This document discusses different types of drugs used to treat diabetes mellitus. It describes two major types of oral anti-diabetic drugs: insulin secretagogues like sulfonylureas that stimulate insulin release from the pancreas, and insulin sensitizers like biguanides and thiazolidinediones that improve insulin sensitivity. It provides details on mechanisms of action, pharmacokinetics, uses, and side effects of representative drugs in each class.

1. Anti-Diabetic drugs

2. Diabetes Mellitus
• Diabetes mellitus (DM), commonly
referred to as diabetes, is a group of
metabolic diseases in which there are
high blood sugar levels over a
prolonged period.

3. Types of Diabetes
Type-I D.M
• It results from the body's failure to produce insulin
• requires the person to inject insulin
• Also referred to as insulin-dependent diabetes mellitus, (IDDM)
or juvenile diabetes
Type-II D.M
• It results from insulin resistance, a condition in which cells fail
to use insulin properly
• sometimes combined with an absolute insulin deficiency
• Also referred to as non-insulin-dependent diabetes mellitus
(NIDDM) or adult-onset diabetes
GESTATIONAL DIABETES:
• It is when pregnant women, who have never had diabetes
before, have a high blood glucose level during pregnancy.
• It may precede development of type-2 DM 5-10%.

7. Treatment of DM:
Insulin
Oral hypoglycemic agents

8. Classification

9. B- Oral anti – diabetic drugs:
1. Sulphonylureas:
I) 1ST Generation:
Chlorpropamide
Tolbutamide
Tolazamide
Acetohexamide
II) 2nd – Generation:
Gliburide (glibenclamide)
Glipizide
Glimipride
Glycazide

10. 2 Biguanides:
Metformin
Phenformin
Buformin
3 Thiazolidinediones:
Ciglitazone
Englitazone
Pioglitazone
Rosiglitazone
Troglitazone
4 Alpha – Glucosidase inhibitors:
Acarbose
Miglitol
5 Other Mis. Agents:
Alpha 2 – Antagonists

11. INSULIN PREPARATIONS

13. Mechanism of action
• Insulin binds to its receptor (1), which starts
many protein activation cascades (2). These
include translocation of Glut-4 transporter to
the plasma membrane and influx of glucose
(3), glycogen synthesis (4), glycolysis (5) and
triglyceride (6).

14. Ultra-short acting Insulin's
Insulin lispro
• rapid absorption and
• shorter duration of action
• hypoglycemia is reduced by 20% to 30% with lispro
• Glucose control MODESTLY improved lower rates
of nocturnal hypoglycemia
Insulin aspart is formed by the replacement of
proline at B28 with aspartic acid.
insulin glulysine glutamic acid replaces
lysine at B29, and lysine replaces
asparagine at B23.

15. Short acting
Regular (soluble) insulin:
 Crystalline Zn insulin complex at neutral pH
 Clear sol.
 Immediate onset  Peak 30 – 60min
 Human sol insulin  Quicker onset
Shorter duration
 Only insulin which can be given i/v (less cost c/co lispro)
in emergencies.
Ketoacidosis
D. Coma
Ac. Infections
After surgery

16. Intermediate acting
Lente – insulins:
Semilente:
It is amorphous precipitate of insulin ē Zn ions in acetate buffer.
Quick onset 30 – 60 min
Shorter duration of action

17. Lente:
Mixture of 30 % semi – lente & 70% ultra – lente
Rapid onset
Optimal duration
Ultra – lente: (Long acting)
Poorly sol crystal of Insulin with Zn delayed onset longer duration

18. Intermediate acting NPH or Isophane Insulin:
 Intermediate acting
 comb. of insulin with protamine in a wt. ratio of 10:1
or 4 mg (100 units) insulin : 0.3 – 0.4 mg protamine
or 6 molecules of insulin : one of protamine
 So neither is present in uncomplexed form
 After s/c inj enzymatic proteolysis insulin
 Can be mixed with regular insulin & given. twice daily.
Biphasic insulin:
 Premixed mixture of 30% regular + 70% NPH
 Pre mixed 25% lispro + 75% NPI. (Neutral protamine l is pro.)

