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Mechanism of action

  1. Sulforylureas
    1. Sulphonylureas (Block ATP sensitive potassium channels; depolarize islet cells)
    2. Increase release of preformed insulin
    3. Increase glucose uptake (Increase expression of GLUT-II)
    4. S/E : Hypoglycemia 
  2. Bigunides
    1. Inhibit neoglucogenesis in liver
    2. Reduce absorption of glucose from intestine
    3. Increase insulin receptor sensitivity
    4. Has the ability to delay the onset of diabetes 
  3. Alpha glucosidase inhibitors
    1. Inhibit conversion of complex to simple carbohydrates
    2. These are competitive and reversible inhibitors of alpha glucosidase enzymes
    3. Slow down rate and extent of carbohydrate absorption in small intestine
    4. Reduce postprandial blood sugar mainly also reduce fasting levels
    5. Used mainly in combination with other agents
    6. Donot affect insulin levels
    7. No weight gain
    8. Hypoglyecemia in overdose is not severe 
  4. Meglitinides
    1. Increase release of insulin from pancreas in response to meals
    2. Reduce postprandial hyperglyecemia  
  5. Thiozolidinediones
    1. Reduce insulin resistance by binding to PPRAP-gamma
    2. Act in insulin responsive tissues such as fat, muscle etc
      1. Donot affect insulin action therefore are associated with mild or no hypoglycemia
      2. Reduce Hb1Ac

New drugs

Incretin like drugs
(a). GLP 1 analogue
  1. Exenatide  
  2. Liraglutide
(b). Dipeptidyl peptidase inhibitors (DPP IV)
a. Sitagliaptin         
b. Ritagliaptin          
c. Validagliaptin                
d. Alogliaptin
  1. Incretin is an insulinomimetic peptide
  2. GLP-1 analogue increase activity of INCRETIN
  3. DPP-IV inhibitors reduce break down of GIP & GLP-1
  4. Incretin:
    ↑Insuline Release
    ↓Glucacone Release
    ↓Gastric Clearance
    ↑β cell mass of Pancreas
  5. GLP-1 is released from the upper and lower bowel that augment glucose-dependent insulin secretion. This hormones is termed as incretin.
  6. GLP-1 significantly augments glucose-dependent insulin secretion. Studies have shown that it increases beta cell mass of pancreas.
  7. GLP-1 also reduces glucagon secretion, slows gastric emptying, and decreases appetite by acting on CNS. By slowing gastric emptying, it retards the quantity of food reaching the small intestine and hance reduces, post parandial hyperglycemia. By reducing appetite, it is also helpful in reducing weight of patient in DM 2.  It also improves Hb1Ac level in blood. 
  8. Circulating GLP-1 is rapidly (1 to 2 minutes) inactivated by the dipeptidyl peptidase IV enzyme (DPP-IV) present in body but exenatide is resistant to DPP-IV and has full agonist activity at GLP-1 receptors. It is given as sudcutaneous injections in combination therapy with other agents in subjects with type 2 DM.
  9. Exenatide is a glucagon-like peptide (GLP-1) receptor agonist.
  10. Exenatide side effects include a self-limiting nausea and it can cause hypoglycemia when used in conjunction with oral insulin secretagogue.
  11. Liraglutide is another GLP-1 agonist with long half life.
  12. An alternative approach to GLP-1 therapy is to inactivate the DPP-IV protease, thereby increasing endogenous circulating GLP-1 levels. Sitagliptin and vildagliptin is orally effective DPP-IV inhibitors.
  13. These agents are well tolerated and appear to result in less nausea than the GLP-1 analogs. However, since DPP-IV can metabolize a wide range of peptides, there is a theoretical concern about the long-term safety of these compounds.
  14. DPP-IV inhibitors prolong the action of neuropeptides such as substance P and macrophage-derived chemokines. Prolonging these messengers may produce inflammation (effect on substance P), increase blood pressure (effect on neuropeptide Y), or cause allergic reactions (effect on chemokines).
  • Other events are often mild and include nasopharyngitis, upper respiratory tract infection, headache, and cough.
Amylin analogue
  • Pramlintide
  1. Pramlintide, a synthetic analog of amylin
  2. It is rapidly absorbed after subcutaneous administration;
  3. approved for preprandial use in persons with type 1 and type 2 diabetes.
  4. Pramlintide suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects.
  5. Pramlintide is renally metabolized and excreted
  6. The major adverse effects of pramlintide are hypoglycemia and gastrointestinal symptoms including nausea, vomiting, and anorexia. 
Renal glucose transporter inhibitors (Sodium Glucose-2 inhibitors)
  1. Phlorozin              
  2. Dapagliflozin        
  3. Sergliflozin            
  4. Remogliflozin
    1. SGLT-2 inhibitors, required for glucose reabsorption in PCT of kidney
    2. By inhibiting this pump,these drugs will enhance elimination of glucose from body and hence control glucose level
    3. Can be used as a adjunctive drug for DM-2 alongwith insulin
    4. Associated with weight loss and frequent UTI
    5. There is rare association with breast and bladder carcinoma
Bromocriptine(D2) receptor agonist
Dopamine receptor agonist bromocriptine, has been approved by the FDA for the treatment of type 2 diabetes. 

