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

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Sulfonylureas may interact with Azole antifungals (Fluconazole), Fibrates (Gemfibrozil), Sulphonamides (Trimethoprim), Macrolide antibiotics (Erythromycin), Rifampin, Bosentan, Antacids, Alpha glucosidase inhibitors, Bile-acid binding resins (Colestyramine, colestipol, and colesevelam), ACE inhibitors, Allopurinol and Alcohol. – PowerPoint PPT presentation

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Title: 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
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