Pharmacology
Summary
Non-insulinotropic antidiabetic agents act by altering glucose metabolism rather than affecting insulin itself. Endogenous insulin is necessary for the functioning of these agents, which are only are suitable only for the management of type 2 diabetes mellitus (T2DM). Metformin, a staple oral medication for Type 2 diabetes, reduces serum glucose by regulating enzymatic actions, curbing hepatic gluconeogenesis, diminishing intestinal glucose absorption, and promoting peripheral glucose uptake. Notably, metformin neither induces hypoglycemia nor does it lead to significant weight loss.
Further explored are thiazolidinediones, which are PPAR-gamma agonists. They amplify the insulin sensitivity of peripheral tissues while reducing glucose synthesis in the liver, but they can also result in fluid retention, potentially worsening heart failure. Pramlintide, an amylin analog, tempers gastric emptying and curtails post-meal glucose fluctuations and glucagon secretion. Pramlinitide is applicable in both T1DM and T2DM but with a hypoglycemia risk. SGLT2 inhibitors increase urinary glucose excretion, benefiting those with persistent glycemic imbalance, but they can predispose to hypotension and urinary infections due to heightened urinary glucose. Finally,alpha-glucosidase inhibitors are beneficial in mitigating postprandial glucose spikes by inhibiting intestinal breakdown of complex polysaccharides into simpler monosaccharides, but can provoke GI discomfort, largely from increased bacterial digestion of unabsorbed sugars in the colon.
Lesson Outline
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FAQs
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Metformin acts primarily by modulating key enzymes, which leads to reduced hepatic gluconeogenesis, diminished intestinal glucose absorption, and enhanced peripheral glucose uptake. Its mechanism involves the inhibition of mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) and the activation of AMP-activated protein kinase (AMPK). While metformin can induce weight loss, it can also present side effects such as gastrointestinal discomfort, nausea, and vomiting. A rare but serious adverse event is lactic acidosis, especially in patients with organ dysfunction or failure, necessitating careful monitoring and dosage adjustments in these populations.
Thiazolidinediones, recognizable by their “-glitazone” suffix, are PPAR-gamma agonists. They modulate genes crucial for lipid and glucose metabolism, thereby amplifying the insulin sensitivity of peripheral tissues. Although not the primary choice for treating type 2 diabetes mellitus (T2DM), they offer benefits to those with renal disease. Nonetheless, potential complications include exacerbation of congestive heart failure, weight gain, and a decrease in bone density.
Pramlintide, an amylin analog, complements the action of insulin by decelerating gastric emptying and stabilizing post-meal blood sugar levels. It’s suitable for both type 1 and type 2 diabetes mellitus for postprandial glucose management. Some notable effects include weight loss, nausea, and postprandial hypoglycemia.
SGLT2 inhibitors, bearing the “-flozin” suffix, function by blocking the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule. This inhibition results in glucose excretion through urine. Benefits of this class include weight loss and a potential reduction in cardiovascular mortality. Risks of SGLT2 inhibitors include osmotic diuresis leading to hypotension, increased urinary and genital infections due to elevated urinary glucose, and inefficacy coupled with heightened adverse effect risks in cases of renal insufficiency.
Alpha-glucosidase inhibitors, including acarbose and miglitol, hinder the intestinal conversion of complex polysaccharides into simpler monosaccharides. This action curtails the post-meal glucose surge, offering cardiovascular advantages like reduced myocardial infarction and hypertension risks. However, gastrointestinal disturbance is common with alpha-glucosidase inhibitors, especially flatulence, resulting from colonic bacterial fermentation of the unabsorbed polysaccharides.
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