Link to [[2.1.7.1.2 Sulphonylureas Teaching Resources]]
Link to [[Problems for Discussion- 2- Biguanides, Sulphonylureas and Insulin|Problems for Discussion]]
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=Sulphonylureas=

==DRUGS INCLUDED IN THIS CATEGORY==

* Acetohexamide
* Chlorpropamide
* Glibenclamide (Glyburide)
* Glibornide
* Gliclazide
* Glimepiride
* Glipizide
* Gliquidone
* Tolazamide
* Tolbutamide

See also [[2.1.7.1.3.1 Biguanides|biguanides]]

==OVERVIEW==

The toxicity of sulphonylureas in overdose is due to hypoglycaemia. The duration of the hypoglycaemic effect depends on the drug ingested (half-life/duration of action), the dose ingested and renal function, age and other factors that may prolong the duration of action of these drugs.

Treatment is with 50% glucose IV, food (and lots of it) and close observation. Octreotide may have a role in resistant cases.

==MECHANISM OF TOXIC EFFECTS==

Sulphonylureas stimulate the release of insulin from the pancreatic islet cells. The earliest event in glucose-stimulated insulin secretion is a decrease in potassium movement out of the cell. This causes the opening of calcium channels and the ensuing movement into the cell of calcium triggers insulin release. Sulphonylureas work by potentiating this sequence of events. They increase [[Factitious Hypoglycaemia|release]] but not synthesis of insulin.

They also have other minor actions, increasing the sensitivity of peripheral tissues to insulin, decreasing the production of [[3.3.1.3.2 Glucagon|glucagon ]]and increasing somatostatin release. In overdose, these drugs may be more toxic to non-diabetics, who do not have insulin resistance (i.e. diabetics are less sensitive to insulin).

==KINETICS IN OVERDOSE==

===Absorption===
All sulphonylureas are well absorbed and have high bioavailability.

===Distribution===
They are 90 to 99% protein bound and have a volume of distribution of about 0.2 L/kg.

===Metabolism - Elimination===
The major difference between these drugs is the duration of action, which is closely related to their half-life. Second generation sulphonylureas are more potent but have quite short half-lives. However, their duration of action is somewhat longer than would be expected from their half-life alone.

Further, the half-life of elimination varies according to the dose. For glibenclamide, it is 1.4 to 2.9 hours following therapeutic doses. The half-life was 6 hours in a patient who ingested 100 mg and 37 hours in a 25-year-old patient who ingested 250 mg. A terminal half-life of 199 hours was reported in a young diabetic patient who surreptitiously ingested glibenclamide. As a result the duration of hypoglycaemia after glibenclamide overdose may be very prolonged. Recurrent hypoglycaemia is a problem in about half the cases and the required duration of treatment required varies from 6 to 72 hours or more. In at least one case, glucose infusions were required for 5 days. Even after daily administration of usual therapeutic doses, hypoglycaemia may occur up to 2 days after the last dose.

===Pharmacokinetic parameters of importance to sulphonylurea overdose===
* Figures are for therapeutic use and may be later/longer in overdose: information from Harrower, 1996; Seger, 1988; Marchetti & Navalesi, 1989; Marchetti et al, 1991, Robertson & Home, 1993)
|| || **Time to maximum concentration (h)** || **Urinary Excretion** || **Half-life (h)** || **Duration of action (h)** || **Prolonged action in renal failure** ||
|| Acetohexamide 1-hydroxyhexamide * || 2 - 5 || 0% ?100%* || 0.8 - 2.4 || 10 - 18 || Yes ||
|| Chlorpropamide || 2 - 6 || 20% || 25 - 60 || 24 - 72 || Yes ||
|| Glibenclamide (Glyburide) || 2 - 6 || 3% || 2 - 4 || 16 -24 || Yes ||
|| Glibornide || || || 5 - 12 || 16 - 24 || No ||
|| Gliclazide || || < 5% || 10 - 23 || 16 - 24 || No ||
|| Glipizide || 1.5 - 3.5 || < 5% || 2 - 4 || 16 - 24 || No ||
|| Gliquidone || || < 5% || 24 || ?24 || No ||
|| Tolazamide || 2 - 5 || 7% || 4 - 8 || 12 - 14 || Minor ||
|| Tolbutamide || 2 - 5 || 2% || 4 - 10 || 6 - 12 || ||
* active metabolites
Peak concentration has occurred much later (> 28 h) in overdose (Palatnick et al, 1991).

