ANTI-DIABETIC AGENTS (OHAs)

ANTIDIABETIC
AGENTS
CLASSIFICATION
Insulin preparations
 Conventional insulin preparations

1. Bovine (beef) insulin
2. Porcine(pig) insulin
 Monocompetent insulins
 Human insulins
 Insulin analogues.
Insulin preparations based on onset &
DOA
• Rapidly acting insulin analogues:
1. Insulin lispro,
2. Insulin aspart,
3. Insulin glulisine.
• Short acting insulins:
1. Regular (soluble) insulin
• Intermediate-acting insulins:
1. NPH (Neutral Protamine Hagedorn) insulin/isophane insulin.

Long acting insulin analogues:
1. Insulin glargine
2. Insulin detemir
Oral antidiabetic drugs
1) Sulfonylureas
a) 1st generation: Tolbutamide
b) 2nd generation: Glyburide(glibenclamide), glipizide, glipizide,
Glimepiride
2) Biguanide: Metformin
3) Meglitinide analogue: Repaglinide
4) D-phenylalanine derivative: Nateglinide
5) Thiazolidinediones: Pioglitazone
6) α-glucosidase inhibitors: Acarbose, Miglitol, Voglibose.
INSULIN
Introduction
• Discovered by Banting & Best.

• Synthesised by B cells of pancreatic islets.
• Formed by the removal of C-peptide from proinsulin by proteolysis.
• Consists of 2 peptide chains-A & B, which are connected by 2 disulfide
bridges.
Regulation of insulin secretion
Insulin secretion is regulated by chemical, hormonal & neural mechanisms.
Mechanism of action
• Insulin binds to tyrosine kinase receptors present on cell membrane.
• Binding of insulin to alpha subunit activates T K activity of beta subunits.
• Phosphorylation of tyrosine residues of receptor.
• Series of phosphorylation-dephosphorylation reactions.
• Promotes entry of glucose into the cell.
• Mediates various actions of insulin.

Pharmacokinetics
• Insulin is destroyed by proteolytic enzymes in gut, hence not effective orally.

• Insulin is administered usually by s.c, but in emergencies, regular insulin by
i.v.
• After I.V injection, insulin is rapidly metabolised by liver & kidney, with a
half life of 6 min.
Insulin administration
• Insulin syringes & needles

• Pen devices
• Insulin pumps
Site of administration
• Insulin is administered s.c in the :

 abdomen,
 buttock,
 anterior thigh or
 dorsal arm.
Indications
1. Type-1 DM
2. DKA
3. Non ketotic hyperglycaemia coma
4. Diabetes during pregnancy
5. Stress of surgery, infections & trauma in diabetics
6. Type-2 DM with oral antidiabetic drugs.
Complications
1. Hypoglycaemia: most common & dangerous, as prolonged hypoglycaemia causes permanent
brain damage.
2. Allergic reactions: rare. May cause local skin reactions (swelling, redness)
3. Lipodystrophy at the site of injection
4. Insulin resistance: patient requires > 200 U insulin/day.
5. Oedema, due to salt & water retention.

Drug interactions
• Beta blockers × insulin
• Salicylates × insulin:
Salicylates exert hypoglycaemia effect by increasing the sensitivity of pancreatic beta cells to
glucose & potentiating insulin secretion.

SULFONYLUREAS
Introduction
• Sulfonylureas are divided into two generations.

• All these have same MOA, but differ in potency, DOA.
• 2nd generation drugs are more potent.
Mechanism of action
1. Sulfonylureas stimulate insulin secretion from beta cells.

Sulfonylureas 》
Bind to specific receptors on beta cells of islets 》
Block ATP-sensitive K+ channels 》
Depolarisation & influx of Ca+2 ions into beta cells 》
Degranulation & increased release of stored insulin from beta cells.

MOA-cont‘d
2. Sulfonylureas increase sensitivity of peripheral tissues to insulin by
increasing the number of insulin receptors.
3. They reduce the release of glucagon.

Pharmacokinetics
• Sulfonylureas are well absorbed after oral administration.

