Pharmacology PPT

1. ORAL AND PARENTRAL
HYPOGLYCEMIC AGENTS

2. CLASSIFICATION
• SULFONYLUREAS :
• First Generation : Tolbutamide ,
Chlorpropamide
• Second Generation : Glibenclamide
Glipizide
Gliclazide
Glimepiride

3. CLASSIFICATION cont …
• MEGLITINIDE/ - Repaglinide
PHENYL ALANINE - Nateglinide
ANALOUGES:
• BIGUANIDE : - Phenformin
- Metformin
• THIAZOLIDINEDIONES : - Rosiglitazone
- Pioglitazone

4. CLASSIFICATION cont…
• ALFA GLUCOSIDASE INHIBITORS : -Acarbose
- Miglitol
- Voglibose
• DIPEPTIDYL PEPTIDASE -4 (DPP-4)INHIBITOR:
- Sitagliptin
- Saxagliptin
- Alogliptin
- Vildagliptin
• SODIUM-GLUCOSE CONTRANSPOTER -2 (SGLT-
2) INHIBITOR : - Dapaglifozin
- Serglifozin
- Remoglifozin

5. CLASSIFICATION con…
• INCRETIN-MIMETICS : -Exenatide,
- Liraglutide
- Lixisenatide
- Albiglutide
• AMYLIN-MIMETIC DRUGS :- Pramlintide
• Dopamine-D2 receptor agonist:-Bromocriptin

6. SULFONYLUREAS
• MECHANISM OF ACTION :
1) Main action on β-cells to stimulates insulin
secretion and reduces blood glucose.
• Reduces permeability of K+ by competitively
blocking sulfonylures receptor (SUR1) present
on ATP-sensitive K+ channels
Depolarization

7. • Enhances Ca +2 influx - degranulation
• Increase the rate of the insulin secretion
2) Suppress glucagon levels – contribute to
hypoglycemic effect
SULFONYLUREAS CONTIN..

8. 3) Bind to Sulfonylurea receptor on the K+
Channels in extra pancreatic cells
• Increase the number of insulin receptors on
target cells particularly in liver
4) 2nd generation SU have an additional effect of
increase sensitivity of peripheral tissue to the
insulin .
SULFONYLUREAS CONTI…

9. PHARMACOKINETICS
• Well absorbed Orally
• Highly Protein bound – 90-98%
• Low volume of distribution (0.2-0.4 L/kg)
• Onset of action is approximately 1-3 hrs
• Duration of action of second generation is
around 24 hrs
• Metabolized by the liver, and the metabolites
are excreted in the urine.
• second-generation agents are approximately
100 times more potent than first generation.

10. ADVERSE EFFECT
• Hypoglycemia : most common in elderly patients with
impaired renal and hepatic function with long acting agents
• Increase Weight : due to fluid retention and edma
• Hypersensitivity: photosensitivity,rash,purpura
• Chlorpropamide causes
 cholestatic jaundice
 dilutional hyponatremia
 disulfuram like reaction

11. MEGLITINIDE ANALOGUES
• Quick and short acting insulin secretion
enhancers
• REPAGLINIDE : Action is similar to SU by
blocking ATP-sensitive potassium channels in
beta cells .
• Should be administered before each major
meal to control postprandial hyperglycemia.
• Dose should be omitted if a meal is missed.
• PK: metabolised by liver and excreted through
kidney .

12. • AE: hypoglycemia,headache,dyspepsia,arthralgia,
weight gain
• NATEGLINIDE :
• D-phenylalanine derivative.
• Stimulates 1st phase of insulin secretion
• So rapid onset and shorter duration of
hypoglycemic action than repaglinide .
• AE : dizziness, nausea, flu like symptoms,
hypoglycemia(rare)
MEGLITINIDE ANALOGUES

13. BIGUANIDES
MECHANISM OF ACTION :
1) Increases uptake and utilization of glucose
by skeletal muscle, which reduces insulin
resistance .
• At a molecular level, this action is mediated
by activation of the AMP-activated protein
kinase (AMP kinase)
2)Inhibition of hepatic as well as renal
gluconeogenesis, which decrease glucose
output

14. 3) Slowing of glucose absorption , increase
availability of glucose for it’s conversion to
lactate by enterocytes.
4) Promotion of insulin binding to it’s receptor
• Unlike sulfonylureas it does not lower blood
glucose level in normal person.
• Besides lowering elevated blood glucose level,
it also lowers LDL,VLDL and elevate HDL
• Half life – 2-3 hrs
• Duration of action : 6-10 hrs
BIGUANIDES

15. • Instead of increase in appetite it causes
anorexia so it is a DOC for the Obese patient
with type-2 DM.
• It can be combined with sulfonylureas ,
meglitinides and with glitazone to treat insulin
resistance syndrome.
• It reduces the risk of macrovascular as well as
microvascular complications .
BIGUANIDES

