Oral hypoglycemic 2018

Oral hypoglycemic 2018

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  Oral hypoglycemic drugs Dr.Omozuapo Rebecca 2018
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  Antidiabetic Drugs  Drugsused to control diabetes mellitus - a chronic disease that affects carbohydrate metabolism  2 groups of antidiabetic agents: Insulin & oral hypoglycemic agents - Oral hypoglycemic agents = synthetic preparations that stimulate insulin release or alter metabolic response to hyperglycemia - Insulin = a protein secreted from the beta cells of the pancreas - necessary for carbo metabolism & an important role in protein & fat metabolism
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  Meglitinide Analogs Sulphonylureas Thiazolindinediones Metformin (Biguanides) AlphaGlucosidase Inhibitors
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  •Metformin (Biguanides) •Glybenclemide, Glicliazide Glipizide,Glimepiride • Acarbose , Miglitol, Voglibose • Repaglinide, Nateglinide • Rosiglitazone , Pioglitazone • Sitagliptin, Vildagliptin, Saxagliptin Spectrum of Oral Hypoglycaemic Agents •Biguanides •Sulphonylureas •-Glucosidase inhibitors •Meglitinide analogues •Thiazolidinediones
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  What is therole of an ideal oral hypoglycaemic agent? Conserve islet cell function - delay the subsequent use of insulin. Improve patient compliance- single daily dosing. Reduce the incidence of hypoglycaemic events
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  Oral hypoglycemic drugs 1.Sulfonylurea drugs 2. Meglitinides 3. Biguanides 4. alpha-glucosidase inhibitors. 5. Thiazolidinediones. 6. Dipeptidyl peptidase-4 (DPP-4) inhibitors
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  Insulin secretagogues  Sulfonylureadrugs  Meglitinides Insulin sensitizers  Biguanides  Thiazolidinediones Others  Alpha glucosidase inhibitors  Gastrointestinal hormones Oral hypoglycemic drugs
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  Insulin secretagogues Are drugswhich increase the amount of insulin secreted by the pancreas Include: • Sulfonylureas • Meglitinides
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   First generationare essentially obsolete  glipizide (Glucotrol), glyburide (Diabeta) and glimepiride (Amaryl)  Stimulate insulin release from functioning B cells by blocking of ATP-sensitive K channels which causes depolarization and opening of voltage- dependent calcium channels, which causes an increase in intracellular calcium in the beta cells, which stimulates insulin release. Mechanism of action of sulfonylureas:
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  •displacement from proteinbinding sites – salicylates and sulphonamides •interference with hepatic metabolism – inducers: rifampicin, phenytoin – inhibitors: cimetidine •reduction of renal elimination – allopurinol, salicylates Sulfonylureas – important drug interactions:
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  Mechanisms of InsulinRelease
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  Classification of sulfonylureas TolbutamideAcetohexamide Tolazamide Chlorpropamide Glipizide glibenclamide (Glyburide) Glimepiride First generation Long acting Short acting second generation Short acting Intermediate acting Long acting
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  Pharmacokinetics of sulfonylureas: Orally, well absorbed.  Reach peak concentration after 2-4 hr.  All are highly bound to plasma proteins.  Duration of action is variable.  Second generation has longer duration than first generation.
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   Metabolized inliver  excreted in urine (elderly and renal disease) Pharmacokinetics of sulfonylureas:
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  Tolbutamide short- acting Acetohexamide intermediate- acting Tolazamide intermediate -acting Chlorpropam ide long- acting Absorption WellWell Slow Well Metabolism Yes Yes Yes Yes Metabolites Inactive Active Active Inactive Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs Duration of action Short (6 – 8 hrs) Intermediate (12 – 20 hrs) Intermediate (12 – 18 hrs) Long ( 20 – 60 hrs) Excretion Urine Urine Urine Urine First generation sulfonylureas
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  Tolbutamide: safe for olddiabetic patients or pts with renal impairment. First generation sulfonylureas
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  Glipizide - glyburide(Glibenclamide)  More potent than first generation  Have longer duration of action.  Less frequency of administration  Have fewer adverse effects  Have fewer drug interactions Second generation sulfonylureas
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  Glipizide Glibenclamide (Glyburide) Glimepiride Absorption WellWell Well Metabolism Yes Yes Yes Metabolites Inactive Inactive Inactive Half-life 2 – 4 hrs Less than 3 hrs 5 - 9 hrs Duration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs action short long long Doses Divided doses 30 min before meals Single dose Single dose Excretion Urine Urine Urine Second generation sulfonylureas
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  Unwanted Effects: 1. Hyperinsulinemia& Hypoglycemia:  Less in tolbutamide.  More in old age, hepatic or renal diseases. 2. Weight gain due to increase in appetite 3. GIT upset.
