Drug Interactions of Antidiabetics (Part 3):Interactions of SULFONYLUREAS:

1
Drug Interactions of antidiabetics(PART 3)

• Dr.P.Naina Mohamed
• Pharmacologist

2
ORAL Antidiabetic Drugs

• Secretagogues
• Sulfonylureas
• First-generation agents
• Tolbutamide (Orinase)
• Acetohexamide (Dymelor)
• Tolazamide (Tolinase)
• Chlorpropamide (Diabinese)
• Second-generation agents
• Glipizide (Glucotrol)
• Glyburide or Glibenclamide (Diabeta, Micronase,
  Glynase)
• Glimepiride (Amaryl)
• Gliclazide (Diamicron)
• Glycopyramide
• Gliquidone.

3
Sulfonylureas azole antifungals

• Sulfonylureas
• Azole Antifungals (Fluconazole, Itraconazole,
  Ketoconazole, Miconazole, Variconazole)
• Azole antifungals inhibit CYP2C9
• Inhibition of metabolism of sulfonylureas
• Accumulation of sulfonylureas
• Increased Risk of Hypoglycemia
• Concurrent use need not be avoided.
• But it should be monitored and the dose of the
  sulfonylurea reduced if necessary.

4
Sulfonylureas fibrates

• Sulfonylureas
• Fibrates (clofibrate, bezafibrate, ciprofibrate,
  fenofibrate and gemfibrozil)
• Fibrates inhibit CYP2C9
• Inhibition of metabolism of sulfonylureas
• Accumulation of sulfonylureas
• Exacerbation of hypoglycemia
• Fibrates may induce displacement of the
  sulfonylureas from their plasma protein binding
  sites, alterations in their renal excretion, and
  a decrease in insulin resistance which exacerbate
  hypoglycemia.
• Concurrent use of sulfonylureas and fibrates may
  not be avoided.
• The dose of the antidiabetic may need adjustment.
  
• Patients should be warned that excessive
  hypoglycaemia occurs occasionally and
  unpredictably.

5
Sulfonylureas Sulfonamides

• Sulfonylureas
• Sulfonamides
• Sulfonamides inhibit CYP2C9
• Inhibition of metabolism of sulfonylureas
• Accumulation of sulfonylureas
• Warn the patient that increased blood
  glucose-lowering effects is expected.
• The cautious approach would be to increase the
  frequency of blood glucose monitoring.
• Among sulfonamides Sulfaphenazole is a potent
  inhibitor of CYP2C9, with sulfadiazine,
  sulfamethizole, sulfafurazole (sulfisoxazole) and
  sulfamethoxazole being moderate to minor
  inhibitors, and sulfapyridine, sulfadimethoxine
  and sulfamonomethoxine having little inhibitory
  activity.

6
Sulfonylureas macrolides

• Sulfonylureas (Glibenclamide or Glipizide)
• Macrolides (Erythromycin, Clarithromycin)
• Inhibition of CYP enzymes P-glycoprotein
• Increased risk of Hypoglycemia
• Some caution may be warranted on concurrent use.
• The dose of the sulfonylurea may need to be
  reduced.

7
Sulfonylureas rifampin

• Sulfonylureas
• Rifampin
• Rifampin induce cytochrome P450 2C9
• Increased clearance of gliclazide
• Reduction of glucose-lowering effects of
  gliclazide
• Monitor blood glucose carefully, when rifampin is
  with sulfonylureas.
• Dosage adjustment of the oral hypoglycemic may be
  necessary.

8
Sulfonylureas Bosentan

• Sulfonylureas
• Bosentan
• Bosentan induce cytochrome P450 2C9
• Increased clearance of glibenclamide
• Reduction of glucose-lowering effects of
  glibenclamide
• Bosentan (Endothelin receptor antagonist) is an
  inducer of the cytochrome P450 isoenzymes CYP2C9
  and CYP3A4, both of which may be responsible for
  glibenclamide metabolism.
• Based on the limited evidence available about the
  increased risk of liver toxicity, the
  manufacturer of bosentan recommends that bosentan
  should not be used with glibenclamide.
• The combination of glibenclamide and bosentan
  should be avoided.

9
Sulfonylureas antacids

• Sulfonylureas
• Antacids
• Increase in gastric pH
• Increased solubility of sulfonylureas
• Increased absorption of sulfonylureas
• Patients taking glipizide with sodium bicarbonate
  or magnesium hydroxide, or tolbutamide with
  magnesium hydroxide may experience transient
  hypoglycaemia.
• Giving glibenclamide 30 minutes to one hour
  before the antacid has been suggested as a
  strategy to minimise any interaction.

