Oral Hypoglycemic Agents

Biguanides

Biguanides are derivatives of the antimalarial agent Chloroguanide. Which is found to have hypoglycemic action. The most commonly used member of biguanides is Metformin.
Indication:
Type 2 diabetes failed on diet Metformin can be given alone or in combination with sulfonylureas or Insulin

Mode of action
  • Biguanides (Metformin) is an Antihyperglycemic and not Hypoglycemic agent.
  • It does not stimulate pancreas to secrete insulin and does not cause hypoglycemia (as a side effect) even in large doses.
  • Also it has no effect on secretion of Glucagon or Somatostatin.
  • Decreases the intestinal absorption of CHO
  • Increases glucose uptake (GLUT 4)
  • Increases glucose utilization (glycogensynthase)
  • Increases glycolysis via anaerobic pathway (lactic acidosis)

Pharmacokinetics:
Metformin is well absorbed from small intestine, stable, does not bind to plasma proteins, excreted unchanged in urine.
Half life of Metformin is 1.5 - 4.5 hours, taken in three doses with meals.

Side effects:
Occur in 20-25 % of patients ; include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B12.

Contraindications
  • Patients with renal or hepatic impairment.
  • Past history of lactic acidosis.
  • Heart failure, Chronic lung disease.

These conditions predispose to increased lactate production which causes lactic acidosis which is fatal.

Sulfonylurea

SUs., have been discovered during the 2nd. World war (sulfonamide).
SUs are drugs that used orally to control blood glucose levels of type 2 diabetes.

Types:
First generation: Chlorpropamide ,Tolbutamide
Second generation: Gliclazide, Glibenclamide, Glipizide
Third generation: Glimepiride

Mechanism of action:

Pancreatic effect

Increase insulin release from pancreas
Suppress secretions of Glucagon

Extra pancreatic effect

Increases the number of insulin receptors
Increases post-receptor insulin sensitivity
Increases glucolysis
Increases glycogen storage in muscle and liver
Decreases the hepatic output of glucose

Pharmacokinetics:
  • They are effectively absorbed from gastrointestinal tract.
  • Food can reduce the absorption of sulfonylurea.
  • Sulfonylurea are more effective when given 30 minutes before eating.
  • Plasma protein binding is high 90 – 99 % , mainly bind to albumen.
  • 1st generation members have short half lives.
  • 2nd generation is administered once, twice or several times daily.
  • 3rd generation is administered once daily.
  • All sulfonylurea are metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged.
  • Sulfonylurea should be administered with caution to patients with either renal or hepatic insufficiency.
     
Adverse Reactions:
  • Very few adverse reactions (4 %) in the first generation and rare in the 2nd and 3rd generation.
  • SUs may induce hypoglycemia especially in elderly patients with impaired hepatic or renal functions-These cases of hypoglycemia are treated by I/V glucose infusion.
  • First generation may induce other side effects as: Nausea and vomiting & dermatological reactions

"Those side effects are fewer in the 2nd generation and rare in the 3rd generation"

Drug interactions:
Some drugs may enhance or suppress the actions of sulfonylurea Either by affecting:
  • Their metabolism and excretion
  • The concentration of free sulfonylureas in plasma through competing them on plasma proteins.

NSAIDs

Salicylates
Sulfonamide
ß-blockers
Chloramphenicol
Diazepam
MAOI

Barbiturates

Thiazide and loop diuretics
Sympathomimetics
Corticosteroids
Oestrogen / Progesterone combinations

Contraindications:
Type 1 DM
Pregnancy and Lactation.
Significant hepatic or renal failure.

α- glucosidase inhibitors

Example:
Acarbose is indicated for type 2 diabetes In addition with diet In addition with other anti-diabetic therapies

Mode of action:
Poorly absorbed 1% (act locally in G.I.T.) inhibits α glucosidase, so inhibits CHO degradation

Dose: 50mg to 100mg 3 times daily before meals

Side effects:

Thiazolidinediones

Mode of action:
  • Insulin sensitizer (increase insulin sensitivity in muscle, adipose tissue & liver)
  • They are not insulin secretagogues (Not insulin releasers)

Drawbacks:
They are not effective alone in case of severe insulin deficiency and should be combined with sulfonylurea or metformin or both

Side effects:
  • Hepatotoxicity
  • Weight gain
  • Dyslipidaemia (increases LDL)

Prandial Glucose Regulator

Example: Repaglinide

Rational: Fast acting, short duration non-sulfonylurea Designed to minimize mealtime blood glucose peaks.

Mechanism of action:
  • Stimulation of pancreatic insulin release by closing ß-cells KATP channels
  • Very rapid onset of action and short duration (TMAX = 1 hour, metabolized by liver T1/2 = 70 minutes)
  • No hypoglycemic metabolites
Clinical efficacy:
  • Improves postprandial glycemia
  • Less effective in decreasing fasting blood glucose levels and HbA1C
Drawbacks:
  • Fails to provides a stable 24 hours blood glucose control
  • Complicated dosage style (3-8 tablets/daily)
  • How to adapt the dosage to the meal volume?

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