Sulfonylureas

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Chapter: Essential pharmacology : Insulin, Oral Hypoglycaemic Drugs and Glucagon

All have similar pharmacological profile—sole significant action being lowering of blood glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics.


SULFONYLUREAS

 

The generic formula of sulfonylureas is—

 


 

All have similar pharmacological profile—sole significant action being lowering of blood glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics.

 

Mechanism Of Action

 

Sulfonylureas provoke a brisk release of insulin from pancreas. They act on the so called ‘sulfonylurea receptors’ (SUR1) on the pancreatic β cell membrane—cause depolarization by reducing conductance of ATP sensitive K+ channels. This enhances Ca2+ influx degranulation. The rate of insulin secretion at any glucose concentration is increased. In type 2 DM the kinetics of insulin release in response to glucose or meals is delayed and subdued. The sulfonylureas primarily augment the 2nd phase insulin secretion with little effect on the 1st phase. That they do not cause hypoglycaemia in pancreatectomised animals and in type 1 diabetics (presence of at least 30% functional β cells is essential for their action) confirms their indirect action through pancreas.

 

A minor action reducing glucagon secretion, probably by increasing insulin and somatostatin release has been demonstrated. Hepatic degradation of insulin is slowed.

 

Extrapancreatic Action 


After chronic administration, the insulinaemic action of sulfonylureas declines probably due to down regulation of sulfonylurea receptors on β cells, but improvement in glucose tolerance is maintained. In this phase, they sensitize the target tissues (especially liver) to the action of insulin. This is due to increase in number of insulin receptors and/or a postreceptor action—improving translation of receptor activation. It is hypothesized that long term improvement in carbohydrate tolerance leads to a decreased insulin concentration in blood which reverses the down regulation of insulin receptors—apparent increase in their number. A direct extrapancreatic action of sulfonylureas to increase insulin receptors on target cells and to inhibit gluconeogenesis in liver has been suggested, but appears to have little clinical relevance.

 

Pharmacokinetics

 

All sulfonylureas are well absorbed orally, and are 90% or more bound to plasma proteins: have low volumes of distribution (0.2–0.4 L/kg). Some are primarily metabolized—may produce active metabolite; others are mainly excreted unchanged in urine. Accordingly they should be used cautiously in patients with liver or kidney dysfunction.

 

The distinctive features of different sulfonylureas are given in Table 19.2.

 

Interactions

 

Drugs that enhance sulfonylurea action (may precipitate hypoglycaemia) are—

 

a.     Displace from protein binding: Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides, PAS.

 

b.     Inhibit metabolism/excretion: Cimetidine, sulfonamides, warfarin, chloramphenicol, acute alcohol intake (also synergises by causing hypoglycaemia).

 

c.      Synergise with or prolong pharmacodynamic action: Salicylates, propranolol (cardioselective β1 blockers less liable), sympatholytic antihypertensives, lithium, theophylline, alcohol (by inhibiting gluconeogenesis).

 

Drugs that decrease sulfonylurea action (vitiate diabetes control) are—

 

a.     Induce metabolism: Phenobarbitone, phenytoin, rifampicin, chronic alcoholism.

 

b.     Opposite action/suppress insulin release: Corticosteroids, diazoxide, thiazides, furosemide, oral contraceptives.

 

Adverse Effects

 

Incidence of adverse effects is quite low (3–7%).

 

1. Hypoglycaemia It is the commonest problem, may occasionally be severe and rarely fatal. It is more common in elderly, liver and kidney disease

patients and when potentiating drugs are added. Chlorpropamide is a frequent culprit due to its long action. Tolbutamide carries lowest risk due to its low potency and short duration of action. Lower incidence is also reported with glipizide, glibenclamide, glimepiride.

 

Treatment is to give glucose, may be for a few days because hypoglycaemia may recur.

 

2. Nonspecific side effects Nausea, vomiting, flatulence, diarrhoea or constipation, headache, paresthesias and weight gain.

 

3. Hypersensitivity Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis.

 

Chlorpropamide in addition causes cholestatic jaundice, dilutional hyponatremia (sensitises the kidney to ADH action), intolerance to alcohol in predisposed subjects (flushing and a disulfiram like reaction); other sulfonylureas are less prone to this interaction.

 

Tolbutamide reduces iodide uptake by thyroid but hypothyroidism does not occur.

 

Safety of sulfonylureas during pregnancy is not established—change over to insulin. They are secreted in milk: should not be given to nursing mothers.

 

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