10
Sulfonylureas alpha-glucosidase inhibitors

• Sulfonylureas
• Alpha glucosidase inhibitors
• Alpha glucosidase inhibitors may increase the
  blood glucose-lowering effects of sulfonylureas
• Increased risk of Hypoglycemia
• It may be necessary to reduce their doses.
• Any hypoglycaemic episodes should be treated with
  glucose (dextrose), not sucrose, because
  alpha-glucosidase inhibitors delay the digestion
  and absorption of disaccharides such as sucrose,
  but do not affect monosaccharides.

11
Sulfonylureas Bile acid binding resins

• Sulfonyureas
• Bile-acid binding resins (Colestyramine,
  colestipol, and colesevelam)
• Bind with acidic drugs (Glipizide, Glibenclamide)
• Reduced absorption
• Glipizide should be taken one to 2 hours before
  the colestyramine.
• Colestipol may not be suitable for diabetics
  taking chlorpropamide, tolbutamide, Tolazamide.
• Take Glibenclamide 4 hours before colesevelam.
• Monitor the effects of concurrent use in
  patients.

12
Sulfonylureas ACE inhibitors

• Sulfonylureas
• ACE inhibitors
• Increased glucose utilisation
• increased insulin sensitivity
• Enhanced reduction of blood glucose levels
• Increased risk of Hypoglycemia
• Hypoglycaemia, has occurred in a small number of
  diabetic patients taking sulfonylureas with
  captopril, enalapril, lisinopril or perindopril.
• To be on the safe side, warn all patients
  receiving sulfonylureas who are just starting any
  ACE inhibitor that excessive hypoglycaemia has
  been seen very rarely and unpredictably.
• The problem has been resolved in some patients by
  reducing the sulfonylurea dose by 50 to 75.

13
Sulfonylureas allopurinol

• Sulfonylureas
• Allopurinol
• Increased risk of Hypoglycemia
• Marked hypoglycaemia and coma occurred in one
  patient taking gliclazide and allopurinol.
• Allopurinol causes an increase in the half-life
  of chlorpropamide.
• In the case of chlorpropamide it has been
  suggested that the interaction possibly involves
  some competition for renal tubular mechanisms.

14
Sulfonylureas Alcohol

• Sulfonylureas
• Alcohol
• Inhibition of gluconeogenesis
• Exacerbation of hypoglycaemia
• Moderate and rapid interaction may occur between
  antidiabetics and alcohol.
• Diabetes UK (formerly The British Diabetic
  Association) advises diabetics not to exceed 2
  drinks (for women) or 3 drinks (for men) daily.
• Diabetics should not drink on empty stomach.
• Diabetics with peripheral neuropathy should not
  have more than one drink daily.

15
Sulfonylureas alcohol

• Sulfonylureas
• Alcohol
• Disulfiram-like flushing reaction
• About one-third of patients taking chlorpropamide
  who drink alcohol, even in quite small amounts,
  experience a warm, tingling or burning sensation
  of the face, neck and arms.
• This can begin within 5 to 20 minutes of
  drinking, reaching a peak within 30 to 40
  minutes, and may persist for one to 2 hours.
• Very occasionally headache occurs, and
  light-headedness, palpitations, wheezing and
  breathlessness have also been experienced.
• A similar reaction can occur, but much less
  frequently, with other sulfonylureas including
  carbutamide, glibenclamide (glyburide),
  gliclazide, glipizide, tolazamide, and
  tolbutamide.

16
Conclusion

• The diabetics should consult their physician and
  pharmacist.
• The diabetics should bring a list of all of the
  drugs they are taking (or simply bring the drugs
  themselves), including prescription drugs,
  over-the-counter drugs, and any supplements,
  herbal or otherwise, during their visit to the
  doctor or pharmacist.
• They are encouraged to ask their doctor or
  pharmacist to look over their list for any
  potentially dangerous combinations.
• It is recommended that people fill all their
  prescriptions at one pharmacy, if possible. In
  addition, they should maintain a list of all of
  their medicines and update it when one is added
  or removed.
• They should review their list with their doctor
  or pharmacist regularly, particularly when they
  begin to take a new medicine.

17
References

• Stockleys Drug Interactions, 9e
• Karen Baxter
• British National Formulary
• June 2013
• Basic Clinical Pharmacology, 12e Bertram
  G. Katzung, Susan B. Masters, Anthony J. Trevor
• Goodman Gilman's The Pharmacological Basis of
  Therapeutics, 12e Laurence L. Brunton, Bruce
  A. Chabner, Björn C. Knollmann

18
References

• http//www.ncbi.nlm.nih.gov/pmc/articles/PMC301938
  7/
• http//spectrum.diabetesjournals.org/content/19/4/
  202.full.pdfhtml
• http//www.fda.gov/cder/consumerinfo/druginteracti
  ons.htm
• http//medicine.iupui.edu/clinpharm/ddis/
• http//www.australianprescriber.com/magazine/24/4/
  83/5
• http//www.micromedexsolutions.com