• Antidiabetics
  • Pharmacology

Oral hypoglycemic drugs: Oral Antihyperglycemic Drugs

  • 7 minutes, 52 seconds
  • Antidiabetics
  • 2020-08-04

Estimated read time is 7 minutes, 52 seconds

Article Details

Antidiabetics are basically classified into two types;

  • Oral hypoglycemic drugs and,
  • Insulin.

Diabetes is classified into various types but the most common ones are;

  1. Type I diabetes mellitus was formerly known as IDDM(Insulin-dependent diabetes mellitus) or Juvenile diabetes due to autoimmune or viral diseases.
  2. Type II diabetes mellitus formerly NIDDM (Non-Insulin dependent diabetes mellitus or adult diabetes due to genetic factors.
  3. Gestational diabetes following pregnancy

Types of diabetes

Diabetes mellitus type 1 has the following characteristics;

  • The age of onset is usually < 30 years.
  • The type of onset is abrupt.
  • In terms of nutritional status, the patient is usually thin.
  • Clinical symptoms present are Polydipsia, polyphagia, polyuria, weight loss.
  • Endogenous insulin is absent.
  • Hypercholesterolemia is frequent, all lipid fractions are elevated in ketosis.
  • Ketosis is frequent in these patients.
  • Hypoglycemic drugs are not indicated.
  • Moderate genetic predisposition.

Diabetes mellitus type 2 has the following features;

  • The age of onset is usually > 40 years.
  • It has a gradual onset.
  • The patients are usually obese.
  • Often asymptomatic.
  • Ketosis is usually absent.
  • Endogenous insulin is usually present, but relatively ineffective.
  • Cholesterol & triglycerides often elevated; carbohydrate induced hypertriglyceridemia common indicated.
  • Insulin therapy is required in 20 - 30% of patients.
  • Strong genetic predisposition.
  • There is inadequate insulin secretion.
  • Insulin resistance in target tissues.

Complications of diabetes

  1. Cardiovascular problems.
  2. Renal failure (nephropathy).
  3. Blindness (retinopathy).
  4. Neuropathy (neuropathy).
  5. Risk of foot amputation

Oral hypoglycemic drugs

oral hypoglycemic drugs are divided into the following classes;

  1. Sulfonylurea drugs.
  2. Meglitinide analogs.
  3. Alpha-glucosidase inhibitors.
  4. Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin.

Insulin secretagogues

  • Sulfonylurea drugs.
  • Meglitinide analogs.
  • D-phenylalanine derivatives.

Insulin sensitizers

  • Thiazolidinediones or glitazones.
  • Alpha-glucosidase inhibitors.
  • Gastrointestinal hormones.

Insulin secretagogues

  1. Sulfonylureas:

Sulfonylureas are classified to as;


  • Tolbutamide
  • Tolazamide
  • Acetohexamide
  • Chlorpropamide

Second-generation sulfonylureas are;

  • Glipizide
  • Glyburide (Glibenclamide)
  • Glimepiride

Mechanism of Action:

Stimulate insulin release from functioning B cells by blocking ATP-sensitive K channels resulting in depolarization and calcium influx.

Reduction of serum glucagon concentration

Increase tissue sensitivity to insulin.


Orally, well absorbed.

Reach peak concentration after 2-4 hr.

All are highly bound to plasma proteins.

The duration of action is variable.

The second generation has a longer duration.

Metabolized in liver

Excreted in urine (elderly and renal disease)

Cross placenta, stimulates fetal B cells to release insulin → hypoglycemia at birth.


  • Short-acting: Tolbutamide (8 h)
  • Intermediate-acting: Tolazamide –Acetohexamide (20 h)
  • Long-acting: Chlorpropamide (60 h)

First-generation sulfonylurea

Tolbutamide is a short-acting sulfonylurea with good absorption.

It has inactive metabolites and a half-life of 4-5 hours.

Its duration of action is 6-8 hours.

It is excreted via urine.

Tolbutamide safe for old patients or patients with renal impairment

Acetohexamide is an intermediate-acting sulfonylurea with good absorption.

It has active metabolites.

Half-life is 6-8 hours.

Its duration of action is 12-20 hours.

Tolazamide is also an intermediate-acting sulfonylurea with a relatively slow absorption rate.

It has active metabolites.

The half-life of 7 hours and duration of action of 12-18 hours.

Chlorpropamide is a long-acting sulfonylurea with a good absorption rate.

