diabetesmellitus-161107093232.pdf

1. Pharmacotherapy
of
Diabetes Mellitus
RVS Chaitanya Koppala

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)

7. Type 2 Diabetes

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 5
3 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