19. Protamine Zn insulin (PZI)
 Delayed onset
 Long duration
 Given once daily with regular insulin

20. Uses:
 IDDM ( Which about 8 – 10% of total diabetics)
 NIDDM

21. Kinetics
 S/C commonly
 I/V infusion  Emergencies
 I/Peritoneal infusion
 I/Nasal sprays
 Pump syst

22. Complications. (Adv. Eff.):
1. Hypoglycemia:
 High dose
 Delay in taking meal
 Unusual exertion
 More with human insulin
Signs & symp:
 Mental confusion
 Inability to concentrate
 Headache
 Disturb. Of speech & vision
 Tachycardia & palpitation
 Sweating
 Tremors
 hunger
 Convulsions & coma.

23. Drug interactions of insulin:
A) Drugs ↑ I nsulin requirements: (diabetogenic)
 Glucocorticoids
 Oral contraceptives
 Growth hormone & analogues
 Sympathomimetics
 Thyroid hormone
 Thiazide diuretics.
B) Drugs that may Dec. insulin requirement:
MAO inhibitors
Anabolic steroids
Sulfonylureas
C) Those masking symp. Of hyper or hypoglycemia.
Βeta blockers

24. Oral-hypoglycemic agents
Anti-diabetic agents II

25. ORALAGENTS:
INSULIN SECRETAGOGUES

26. Oral hypoglycemics:
1- Sulfonylureas:
MOA:
↑Insulin release from β – cells
↑ Sensitivity of β – cells to glucose
↑ 2nd gen. drugs ↑ β – cells in islets
↑ No of receptors. (Up – regulation)
↑ Binding of insulin with receptors
↑ Effect Insulin
↓Serum glucagon.

28. Kinetics:
 Well oral absorption
 Peak in 2 – 4 hrs.
 Duration varies  determines dose freq.
 Highly protein bound  drug interactions
 Exc  kidneys. Eff
Elderly
Renal insuff.
Diuretic therapy

29. Uses:
1. NIDDM
2. Combination therapy with insulin to ↓ dosage requirements
Adverse eff;
 Hypoglycemia
 Dilutional hyponatremia (chlorpropamide)
 G.I.T: nasuea, vomiting and diarrhea
 Photosensitivity
 Allergic reactions (rashes)
 ↑Appetite  wt. Gain.
 Leukopenia, thrombocytopenia, agranulocytosis, pancytopenia,
hemolytic anaemia,

30. Contra – indications:
Hypersensitivity
Renal, hepatic & endocrine dysfunction
Pregnancy

31. Tolbutamide:
 Metabolized in liver  hydroxy der. (Active)
 t ½  4 HRS.
Duration  6 – 12 hrs.
 Safer drug for elderly
 May ↓ iodide uptake by thyroid
 Tolerance may dev. To its eff.
Dose:
0.5 – 2 gm (500mg BEFORE EACH MEAL & BEDTIME)

32. Chlorpropamide: (diabenese)
 6 times more potent.
 t ½  25 – 60 hrs.
Duration  24 – 72 hrs.
 Hypoglycemic reactions more in elderly
 High doses  may cause jaundice
 Disulfiram like eff.
 Dilutional hyponant:
↑ADHsec.
↑Targe eff. Of ADH
Dose:
100 – 500 mg SINGLE DOSE

33. Acetohexamide:
 2.5 times more potent than tolb.
 t½  1 hr for parent drug (5 hrs for active metabolite)
Duration  10 – 16 hrs.
 Has diuretic eff.
Dose:
0.25 – 1.5 g/day

34. Tolazmide:
 05 times more potent.
 T ½  7 hrs. (Duration 18 – 24 hrs).
 Onset of action  delayed for hrs.
 Slow absorption.
Dose:
– 1gm Single or D.D.

35. Glibenclamide:
 150 times more potent.
 Duration  18 – 24 hrs. t ½  10 hrs.
 More risk of hypoglycemia
Dose:
1.25 – 20 mg SINGLE DOSE.