It has inactive metabolites.

Half-life is 24 – 40 hours.

The duration of action is 20 – 60 hours.

Chlorpropamide causes the following adverse effects;

  • Prolonged hypoglycemia in patients with hepatic-renal disease and old patients.
  • Dilutional hyponatremia
  • Hyperemic flush after alcohol ingestion
  • Leukopenia, thrombocytopenia

Advantages of first-generation sulfonylureas;

  1. More potent.
  2. Has fewer adverse effects.
  3. Has fewer drug interactions.
  4. It has a longer duration (24 hours) e.g. Glipizide, glyburide (Glibenclamide), glimepiride

Contraindicated in hepatic impairment or renal insufficiency.

Second generation sulfonylurea

  1. Glipizide
  2. Glibenclamide (Glyburide)
  3. Glimepiride


It has good absorption but reduced by food.

The drug is metabolized and produces inactive metabolites.

It has a half-life of 2 – 4 hours and a duration of action of 10 – 16 hours.

Glipizide is given in divided doses 30 minutes before meals.

Glibenclamide (glyburide)

It has a good absorption rate.

The drug is metabolized and produces inactive metabolites.

It has a half-life of fewer than 3 hours and a duration of action is 12-24 hours.

It is given as a single dose.

Excretion is by urine.


It has a good absorption rate.

The drug is metabolized and produces inactive metabolites.

Glimepiride has a half-life of 5-9 hours and a duration of action of 12-24 hours.

It is given as a single dose of 1 mg.

Excretion is by urine.

Unwanted Effects include:

  1. Hyperinsulinemia and Hypoglycemia.
    1. More in chlorpropamide and glibenclamide but less in tolbutamide.
    2. More in the elderly and patients with renal disease.
  2. Weight gain due to an increase in appetite
  3. Gastrointestinal upset.
  4. Dilutional hyponatremia, water intoxication (Chlorpropamide) vasopressin effect.
  5. Disulfiram-like reaction with alcohol (chlorpropamide).
  6. Tachyphylaxis (secondary failure).

Drug Interactions

Drugs which augment hypoglycemic effect:

  • NSAIDs: Phenylbutazone and salicylates
  • Coumarin anticoagulants.
  • Antibiotics: Sulphonamides
  • Antifungal Drugs: Fluconazole.

Drugs which decrease hypoglycemic effect:


Pregnancy (use insulin).

Hepatic or renal insufficiency.

Type I diabetes.

Meglitinide analogs

They are rapidly acting insulin secretagogues

  • Repaglinide (Prandin).
  • Nateglinide (Starlix).

Mechanism of Action:

Stimulate insulin release from functioning B cells by modulating K efflux via blocking ATP-sensitive K channels resulting in depolarization and calcium influx.

Pharmacokinetics of Meglitinides

Orally, well absorbed.

Very fast onset of action, peak 1 h.

The short duration of action (4 h).

Metabolized into inactive products in the liver (CYP3A4).

Pharmacokinetics of Meglitinides

Excreted mainly in the bile

Effective in an early release of insulin after a meal (Postprandial glucose regulators)

Taken just before each meal (3 times/day).

Uses of Meglitinides

  1. Type II diabetes as monotherapy or combined therapy with metformin (better than monotherapy).
  2. Patients who are allergic to sulfur or sulfonylurea.

Adverse effects of meglitinides

These drugs have less incidence of side effects than sulfonylureas.

  • Hypoglycemia (meal is delayed).
  • Weight gain.


Hepatic and renal impairment.

Drug Interactions

  1. Enzyme inhibitors as cimetidine, fluconazole, erythromycin.
  2. Enzyme inducers barbiturates, rifampicin, and phenytoin.
  3. Gemfibrozil augments the action of repaglinide.

Insulin sensitizers

  1. Biguanides
  2. Thiazolidinediones or glitazones


In general, biguanides work by decreasing hepatic glucose production, decreasing absorption of glucose from the gastrointestinal tract, and increasing target cell insulin sensitivity.

The common drug is metformin.


Mechanism of action of metformin

Metformin does not require functioning B cells.

  • It does not stimulate insulin release.
  • Increases peripheral glucose utilization (tissue glycolysis).
  • Inhibits gluconeogenesis.
  • Impairs glucose absorption from GIT.
  • Reduces plasma glucagon level.
  • Reduces low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL).
  • Increases high-density lipoproteins (HDL).

