Biguanide

oral hypoglycaemic

1. Biguanide
Thiazolidinedione
Dr. Sanooz Raheem

2. Objectives
•List examples, mechanism of action, adverse effects and clinical uses
of biguanides
•List examples, mechanism of action, adverse effects and clinical uses
of thiazolidinediones
•Describe the uses and effects of acarbose as an oral hypoglycemic
•List clinical uses of glucagon

3. Biguanide
•Phenformin and metformin introduced in 1950s
•Phenformin had high risk of lactic acidosis and withdrawn

4. Metformin
•Little or no hypoglycaemic effect in non diabetics
•Hypoglycaemia in diabetics is very rare
•Does not stimulate pancreatic beta cells
•Improve lipid profile in diabetics

5. MOA
•Does not cause insulin release
•Presence of insulin essential for action
•Actions are mediated through activation of AMP-dependant protein
kinase

6. Key features in MOA
1.Mainly suppress gluconeogenesis and glucose output from liver
2.Enhances insulin mediated glucose uptake and disposal in skeletal
muscle and fat
insulin resistance is overcome
- glycogen storage in skeletal muscle
- reduced lipogenesis in adipose tissue and enhanced fatty acid
oxidation
3. Interferes mitochondrial respiratory chain and promotes peripheral
glucose utilization by anaerobic glycolysis
* Metformin retards intestinal absorption of glucose, amino acids and
Vit B12

7. PK
•T ½ - 1.5 to 3 hours
•Duration of action 6-8 hours
•Cleared by kidneys
•Clearance of metformin approximates GFR
•Accumulates in renal failure and increases the risk of lactic acidosis

8. Adverse effects
•No serious side effects
•Abdominal pain
•Anorexia
•Bloating
•Nausea
•Metallic taste
•Mild diarrhea
•Tiredness
•Does not cause hypoglycaemia except very high doses
•Lactic acidosis- rare, alcohol ingestion can precipitate
•Vit B12 def rarely

9. Contraindications
•Hypotension
•Heart failure
•Severe hepatic, respiratory and renal disease
•Alcoholics
•Ketoacidosis
•Use of GA

10. Interactions
•Cimetidine and furosemide compete with metformin excretion and
enhance its toxicity

11. Uses
•First choice drug in all T2 DM except not tolerated/ contraindicated
•Advantages:
-Nonhypoglycaemic
-Weight loss promoting
-Prevent micro and macro vascular DM complications
-No acceleration/ failure of beta cells in T2 DM
-Equivalent anti hyperglycaemic efficacy to other drugs
-Can be combined with other hypoglycaemic drug
* Improve ovulation and fertility in PCOS

12. Dose
DM:
Initially 500 mg at morning after 1 wk
Then 500mg bd after 1 wk
Then 500mg tds
Usual max dose 2g but upto 3g used
Modified release:
Initially 500mg once daily
Increased every 10-15 days
Max 2g once daily with evening meal
If no control achieved 1g twice daily

13. Pioglitazone
•Only one thiazolidinedione available
•Rosiglitazone withdrawn due to increased risk of MI,CHF, stroke and
death

14. MOA
•Selective agonist for nuclear peroxisome proliferator- activated receptor
gamma
•Mainly expressed in fat cells, also in muscle and other cells
•Enhances transcription of several insulin responsive genes
•Tend to reverse insulin resistance by enhancing GLUT4 expression and
translocation
•Glucose entry into muscle and fat improved hepatic gluconeogenesis
suppressed
•Activation of genes regulating fatty acid metabolism and lipogenesis in
adipose tissue contributes to insulin sensitizing action
•Reduction in lipolysis and plasma fatty acid level
•Increased turnover and differentiation of adipose tissue

15. •Degree of blood sugar reduction is less than SU and metformin
•Lowers TG, raises HDL, no significant change in LDL
•Due to induced expression of reverse cholesterol transporter and
some apoproteins

16. PK
•Well tolerated
•T ½ : 3-5 hours
•Duration of action – 24 hours
•Metabolized in liver
•Interact with OCP and contraceptive failure occurs
•Keatconazole inhibits and rifampicin induces metabolism

17. AR
•Plasma volume expansion
•Edema
•Weight gain
•Headache
•Myalgia
•Mild anaemia
•Monotherapy not associated with hypoglycaemia
•Rarely hepatic dysfunction
•CHF worsened or precipitated
•Increases the risk of fracture in elderly
CI- liver disease, CHF

18. Indications
•Type 2 DM
-Reduce blood glucose and HbA1C
-Do not increase insulin
-Do not work in low insulin base line
-Stooped if <0.5% reduction in HbA1C in 6 months
•Supplement SU/Metformin and in case of insulin resistance
•Monotherapy in mild cases
•When used with insulin- greater fluid retention, weight gain, precipitation
of CHF
•Should not be used during pregnancy

19. Dose :
15- 30 mg initially once daily
Increased upto 45mg

20. Alpha glucosidase inhibitors
Acarbose
•Complex oligosaccharide
•Reversibly inhibits alpha glucosidase ( final enzyme for digestion in the brush
border of small intestine mucosa)
MOA
-Slows down and decreases digestion and absorption of polysaccharides and
sucrose
- Increases GLP-1 release
-Postprandial glycaemia is reduced
-Regular use lowers HbA1C modestly , change in body weight and lipid level
minimal
-In diabetics reduces CVS events

21. Uses :
•Mild antihyperglycaemic and a hypoglycaemic
•Used as adjuvant with diet/ SU/ metformin in obese
PK:
Only a small fraction of the dose absorbed
AR:
Flatulence, abdominal discomfort, loose stools
Patient’s acceptability is poor due to GIT side effects
++ other alpha glucosidase inhibitors:
Ex: Miglitol, Voglibose

22. Contra indications-
IBD, predisposition to partial intestinal obstruction, hernia and previous
abdominal surgery
Dose:
Initially 50mg daily
Then 50mg tds
After 6-8 weeks 100mg tds
Max 200 mg tds

23. Advice:
Chew with mouthful of food or swallow whole with little fluid
immediately before food

24. Miscellaneous drugs
Amylin analogue :
-Islet amyloid polypeptide, produced in beta cells
-Acts in brain to reduce glucagon secretion, delay gastric emptying, retard glucose
absorption, promote satiety
Ex: pramlintide- synthetic, S.C injection before meal, used in Type 1 and 2 DM
Bromocriptine:
Quick release oral formulation used
Adjunctive in T2 DM treatment
Act on hypothalamic dopaminergic control of circardian rhythm of hormones (GH,
Prolactin, ACTH)
Used alone/ with metformin or SU or both

25. Oral hypoglycaemics mainly preferred in
•Age above 40 at disease onset
•Obesity at the time of presentation
•Duration of disease < 5 years when starting treatment
•FBS < 200mg/dl
•Insulin requirement < 40 U/day
•No ketoacidosis or history of it

26. Glucagon
•Single chain polypeptide
•Secreted by alpha cells
•Secretion regulated by glucose levels, other nutrients, paracrine
hormones, nervous system
•GLP-1, FFA, ketone bodies inhibit glucagon release
•Enhance glycogenolysis and gluconeogenesis in liver
•Increases the force and rate of cardiac contraction

27. Uses:
1.Hypoglycaemia – during emergency, not useful when hepatic
glycogen is depleted Dose 0.5-1mg IV or IM
2.Cardiogenic shock- not very marked action
3.To facilitate radiographic examination of upper/lower GIT tract by
relaxing stomach and intestines
Other hyperglycaemics:
Diazoxide, Somatostatin, Streptozocin

28. THANK
YOU