This document discusses antidiabetic drugs used to treat diabetes mellitus. It describes the two main types of diabetes and then focuses on insulin and oral hypoglycemic agents. Insulin is described in detail including its mechanism of action, types, administration, and potential complications. Oral hypoglycemic agents discussed include sulfonylureas, which stimulate insulin release, and biguanides like metformin, which lower hepatic glucose production and increase insulin sensitivity. The document provides information on the mechanisms, pharmacokinetics, uses, and adverse effects of these important antidiabetic medications.

1. Antidiabetic Drugs

3. Antidiabetic Drugs
• Diabetes mellitus (DM) is a group of metabolic disorders
characterized by hyperglycemia.
• It is associated with abnormalities in carbohydrate, fat, and protein
metabolism and results in chronic complications including
microvascular, macrovascular, and neuropathic disorders.

4. Diabetes Mellitus
2 major categories:
I. Type- I or Insulin Dependent Diabetes Mellitus (IDDM)
Selective B cell destruction and severe or absolute insulin deficiency.
II. Type- II or Non-Insulin Dependent Diabetes Mellitus (NIDDM)
Insulin is produced by the B cells, it is inadequate to overcome the resistance, and the blood
glucose rises.
III. Gestational Diabetes (GDM) is defined as any abnormality in glucose levels
noted for the first time during pregnancy.
IV. Other

5. Fig: In Type 2 diabetes there is a progressive decline in β-cell function and insulin secretion. As a result,
most patients with type 2 DM will eventually need insulin. Adapted from Kendall et al (2009).

6. Treatment Goals of DM
• To achieve best possible control of plasma glucose level
• To relieve the immediate signs and symptoms of diabetes
• Normalize nutrition and achieve ideal body weight.
• Improve quality and quantity of life by preventing and/or slowing the onset and
progression of the diabetes-associated complications.

7. Antidiabetic agents
Insulin analogs
Oral hypoglycemic agents

8. Insulin and its analogs

9. Insulin receptor
• Its cytoplasmic domain contains tyrosine kinase.
• Its contains two alpha sub-units and two beta sub-units; the tyrosine kinase
resides within the beta sub-units.
• The extracellular domain, ie, that part of the receptor which projects into the ECF,
combines with the ligand (eg.insulin) ----- this results in autophosphorylation of
the receptor and tyrosine kinase becomes active ------- eventually the
physiological-pharmacological actions (eg. Entry of glucose molecule from the ECF
into the inside of the cell) occur.

10. Fig : - Insulin receptor

11. Insulin release
• Insulin release from the pancreatic B cell by glucose and by sulfonylurea drugs.
• In the resting cell with normal (low) ATP levels, potassium diffuses down its
concentration gradient through ATP-gated potassium channels, maintaining the
intracellular potential at a fully polarized, negative level. Insulin release is minimal.
• If glucose concentration rises, ATP production increases, potassium channels close, and
depolarization of the cell results.
• As in muscle and nerve, voltage-gated calcium channels open in response to
depolarization, allowing more calcium to enter the cell. Increased intracellular calcium
results in increased insulin secretion.

13. Insulin secretagogues close the ATP-dependent potassium channel,
thereby depolarizing the membrane and causing increased insulin
release by the same mechanism.

14. Glucose Transporters

15. Insulin…
Pharmacodynamics
 Affects all major metabolic pathways
• carbohydrate, fat, protein
 Major target tissues are
• Liver, adipose, and skeletal muscle
 Liver (decreases hepatic glucose production)
• Decreases gluconeogenesis, glycogenolysis, ketogenesis, promotes glycogenesis

16. Muscle cells
• Increases GLUT-4 glucose uptake, glucose oxidation, glycogen synthesis,
amino acid uptake, protein synthesis
• Decreases glycogenolysis, amino acid release
• Adipocytes
• Increase glucose uptake, triglyceride synthesis; Decrease FFA and
glycerol release
• Net effect is to cause hypoglycemia and increase fuel storage in muscle, fat
tissue and liver.

