pharmacological notes on drugs used in treatment of type 1 and type 2 diabetes mellitus

1. Pharmacology of Diabetes Mellitus
(Insulin & oral anti-diabetic drugs)
Dalia K. Zaafar
Lecturer of Pharmacology

2. What is Diabetes Mellitus
• A metabolic disease characterized by
• Hyperglycemia
• altered metabolism of lipid, CHO &
Proteins.
• increase risk of complications from
vascular diseases

3. Classification of diabetes
I) Type 1 DM ( IDDM )
a) Autoimmune (Type 1 A)
b) Non auto-immune/ idiopathic (Type 1 B)
II) Type 2 DM (NIDDM)
III) Type 3 DM (Other specific types of DM)
a)Specific defined gene mutation
b)Diabetes Secondary to Pancreatic
diseases
C) Diabetes secondary to Endocrinopathies
IV) Type 4 DM Gestational diabetes
mellitus (GDM)

4. Symptoms of DM

5. Symptoms of DM
• ↑PGL→ incomplete reabsorption in prox.
Renal tubules→ Glycosuria→↑ osmotic
pressure of urine →↓reabsorption of water
→polyuria
• →↑Fluid loss → Dehydration → polydipsia
• Glucose absorption →changes in shape of
lenses → Blurred vision
• Diabetic ketoacidosis- Kaussmaul
breathing, polyuria, nausea, vomiting,
altered state of consciousness, coma,
death

6. Diagnosis of DM
Test Normal GT Impaired GT Diabetic
Fasting PG
(mg/dl)
<100 100-125 ≥ 126
2h after
glucose load
(mg/dl)
<140 > 140-199 ≥ 200
Glycated Hb 4-5.6% 5.7-6.4% >6.5%

7. Comparison between type I & II DM
Type I DM Type II DM
Age of onset Childhood/ puberty Over 35 years old
Primary defect Immune or viral
destruction of β cells
Inadequate insulin
production or insulin
resistance
Prevalence 10-20% 80-90%
Genetic
predisposition
Moderate Very strong
Ketoacidosis common rare
Anti-islet cell
antibody
>80% <5%
Insulin TTT Always necessary May be required

8. Honeymoon period
• It is a phase that some people with type 1
diabetes experience shortly after being
diagnosed.
• During this time, a person with diabetes
seems to get better and may only need
minimal amounts of insulin.
• This happens because your pancreas is
still making some insulin to help control
your blood sugar.

9. Management of T1DM
• Education
• Diet and meal planning
• Insulin therapy
• Monitoring
Educate child & care givers about:
 Diabetes
 Insulin
 Life-saving skills
 Recognition of Hypo & DKA
 Meal plan

10. Management of T1DM
Diet and meal planning
 Regular meal plans with calorie exchange
options are encouraged.
 50-60% of required energy to be obtained
from complex carbohydrates.
 Distribute carbohydrate load evenly
during the day preferably3 meals & 2
snacks with avoidance of simple sugars.
 Encouraged low salt, low saturated fats
and high fiber diet.

11. Insulin
• Mechanism of action

12. Insulin
• Role of insulin
 ↑glucose uptake
 ↑glycogen synthesis
 ↑lipogenesis
 ↑protein synthesis
 ↑triglyceride formation
• So it is an anabolic hormone

13. Classification of insulin

14. Classification of insulin

15. Classification of insulin

16. Classification of insulin

17. Indications of Insulin
• 1) DIABETES MELLITUS
• 2) DIABETIC KETOACIDOSIS

18. Indications of Insulin
• 3) Hyperosmolar Nonketotic
(Hyperglycemia) Coma
• 4) pregnant diabetic patients

19. Adverse reactions of Insulin
1) hypoglycemia
2) Lipoatrophy & Lipohypertrophy
Atrophy→ immune response to insulin
Lipohypertrophy→ lipogenic action of
high local conc.
3) Insulin allergy & resistance
4) Insulin edema

20. Drug interactions

21. Type 2 DM
• Management
A- Oral Hypoglycemic agents
1- Sulfonylureas
• First Generation: Tolbutamide,
Chlorpropamide
• Second Generation: Glibenclamide
(glyburide), Glipizide, Gliclazide,
Glimepiride

