Sulfonylureas

  1. Introduction
    • Sulfonylureas lower blood glucose in normal persons and type 2 diabetics.
    • Not effective in type 1 diabetics.
  2. Mechanism of action
    • SUR1 receptors on pancreatic β cell membrane
    • Binding to receptor
    • Reduced conductance of ATP sensitive K+ channels
    • Depolarization of membrane
    • Enhanced Ca2+ influx
    • Degranulation of insulin vesicles
    • Augment 2nd phase of insulin secretion
    • At least 30% functional β cells required
  3. Mechanism of action
    • Augment 2nd phase of insulin secretion
    • At least 30% functional β cells required
  4. Extrapancreatic action
    • Chronic administration – downregulation of sulphonylurea receptors – Insulin release decreased
    • But control of blood sugar is maintained
    • Tissues are sensitized to insulin – By Increase in insulin receptors and/or postreceptor action
  5. Pharmacokinetics
    • Well absorbed orally
    • High plasma protein binding – 90%
    • Low volume of distribution – 0.2-0.4 L/kg
  6. Interactions increasing sulfonylurea action – Displacement from plasma proteins
    • Phenylbutazone
    • Sulphinpyrazone
    • Salicylates
    • Sulfonamides
    • PAS
  7. Interactions increasing sulfonylurea action – Decrease in metabolism
    • Cimetidine
    • Sulfonamides
    • Warfarin
    • Chloramphenicol
    • Acute alcohol intake
  8. Interactions increasing sulfonylurea action – Synergistic action
    • Salicylates
    • Propranolol
    • Sympatholytic antihypertensives
    • Lithium
    • Theophylline
    • Alcohol (inhibits gluconeogenesis)
  9. Interactions decreasing sulfonylurea action – Increase in metabolism
    • Phenobarbitone
    • Phenytoin
    • Rifampicin
    • Chronic alcoholism
  10. Interactions decreasing sulfonylurea action – Antagonistic action
    • Corticosteroids
    • Diazoxide
    • Thiazides
    • Furosemide
    • Oral contraceptives
  11. Adverse Effects – General
    • Hypoglycemia
      • Commonest
      • More in elderly, liver+kidney disease
      • More with Chlorpropamide – long action
      • Least with Tolbutamide – low potency, short action
    • Non specific side effects
      • Nausea
      • Vomiting
      • Flatulence
      • Diarrhoea/constipation
      • Headache
      • Paresthesias
      • Weight gain
      • Hypersensitivity
    • Hypersensitivity
      • Rashes
      • Photosensitivity
      • Prupura
      • Transient leukopenia
      • Agranulocytosis (rare)
  12. Adverse Effects
    • Chlorpropamide
      • Cholestatic jaundice
      • Dilutional hyponatremia (sensitise kidney to ADH)
      • Disulfuram like reactions
    • Tolbutamide
      • Reduce iodine uptake by thyroid – Does not cause hypothyroidism
  13. Note: Should changeover to insulin during pregnancy!

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