Review of Pharmacology - 9E (2015)

Review of Pharmacology
Sulfonylureas and meglitinides inhibit ATP sensitive K + channels
↓
K + cannot go out resulting in more positive charge in β-cells
↓
Depolarization starts
↓
Leads to opening of Ca 2+ channels and thus entry of Ca 2+ in β-cells
↓
Release of insulin from granules
↓
Decrease in blood glucose
Endocrinology
Sulfonylureas (except glyburide)
and meglitinides (nateglinide
and repaglinide) are safe in renal
failure.
Metformin is drug of choice
for type 2 diabetes mellitus
(a) Sulfonylureas
These may be first generation (chlorpropamide, tolbutamide, tolazamide and acetohexamide) or
second generation (glibenclamide also known as glyburide, glipizide, gliclazide and glimepiride)
compounds. Tolbutamide is the shortest acting whereas chlorpropamide is the longest acting
sulfonylurea. Second generation drugs are more potent than the first generation agents. Sulfonylureas
can cause weight gain (less chance with glipizide and gliclazide). All these drugs can cause
hypoglycemia (maximum with chlorpropamide and with glyburide) and chlorpropamide has
additional actions as well. It can cause dilutional hyponatremia (ADH like action), cholestatic
jaundice and disulfiram like reaction (intolerance to alcohol). Gliclazide has additional
antiplatelet action also. Glimepiride exerts beneficial effects with regard to ischemic preconditioning.
(b) Meglitinides
These drugs have similar mechanism to cause release of insulin. Nateglinide and repaglinide
are the drugs in this group. These drugs are used for the treatment of post prandial
hyperglycemia due to their rapid onset and short duration of action. These drugs can also
result in hypoglycemic episodes.
Note:
• Glubride has maximum insulinotropic potency whereas tolbutamide has least
• Half-life of glyburide is only 1-2 hours, but its effects persist beyond 24 hours
because
––
It produces an active metabolite
––
Apart from binding to sulfonylurea receptor at the membrane, it also gets
sequestered within β-cells of pancreas (only sulfonylurea with this property)
• Glimepiride decreases blood glucose at lowest dose among sulfonylureas.
• Mitiglinde is another sulfonylurea approved in Japan
244
M – Metformin preferred in
O – Obese patients
S – Sulfonylureas preferred in
T – Thin Patients
2. Drugs acting by other Mechanisms
These drugs do not cause hypoglycemia because these are not increasing serum insulin
concentration.
(a) Biguanides
• Metformin and phenformin are biguanides and are preferred agents for obese
patients (as these are weight neutral and may even cause weight loss). These drugs
decrease blood glucose by activating AMPK (Adenosine Mono Phosphate-activated
protein Kinase) that helps in decreasing the production (inhibit gluconeogenesis and
glycogenolysis) and increasing the utilization (stimulation of glycolysis and tissue
uptake of glucose). These drugs also inhibit the intestinal absorption of glucose.
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