• They are highly bound to plasma proteins.
• They have low volume of distribution.
• They are metabolised in liver.
• They are excreted mainly in urine.
Use
• Type-2 DM.
Adverse effects
1. Hypoglycaemia: common, especially with glibenclamide & chlorpropamide.
2. GI disturbances: nausea, vomiting, diarrhoea & flatulence.
3. Weight gain, due to stimulation of appetite.
4. Allergic reactions: skin rashes, itching, photosensitivity.
5. Teratogenicity
6. Alcohol intolerance: chlorpropamide.

Drug interactions
1. Sulfonylureas × Salicylates/sulphonamides
2. Propranolol × sulfonylureas
3. Rifampicin, phenobarbitone × sulfonylureas
4. Warfare, sulphonamides × sulfonylureas..
BIGUANIDES -
METFORMIN
Mechanism of action
• It activates the enzyme AMP dependent protein kinase

(AMPK)
• This results in:-
1. Decreased hepatic gluconeogenesis
2. Increased peripheral utilisation of glucose in skeletal muscle
3. Inhibition of alimentary absorption of glucose.

Pharmacokinetics
• Metformin is taken orally
• Well absorbed through GIT
• Excreted mostly unchanged in urine.

Use
• Type-2 DM either alone or in combination with other antidiabetic agents.

Adverse effects
1. Metallic taste, anorexia, nausea, vomiting, diarrhoea

2. Weight loss; skin rashes
3. Lactic acidosis: most serious but rare
4. Vitamin B12 deficiency with prolonged use due to malabsorption
5. NO hypoglycaemia even in large doses.
Repaglinide & Nateglinide
• Stimulate insulin release by closure of ATP- sensitive K+ channels in beta cells of islets >
Depolarisation > insulin release.
• Well absorbed from GIT; Metabolised mainly in liver.
• C/I in hepatic failure.
• Used only in Type-2 DM to control postprandial hyperglycaemia.
• Side effects of Repaglinide: weight gain & hypoglycaemia.
• Side effects of meglitinide: nausea & flu-like symptoms.

DPP-4 Inhibitors
• E.g. Sitagliptin, saxagliptin, vildagliptin
• Sitagliptin inhibits DPP-4 competitively
• Saxa/vildagliptin bind covalently with the enzyme.
• They Inhibit enzyme DPP-4 》 prevent inactivation of GLP-1 》 increase plasma concentration of
GLP-1 》 increases insulin secretion, suppresses glucagon release & improves control of fasting &
postprandial hyperglycaemia.
They do not affect gastric emptying, satiety & body weight.
Route: Orally as adjuvants in type-2 DM.
Adverse effects:
1. Sitagliptin: allergic reactions
2. Vildagliptin: hepatotoxicity & rarely drug interactions.
3. Risk of hypoglycaemia is low.
THIAZOLIDINEDIONES
• They increase sensitivity of peripheral tissues

to insulin.
• Pioglitazone reduces serum triglyceride &

increases HDL levels.
Pharmacokinetics
• Pioglitazone is almost completely absorbed from GIT.
• Highly bound to plasma proteins (95%)
• Metabolised in the liver.

Adverse effects
• Nausea, vomiting
• Anemia, oedema, weight gain
• Precipitation of heart failure in patients with low cardiac reserve
• Hepatotoxicity & bladder cancer rarely
Uses
• Pioglitazone is used alone / in combination with sulfonylureas/metformin

in patients with type-2 DM.
α-GLUCOSIDASE INHIBITORS
• Acarbose, Miglitol & Voglibose
• MOA: They reduce intestinal absorption of carbohydrates by inhibiting the enzyme α-

glucosidase in brush border of SI & reduce postprandial hyperglycaemia.
• Uses: In obese patients with type-2 DM.
• Adverse effects: Mainly on GIT: flatulence, fullness, diarrhoea.

GLP-1 ANALOGUES
• Exenatide, Liraglutide
• MOA:
 It stimulates glucose dependent insulin secretion,
 Suppresses glucagon release,
 Slows gastric emptying.

