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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