==CLINICAL EFFECTS==

===Hypoglycaemia===
The onset of clinical effects from hypoglycaemia may be very rapid but also quite late (up to 48 hours with chlorpropamide overdose and 24 hours with other sulphonylureas (Palatnick et al, 1991).

Paediatric ingestions generally become symptomatic within 8 hours (Spiller et al, 1997). Clinical effects are predominantly due CNS effects of hypoglycaemia (confusion, coma, seizures, cerebral oedema) and to the effects of reactive sympathetic stimulation (tachycardia, sweating, tremor, ischaemic chest pain).

===Other effects===
Aspiration pneumonia or pulmonary oedema is sometimes seen particularly after seizures or prolonged hypoglycaemia. Hypokalaemia, and other electrolyte imbalance, often occurs during prolonged treatment with glucose.

==INVESTIGATIONS==

===Blood glucose===
Blood glucose should be measured at least hourly for at least 6 to 8 hours. This is usually sufficient for accidental ingestions, but larger overdoses should be observed for at least 24 hours (Palatnick et al, 1991). Subsequent frequency will depend on the clinical situation and previous results. If glucose treatment is required, then measurements should be made for 6 to 8 hours after glucose has been ceased.

Normal range 4.2-6.4 mmol/L (75-115 mg/dL)

Conversion factor
* mg/dL x 0.555 = mmol/L
* mmol/L x 18 = mg/dL

===Biochemistry===
Renal function should be measured as some of these drugs or their active metabolites are renally eliminated. Poor renal function will mean a longer duration of potential hypoglycaemia. Hypokalaemia may occur if large amounts of glucose are required. Insulin and glucose move potassium from the extracellular to the intracellular compartment. Hyponatraemia may occur due to inappropriate ADH secretion/increased ADH sensitivity in chlorpropamide (and perhaps tolbutamide) overdose and from excessive water given with glucose.

===Blood concentrations===
Blood concentrations of sulphonylureas are unhelpful in acute management but may be able to differentiate hypoglycaemia from overdose from therapeutic misadventures and help in sorting out [[Factitious Hypoglycaemia|factitious hypoglycaemia]].

===ECG===
The ECG should be monitored if significant hypokalaemia occurs.

==DIFFERENTIAL DIAGNOSIS==

A rapid response to glucose in a patient who has coma and/or seizures strongly suggests hypoglycaemia. There are a number of other drugs that may cause hypoglycaemia in overdose other than [[2.1.7.1.1 Insulin|insulin]] and sulphonylureas. [[3.4.3.4.2 Beta-blockers|Beta-blockers]], [[2.1.1.4 Salicylates|salicylates]] and [[2.1.11.5.1 Acute Management of Alcohol Problems|alcohol]] would be the most important drugs to consider but should be readily differentiated on clinical grounds.

Factitious hypoglycaemia (overdose with sulphonylureas or insulin overdose) and insulinoma can be distinguished by a combination of insulin, C-peptide and drug concentrations (Lebowitz & Blumenthal, 1993).

==DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS==

The major difference relates to their onset of action, their duration of action, and whether they will accumulate in patients with renal impairment (see pharmacokinetic properties).

==TREATMENT==

===Supportive===
IV access should be secured as soon as possible. If there is any doubt as to whether the patient is thiamine deficient (e.g. alcohol abuse, anorexia nervosa), then [[Thiamine|thiamine]] should be given IMI. If prolonged use of very hypertonic solutions (i.e. 25 or 50% glucose) is likely to be required, then a central line should be inserted. Avoid drug interactions that may increase sulphonylurea concentrations by displacing them from protein binding or reducing their elimination (Scheen & Lefebvre, 1995).

===Glucose===
Intravenous glucose (50%) should be given to all symptomatic patients. A prolonged infusion may be necessary. Lower concentrations of glucose have very low caloric value and will be unable to maintain blood sugar without requiring massive water overload. If patients are able to eat, they should be encouraged to eat small but very frequent carbohydrate-based meals (see [[Caloric Content|caloric content of IV glucose and some foods]]). The blood glucose should be maintained above 3.5 mmol/L (60 mg/dL). If this is not possible with food and glucose, the use of octreotide or [[Diazoxide|diazoxide]] should be considered.

