Treatment for Type II DM

• What are the methods to achieve glycemic control in type II DM?

  • Increasing insulin secretion
  • Improving insulin resistance
  • Reducing glucose absorption
  • Enhancing glucose excretion
• What are the classes of oral anti-diabetic drugs?

  • Insulin secretagogues: Stimulates insulin release
  • Insulin sensitizers: Increase inuslin responsiveness
  • Alpha-glucosidase inhibitors: Reduce itestinal absorption of carbohydrates
  • SGLT inhibitor: Increases glucose secretion
  • Drugs acting via GLP-1: Improve incretin action
  • Amylin analog
• What class of drugs are euglycemics?

  Insulin sensitizers, Alpha-glucosidase inhibitors & SGLT inhibitor
• What class of drugs does not cause hypoglycemia?

  Drugs acting via GLP-1 & amylin analog
• What are the two types of medications under insulin secretagogues?

  • Sufonylureas-Glyburide
  • Meglitinides-Repaglinide
• What is the MOA of insulin secretagogues?

  Both has similar MOA

  Bind to ATP sensitive K+ channel → prevent K+ efflux → K+ accumulates → activates depolarization → stimulate insulin containing vesicles → release of insulin
• What is the pharmacokinetics of sufonylureas?

  Binds tightly to plasma protein, metabolised by cytochrome P450, excreted by liver and kidney
• What is the pharmacokinetics of megalitinides?

  Rapid absorption, very fast onset of action, short duration of action
• Which is the 1st line of action in this class?

  Sufonylureas
• When are meglitinides used?

  When the patient has sufonylurea allergy
• What are the adverse effects of insulin secretagogues?

  Hypoglycemia, weight gain, secondary resistance
• When is insulin secretagogues contraindicated?

  Pregnancy, hepatic or renal insufficiency
• Important note for sufonylureas

  Hypoglycemic action may increase if taken with salicylates, warfarin
• Important note for meglitinides

  Postprandial effect, administered just before meal

  (not effective in decreasing random glucose)
• What are the type of medications under insulin sensitizers?

  • Biguanides: Metformin
  • Thiazolidinediones: Rosiglitazone
  • Alpha-glucosidase inhibitors: Acarbose
• What is the MOA of biguanides (METFORMIN)?

  Impairs mitochondrial respiration → reduced ATP generation → AMP accumulates → activation of AMP kinase → gene expression
• What is the MOA for thiazolidinediones (ROSIGLITAZONE)?

  Bind to receptor PPAR-gamma → activate receptor → migration of drug receptor complex to the DNA → activation of transcription of genes in glucose and fatty acid metabolism
• What is the MOA for alpha-glucosidase inhibitor (ACARBOSE)?

  Competitively inhibits intestinal membrane bound alpha-glucosidases → inhibits glucose absorption → starch blocker
• Pharmacokinetics use for biguanides

  Well absorbed in GIT, not bound to plasma proteins, not metabolised, excreted unchanged in urine
• Why is biguanides a drug of choice for type II DM?

  • Increase insulin sensitivity
  • Increase uptake of glucose
  • Increase fatty acid uptake and oxidation
  • Decrease intestinal absorption of glucose
  • Decrease hepatic output of glucose
• What are the adverse effects of biguanides?

  Diarrhoea, dyspepsia, lactic acidosis
• When is biguanides contraindicated?

  Heart failure,hypoxia, renal failure, lung disease, liver disease
• What are the benefits of using biguanides?

  Does not cause hypoglycemia even in large doses

  Promotes weight loss in type 2 diabetes
• Pharmacokinetics uses for thiazolidinediones

  Rapidly absorbed, highly protein bound, metabolised in the liver, slow onset and offset of action (weeks - months)

  *Slow because expression of genes, proteins and cell function takes time
• When is thiazolidinediones prescribed?

  Improve insulin sensitivity

  Increase expression of GLUT4 → increase glucose uptake

  Change in fat metabolism

  Redistribution of fat
• What are the adverse effects of thiazolidinediones?

  Fluid retention, hepatotoxicity, weight gain
• When is thiazolidinediones contraindicated?

  Heart failure, hepatic failure, pregnancy
• Important note for thiazolidinediones

  Peroxisome proliferating activated receptor gamma
• What is the pharmacokinetic profile of alpha-glucosidase inhibitors?

  Relatively weak antidiabetic effect

  *Taken at the start of main meals to have maximal inhibition of glucose absorption
• What is the therapeutic effect of alpha-glucosidase inhibitor?

  Decrease postprandial glucose
• What are the adverse effects of alpha-glucosidase inhibitor?

  Flatulence, diarrhoea, abdominal pain
• What are the drug classes that increase glucose excretion?

  • SGLT inhibitor: Dapagliflozin
  • Drugs acting via GLP-1: Sitagliptin & Exenatide
  • Amylin analog: Pramlintide
• What is the MOA of SGLT inhibitor?

  Blocks SGLT-2 → prevents reabsorption of filtered glucose
• What is the MOA of Drugs acting via GLP-1?

  Increase insulin secretion and reduce appetite

  GLP-1 binds to the receptor and activates adenylate cyclase → increases cAMP conc. → antidiabetic effect kicks in only when glucose levels are hig
• What is the significance of GLP-1?

  • GLP-1 is secreted from the L-cells in the jejunum and ileum.
  • It slows gastric emptying, reduces food intake, suppresses glucagon secretion and stimulates insulin secretion.
  • It may also increase beta-cell cell mass and maintain beta-cell efficiency.
• Why is SGLT inhibitor used?

  Elimination of glucose through the urine

  Eliminates water by osmotic diuresis → lowers BP
• What is the adverse effects of SGLT inhibitor?

  Higher risk of UTI
• Pharmacokinetic uses of sitagliptin

  Well absorbed in GIT, excreted unchanged in the urine
• When is sitagliptin used?

  Enhances the availability of endogenous GLP-1 incretin hormones
• What are the adverse effects of sitagliptin?

  Headache, diarrhoea, increased risk of pancreatitis