17. Insulin….
Pharmacokinetics
• Ineffective orally
• Given parenterally; SC or I/M; I/V in emergency, (inhalational?)
• Plasma t½ : 5-9 mins
• Metabolized in liver (primarily) and kidney & muscles ( small extent)
 Sources of commercial insulin
• Animal (beef or pork)
• Human (recombinant )

18. Goal of subcutaneous insulin therapy
 To mimic both the normal prandial (mealtime) insulin secretion and the basal
(overnight, fasting, and between meal) between-meal insulin levels as close as possible
 To accomplish this goal most current regimens use at least four different insulin
analogs:
Long-acting or Intermediate acting insulins are used to provide basal insulin levels
Rapid or Short-acting insulins are used to correct the transient (prandial)
hyperglycemia associated with meals.

19. Goal of subcutaneous insulin therapy…
 Several different regimens have been developed involving multiple subcutaneous
injections per day when insulin is used alone in the treatment of Type 1 diabetes
 Another available option is the use of an insulin pump, in the form of a battery
powered pump controlled by a microprocessor

20. Principal Types and Duration of Action of Insulin Preparations
• Four principal types :
I. Rapid-acting: with very fast onset and short duration;
II. Short-acting: with rapid onset of action;
III. Intermediate-acting: and
IV. Long-acting: with slow onset of action

21. Types of Insulin….
• Rapid-acting: Insulin Lispro, Insulin aspart and, insulin glulisine
• Short-acting: Regular, semilente
• Intermediate acting: NPH (Neutral Protamine Hagedorn) and Lente
• Long-acting: Ultralente, glargene

22. Fig: Subtypes and approximate DOA of different insulin formulations. The DOA of regular & NPH insulin
increases at higher doses. Adapted from Kennedy & Masharani (2015).

23. Fig: A) Once-daily long-acting insulin glargine B) Intermediate-acting NPH is the oldest basal insulin that is still
in common use. Figure adapted from DeWitt & Hirsch (2003).

24. Fig: Examples of physiologic insulin delivery.

25. Fig: Insulin stacking. The combination of intermediate-acting NPH and short-acting regular insulin were used to mimic the
physiologic time course of insulin secretion by the normal pancreas.

26. Fig: Insulin infusion protocol for patients using a computerized, battery operated
insulin pump. Adapted from Kroon et al. (2009).

27. Insulin pump
 Picture: Insulin pump. Patient with Type 1 diabetes
wearing a Medtronic Paradigm insulin pump. The
device contains an insulin reservoir connected to a
SC catheter. A battery powered pump and
microprocessor are used to provide both a basal
infusion of insulin, as well as pre-mealtime boluses
(the size of the pre-meal insulin bolus is varied to
match the amount of carbohydrate to be
consumed).

28. • Insulin Regimens for type 1 DM
• Overall, patients using insulin analogues (lispro, aspart, glargine) in
physiologic regimens (e.g. Fig.13A), including patients with
hypoglycemia unawareness, have fewer hypoglycemic episodes than
patients using traditional insulins (regular and NPH) (Fig 14).
• It may be that the main impact of physiologic insulin regimens and
insulin glargine, in particular, is that the separation of prandial and
basal components improves our understanding of insulin use,
simplifies dosing adjustments, and allows patients more flexibility in
meal timing.

29. Pharmacokinetics of Insulin Preparations
• Commercial insulin preparations differ in a number of ways, such as
differences in the recombinant DNA production techniques, amino
acid sequence, concentration, solubility, and the time of onset and
duration of their biologic action.

30. Pharmacokinetics of Insulin Preparations…

31. Pharmacokinetics of Insulin Preparations…

32. Insulin Regimens
• Choice of regimen depends on desired degree of glycemic control, the
patients lifestyle, and his or her ability to adjust insulin dose.
• Once daily injections are rarely satisfactory.

33. Insulin Regimens
• 2 shots: most commonly used regimen
• Rapid + intermediate acting (1:2)
• 2/3rd of dose to be given in the morning and the remaining in the evening.
e.g -10 units of regular and 15 units of NPH insulin in the morning and 5 units of
regular and 5 units of NPH in the evening.