36. Glipizide:
 100 times.
 t½  7 hrs. Duration  16 – 24 hrs.
 90% metab  liver (inactive)
 10% exc kidneys.
Dose:
5 – 30 mg

37. Meglitinide analogues
• This class includes repaglinide and nateglinide
Mechanism of action:
• action is dependent on functioning pancreatic β- cells.
• bind to a distinct site on the sulfonylurea receptor of ATP-sensitive potassium
channels initiating a series of reactions culminating insulin release
• rapid onset & short duration of action c/w sulphonylureas.
• effective in the early release of insulin that occurs after a meal categorized as
postprandial glucose regulators.
• Combined therapy with metformin or the glitazones  better than monotherapy
with either agent in improving glycemic control.
• should not be used in combination with sulfonylureas (due to overlapping
action)

38. Meglitinide analogues
Pharmacokinetics and fate:
• well absorbed orally a/f being taken 1 to 30 minutes before meals.
• metabolized to inactive products by CYP3A4
• excreted through the bile.
Adverse effects:
• hypoglycemia ( lower than with sulfonylureas).
• Wt gain
Drug interactions
• Drugs that inhibit CYP3A4, like ketoconazole, itraconazole, fluconazole,
erythromycin, and clarithromycin  enhance the glucose-lowering effect of
repaglinide
• drugs that increase levels of this enzyme, such as barbiturates, carbamazepine,
and rifampin may have the opposite effect.

39. ORALAGENTS:
INSULIN SENSITIZERS

40. Biguanides:
M.O.A:
 Directly stim. Glycolysis in periph. Tissues.
 ↓Hepatic gluconeogenesis
 ↓ Glucose abs. From G.I.T
 ↓ Plasma glucagon.
 ↑Binding of insulin to receptors
Clinical uses:
NIDDM, Refractory obesity (whose hyperglycemia is due to ineffective
insulin action)
Adverse effects:
Metallic taste, anorexia, nausea, vomiting

41. Contraindications
• Renal disease
• Hepatic diseases
• Alcoholism
• Chronic cardiopulmonary dysfunction

42. Thiazolidinediones or glitazones
• pioglitazon and rosiglitazone are commonly used agents
Mechanism of action:
• target the peroxisome proliferator activated receptor-γ (PPAR-γ), a nuclear
hormone receptor.
• Ligands for PPAR-γ regulate
• adipocyte production
• secretion of fatty acids
• glucose metabolism  resulting in increased insulin sensitivity in adipose tissue,
liver, and skeletal muscle.
• Hyperglycemia, hyperinsulinemia, hypertriacylglycerolemia, and elevated
HbA1c levels are improved.
• LDL levels  not affected by pioglitazone monotherapy or when the drug
is used in combination with other agents
• LDL levels  increased with rosiglitazone.
• HDL levels increase with both drugs.
• TZDs lead to a favorable redistribution of fat from visceral to subcutaneous
tissues.

43. Thiazolidinediones or glitazones
Adverse effects:
• liver toxicity (rare cases  Troglitazone, withdrawn)
• Wt increase can occur (possibly through the ability of TZDs to
increase subcutaneous fat or due to fluid retention).
• osteopenia and increased fracture risk.
• increased risk of myocardial infarction and death from
cardiovascular causes (need further investigation)
• headache
• anemia

44. Oral Agents: α-Glucosidase Inhibitors
• Acarbose & miglitol  orally active drugs used
for the t/m of pts with Type 2 diabetes.
Mechanism of action
• are taken at the beginning of meals.
• act by delaying the digestion of carbohydrates
resulting in lower postprandial glucose levels.
• exert their effects by reversibly inhibiting
membrane-bound α-glucosidase in the intestinal
brush border.
• This enzyme is responsible for the hydrolysis of
oligosaccharides to glucose and other sugars.

45. Oral Agents: α-Glucosidase Inhibitors
• Acarbose also inhibits pancreatic α-amylase
 interfering with the breakdown of starch to
oligosaccharides  the postprandial rise of
blood glucose is blunted.
• do not stimulate insulin release & nor do
increase insulin action in target tissues.
• do not cause hypoglycemia,
• when used in combination with the
sulfonylureas or with insulin hypoglycemia
may develop.

46. Oral Agents: α-Glucosidase Inhibitors
Pharmacokinetics
• poorly absorbed.
• metabolized by intestinal bacteria
• some of the metabolites are absorbed and excreted into the
urine.
• miglitol is very well absorbed but has no systemic effects.
• & excreted unchanged by the kidney.
Adverse effects
• Flatulence
• Diarrhea
• Abdominal cramping
• Pts with inflammatory bowel disease, colonic ulceration, or
intestinal obstruction should not use these drugs.