Presentation includes an account on overview about oral anti diabetics, toxicity of sulfonylureas, biguanides, alpha-glucosidase inhibitors, DPP4 inhibitor, SGLT2 inhibitor and its managemnt.

1. TOXICOLOGYOF
ORALANTIDIABETIC
MEDICATIONS
DR KTD PRIYADARSHANI
REGISTRAR IN EMERGEMCY MEDICINE
2023/04/10

2. SCOPE
 Overview
 Toxicity of Sulfonylureas
 Toxicity of Biguanides
 Alpha Glucosidase inhibitors
 DPP 4 inhibitors
 SGLT 2 inhibitors and Euglycemic
DKA

3. OVERVIEW
 Type 2 Diabetes is increasing to near
pandemic proportions.
 Two groups of antidiabetics
1)hypoglycemic agents- sulfonylureas,
meglitinides
2)anti hyperglycemic- biguanides and
alpha glucosidase inhibitors
 The hypoglycemic agents pose a significant
mortality and morbidity and permanent
sequelae of prolonged hypoglycemia.
 But with timely interventions may results
better outcome.

4. SULFONYL
UREAS
 Commonly used oral antidiabetic agent.
 Glibenclamide
 Gliclazide
 Glipizide
 Overdose is common (in US >4000 cases
annually to the poison center)
 The primary pharmacologic effect is
hyperinsulinemia.
 In overdose clinical effects occurs
secondary to hypoglycemia.

6. Toxicokinetic
 Well absorbed
 Peak level 4-8 hours
 Elimination t1/2 – variable and prolonged in
overdose
 Onset of hypoglycemia
 acute overdose occurs in less than 8 h.
 chronic mis dosing- delayed for few days.

7. Clinical
features
 Occurs primarily for two reasons
 neuroglycopenic effect
 counter regulatory hormone response
 Neurological effects
 Most important
 Occurs direct reduction of intracellular ATP
mainly in neurons
 Counter regulatory hormone response
(epinephrine, Norepinephrine, Cortisol, Growth
hormone)
 Tachycardia
 diaphoresis

8. Resuscitation
 A, B
 C
 D
 Hypoglycemia (<4 mmol/L)
 Adult- 50 ml bolus of 50 % dextrose IV, repeat as
required
 Children- 2ml/kg of 10% dextrose IV repeat as
required
 Repeated hypoglycemia
 10% glucose infusion- starting at 100ml/hr and
monitor the blood glucose
 Children – maintenance 0.9% NS+ 5% Dex +/-
potassium
 Supplement potassium to a low- normal range

9. Risk
assessment
In nondiabetic- 1 tablet can cause
profound hypoglycemia
Hypoglycemia is profound and prolonged
( up to several days)
Hepatic or renal impairment
Children- 1 tablet can cause fatal
hypoglycemia

10. Decontamination
Activated charcoal – 50 g
Standard preparation <1hr
Modified release <4hrs
Pediatric 1g/kg

11. Antidote
retrospectivecaseseriesand
individual casereports
 Octreotide is a synthetic somatostatin
analogue
▪ binds somatostatin type 2 receptor in pancreatic beta cells
▪ inhibit opening of Ca+ channels
▪ reduces Ca+ influx
▪ reduce release of insulin
 BSL <4mmol/L
 50 microg IV
 Infusion 25 microg/hr
 Alternatively give 100 microg SC or IM every 6 hours-
breakthrough hypoglycemia may occur
 Euglycemia- 12 hours

12. Disposition
 Asymptomatic pt
▪ Direct clinical observation with
repeated blood glucose in 1-2 hourly
for initial 8h.
▪ Can take food and drink
▪ Observation
▪ Children – 18 hours
▪ Adult 8 hours- 12 hours

13. BIGUANIDES
 Metformin
 Poorly and slowly absorbed
 In massive overdose absorption may be prolonged.
 Peak concentration 2-3.5 hrs
 Renal excretion unchanged 90- 100%
 Oral bioavailability 40 - 60%.
 Overdose >10 g ( children > 1.7g)
 Metformin associated lactic acidosis(MALA) is the
common complication.
 MALA incidence is 3-9 in 100000 cases.

14.  Metabolic effects
 Lactic acidosis +
large anion gap
(Profound lactic
acidosis may take 4-
8h,persist 24-48h
post ingestion.)
 Hyperkalemia
 Hypoglycemia- not
common
 Cardiac effects
 Hypotension &
tachycardia >
cardiogenic shock
 CNS effects
 Nausea & vomiting
 Delirium, sedation,
coma
 Seizures
 Other
 Tachypnea
 Hypothermia
 ARF
 PE, Pneumonia
 Metformin induced
acute pancreatitis.
Clinical
features

