BY, SARANG

SREE RAMACHANDRA COLLEGE OF PHARMACY 1

ORAL HYPOGLYCAEMIC DRUGS

Oral hypoglycemics• Drugs that are given orally to reduce the blood

glucose levels in diabetic patients• Five types of oral antidiabetic drugs are

currently in use:• Sulfonylureas • Biguanides

• Meglitinides

• Thiazolidinediones • Alpha -glucosidase inhibitors

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Sulfonylureas I Generation

– Tolbutamide– Chlorpropamide

II Generation– Glipizide– Gliclazide– Glibenclamide (Glyburide) – Glimepiride

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First Generation Tolbutamide

• O.O.A. is within one hour & lasts for 6-12 Hrs

• It is weaker, short acting, less likely to cause hypoglycemia

Chlorpropamide

• O.O.A. is within one hour & lasts for 24-60 Hrs

• It is more potent, long lasting, risk of prolonged hypoglycemia

• Potentiates ADH action

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Second Generation Glibenclamide (glyburide)• O.O.A. is within 1-4 hours & lasts for 10-24 Hrs• It is more potent than tolbutamide, risk of severe hypoglycaemia. Glipizide• O.O.A. is within 1-3 hours & lasts for 10-24 Hrs• Less potent than glibenclamide but more potent than tolbutamide• Risk of prolonged hypoglycemia

Gliclazide• O.O.A. & D.O.A, same as glipizide• More potent than tolbutamide• Has an antioxident and antiplatelet action• Less weight gain Glimepiride: • Same as glipizide

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Sulfonylureas - MOA

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Sulphonylureas Pharmacokinetics• Well absorbed• PPB is high• Metabolized in liver or kidney and excreted in urine Adverse effects• Hypoglycemia• Weight gain• Cross placental barrier – fetal hypoglycemia (avoid in gestational DM)

Contra indications• Ketocanazole, chloramphenicol and anticoagulants- inhibit their metabolism• Sulfonamides, salicylates etc- protein binding displacement• Propranolol masks the symptoms of sulfonylureas

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BIGUANIDESMetformin :• The primary drug of choice for diabetes by ADA guidelines.

Dose: 0.5 to 2.5 g/day in 2-3 divided doses

Phenformin : Its use has been discontinued because of lacticacidosis

MOA:• Suppress hepatic & renal gluconeogenesis• Increases uptake & utilization of glucose by skeletal muscles which

reduces insulin resistance • Inhibit alimentary absorption of glucose• Interfere with mitochondrial respiratory chain & promote peripheral

glucose utilization by enhancing anaerobic glycolysis.

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• PHARMACOKINETICS:• Taken orally, well absorbed through GI tract• Not metabolized at all • Excreted unchanged in urine

• INDICATIONS:• Obese Type 2 Diabetes.• Secondary Sulfonylurea Failure state.• To reduce Insulin requirements.• Can be combined with Sulfonylureas, Glitazones,

Insulin.

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ADVERSE EFFECT:• Anorexia, nausea, vomiting, diarrhoea• Metallic taste • Loss of weight • Skin rashes • Lactic acidosis: rare • Vitamin B12 deficiency: due to malabsorption • Usually does not cause hypoglycemia even in large doses

Contraindications:• Renal failure• Advanced Liver Disease.• Alcohol abusers.• Cardiac Disease.• Pregnancy.

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Meglitinide analogs• This class of agents includes repaglinide and

nateglinide. Although they are not sulfonylureas, they have common actions.

MOA:• Their action is dependent on functioning pancreatic β cells.• They bind to a distinct site on the sulfonylurea receptor of ATP-

sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin.

• However, in contrast to the sulfonylureas, the meglitinides have a rapid onset and a short duration of action.

• They are are categorized as postprandial glucose regulators. • Meglitinides should not be used in combination with sulfonylureas

due to overlapping mechanisms of action.

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Pharmacokinetics:• These drugs are well absorbed orally after being taken 1

to 30 minutes before meals. • Both meglitinides are metabolized to inactive products by

CYP3A4 in the liver.• Excreted through the bile.Adverse Effects:• Incidence of hypoglycemia is lower than that of the

sulfonylureas. • Repaglinide has been reported to cause severe

hypoglycemia in patients who are also taking the lipid-lowering drug gemfibrozil.

• Weight gain is less of a problem with the meglitinides than with the sulfonylureas.

• Must be used with caution in patients with hepatic impairment. 13

Thiazolidinediones (Glitazones) Rosiglitazone & pioglitazone Selective agonists of PPAR

Bind to nuclear PPARActivate insulin responsive genes - regulate carbohydrate & lipid metabolism

Sensitize the peripheral tissues to insulin

↓blood glucose by

↑ Glucose transport into muscle & adipose tissue

Inhibit hepatic gluconeogenesis

Promote lipogenesis 14

• Pharmacokinetics:• Both pioglitazone and rosiglitazone are absorbed very

well after oral administration and are extensively bound to serum albumin.

• Both undergo extensive metabolism by different cytochrome P450 isozymes.

• Pioglitazone:• Renal elimination is negligible, with the majority of the

active drug and metabolites excreted in the bile and eliminated in the feces.

• Rosiglitazone:• The metabolites are primarily excreted in the urine.

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• Adverse Effects:• Very few cases of liver toxicity have been reported with

rosiglitazone or pioglitazone.• Weight increase can occur, possibly through the ability of

TZDs to increase subcutaneous fat or due to fluid retention.

• Glitazones have been associated with osteopenia and increased fracture risk.

• Other adverse effects include headache and anemia.

• DOSE:• Pioglitazone: 15 to 45 mg once daily orally

• Rosiglitazone: 4 to 8 mg once daily orally

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α-glucosidase inhibitors• Alpha-glucosidase inhibitors works by preventing the

digestion of carbohydrates (such as starch and table sugar).

• Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.

• Acarbose and miglitol are orally active drugs used for the treatment of patients with Type 2 diabetes.

Dose:• Acarbose - 50mg to 100mg TDS• Miglitol - 25mg to 100mg TDS• Voglibose - 0.2 to 0.3 mg TDS

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• MOA:• These drugs are taken at the beginning of meals. • They act by delaying the digestion of carbohydrates,

thereby resulting in lower postprandial glucose levels.• Both drugs 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.

• Consequently, the postprandial rise of blood glucose is blunted.

• Unlike the other oral hypoglycemic agents, these drugs do not stimulate insulin release, nor do they increase insulin action in target tissues.

• Thus, as monotherapy, they do not cause hypoglycemia.• However, when used in combination with the

sulfonylureas or with insulin, hypoglycemia may develop.

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PHARMACOKINETICS:• Acarbose is poorly absorbed. It is metabolized primarily

by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine.

• On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.

ADVERSE EFFECTS:• The major side effects are flatulence, diarrhea, and

abdominal cramping. Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs

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What is the role of an ideal oral hypoglycaemic agent?

• Conserve islet cell function - delay the subsequent use of insulin.

• Improve patient compliance- single daily dosing.

• Reduce the incidence of hypoglycaemic events

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Adverse effects of OHAsMeglitinideSulfonylureas

Hypoglycemia

Biguanidesα-Glucosidase inhibitors

GI disturbance

Biguanides

Nausea

Thiazolidinediones

Risk of hepatotoxicity

SulfonylureasMeglitinidesThiazolidinediones

Weight gain21

THANK YOU22