Transcript Oral Hypoglycemic Agents

Oral hypoglycemic agents
Biguanides 
Sulfonylureas 
α- glucosidase inhibitors 
Thiazolidinediones 
Prandial glucose regulator 
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.
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)
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
Biguanides
Side effects:
occur in 20-25 % of patients. 
include.. Diarrhea, abdominal 
discomfort, nausea, metallic
taste and decreased absorption
of vitamin B12.
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.
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.
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 
SULFONYLUREAS
Pancreatic effect:
Increase insulin release from
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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
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.
SULFONYLUREAS
1st
Pharmacokinetics: 
generation members have 
short half lives.
2nd generation is administered
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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.
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.
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.
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.
Drug – Drug interaction
NSAIDs 
Barbiturates 
Salicylates 
Thiazide and loop 
diuretics
Sulfonamide 
ß-blockers 
Chloramphenicol 
Diazepam 
MAOI 
Sympathomimetics 
Corticosteroids 
Oestrogen / 
Progesterone
combinations
SULFONYLUREAS
Contraindications : 
Type 1 DM
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Pregnancy and Lactation.
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Significant hepatic or renal
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failure.
α Glucosidase Inhibititor
Acarbose
Indicated for type 2
diabetes
In addition with diet
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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 α glucosidase, so inhibits 
CHO degradation
Dose: 
50mg to 100mg 3 times daily 
before meals
Acarbose (Glucobay)
Side effects: 
Flatulence (77%)
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Diarrhea 
Abdominal pain (21%) 
Decreased iron absorption 
Thiazolidenedione
Rosiglitazone
Pioglitazone
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
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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
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 
Repaglinide
Clinical efficacy: 
Improves postprandial glycemia
Less effective in decreasing fasting
blood glucose levels and HbA1C
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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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