17. MILA MALA MULA
• High levels of metformin are
the primary cause of illness.
• Acute metformin overdose:
• Precise amount of metformin required
to do this is unclear, but seems to be
high (e.g., >20 grams).)
• Patients with acute ingestion look fine
initially, but deteriorate subsequently
• Subacute accumulation of metformin due
to renal failure:
• Metformin is renally cleared.
• Progressive renal failure (with GFR <<
30 ml/min) eventually leads to
metformin accumulation and toxicity.
• These patients may present with
marked lactic acidosis, yet have fairly
preserved hemodynamics and look
OK.
• Patient on metformin
develops an acute life-
threatening illness (e.g.
,septic shock, cardiogenic
shock).
• Metformin amplifies the
degree of lactic acidosis,
but it's not the sole cause
of the illness.
• Risk factors include renal
insufficiency, higher doses
of metformin, and
alcoholism
• Metformin is an
innocent
bystander. Metf
ormin levels
are low.
• Clinically it may
be impossible to
differentiate this
from MALA.

18. Resuscitation
 Rarely required
 A
 B
 Tachypneic?
 need for ventilation
 C
 Hypotension, Cardiogenic shock
 monitor
 IV Fluids
 D
 RBS
 Dextrose

19. Risk
assessment
 Patient factors
 Elderly (>60)
 Comorbidities
 Diabetes
 Overdose
 Hypotension
 Renal failure
 Low pH on presentation (pH <7)
 Low bicarbonate on presentation (HCO3 <6 mmol/L)
 High lactate (>17 mmol/L)
None of these are good predictors of outcome

20. Investigations
ABG – in regular intervals
SE
RBS
RFT
ECG- continuous monitoring in severe
acidosis or hyperkalemia

21. Decontamination
 Activated charcoal 50 g - slow absorption
(<2hr)
 Repeated doses- unlikely to be benefited

22. Enhanced
elimination
 Clearance is enhanced by hemodialysis
 No clear cut indications for hemodialysis but in
favor if clinical instability, renal failure or
electrolyte imbalance present.
 HD correct the acid base disturbance.
 Normalize potassium and sodium
 Effectively removes metformin and lactate from
plasma.
 In unstable pt, veno venous renal replacement
has been recommended.

23. Antidotes
Acidosis
 Bicarbonate – rapid correction of acidemia (1-2
mmol/kg)
 Worsens intracellular & CNS acidosis-CO2 cross BBB
 Decreased oxygen deliver (ODC)
 No evidence to support though it is common treatment
Dichloroacetate
 Stimulate pyruvate dehydrogenase, decrease
glycolysis ( decrease lactate formation), increase
gluconeogenesis
 50 mg/kg as a 10% solution infused over 30 min
repeated 2 hours later
 Stacpoole et al, 1992- effective in reducing lactic
acidosis but no effect on outcome

24. Disposition
>10g
admit and observe – 8 hours
Unwell with lactic acidosis
Hemodialysis
HDU/ICU care

25. Alpha
Glucosidase
inhibitors
( acarbose ,
miglitol)
 Competitively and reversibly inhibit
glucoamylase, sucrase, maltase and isomaltase
in brush border cells in Small intestine.
 Less than 2% of acarbose is absorbed as the
parent drug due to large molecular size.
 No reported overdose with serious
complications.
 Diarrhea and abdominal pain reported as
adverse effects in therapeutic dose and hepatic
injury with chronic use.
 Does not cause hypoglycemia with
monotherapy but expected to cause
hypoglycemia in overdose.

26. Sitagliptin
 DPP-4 inhibitor
 Break down of incretin hormone
 Hypoglycemia is potential risk in overdose.
 Correct hypoglycemia promptly.
 If awake oral glucose followed by carbohydrate
meal.
 Unconscious 250 ml of IV 10% dextrose/125 ml of
IV 20% dextrose followed by 10% glucose 100ml/h.
 Glucagon 1-2mg IM in adults and 1mg in children
>25kg/0.5mg in <25kg, if IV access difficult. Effects
depend on glycogen stores.

27. SGLT 2
inhibitors
(Empagliflozin
, canagliflozin)
Euglycemic DKA (RBS <250 mg/dL)
 The mechanism is unclear.
 Leads to decrease both endogenous and
exogenous insulin.
 Increase glucagon production.
 Evidence are limited to case reports.
 Management is almost similar to DKA
 Hydration
 Insulin & dextrose
 Supportive care

28. References
1. Wikitox
2. Life in the fast lane
3. Management of Poisoning” Second Revised and Updated Edition.
Published by the National Poisons Information Centre, Colombo.
Sponsored by the World Health Organization. 2002. ISBN 955-8083-
02-3
4. American Journal of Health-System Pharmacy Toxicology of Oral
Antidiabetic Medications Henry A. Spiller; Tama S. Sawyer
DISCLOSURES Am J Health Syst Pharm. 2006;63(10):929-938.
5. American journal of health-system pharmacy: AJHP: official journal of
the American Society of Health-System Pharmacists 63(10):929-3
DOI:10.2146/ajhp050500