Oral hypoglycemic agents are classified based on their mechanism of action. Sulfonylureas work by blocking potassium channels in pancreatic beta cells, increasing calcium influx and insulin secretion. Meglitinides like repaglinide have a similar quick-acting mechanism. DPP-4 inhibitors like sitagliptin increase GLP-1 and GIP action. Biguanides like metformin activate AMPK, suppressing glucose production and enhancing uptake. Thiazolidinediones like pioglitazone activate PPARγ, enhancing insulin sensitivity. Other agents include alpha-glucosidase inhibitors, amylin analogues, and SGLT2 inhibitors. While effective at lowering blood glucose,

1. ORAL
HYPOGLYCAEMIC
AGENTS
Dr. Pravin Prasad
MBBS, MD Clinical Pharmacology
Assistant Professor, Department of Clinical Pharmacology
Maharajgunj Medical Campus
6 July 2020 (22 Asar 2077), Monday

2. Classification
 Enhance Insulin Secretion
o Sulfonylureas (K+ATP channels blockers)
 First Generation: Chlorpropamide,Tolbutamide
 Second Generation: Glibenclamde (Glyburide), Glipizide,
Gliclazide, Glimepiride
o Meglitinide/phenylalanine analouges:
 Repaglinide, Nateglinide
o Glucagon-like peptide (GLP-1) receptor agaonists (injectable):
 Exenadite, Liraglutide
o Dipeptidyl peptidase-4 (DPP-4) inhibitors:
 Sitagliptin,Vildagliptin, Saxagliptin, Alogliptin, Linagliptin

3. Classification
 Overcome Insulin Resistance
o Biguanides (AMPK activators):
 Metformin
o Thiazolidinediones (PPARγ activator):
 Pioglitazone
 Miscellaneous
α-Glucosidase inhibitors Acarbose, Miglitol,Voglibose
Amylin analogue Pramlintide
Dopamine D2 receptor agonist Bromocriptine
Sodium Glucose Co-Transport 2 (SGLT 2)
inhibitor
Dapagliflozine

4. Mechanism of Action: In a nutshell

5. Sulfonylureas
 Mechanism of action:
o Blocks the K+
ATP channel and reduced influx of K+ ion
o Partial depolarization of pancreatic beta-cells 
o Increased influx of Ca++ ions as well as release of Ca++ from intracellular stores

o Exocytotic release of insulin
 Minor action:
o Reduces glucagon secretion
o Reduced hepatic degradation of insulin
 Extra-pancreatic action:
o Sensitizes the peripheral tissues to the action of insulin
 Seen on prolonged use

6. Sulfonylureas
 Adverse Effects:
o Hypoglycaemia
o Non specific Side effects (mild and infrequent):
 Weight gain, nausea, vomiting, flatulence, diarrhoea,
paraesthesia
o Hypersensitivity
o SU + alcohol:
 Flushing, disulfiram-like reaction
Should not be used in pregnancy and lactating mothers

7. Repaglinide and Nateglinide:
 K+ATP channel blockers
 Quick and short lasting action
o Quick absorption and rapid metabolism
 Administered before each major meal
o Normalises meal time glucose levels
o Lower incidence of hypoglycaemia
 S/E: Mild headache, dyspepsia, arthralgia, weight gain
 Indication:
o Type 2 DM with pronounced postprandial hyperglycaemia
o Along with Metformin/long acting insulin
 Avoid in liver disease
Meglitinide/Phenylalanine analogues
(Repaglinide, Nateglinide)

8. Dipeptidyl peptidase-4 (DPP-4) inhibitors
 Sitagliptin:
o Competitive and selective DPP-4 inhibitor
 Potentiates the action of GLP-1 and GIP
o Body weight neutral, low risk of hypoglycaemia
o Well absorbed orally, little metabolised, largely excreted
unchanged in urine
o Dose reduction needed in renal dysfunction
o S/E: nausea, loose stools, headaches, rashes, allergic
reactions, edema

9. Biguanides (Metformin, Phenformin)
 Mechanism of Action:
o Activation of AMPK, leading to:
 Suppression of hepatic gluconeogenesis
 Enhances insulin-mediated glucose uptake and disposal in
skeletal muscle and fat
 Interferes with mitochondrial respiratory chain and
promotes peripheral glucose utilization
 Retards glucose absorption of glucose, hexose, amino
acids,Vit B12

10. Biguanides (Metformin, Phenformin)
 Advantages:
o Non-hypoglycaemic
o Weight loss
o Prevents long term complications
o Prolongs beta cell life

11. Biguanides (Metformin, Phenformin)
 Adverse Effects:
o Limiting feature: gastro-intestinal intolerance
o Hypoglycaemia in overdose
o Lactic acidosis
o Vitamin B12 deficiency
 Contraindications:
o Hypotensive states
o Heart failure
o Severe respiratory, hepatic and renal disease
o Alcoholics

12. Thiazolidinediones (PPARγ activator):
Pioglitazone
 Multiple actions:
o Enhances transcription of insulin responsive genes
o Reverses insulin resistance
o Suppresses hepatic gluconeogenesis
 Additional actions: lowers serum triglyceride, raises HDL
 Well tolerated
 S/E: plasma volume expansion, edema, weight gain, headache,
myalgia, mild anaemia, increased risk of fracture esp. in elderly
women
 Contraindicated in liver disease and in CHF

13. Miscellaneous OHA
 Acarbose:
o Inhibits α-glucosidases enzyme slow down and decrease
digestion and absorption of polysaccharides and sucrose.
o Additionally promotes GLP-1 release
o S/E: Flatulence, abdominal discomfort, loose stool; Poor patient
acceptability
 Pramlintide:
o Synthetic amylin analogue
o Attenuates postprandial glycaemia and exerts centrally mediated
anorectic action
o Reduction in body weight ++

14. Miscellaneous OHA
 Bromocriptine:
o Dopamine D2 agonist;
o Acts on hypothalamic dopaminergic control of the circadian
rhythm of hormone (GH, prolactin, ACTH) release and reset
it to reduce insulin resistance.
Dapagliflozin:
o SGLT-2 inhibitor  glycosuria
o Prone to cause urinary tract infection

15. Glucagon
 An Hyperglycaemic agent
 Polypeptide chain, released as prohormone from alpha cells of
pancreas
 Acts by:
o Binds to glucagon receptor  stimulates cells
 Liver: increased glycogenolysis, gluconeogenesis
 Muscle, fat cells: decreased glucose utilization
 Heart: increased force and rate of contraction
 Uses: Hypoglycaemia,Cardiogenic shock

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