Pharmacotherapy of Diabetes mellitus
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Types of Diabetes mellitus and its pharmacotherapy
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Pharmacotherapy of Diabetes mellitus
- 2. Diabetes • Diabetes is a group of metabolic disorders characterized by chronic hyperglycemia associated with disturbances of carbohydrate, fat and protein metabolism due to absolute or relative deficiency in insulin secretion and/or action • Diabetes causes long term damage, dysfunction & failure of various organs
- 3. Diagnosis of diabetes • Fasting Plasma Glucose ≥ 126 mg / dl • Symptoms of DM and a random blood glucose level of ≥ 200 mg/dl • Oral glucose tolerance test – 2 hr after 75 gm glucose load ≥ 200 mg / dl
- 4. Classification of Diabetes Proposed by ADA - 1997. • Type I: – Absolute Insulin Deficiency due to islet cell destruction • Either immune mediated or idiopathic • Type II: – Relative insulin deficiency due to impaired -cell function – Marked ↑ peripheral insulin resistance • Type III: Other Specific types • Type IV: Gestational Diabetes
- 5. Other specific types A) Genetic defects of Beta cell function (MODY syndromes) B) Genetic defects in Insulin action (Lipo atrophic Diabetes) C) Diseases of the Exocrine Pancreas (pancreatitis) D) Secondary to Endocrinopathies (Acromegaly, Cushings syndrome) E) Drugs / Chemical induced (Steriods, thiazides) F) Infections (Congenital Rubella ) G) Uncommon form of Immune Mediated Diabetes. (Anti insulin receptor antibodies) H) Other Genetic Syndromes associated with Diabetes (Down’s syndromes, Turners syndromes, Klinefelters syndrome)
- 10. β cells : insulin 65-70 % cells : glucagon 25 % δcells : somatostatin 10 % PP (or F cells): pancreatic polypeptide 2 %
- 11. Insulin
- 12. • Glucose transporters – • GLUT 1 Non insulin mediated glucose uptake • GLUT 3 • GLUT 2 – Beta cell – Glucose sensors • GLUT 4 – Insulin mediated glucose uptake in muscle & Adipose tissue
- 13. Cell at rest
- 14. Secretion of insulin > 70 mg/ml GLUT 2
- 15. • Direct stimulation • Plasma glucose or Amino Acids , ketones • Hormonal regulation • Gastrointestinal hormones (GIP, CCK) directly stimulate β cells • Neural regulation • Parasympathetic stimulates insulin release through IP3/ DAG • Sympathetic NS inhibits insulin release through 2 receptor activation Regulation of insulin secretion
- 17. Carbohydrate metabolism • Over all action of insulin is to ↓ glucose level in blood – ↑ Transport of glucose inside the cell – ↑ Peripheral utilization of glucose – ↑ Glycogen synthesis – ↓ Glycogenolysis – ↓ Neoglucogenesis
- 18. Lipid metabolism • ↓ Lipolysis • ↑ Lipogenesis • ↓ Ketogenesis • ↑ Clearance of VLDL & chylomicrons from blood through enzyme Vascular Endothelial Lipoprotein Lipase
- 19. Protein metabolism • Protein synthesis • ↑ entry of amino acids in cells Electrolyte metabolism • ↑ transport of K+, Ca++, inorganic phosphates
- 20. Other actions • Vascular actions: – Vasodilation ? Activation of endothelial NO production • Anti-inflammatory action – Especially in vasculature • Decreased fibrinolysis • Growth • Steroidogenesis
- 21. Mechanism of action of insulin
- 22. Conventional insulin preparations Type Onset (Hr) Peak (Hr) DOA (Hr) Short acting Regular insulin Semilente 0.5 -1 1 2-4 3-6 6-8 12-16 Intermediate acting Lente Isophane(NPH) 1-2 8-10 20-24 Long acting Ultra lente Protamine Zinc Insulin (PZI) 4-6 14-18 24-36
- 23. Newer Insulin analogs Type Onset Peak (Hr) DOA (Hr) Rapid acting Lispro Aspart Glulisine 5-15 min 10-15 min 5-15 min 1 1 1 3-5 3-5 5-6 Long acting Glargine Detemir 1-2 hrs 2-3 hrs No peak 6-8 hr 24 hr 24 hr