Colesevelum (bile acid sequestrant agent) 
  1. Bile acid metabolism is abnormal type 2 diabetes.
  2. The bile acid–binding resin colesevelam has been approved for the treatment of type 2 diabetes Colesevelam (available as a powder for oral solution and as 625-mg tablets) is prescribed as 3–6 tablets prior to meals.
  3. The most common side effects are gastrointestinal (constipation, abdominal pain, and nausea).
  4. Bile acid–binding resins can increase plasma triglycerides and should be used cautiously in patients with a tendency to hypertriglyceridemia. The role of this class of drugs in the treatment of type 2 diabetes is not yet defined.
Aldolase reductase inhibitor
  1. Epalrestat (This is used to prevent diabetic complication specially Neuropathy. 
P/K of all drugs 
  1. Well absorbed (Except newer ones; parenteral drugs)
  2. Tolbutamide –shortest, least potent, safest
  3. Phenylbutazone, sulfonamides displace & cause hypoglycemia
  4. Chlorpropamide, longest (half life 36 hours), maximally protein bound, C/I-renal failure
  5. Metformin : Metabolized in liver
                      Eliminated by kidneys;
  6. Repaglinide, Tolbutamide
    1. Eliminated by bile
    2. Safe in renal failure
  1. Acarbose (AIIMS Nov 08)
    1. Mild diabetes (e.g. impaired glucose tolerance-IGT)
    2. Useful even in type-I
    3. Oral complex carbohydrate should not be given to correct hypoglycemia in overdose. Glucose is given (monosacehride)
  2. Tolbutamide
    1. Used in elderly
    2. Used in diabetes with renal failure       
      1. Obese diabetic patients (DOC)
      2. Prevention of diabetes (delays onset)
      3. PCOD
  3. Metformin
  4. Maglitinides
    Postprandial hyperglyecemia
  5. New drugs also have same indication  
Side effects 
  1. MC-Hypoglycemia
    1. Does not occur with metformin (Antihyperglyecemic)
    2. ‘Silent’ in patients on beta-blockers
    3. Maximum with chlorpropamide
    4. Minimum with tolbutamide
    5. Moderately severe with glyburide (glibencalamide)
  2. Weight gain
    1. weight loss with metformin; no weight gain with acarbose
    2. Weight gain is particularly common with thiozolidinediones and is due to increase in subcutaneous fat.
  3. Plasma volume expands with thiozolidinedione   
    1. This increases the risk of CHF
    2. American Diabetes & American Heart Association recommends screening patients before using these drugs in CHF and avoiding them inNYHA-III, IV patients (New York Heart Association class-III, IV means severe CHF)   
  4. Metabolic acidosis (More with phenformin, less with metformin)
  5. Hepatitis
  6. Agranulocytosis
  7. SIADH
    1. Dyspepsia            
    2. Bloating
  8. Maglitinides
    Can precipitate CHF
    1. GI upset (MC)
    2. Megaloblastic anemia
    3. Alpha glucosidase inhibitors
    4. Hepatic failure
  9. Metformin
C/I of Metaformin
  1. Renal & hepatic failure          
  2. Chronic alcoholism        
  3. CHF

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