34. Representative Plasma Insulin Times

35. • Advantages:
Controls Postprandial glycaemia at breakfast and dinner.
• Disadvantages:
 Pre-breakfast hyperglycemia is common.
Increased risk of nocturnal hypoglycemia in attempt to control pre-breakfast
hyperglycemia.

36. Intensive Insulin therapy (3 shots & 4 shots)
• 3 shots
• Rapid/short + intermediate at breakfast
• Rapid/short acting at supper (evening meal)
• Intermediate at bedtime
e.g. 10 units of regular insulin mixed with 10 units of NPH in the morning, 8 –
10 units of regular insulin before the evening meal, and 6 units of NPH insulin
at the bedtime.

37. Representative Plasma Insulin Times

38. Insulin Regimens
• 4 shots
• Rapid/short acting at breakfast, lunch and supper
• Long acting at bedtime

39. Intensive Insulin therapy (3 shots & 4 shots)
• Advantages:
- Controls PP glycemia. Allows flexibility of meal schedule and quantity.
- Tight glycemic control possible with least risk of hypoglycemia.
• Disadvantages
- Pumps( insulin syringe) are expensive, add risk of skin infections and pump failure.

40. Some important guidelines for insulin therapy
• Initiate with the daily dose with 0.3 U/kg (16 – 20 U/d), increasing to 1 U/kg
• Adjust the dose according to the usual monitoring of blood glucose
• Daily increment should not be more than 4 Units
• Peak action of insulin injected should coincide with the postprandial rise in blood
glucose.

41. • Aim of therapy:
* Blood glucose level of 90 – 130 mg/dl before meal, and after overnight fast
* ≤ 180 mg/dl 1 hr after meal & 150 mg/dl 2 hr after meal

42. Factors Affecting Absorption
• Absorption depends on :
• Blood flow to site,
- Site of injection,
Abdomen>Arm>Buttock>Thigh
• Exercise will increase absorption, as will local massage

43. Therapeutic Uses of Insulin
• Type I diabetes
• Type II diabetes when pregnant
• Type II diabetes under stress
• Type II diabetes poorly controlled by diet and oral agents
• Complications of diabetes (ketoacidosis)

44. Complication of Insulin Therapy
I. Hypoglycemia : Rapid development of hypoglycemia causes signs of autonomic
hyperactivity—both sympathetic (tachycardia, palpitations, sweating,
tremulousness) and parasympathetic (nausea, hunger)—and may progress to
convulsions and coma if untreated
 They usually result from inadequate carbohydrate consumption, unusual physical
exertion, or too large a dose of insulin

45. Complication of Insulin Therapy
I. Treatment of Hypoglycemia
• All the manifestations of hypoglycemia are relieved by glucose administration.
• To expedite absorption, simple sugar or glucose should be given, preferably in
liquid form.
• Dextrose tablets, glucose gel, or any sugar-containing beverage or food may
be given.
• Unconsciousness or stupor: 20–50 mL of 50% glucose solution by IV infusion
over a period of 2–3 minutes.

46. Complication of Insulin Therapy
I. Treatment of Hypoglycemia
• 1 mg of glucagon injected either SC or IM
• If the patient is stuporous and glucagon is not available, small amounts of honey
or syrup can be inserted into the buccal pouch.
• In general, however, oral feeding is contraindicated in unconscious patients.
• Emergency medical services should be called immediately for all episodes of
severely impaired consciousness.
• If no response is shown, it may be due to cerebral edema treat with iv dexamethasone or mannitol

47. Complication of Insulin Therapy….
ii. Lipodystrophy  atrophy of subcutaneous fatty tissue leading to depressed areas
at the site of injection.
result from an immune reaction
iii. Lipohypertrophy (accumulation of extra fat) (local)
 seen as a consequence of pharmacological effect of insulin
iv. Insulin allergy  rare with human insulin  mainly due to contaminating proteins
in the preparation  hypersensitivity reactions such as local or systemic urticaria,
rarely anaphylaxis reaction antihistamines, corticosteroids may be required