===GI Decontamination===
Oral [[3.2.2.2.3 Activated charcoal|activated charcoal]] should be given to all patients who have ingested these drugs within the last 1-2 hours. Many of these drugs are quite slowly absorbed (Neuvonen et al, 1983), and if there is any doubt charcoal should be administered.

[[3.2.2.2.2 Gastric lavage|Gastric lavage]] without intubation should be avoided due to the risk of sudden onset of coma or seizures.

===Antidotes===
**Octreotide**
Octreotide, a somatostatin analogue, suppresses insulin release and has been used in a randomised controlled trial of glipizide overdose in volunteers with dramatic success (Boyle et al, 1993). It was dramatically more effective than diazoxide & glucose or glucose alone in combating hypoglycaemia.

In patients, it has been shown to reduce hypoglycaemic episodes following sulphonylurea poisonings although patients still require frequent monitoring. The duration of admission is still likely to be determined by the duration of action of the ingested drug. Octreotide would appear to be the best second line therapy if dextrose and feeding does not maintain adequate euglycaemia. The initial dose is not well defined but appears relatively low in case series. Our starting dose would be 0.05 mg SCI repeated at 8 or 12 intervals if needed.

**Diazoxide**
[[Diazoxide]], has a similar effect on insulin release to octreotide, and has been used more widely in patients (Palatnick et al, 1991). Bolus doses (300 mg slow IVI, PRN) and infusions (50 to 100 mg/hr IV) have both been used. The blood pressure should be monitored but is unlikely to be a problem if the patient is not upright or dehydrated. Glucagon is not recommended in sulphonylurea overdose. It relies on hepatic glycogen stores for its effect and in severe overdoses these are likely to be exhausted. Corticosteroids are ineffective for similar reasons. Glucagon also stimulates insulin release from the pancreas and thus may potentially worsen the situation.

===Treatment of specific complications===
**Seizures**
These should be treated with IV glucose. Late onset or prolonged [[Status Epilepticus and Treatment of Seizures|seizures]] may be due to CNS damage. If there is no hypoglycaemia, then diazepam and phenytoin would be appropriate.

Phenytoin also inhibits the secretion of insulin from the pancreas in high doses! (Malherbe et al,1972)

**Cerebral oedema and severe brain injury**
The patient who remains comatose despite normal blood glucose has generally sustained a significant neurological insult if there is no other drug ingestion. Raised intracranial pressure often occurs in this situation. The treatment is similar to raised intracranial pressure from any brain injury and includes hyperventilation, raising the head of the bed, blood pressure control, mannitol and fluid restriction. In this context, it is important that the treatment of hypoglycaemia is not exacerbating the neurological injury. So the highest concentrations of glucose (50%) only should be used, and if diazoxide or sodium bicarbonate are given this should be done cautiously to avoid fluid overload. A central venous line is essential to administer glucose and monitor hydration.

===Elimination enhancement===
Due to the lack of significant enterohepatic circulation of these drugs, there is unlikely to be significant benefit from [[3.2.2.2.3.1 Repeated doses of Activated Charcoal|repeated doses of activated charcoal]]. The renal excretion of chlorpropamide is enhanced in an alkaline urine, so giving small doses of sodium bicarbonate to [[Alkaline Diuresis and Ion Trapping|raise the urinary pH]] to > 7.5 is recommended. The clearance of other sulphonylureas is not altered. Oral antacids may enhance the absorption of sulphonylureas, therefore if bicarbonate is required it should be given IV early after the ingestion (Neuvonen & Kivisto, 1994). The half life of chlorpropamide can be reduced by charcoal [[3.2.3.1.2 Charcoal Haemoperfusion|haemoperfusion,]] although this would not usually be warranted (Ludwig et al, 1987).

==LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP==

Long term sequelae commonly occur if there has been a prolonged period of hypoglycaemia. Patients should be routinely followed up if there is any doubt and have neuropsychiatric evaluation. Almost any type of neurological damage may occur, although lesions have typically been reported in "watershed" areas of the brain (Kaiser et al, 1981).

==REFERENCES==

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