of a standard preparation. The sulfonylureas consist of glibenclamide, gliclazide, glimepiride and gliplizide.

Toxic Mechanism:

They inhibit potassium efflux in the beta cells of the pancreas. As a result insulin is released resulting in a hyperinsulinaemic state.

Toxicokinetics: 

• Well absorbed
• Peak levels at 4 – 8 hours
• Volumes of distribution are variable but small
• Elimination half life is also variable but prolonged in overdose
• Metabolised in the liver and renal excretion

Resuscitation:

• Hypoglycaemia (<4.0 mmol/L):
  • Adult: 50ml bolus of 50% dextrose IV, repeat as required
  • Children: 2 ml/kg of 10% dextrose IV, repeat as required
  • Repeated hypoglycaemia: commence 10% glucose infusion, starting at 100ml and hour and monitor the blood glucose (children start maintenance fluids with o.9% saline and 5% dextrose +/- potassium). If further episodes of hypoglycaemia occur, treat with another bolus.
  • Ultimately the dextrose is partly a temporising measure until octreotide can be given to halt the process
  • Supplement potassium to a low-to-normal range.

Risk Assessment

• Ingestion of one tablet in the non-diabetic patient can cause a profound hypoglycaemia
• Onset of hypoglycaemia is usually within 8 hours (longer if extended release preparations, 18 hours and can be delayed up to 48 hours later)
• Hypoglycaemia is profound and prolonged (up to several days)
• Recent impairment of hepatic or renal function will predispose patients to hypoglycaemia even at therapeutic doses (the elderly are particularly vulnerable).
• Children: One tablet can cause fatal hypoglycaemia

Supportive Care

• Hypoglycaemia, if present can be managed with dextrose.
• It is rare that higher doses of dextrose will be required once octreotide has commenced, however if greater than 100ml of 10% dextrose in adults or maintenance in paediatrics (0.9% saline + 5% dextrose solution) is required consider a central line to administer higher concentrations of dextrose.

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level
• Specific:
  • Regular blood glucose at least hourly until the patient is stable on octreotide
  • EUC – monitor potassium and renal function

Decontamination:

• 50 grams of charcoal to the co-operative patient who presents <1 hour with a standard preparation or <4 hours with a modified release preparation.
• Paediatric dose 1 g/kg

Enhanced Elimination

• Not clinically useful

Antidote

• Octreotide
• Do not start the antidote until a documented hypoglycaemia has occurred, equally giving boluses of dextrose without an episode of hypoglycaemia complicates the risk assessment.
• Once hypoglycaemia does occur may sure you have enough supply of octreotide

Disposition

• All children require blood sugar level monitoring for 18 hours before medical clearance with advice to the parents.
• Adults require 8 hours of monitoring for standard preparations and 12 hours of monitoring for modified release. If asymptomatic and euglycaemic they can be medically cleared with advice (do not discharge at night)
• All symptomatic patients and those receiving treatment require admission and can be medically cleared once they can maintain euglycaemia on a normal diet for 12 hours post octreotide discontinuation.
• If hypoglycaemia occurred on therapeutic dosing they require management of any underlying disease and an endocrine review for ongoing therapy.

References and Additional Resources:

Additional Resources:

• CCC – Octreotide
• Tox Conundrum 029 – Two pills can kill
• Tox Conundrum 037 – Hypoglycaemia

References:

• Harrigan RA, Nathan MS & Beattie P.  Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity and treatment. Annals of Emergency Medicine 2001; 38:68-78
• Lung DD, Olson KR. Hypoglycaemia in paediatric sulfonylurea poisoning: an 8-year poison centre retrospective study. Paediatrics 2011; 127:e1558
• Spiller HA et al. Prospective multicenter study of sulfonylurea ingestion in children. Journal of Pediatrics 1997; 131:141-146.