48. Complication of Insulin Therapy….
 Other:
• Insulin resistance (activating antibodies, tissue unresponsiveness due to
excess insulin)
• Weight gain
• Peripheral oedema
• Insulin antibody formation
• Increased Cancer Risk

49. How Much Insulin Does the patient Need?
• Different in different individuals.
• Amount depends on
• Body weight
• Level of physical activity
• Daily food intake
• Other medicines

50. Insulin…
Drug interactions
• β – blockers (prolong hypoglycemia)
• Alcohol (precipitate hypoglycemia)
• Salicylates, lithium & theophylline (accentuate hypoglycemia)

51. Oral Hypoglycemic Agents

52. Oral hypoglycaemic agents
1. Sulfonylureas
• First generation
• Tolbutamide
• Chlorpropamide
• Tolazamide
• acetohexamide
• Second generation
• Glibenclamide
• Glipizide
• Gliclazide
• Glimepiride
2. Biguanides
Metformin
3. Meglitinide analogues
Repaglinide, Nateglinide
5. Thiazolidinediones
Rosiglitazone, Pioglitazone
6. Αlpha glucosidase inhibitors
Acarbose, Miglitol
7. Dipeptidyl peptidase-4 inhibitors
Saxagliptan, Linagliptan

53. 1. Sulfonylureas
• Classified as insulin secretagogues
Promote insulin release from the β-cells of the pancreas.
• The sulfonylureas in current use are the
Second-generation drugs: glyburide, glipizide, and glimepiride
• All are orally active
• All bound to plasma protein (90-99%)

54. Sulfonylureas…
Mechanism of action
Bind with the receptors present close to the ATP sensitive K+ channels on pancreatic β
cell membrane → inhibits the channel → no K+ efflux (accumulation of K+) →
depolarization → opens Ca2+ channel → entry of Ca2+ → degranulation → release of
insulin
Extra-pancreatic action
• Increase the concentration of insulin receptors on the target cells
oIncrease peripheral insulin sensitivity
• Inhibits gluconeogenesis in liver

55. Mechanism of action of sulfonylureas

56. Sulfonylureas…
• Pharmacokinetics
• Good oral bioavailability
• ≥ 90% plasma protein bound
• Metabolised in liver
• Excreted via urine
• Once daily dosing
 Use: Type-II DM only

57. Sulfonylureas…
Adverse effects
• Weight gain
• Hyperinsulinemia and Hypoglycemia
• Use with caution in hepatic or renal insufficiency
• Renal impairment is a particular problem for glyburide
• Glipizide or glimepiride are safer options in renal dysfunction and in elderly
patients.
• Glyburide has minimal transfer across the placenta -

58. 2. Biguanides
• Drugs: Metformin and phenformin (withdrawn due to serious lactic acidosis)
• Metformin: insulin sensitizer; ↑es glucose uptake and use
• It does not stimulate insulin release or cause hypoglycemia
o Hyperinsulinemia is not a problem: risk of hypoglycemia is far less than that with
sulfonylureas.
• Does not bind plasma proteins
• Excreted unchanged in urine
• Often combined with sulfonylurea drugs

59. Biguanides…
- Mechanism of action
- Reduce hepatic production of glucose
- Other minor actions may include
- Increases glucose uptake by skeletal muscle and
- Increase peripheral utilization of glucose by enhancing anaerobic glycolysis.
- Slows down GI absorption of glucose and increase uptake by skeletal muscles.
- reduction of plasma glucagon levels
- Weight loss may occur because metformin causes loss of appetite.

60. Fig: Metformin acts primarily to suppress glucose production in the liver.

61. Biguanides…
Use: Type II DM
oDrug often preferred for obese patient as it stimulates weight loss in patients
not controlled by diet and exercise
• Other use: Metformin is effective in the treatment of polycystic ovary syndrome.
oIt lowers insulin resistance seen in this disorder and can result in ovulation
and, therefore, possibly pregnancy.

