oral hypoglycemic agents

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oral hypoglycemic agents
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Oral hypoglycemic agents

• Biguanides
• Sulfonylureas
• a- glucosidase inhibitors
• Thiazolidinediones
• Prandial glucose regulator

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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.

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Biguanides

• Indication
• Type 2 diabetes failed on diet
• Metformin can be given alone or in combination
  with sulfonylureas or Insulin

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Biguanides

• 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.

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Biguanides

• Mode of action
• Decreases the intestinal absorption of CHO
• Increases glucose uptake (GLUT 4)
• Increases glucose utilization (glycogensynthase)
• Increases glycolysis via anaerobic pathway
  (lactic acidosis)

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Biguanides

• 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

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Biguanides

• Side effects
• occur in 20-25 of patients.
• include.. Diarrhea, abdominal discomfort, nausea,
  metallic taste and decreased absorption of
  vitamin B12.

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Biguanides

• 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.

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SULFONYLUREAS

• 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.

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SULFONYLUREAS

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

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SULFONYLUREAS

• Mechanism of action
• Pancreatic effect
• Extra-pancreatic effect

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SULFONYLUREAS

• Pancreatic effect
• Increase insulin release from pancreas
• Suppress secretions of Glucagon

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SULFONYLUREAS

• 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

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SULFONYLUREAS

• Pharmacokinetics
• They are effectively absorbed from
  gastrointestinal tract.
• Food can reduce the absorption of sulfonylurea.
• Sulfonylureas are more effective when given 30
  minutes before eating.
• Plasma protein binding is high 90 99 ..
  mainly bind to albumen.

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SULFONYLUREAS

• Pharmacokinetics
• 1st generation members have short half lives.
• 2nd generation is administered once, twice or
  several times daily.
• 3rd generation is administered once daily.

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SULFONYLUREAS

• Pharmacokinetics
• 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.

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SULFONYLUREAS

• 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.

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SULFONYLUREAS

• Adverse Reactions
• First generation may induce other side effects as
  nausea and vomiting dermatological reactions
• These side effects are fewer in the 2nd
  generation and rare in the 3rd generation.

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SULFONYLUREAS

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

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Drug Drug interaction

• NSAIDs
• Salicylates
• Sulfonamide
• ß-blockers
• Chloramphenicol
• Diazepam
• MAOI

• Barbiturates
• Thiazide and loop diuretics
• Sympathomimetics
• Corticosteroids
• Oestrogen / Progesterone combinations

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SULFONYLUREAS

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

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a Glucosidase Inhibititor

• Acarbose
• Indicated for type 2 diabetes
• In addition with diet
• In addition with other anti-diabetic therapies

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Acarbose (Glucobay)

• Mode of action
• Poorly absorbed 1 (act locally in G.I.T.)
• Inhibits a glucosidase, so inhibits CHO
  degradation
• Dose
• 50mg to 100mg 3 times daily before meals

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Acarbose (Glucobay)

• Side effects
• Flatulence (77)
• Diarrhea
• Abdominal pain (21)
• Decreased iron absorption

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Thiazolidenedione

• Rosiglitazone
• Pioglitazone

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Thiazolidenedione

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

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Thiazolidenedione

• 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)

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Prandial glucose regulators (Meglitinide)

• Example
• Repaglinide
• Rational
• Fast acting, short duration non-sulfonylurea
• Designed to minimize mealtime blood glucose peaks

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Repaglinide

• 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

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Repaglinide

• 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?