- 24. Action Profiles of Insulins 0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Plasma insulin levels Regular 6–8 hours NPH 12–16 hours Ultralente 18–20 hours Hrs Aspart, glulisine, lispro 4–5 hours Glargine ~24 hours Detemir ~14 hours Danne T et al. Diabetes Care. 2003;26:3087-3092
- 25. Indications of insulin in type II DM • Primary or secondary failure of oral hypoglycemics • Pregnancy • Perioperative period • Steroid therapy • Fasting > 300 mg HbA1c • Unintentional wt loss with or with out ketosis • Type 2 with DKA ( severe beta cell dysfunction)
- 26. Pathogenesis of DKA Insulin deficiency Absolute / relative Counter hormone excess ↓ Anabolism ↑ catabolism ↓Peripheral utilization of Glucose Hyperglycemia Heavy Glucosuria (osmotic diuresis) Loss of water & electrolytes ↑ Glycogenolysis ↑ Glycolysis ↑Gluconeogenesis Dehydration + Hyperosmolarity ↓ Fluid intake
- 27. Pathogenesis of DKA (How ketoacidosis occurs) ↑ FFA to liver ↑ Acetyl coA ↓ Alkali reserve ↑ Lipolysis ↑ Acetoacetyl coA Acetoacetate -Hydroxy butrate Acetone Hyperketonemia Acidosis
- 28. Treatment of DKA • Fluid therapy • Rapid acting regular insulin • Potassium replacement • Bicarbonate replacement • Phosphate replacement • Antibiotics • Treatment of precipitating cause • General measures
- 29. Fluid therapy • Adequate tissue perfusion is necessary insulin action • Normal saline is fluid of choice for initial rehydration – 1 litre in first hour – Next 1 L in next 2 hours – 2 litres in next 4 hours – 2 litres in next 8 hours • i.e 4 to 6 litres in 24 hours • When BSL reaches 300 mg% fluid should be changed to 5 % dextrose with concurrent insulin
- 30. Insulin in DKA • Regular/ short acting insulin IV treatment of choice • Loading dose = 0.1-0.2 U/kg IV bolus • Then 0.1 U /kg/hr IV by continuous infusion • Rate doubled if no significant fall in BSL in 2 hr • 2-3 U/hr after BSL reaches 300mg% • If patient becomes fully conscious encouraged to take oral food & SC insulin started
- 31. Potassium replacement • In initial stage of treatment potassium not administered because in DKA it remains normal or ↑ • In presence of insulin infusion Sr potassium ↓ hence 10 mEq/L potassium can be added with 3rd bottle of normal saline • Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr
- 32. Bicarbonates & phosphates • Bicarbonates – If blood pH > 7.1 no need of sodium bicarbonate – In presence of severe acidosis 50 mEq of sodium bicarbonate added to IV fluid • Phosphates – Non availability of ideal preparation – Replacement not very essential unless < 1 mEq/L – potassium phosphate 5-10 m mol/hr
- 33. Insulin resistance • State in which normal amount of insulin produces subnormal amount of insulin response – ↓ insulin receptors – ↓ affinity for receptors • May be acute or chronic • Requirement of > 200 Units of insulin per day in absence of stress • Common in type II diabetics & obese
- 34. Oral antidiabetic drugs • Sulfonylureas: • Meglitinides: • Biguanides : • Thiazolidinediones: • -glucosidase inhibitors:
- 35. Sulfonylureas I Generation – Tolbutamide – Chlorpropamide II Generation – Glipizide – Gliclazide – Glibenclamide (Glyburide) – Glimepiride
- 37. Adverse effects • Hypoglycemia: • GI disturbances: Nausea, vomiting, metallic taste, diarrhoea & flatulence • Weight gain • Hypersensitivity • Not safe in pregnancy • Chlorpropamide: – cholestatic jaundice, dilutional hyponatremia, antabuse reaction
- 38. Contraindications 1. Allergy to SU 2. Renal failure: 3. Significant hepatic dysfunction 4. Severe infections, stress, trauma, major surgery 5. Pregnancy (except Glibenclamide) 6. T1DM
- 39. METFORMIN - INDICATIONS • Obese Type 2 Diabetes. • Secondary Sulfonylurea Failure state. • To reduce Insulin requirements. • Can be combined with Sulfonylureas, Glitazones, Insulin.