GLP-1 is degraded by DPP-4.
Plasma half life is 1-2 minutes.
Hence, it can't be used therapeutically.
GLP-1 Analogues are Resistant to DPP-4.
Their action is similar to GLP-1.
Injected s.c. 1 hr before breakfast & dinner in type-2 DM patients.
Use: as adjuncts to other antidiabetic agents.
This results in better glycemic control, reduction in HbA1c & body weight.
They may help to prevent progression of beta cell failure in type'2 DM.
Adverse effects:
Nausea mainly.
Hypoglycaemia may occur when used in combination with other antidiabetic
agents.
PRAMLINTIDE
• A synthetic analogue of amylin.
• Decreases glucagon secretion, delays gastric emptying, suppresses appetite & decreases body weight.
• Administered s.c. in patients with type-1 & 2 DM just before meals
• Adverse effects:
• nausea &
• hypoglycaemia are common.
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ANTIDIABETIC

 Conventional insulin preparations

• Short acting insulins:

1. Regular (soluble) insulin

1. NPH (Neutral Protamine Hagedorn) insulin/isophane insulin.

• Discovered by Banting & Best.

• Insulin binds to tyrosine kinase receptors present on cell membrane.

• Binding of insulin to alpha subunit activates T K activity of beta subunits.

• Phosphorylation of tyrosine residues of receptor.

• Series of phosphorylation-dephosphorylation reactions.

• Promotes entry of glucose into the cell.

• Mediates various actions of insulin.

• Insulin is destroyed by proteolytic enzymes in gut, hence not effective orally.

• Insulin syringes & needles

• Insulin is administered s.c in the :

3. Lipodystrophy at the site of injection

4. Insulin resistance: patient requires > 200 U insulin/day.

5. Oedema, due to salt & water retention.

• Beta blockers × insulin

glucose & potentiating insulin secretion.

• Sulfonylureas are divided into two generations.

1. Sulfonylureas stimulate insulin secretion from beta cells.

Bind to specific receptors on beta cells of islets 》

Block ATP-sensitive K+ channels 》

Depolarisation & influx of Ca+2 ions into beta cells 》

Degranulation & increased release of stored insulin from beta cells.

2. Sulfonylureas increase sensitivity of peripheral tissues to insulin by

increasing the number of insulin receptors.

3. They reduce the release of glucagon.

• Sulfonylureas are well absorbed after oral administration.

1. Hypoglycaemia: common, especially with glibenclamide & chlorpropamide.

2. GI disturbances: nausea, vomiting, diarrhoea & flatulence.

3. Weight gain, due to stimulation of appetite.

4. Allergic reactions: skin rashes, itching, photosensitivity.

6. Alcohol intolerance: chlorpropamide.

• It activates the enzyme AMP dependent protein kinase

• This results in:-

1. Decreased hepatic gluconeogenesis

2. Increased peripheral utilisation of glucose in skeletal muscle

3. Inhibition of alimentary absorption of glucose.

• Metformin is taken orally

• Well absorbed through GIT

• Excreted mostly unchanged in urine.

• Type-2 DM either alone or in combination with other antidiabetic agents.

1. Metallic taste, anorexia, nausea, vomiting, diarrhoea

• Well absorbed from GIT; Metabolised mainly in liver.

• C/I in hepatic failure.

• Used only in Type-2 DM to control postprandial hyperglycaemia.

• Side effects of Repaglinide: weight gain & hypoglycaemia.

• Side effects of meglitinide: nausea & flu-like symptoms.

• Sitagliptin inhibits DPP-4 competitively

• Saxa/vildagliptin bind covalently with the enzyme.

• They increase sensitivity of peripheral tissues

• Pioglitazone reduces serum triglyceride &

• Pioglitazone is almost completely absorbed from GIT.

• Highly bound to plasma proteins (95%)

• Metabolised in the liver.

• Pioglitazone is used alone / in combination with sulfonylureas/metformin

• Acarbose, Miglitol & Voglibose

• MOA: They reduce intestinal absorption of carbohydrates by inhibiting the enzyme α-