62. Biguanides…
 Adverse effects
• Nausea, abdominal discomfort, diarrhea, metallic taste, anorexia are more common
• Lactic acidosis (rare)  contraindicated in renal dysfunction
• Vitamin B12 deficiency: interfere with absorption
 Biguanides are contraindicated in patients with renal disease, alcoholism, hepatic
disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary
dysfunction) because of the increased risk of lactic acidosis induced by these drugs.

63. 3. Meglitinide (glinides)
• Drugs: repaglinide and nateglinide
• Insulin secretagogues: Have rapid onset & short duration
• Used to control postprandial glucose levels if diet and exercise fail.
• Should not be combined with sulfonylureas: increased the risk of serious hypoglycemia.
• They bind to an ATP-dependent K+ (KATP) channel on the cell membrane of
pancreatic beta cells in a similar manner to Sulfonylureas but have a weaker binding
affinity and faster dissociation from the SUR1 binding site.

64. Meglitinide (glinides)….
• Glinides should be taken prior to a meal
• Well absorbed after oral administration.
• Both glinides are metabolized to inactive products by cytochrome P4503A4 in the
liver and are excreted through the bile.

65. Meglitinide (glinides)….
• Adverse effects:
• Although glinides can cause hypoglycemia and weight gain, the incidence is lower than
that with sulfonylureas.
• Note: Drugs that inhibit CYP3A4, such as itraconazole, fluconazole, erythromycin,and clarithromycin, may
enhance the glucose lowering effect of repaglinide. Drugs that induce CYP3A4, such as barbiturates,
carbamazepine, and rifampin, may have the opposite effect.]
• By inhibiting hepatic metabolism, the lipid-lowering drug gemfibrozil may significantly
increase the effects of repaglinide, and concurrent use is contraindicated.
• These agents should be used with caution in patients with hepatic impairment.

66. Repaglinide
• Short acting Insulin secretagogue
• Acts similar to sulfonylureas
• Administered before each major meal
• Can be used with metformin
• Used only in Type II DM
• Adverse effects
• Headache, dyspepsia, arthralgia & weight gain; lower risk of serious hypoglycemia

67. Nateglinide
• Stimulates insulin secretion →rapid onset & shorter duration of action than repaglinide
• Administer 10-30 mins before meal
• Adverse effects
• Dizziness, Nausea, flu like symptoms & joint pain; less frequent episodes of
hypoglycemia

68. 4. Thiazolidinediones (Glitazones)
• Drugs: Rosiglitazone and Pioglitazone
• They are insulin sensitizers.
• Used where there is insulin resistance and when other oral agents fail
• Reduce blood glucose without increasing circulating insulin.
• Although insulin is required for their action, the TZDs do not promote its release
from the βcells, so hyperinsulinemia is not a risk.

69. Thiazolidinediones…
• MOA
• Thiazolidinediones or TZDs act by activating PPARs (peroxisome
proliferator-activated receptors), a group of nuclear receptors ( Adipocytes).
• They may act to stimulate production of proteins that increase insulin
sensitivity, such as adiponectin.
• They may also act by blocking transcription of other proteins responsible
for insulin resistance ( e.g. Resistin )

71. Thiazolidinediones…
Pharmacokinetics
• Pioglitazones: taken orally with or w/o food
• Plasma levels peak about 3 hr
• Plasma half-life is 3-7 hr; active metabolites (t1/2= 16-24 h)
• Liver metabolism by CYP2C8 and CYP3A4 and excreted in feces (2/3) and urine (1/3)
• Rosiglitazone is well absorbed; with or w/o food
• Plasma levels peak about 1 hr
• t1/2 is 3-4 hr
• Liver metabolism via CYP2C8

72. Thiazolidinediones…
 Adverse effects
• Edema
• Both drugs tend to cause increase in body weight, causes peripheral edema and
can also precipitate or worsen congestive heart failure.
• Plasma volume expansion
• Dose-related weight gain
• Headache, myalgia & mild anaemia
* Do not cause lactic acidosis, even in patients with renal impairment

73. 5. Alpha-Glucosidase Inhibitors
• Drugs: Acarbose, Miglitol
• Taken orally to act on gut
• Small reductions in blood glucose
• Will not cause hypoglycemia in monotherapy.
• Competitive inhibitors, so take before meals.
• Mechanism of action: Reversible inhibitors of the alpha-glucosidase enzyme on
intestine which delays digestion/absorption of ingested carbohydrate.