- 40. Thiazolidinediones (Glitazones) Rosiglitazone & pioglitazone Selective agonists of PPAR Bind to nuclear PPAR Activate insulin responsive genes - regulate carbohydrate & lipid metabolism Sensitize the peripheral tissues to insulin ↓blood glucose by ↑ Glucose transport into muscle & adipose tissue Inhibit hepatic gluconeogenesis Promote lipogenesis
- 41. • Pioglitazone: – 15 to 45 mg once daily orally • Rosiglitazone: – 4 to 8 mg once daily orally • Pt who benefit most are type II DM with substantial amount of insulin resistance • Monotherapy – Hypoglycemia rare • Add-on Therapy – readjust dosage. • Takes one month to act
- 42. Alpha glucosidase inhibitors • Acarbose • Miglitol • Voglibose
- 43. 43 Voglibose • Advantages over Acarbose and Miglitol – 20-30 times more potent then acarbose – Does not affect digoxin bioavailability unlike acarbose – No dosage adjustment required in renal impairment patients unlike miglitol – Superior tolerability – Dose: 0.2 to 5 mg
- 44. Newer drugs for Type II DM • GLP-1 Analogues – Exenatide – Liraglutide • DPP-IV Inhibitors – Sitagliptin – Vildagliptin – Alogliptin • Amylin analog: Pramlintide
- 45. Principles of treatment of Type 2 DM Grade Diabetes Mellitus as mild, moderate or severe NB: (150 -200 ---mild ) HbA1c < 8 ( 200-250 --- Moderate) HbA1c 8 - 9 ( more than 250 severe) HbA1c 9 - 10 For severe DM start on insulin if there is wt loss & ketosis For mild & moderate DM use metformin if obese & sulfonylureas if not obese
- 47. If diabetes not controlled Look for SU failure Occult infection – TB – UTI Drug history and compliance Food history – hypoglycaemia and compliance
- 48. cardiac problem – avoid glitazones if in failure avoid metformin Renal problem – avoid metformin
- 49. Liver problem – avoid glitazone and metformin In general patients with complication Short acting SU or insulin
- 50. Be ware of other drugs - Diuretics - Corticosteroid - Other hormones - ACE inhibitors
Editor's Notes
- Viz eyes , kidneys, nerves, heart and blood vessels. In nut shell diabetes can be defined as metabolic as well as vascular disorder.
- Diagnosis of DM based on urine sugar is unreliable, when fasting plasma glucose is or random blood sugar is . On more than one ocassion
- Marked increase in peripheral insulin resistance at receptor or post receptor level and increased hepatic glucose output GESTATIONAL DIABETES MELLITUS: FASTING > 126, PP > 140
- Term origins from insel german word for islet/island. 1869: Paul langerhans noticed clumps of cells scattered throughout the bulk of pancreas named them islets of langerhans
- OTHER STIMULANTS FOR INSULIN RELEASE INCLUDE AMINO ACIDS MAINLY ARGININE AND LEUCINE, FATTY ACIDS.
- Islets richly supplied by sympathetic & vagal nerves PRIMARY CENTRAL SITE OF REGULATION OF INSULIN SECRETION IS HYPOTHALAMUS Ventrolaterl nuclei stimulate insulin release Ventromedial nuclei – opposite effect
- Glucagon evokes release of insulin as well as somatostatin Insulin inhibits glucagon secretion Somatostatin inhibits the release of both insulin and glucagon
- Increased storage of fuel ↑ Transport of glucose inside the cell except in tissues where glucose is the only source of energy like brain, RBC, WBC, MEDULLARY CELLS OF KIDNEY
- INSULIN
- Conventional insulin preparations derived from pork and beef pancreas, Prompt insulin Zn suspension (Semilente) Regular insulin has to be injected 2-3 times a day, so it has been modified by zinc or protamine to yield slow absorption and longer action. The protamine zinc insulin and lente insulins are no longer available commercialy NPH insulin does not contain either excess of zinc or protamine hence it can be mixed with regular insulin in any proportion immediately before use.
