Anti diabetic drugs
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Transcript of Anti diabetic drugs
Diabetes mellitus
• DM is characterized by elevated blood sugar levels due to absolute or relative lack of insulin.
• Type 1 diabetes - -cell failure at outset– Insulin dependent
• Type 2 diabetes - Gradual -cell deterioration– Early stages: Diet and Oral agents – Late-stage: Insulin therapy
Diabetes mellitus
• Glycosylated hemoglobin Hb-A1c : It is used to monitor the plasma glucose concentration over prolonged periods of time (4-6 weeks).
• Insulin secretion is promoted by ↑ blood glucose levels, amino acids, GI hormones and by β-2 agonist.
Insulin• Proinsulin is converted to insulin and C
peptide.• Insulin is referred as the storage
hormone as it promotes anabolism and inhibits catabolism of carbohydrates, fatty acids and protein.
• In the absence of insulin, most tissues cannot use glucose and fats/proteins are broken down to provide energy.
Insulin
Mechanism of action :• Insulin binds to insulin receptors on
the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle.
• The Nerves, RBC’s, Kidney, and Lens of the eye do not require insulin for glucose transport.
Insulin
Liver : • Insulin increase the storage of glucose
as glycogen in the liver. • It inserts the GLUT-2 glucose transport
molecule in the cell membrane. • It inhibits gluconeogenesis – thus
significantly ↓ glucose output by the liver.
• It decrease the protein catabolism.
Insulin
Muscle : • Insulin stimulates the glycogen
synthesis and protein synthesis.• Glucose transport into the cells is
facilitated by GLUT-4 into the cell membrane.
• It inhibits the protein catabolism.
Insulin
Adipose tissue :• Insulin facilitates the storage of
triglyceride by activating plasma lipoprotein lipase and inhibiting intracellular lipolysis.
• It increase the glucose uptake by GLUT-4 insertion into the cell membrane.
Insulin
Insulin
• Insulin is a 51 AA peptide• Not active orally.• Insulin is inactivated by insulinase
found mainly in liver and kidney.• Dose reduced in renal insufficiency• Sources of Insulin :
– Beef pancreas / Pork pancreas – Human insulin: recombinant DNA origin
Insulin
Human Insulin : • Do not contain measurable
amounts of proinsulin or contaminants.
• Diminished antibody• Less allergic reactions• Less lipodystrophy• Preferred in gestational diabetes
InsulinInsulin preparations :• Rapid acting insulin :
Lispro, Aspart and Glulisine• Short acting insulin:
Regular (crystalline)• Intermediate acting insulin:
NPH (isophane) and Lente (insulin zinc)
• Long acting insulin: Ultralente, Detimir and Glargine
Insulin Duration Route Features
Lispro 3 – 5 hrs I.V or S.C
Onset within 15 minutes
Regular (crystalline)
7 – 10 hrs I.V or S.C
common
NPH (Neutral protamine hagedorn)
16 – 20 hrs
S.C NPH can mix with regular
Ultralente 24 – 30 hrs S.C Basal level
Insulin
Insulin
Insulin
Adverse effects of Insulin :• Hypoglycemia • Allergic reactions• Lipodystrophy• Others includes
– Seizures– Coma
Oral Anti-diabetic drugsMechanisms to reduce blood sugar :• Stimulation of pancreatic insulin
release – Sulfonylureas, Meglitinide• Reduce the bio-synthesis of glucose
in liver – Biguanides (Metformin)• Increase the sensitivity of target
cells to insulin -- Thiazolidinediones• Retard the absorption of sugars
from the GI tract – Acarbose, Miglitol
Oral Anti-diabetic drugs
Sulfonylureas :• First generation : Acetohexamide,
Chlorpropamide, Tolbutamide, Tolazamide
• Second generation : Glipizide, Glyburide – more potent, more efficacious and fewer adverse effects.
• Third generation : Glimiperide
Sulfonylureas
Sulfonylureas Dose(mg)
Duration(h)
First Generation
Tolbutamide (Orinase) 1000-1500 6-8
Chlorpropamide (Diabinese) 250-375 24-60
Tolazamide (Tolinase) 250-375 12-24
Second generation
Glipizide (Glucotrol) 10 10-24
Glyburide (Micronase) (Glibenclamide)
Third generation
5 16-24
Glimepiride (Amaryl) 1-2 24
Oral Anti-diabetic drugsSulfonylureas : Adverse effects :• Hypoglycemia• Cholestatic jaundice• Weight gain• Cross placenta – fetal hypoglycemia.• Chlorpropamide : It can cause water
retention by ↑ release of ADH (SIADH)• Disulfiram-like reaction with alcohol.
Oral Anti-diabetic drugs
Repaglinide, Nateglinide : • More rapidly acting insulin
enhancers and shorter duration than
sulfonylurea.• Hypoglycemia is the common
adverse effect.• Less weight gain
Oral Anti-diabetic drugs
Repaglinide, Nateglinide• The drug has minimal renal
excretion thus useful in patients with DM and impaired renal function.
• It is designed to be taken with each meal to stimulate insulin release with meal. If a meal is skipped, so is the repaglinide.
Oral Anti-diabetic drugs
Biguanides (Metformin): • Inhibits gluconeogenesis.• Does not promote insulin secretion. • It increase the sensitivity of liver
and muscle to insulin. • It causes modest weight loss.
Oral Anti-diabetic drugs
Metformin (Glucophage) :• It does not cause hypoglycemia.
• It produces a significant ↓ TG and
LDL, and ↑HDL.• There is a serious concern about
lactic acidosis especially in patients with kidney disease.
Oral Anti-diabetic drugs
Thiazolidinediones• Enhance glucose and lipid
metabolism through action on Peroxisome Proliferator Activated Receptor (PPAR–γ)
• Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters.
• E.g. ; Pioglitazone Actos, Rosiglitazone Avandia
Anti-diabetic drugs
Thiazolidinediones : • Beneficial effects on serum lipid;
↓TG and ↑HDL.• Troglitazone is associated with
hepatitis.• Edema.
Anti-diabetic drugs
Alpha-Glucosidase Inhibitors: • It inhibits -glucosidase which
converts dietary starch and complex carbohydrates into simple sugars
• It reduces absorption of glucose after meals.
• The main side effects includes flatulence and diarrhea.
• Acarbose Acarbose (Glucobay)(Glucobay) , Miglitol , Miglitol (Glyset)(Glyset)
Anti-diabetic drugs
Glucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) :
• GLP is an incretin released from the small intestine which increase the glucose dependent insulin secretion.
• Xenatide suppress glucagon release and reduce appetite
• It is administered by SC injection.
Anti-diabetic drugsGlucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) :
Anti-diabetic drugs
Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN (januvia)
Xenatide (Byetta) inj
Sitagliptin(januvia)
Anti-diabetic drugs• Sitagliptin (Januvia) is an oral anti-
diabetic drug.• It inhibit the dipeptidyl peptidase 4
(DPP-4), an enzyme which inactivates the incretins GLP-1 and GIP, that are released in response to a meal.
• It potentiates the secretion of insulin and suppress the release of glucagon by the pancreas.
Endocrine pancreasGlucagon :• It has positive inotropic action and
chronotropic action on the heart.• It acts by stimulation of glucagon
receptors and not through beta 1 receptors.
• This is the basis for using glucagon in beta blocker overdose.