22. Sulfonylureas
• Mech. Of action
1- Stimulates Insulin release from β- cells
2- blocks ATP sensitive K+ channels →
depolarization→ Ca entry →insulin release
3- Glucagon levels are suppressed
• Pharmacokinetics
well absorbed and metabolized in liver or
kidney and excreted in urine

23. Sulfonylureas
• Adverse effects
1- Hypoglycemia
2- Weight gain
3- Cross placental barrier – fetal
hypoglycemia
• Contra indications
1- Ketocanazole, chloramphenicol and
anticoagulants- inhibit their metabolism
2- Sulfonamides, salicylates etc- protein
binding displacement
3- Propranolol masks the symptoms of
sulfonylureas

24. Meglitinides
2- Meglitinide Analogues:
Repaglinide, Nateglinide
• Mech. Of action
1- Stimulate insulin release, same as
sulfonylurea
2- Administered before meal to control PP
blood glucose

25. Meglitinides
• Advantages of Nateglinide/Repaglinide
1- No significant increase in bodyweight
2- Can be utilized in mild to moderate renal
failure
3- Nateglinide: approved in hepatic failure

26. Management
• B- Oral antihyperglycemic agents
1- Biguanides: Metformin and Phenformin
• Metformin is the drug of choice for newly
diagnosed type 2 DM patients according to
ADA.
• Phenformin is an obsolete drug because of
its high lactic acidosis risk
• Metformin is excreted unchanged in urine

27. Biguanides
• Mech. Of action
1- Increased uptake and utilization of glucose
by muscles →reduce insulin resistance
2- Inhibition of hepatic gluconeogenesis →
reduce hepatic glucose output
3- Slowing of glucose absorption from GIT
4- Promotion of insulin binding to its receptor

28. Biguanides
• Contraindications of metformin
1- renal impairment with elevated serum
creatine levels (eGFR < 30 mL/min/1.73 m2).
2- congestive heart failure
3- advanced age (more than 80 years of age).
4- radiologic studies with contrast.
As these patients have higher risk for lactic
acidosis.

29. Management
2- Thiazolidinediones (Glitazones)
• Rosiglitazone: withdrawn from the market
in 2010 b/o risk of Heart failure and MI.
• Pioglitazone:
• M.O.A: Stimulates (PPAR-Ƴ) receptor →
promotes transcription of insulin
responsive genes which control glucose
& lipid metabolism → ↑insulin sensitivity
& ↓ insulin resistance
• Promotes uptake and utilization of
glucose by increasing the GLUT-4
• Inhibit gluconeogenesis

30. α-Glycosidase Inhibitors
C- α-Glycosidase Inhibitors
Ex. Acarbose, Miglitol
• M.O.A:1- Reduce digestion and absorption
of carbohydrates by inhibiting α glucosidase
enzyme
• Do not directly affect insulin secretion
• No hypoglycemia

31. GLP-1 agonists
Glucagon like peptide- 1
• released after meals from the upper &
lower bowel → augment glucose dependent
insulin secretion, during the phase of
nutrition absorption from GIT
• t ½ GLP-1 – 1 to 2 min
• Metabolized quickly by DPP-IV enzyme
• Exenatide

32. GLP-1 agonists
Exenatide: GLP-1 agonist
• Resistant to DPP-IV degradation
• Potent agonist of GLP-1 receptor, Orally
inactive
• Given SC (5-10μg) twice daily, 30-60 min
before meals
• It reduces only post meal glucose rise
M.O.A: Stimulates insulin secretion from β-
cells and decreases glucagon release

33. DPP IV inhibitors
• Dipeptidyl piptedase inhibitors: Sitagliptin,
Vildagliptin, Saxagliptin, Septagliptin,
Allogliptin
• Orally active
• Selective inhibitors of DPP-IV enzyme that
deactivates GLP-1.
• M.O.A
1- Increase insulin secretion
2- Decrease glucagon release
3- Delay gastric emptying
4- Suppress appetite

34. DPP IV inhibitors

35. SGLT-2 inhibitors
• Newer antidiabetic drugs: Dapaglifozin,
Serglifozin, Remoglifozin
• Kidney continuously filters glucose through
glomerulous which is reabsorbed back by
Na2+ glucose co-transporter -2 (SGLT-2)
• Inhibition of SGLT – 2 decreases glucose
re-absorption
• Advantages: Weight loss, No hypoglycemia
• Disadvantages: Increased risk of urinary
infection in presence of glycosuria

36. SGLT-2 inhibitors