- The presently available insulins tend to form hexamers when stored. After SC administration this self associated hexamers dissociate into diamers and then monomers. The monomeric form is the active form of insulin. This sequence of events takes around 30 to 40 min resulting in slow rise & fall in insulin concentration compared to insulin secreted by the beta cells in response to eating. This results in high postprandial hyperglycemia and susceptibility to hypoglycemia particularly before next meal. Further in between the meals and at night the beta cells secrete insulin at a constant rateto maintain basal conc with a flat profile. The conventional isophane and lente preparations are not able to maintain constant basal conc of insulin. Hence presently available soluble insulin or intermediate acting insulin are not able to match the natural insulin profile that occurs post prandially and in post absorptive period. This has prompted the development of designer insulins which will have physiological action profile like normal insulin
- Many type II diabetics can be treated with exercise and controlled diet only
- DKA is a complication of Type I DM very rare in NIDDM, The common precipitating factors are infection, trauma, stress, etc. Clinical features are anorexia, nausea, vomiting, polyuria, abdominal pain, hypotension, tachycardia, hyperventilation, altered consciousness or coma in untreated cases
- ↑ Acetyl coA (substrate for ketone production)
- Treatment of precipitating cause: infection, trauma, acute stress General measures: gastric aspiration, catheterization of urinary bladder, antibiotic cover
- , hence IV infusion of isotonic saline should be started first after blood sample has been collected If serum sodium more than 150 mEq/L hypotonic saline is indicated When BSL reaches 250 mg% fluid should be changed to 5 % dextrose with concurrent insulin administration In order to avoid hypoglycemia, it takes time for acidosis to get corrected than blood glucose Care should be taken
- With this regimen the plasma glucose level should fall at rate of 50 mg/hr it usually comes down to half the initial value in 6 to 8 hrs, if at the end of 2-3 hrs plasma glucose doesn’t show any predictable fall the doses od insulin infusion doubled 12 U/hr
- In initial stage of treatment potassium not administered as in presence of acidosis there will be high potassium it begins to fall with tretment of DKA There is no definite guideline when to start potassium it can be started when urine output is good, potassium levels should be evaluated every 2 hrs or as necessary, tall T waves in ecg so ecg monitoring, ringer lactate and fructose should be avoided in DKA
- Phosphates Serum phosphate changes similar to potassium May cause muscle weakness & lethargy Non availability of ideal preparation Replacement not very essential unless < 1 mEq/L Sometimes potassium phosphate may be administered in place of KCL In absence of facilities to measure ph hurried respiration > 36 /min is clinical pointer to administer bicarboate WITH RESUMPTION OF ORAL FLUID MILK REPLINISHES THE PHOSPHATES RAPIDLY
- Acute: develops rapidly & is of short duration , infection, trauma, emotional stress, corticosteroids , ketoacidosis Chronic: generally seen in patients treated for years with conventional insulin preparations, antibodies to homologus contaminating proteins are formed which also bind insulin. Common in type II Development of such insulin resistance is an indicator to switch over to newer preparations
- I. SU binds to specific binding sites (SUR-1) on the pancreatic β-cell plasma membrane that are coupled to ATP – dependent K+ channels II. Closure of ATP – dependent K+ channels & inhibition of efflux of K+ III. Depolarization of the plasma membrane & opening up of L-type voltage dependent Ca2+ channels IV. Influx of Ca2+ into the cytosol V. Stimulation of extrusion of both mature & immature insulin granules
- 2. Renal failure: serum creatinine: > 2 mgs% (Avoid Glibenclamide, chlorpropamide), > 3 mgs% (Avoid all SU)
- Reduces FPG by 16 % Reduces PPG by 25 % Reduces all cause mortality by 36 % Action in Fasting & Prandial state. Better action in milder disease. No Hypoglycemias.
- PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA RECEPTORS Reverse insulin resistance by stimulating GLUT 4 EXPRESSion and translocation and entry of glucose The first thiazolidinedione, ciglitazone, was synthesized in 1982(1). It was soon thereafter discovered that ciglitazone reduced insulin resistance in obese and diabetic animals. Because of their effects on insulin resistance, thiozolidinediones have been developed as pharmacological agents for the management of type 2 diabetes, although they were initially synthesized as potential lipid-reducing agents. Since their discovery, three thiozolidinediones have been introduced to the market in the U.S. : troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). In March 2000, troglitazone was withdrawn from the market because of liver toxicity. Reset glucose fatty acid cycle by reduction in circulating free fatty acids and by transcription of several genes that are imp for otimal insulin sensitivity as well as glucose and fat metabolism
- Suppresses & Prevents TNF alfa
- Glucagon like peptide I is a hormone released from intestinal L cells in response to orally ingested nutrients. The GLP I hormone is an incretin hormone which has got potent antihyperglycemic action by amplifying nutrient insulin secretion, it is advantageous as this hormone will not produce hypoglycemia when administered, GLP-I is administered subcutaneously is susceptible for enzymatic degradation by dipeptidyl peptidase IV(DPP-IV) , this has prompted the researchers to develop GLP-I analogs which are resistant to DPP-IV degrdation Is released from L cells in ileum and colon – Stimulates insulin response From β cells in a glucose dependent manner – Inhibits gastric emptying – Reduces food intake and body weight – Inhibits glucagon secretion from α cells in a glucose- dependent manner – Effect on β-cell turnover in preclinical models