74. Alpha-Glucosidase Inhibitors….
 Adverse effects
• Flatulence, bloating, diarrhea, and abdominal cramping
 Contraindications
• Patients with major GI disorders including inflammatory bowel disease,
chronic ulcers, malabsorption, or intestinal obstruction.

75. Dipeptidyl peptidase-4 inhibitors
• Alogliptin, linagliptin, saxagliptin, and sitagliptin are orally active dipeptidyl
peptidase-4 (DPP-4) inhibitors used for the treatment of type 2 diabetes.
• Mechanism of action: inhibit the enzyme DPP-4, which is responsible for the
inactivation of incretin hormones such as GLP-1.
• Prolonging the activity of incretin hormones increases insulin release in response to meals and
reduces inappropriate secretion of glucagon.
• DPP-4 inhibitors may be used as monotherapy or in combination with other
hypoglycemic agents.

76. SGLT-2 Inhibitors
• SGLT-2 is a sodium-glucose low affinity & high-capacity co-transporter that is
expressed in the proximal renal tubule and mediates reabsorption of ~90% of
filtered glucose into blood.
• SGLT-1 is a second transporter expressed in a distal segment of the proximal
tubule that acts in concert with SGLT-2. Together these two transporters produce
a relatively complete reabsorption of glucose from the renal tubules, so that
glucose is barely detectable in the urine of healthy adults.

77. SGLT-2 Inhibitors
• Mutations in the SGLT-2 gene cause renal glycosuria and urinary glucose
excretion. SLGT-2 inhibitors reduce glucose reabsorption, resulting in increased
urinary glucose excretion, and lower plasma glucose.
• SGLT-2 inhibitors efficiently lower plasma glucose levels independently of insulin
action and secretion.

78. SGLT-2 Inhibitors
• Efficacy depends on renal function.
• Canagliflozin can be prescribed to patients with normal or moderate
renal function (GFR above 45 ml/min).
• However, dapagliflozin is not recommended in patients with even
moderate to severe renal dysfunction (if the GFR is below 60 ml/min).

80. Fig: ~ 90% of glucose reabsorption is produced by a sodium-glucose transporter (SGLT-2). Its inhibition
results in increased glucose in the urine (glycosuria) and a lowering of plasma glucose level in patients
with type 2 diabetes.

81. SGLT-2 Inhibitors…
• Drugs:
Canagliflozin
Dapagliflozin
Empagliflozin
• Side effects: genito-urinary infections, hypotension, dehydration,
potential for weight loss.

82. Bile acid sequestrants
• Drugs: Colesevelam
• Mechanism of action: lowers LDL cholesterol in patients with primary
hypercholesterolemia.
• Colesevelam's MOA to improve glycemic control is uncertain.
• One possibility is that bile acid sequestrants act in the GIT to reduce glucose
absorption.
• Side Effects: N, , dyspepsiaconstipation, interference with absorption of other
oral meds increase in triglycerides

83. Dopamine agonists
• Drugs: Bromocriptine

84. Injectable non-insulin hypoglycemics
 GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS
• Drugs:
• Exenatide
• Lixisenatide
• Liraglutide
• Albiglutide
• Dulaglutide

85. Injectable non-insulin hypoglycemics
 GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS….
• Stimulates insulin secretion; suppresses glucagon secretion; Slows
down GI absorption rate; reduces appetite; and reduces liver fat.
• These drugs decrease prandial glucose excursions by increasing
glucose-mediated insulin secretion & decreasing glucagons levels.

86. Injectable non-insulin hypoglycemics
 AMYLIN ANALOG
 Drugs: Pramlintide
 Mechanism of Action: exerts its effect by slowing down food
absorption & suppressing appetite.
 Amylin can suppress appetite via hypothalamic receptors (different
receptors than for GLP-1), Suppresses glucagon secretion and slows
gastric emptying.

88. Summary….

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94. Thank you!