16.  Adverse Effect :
• Nausea, Metallic test, Anorexia ,Diarrhea
• In long term use – decrease absorption of vitamin B12
 Doses
• Metformin: 0.5 to 2.5 gm
 Non-diabetic use :
• It is used to treat hirsutism in the patient with PCOD
and enhances the fertility in these women by
decreasing androgen level and enhancing insulin
sensitivity .
BIGUANIDES

17. α- Glucosidase Inhibitor
• MOA: It inhibits α -glucosidase enzyme which
facilitates digestion of complex starches ,
oligosaccharides and disaccharides into
monosaccharides which is important for
absorption .
• So, it reduces postprandial digestion and
absorption of carbohydrates and lowers the
post meal hyperglycemia.
• Pk: mainly excreted through kidney .

18. Adverse Effect :
• Flatulence ,Diarrhea
• Abdominal pain due to fermentation of
undigested carbohydrates in lower GIT
• Cutaneous hypersensitivity
C/I: Bowel obstruction
Inflammatory Bowel disease
Stage 4 renal failure
α- Glucosidase Inhibitor

19. THIAZOLIDENEDIONS
MOA :
1) Acts as agonist to a nuclear receptor called
Peroxisome Proliferator Activated Receptor-
gamma(PPAR-γ).
• Which is expressed mainly in adipose tissue,
skeletal muscle and liver.
• Activation of PPAR- γ promotes transcription
of insulin responsive genes which control
glucose and lipid metabolism.

20. THIAZOLIDENEDIONS
2) Also increase the number of GLUT-4 glucose
transporter in cell membrane of skeletal
muscles and adipose tissue, which promotes
peripheral uptake and utilization of glucose.
3) Also decrease hepatic glucose output by
inhibiting gluconeogenesis.
THIAZOLIDENEDIONS

21. • Insulin sensitizing action of glitazone takes several
weeks to develop.
Adverse Effect :
• Weight gain due to fluid retention and edma
• Increased deposition of subcutaneous fat and
hemodilution - reduction in Hemoglobin
concentration.
• Increase the risk of heart failure and MI
( Rosiglitazone withdrawl from market oct-2010)
• Hepatotoxicity , reduce bone density
THIAZOLIDENEDIONS

22. INCRETIN-MIMETICS
• Incretin is a group of hormone that includes
Glucagon like peptide-1 (GLP-1)
Glucose dependent Insulinotropic
polypeptide(GIP) that are released after
meals from GIT and augment glucose
dependent Insulin secretion.
• Among them GLP-1 is the prominent
insulinotropic incretin.
• It is metabolised by DPP-4 enzyme .

23. Thus GLP-1 agonist
1) Increase insulin secretion
2) decrease glucagon release
3) delay gastric emptying
4) decrease the appetite by acting at the level of
hypothalamus.
INCRETIN-MIMETICS

24. PK :
• Exenatide is given as a s.c injection twice daily
before meals.
• It is rapidly absorbed and reaches peak
concentration in 2 hrs
• Clearance of a drug is primary by glomerular
filteration.
INCRETIN-MIMETICS

25. LIRAGLUTIDE
• It is given as a once daily injection .
• Peak level 8-12 hrs
• Elimination t1/2 is 12-14 hrs.
• Little , renal or intestinal clearance and it is
primarily through the metabolic pathways of
large plasma proteins.
• So, can be given safely in the patient with
renal failure
INCRETIN-MIMETICS

26. Adverse effect :
• Nausea
• Anorexia
• Diarrhea
• Necrotising pancreatitis (rarely)
Doses:
• Exenatide: 5-10 mcg
INCRETIN-MIMETICS

27. DPP-4 INHIBITORS
• DPP-4 is a serine protease that is widely
distributed throughout the body .
• They provide nearly complete and long lasting
inhibition of DPP-4 , increase the proportion
of active GLP-1 from 10-20% to nearly 100%.
• Sitagliptin and alogliptin are competitive
inhibitors of DPP-4 whereas vildagliptin and
and saxagliptin bind the enzyme covalently.

29. DPP-4 INHIBITORS cont…
 Mechanism of Action : Selective inhibition of DPP-4
enzyme which inactivates GLP-1 .
• As a result GLP-1 levels are increased and its actions
prolongs which is responsible for
1) Increase insulin secretion
2) decrease glucagon release
3) delay gastric emptying
4) decreases the appetite by acting at the level of
hypothalamus.

30. Adverse Effect : Nasopharyngitis (because
substance-p is also a substrate of DPP-4 whose
levels get elevated)
• GIT distress
• Diarrhoea
• Pancreatitis
DPP-4 INHIBITORS cont…