Pharmacokinetics of metformin

Absorbed orally.

Metformin is not bound to serum protein.

Not metabolized.

It has a half-life of 3 hours and excreted unchanged in the urine.

Uses of metformin

Has an insulin sparing effect (insulin sensitizer).

Obese patients with type II diabetes (with insulin resistance).

Monotherapy or in combination.


No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia).

Side effects of metformin

  • Metallic taste in the mouth
  • GIT disturbances (nausea, vomiting, diarrhea).
  • Lactic acidosis:
  • Common in patients with renal disease, liver, pulmonary or cardiac disease.
  • Long term use interferes with B12 absorption.


  • Pregnancy.
  • Renal disease.
  • Liver disease.
  • Alcoholism.
  • Conditions predisposing to hypoxia as cardiopulmonary dysfunction.

Insulin sensitizers            

Thiazolidinediones (glitazones)

Pioglitazone (Actos)

Mechanism of action

Activate nuclear receptors (peroxisome proliferator-activated receptor-gamma ) (PPAR-gamma).

Increase the sensitivity of target tissues to insulin.

Increase glucose uptake and utilization in muscle and adipose tissue.

Increase insulin sensitivity (decrease in insulin resistance).

PPAR- α and gamma

Nuclear receptors.

Liver, skeletal muscles, adipose tissue.

Control genes involved in glucose (PPAR- gamma) and lipid metabolism (PPAR- α).

Increase insulin sensitivity in muscle and adipose tissue.

Reduces triglycerides.

Increases high-density lipoproteins (HDL)

Pharmacokinetics of pioglitazone

– Orally (once-daily dose).

– Highly bound to plasma albumins (99%)

– Slow onset of activity

– Half-life 3-4 h

– Metabolized by CYP450.

– Give active metabolites

– Excreted in urine 64% & bile

Uses of pioglitazone

  • Type II diabetes with insulin resistance.
  • Used either alone or combined with sulfonylurea, biguanides or insulin.
  • Anovulatory women (polycystic ovarian syndrome).
  • No risk of hypoglycemia when used alone

Contraindications of pioglitazone

Adverse effects

  • Fluid retention (Edema).
  • Weight gain.
  • Headache.
  • Liver function tests for 1st year of therapy.
  • Failure of estrogen-containing oral contraceptives.

Alpha Glucosidase inhibitors

  • Acarbose (Precose).
  • Miglitol (Glyset).

Reversible inhibitors of intestinal glucosidases in intestinal brush border responsible for the degradation of oligosaccharides to monosaccharides.  include sucrase, maltase, dextranase, glucoamylase.

Glucosidase inhibitors decrease carbohydrate digestion and absorption in the small intestine.

Decrease postprandial hyperglycemia.

Taken just before meals.

No hypoglycemia if used alone.

Kinetics of alpha Glucosidase inhibitors


  • Given orally, poorly absorbed.
  • Metabolized by intestinal bacteria.
  • Excreted in stool and urine.


well-absorbed, no systemic effects.

Excreted unchanged in the urine.

6 times more potent inhibitor for sucrase.

Uses of alpha-glucosidase inhibitor

Type II diabetics inadequately controlled by diet with or without other agents ( SU, Metformin) alone or combined with insulin or sulfonylurea.

Uses of -glucosidase inhibitors GIT: Flatulence, diarrhea, abdominal pain, bloating, increase in liver enzymes.

Adverse effects of glucosidase inhibitors

GIT: Flatulence, diarrhea, abdominal pain, bloating, increase in liver enzymes.

contraindications of glucosidase inhibitors

  • Inflammatory bowel disorders (IBD).
  • Renal disease.
  • Hepatic disease (used with caution).
  • Intestinal obstruction.

Dipeptidyl peptidase-4 inhibitor (DPP- 4 inhibitors)

Sitagliptin, vildagliptin(DPP- 4 inhibitors) Sitagliptin


Given once daily

half-life 8-14 h

The dose is reduced in patients with renal impairment

Mechanism of action of sitagliptin

Inhibit DPP-4 enzyme (GLP-1, glucagon-like peptide-1) and leads to an increase in the incretin hormone level (a gastrointestinal hormone secreted in response to food).

This results in an increase in insulin secretion & a decrease in glucagon secretion.

Clinical uses

Type 2 DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs.

Adverse effects

  • Nausea, abdominal pain, diarrhea
  • Nasopharyngitis

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