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  CONTRAINDICATIONS:  Hepatic impairmentor renal insufficiency  Pregnancy & lactation  Type I diabetes
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  Repaglinide/Nateglinide are rapidly actinginsulin secretagogues Meglitinides (non Sulphonylurea)
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  Mechanism of Action: Stimulateinsulin release from functioning β cells via blocking ATP-sensitive K-channels resulting in calcium influx and insulin exocytosis.
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  Pharmacokinetics of meglitinides Orally, well absorbed.  Very fast onset of action, peak 1 h.  short duration of action (4 h).  Metabolized in liver and excreted in bile.  Taken just before each meal (3 times/day).
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   Type IIdiabetes: monotherapy or combined with metformin (better than monotherapy).  Specific use in patients allergic to sulfur or sulfonylureas.  elderly patients in whom hypoglycaemia is a concern Uses of Meglitinides
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  Advantages of Nateglinide/Repaglinide  Nosignificant increase in bodyweight  Can be utillised in mild to moderate renal failure  Nateglinide: approved in hepatic failure Dosage: Repaglinide: 0.5mg/1mg/2mg/4mg per dose per meal Nateglinide: 60mg/120mg per dose per meal  Lower incidence of hypoglycemia
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  Disadvantages of Metaglinide derivatives Workspredominantly in mild hyperglycaemia Less convincing with fasting hyperglycaemia
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   Hypoglycemia.  Weightgain. Adverse effects of Meglitinides
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   Are drugswhich increase the sensitivity of target organs to insulin. Include  Biguanides  Thiazolidinediones (Glitazones) Insulin sensitizers
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  Metformin By ADA andEASD guidelines The primary drug of choice for diabetes Insulin sensitizers Biguanides
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   Does notrequire functioning B cells.  Does not stimulate insulin release.  Increases peripheral glucose utilization (tissue glycolysis).  Inhibits hepatic gluconeogenesis.  Impairs glucose absorption from GIT.  Reduces plasma glucagon level.  LDL &VLDL.   HDL Mechanism of action of metformin
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   orally.  NOTbound to serum protein.  NOT metabolized.  t ½ 3 hours.  Excreted unchanged in urine Pharmacokinetics of metformin
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   Type IIdiabetes particular, in overweight and obese people (with insulin resistance). Advantages:  No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia). Uses of metformin
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   GIT disturbances:nausea, vomiting, diarrhea  Long term use interferes with vitamin B12 absorption.  Lactic acidosis: in patients with renal, liver, pulmonary or cardiac diseases.  Metallic taste in the mouth. Adverse effects of metformin
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   Renal disease. Liver disease.  Alcoholism.  Conditions predisposing to hypoxia as cardiopulmonary dysfunction. Contraindications of metformin
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  Initiate: - after meals -250 to 500mg twice or thrice a day - Increase gradually if required in 1 or 2 weeks - mild loose stools in 10% initially, which reduces gradually -persistent loose stools in 5% -Sustained released forms: more effective- vehicle excreted in stool
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  Metformin: Dosing from 500mgtwice daily to 1 gramme thrice a day Advantages: Perpetuates weight loss Can be combined with insulin to reduce insulin requirements Disadvantages: Nausea, Vomiting and diarhorrea(5%) Vitamin B12 Deficiency (0.5%)
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  Insulin sensitizers Thiazolidinediones (glitazones) Pioglitazone (Actos)  Rosiglitazone  Troglitazone
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  Thiazolidinediones (TZDs) They increasetissue insulin sensitivity but have serious ADRs and the EMA recommended in Sept (2010) that they be suspended from the EU market: - Rosiglitazone (Avandia) has high cardiovascular risks. - Pioglitazone causes bladder tumors. - Troglitazone causes hepatitis.
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  Mechanism of action Activate PPAR- (peroxisome proliferator-activated receptor -).  Decrease insulin resistance.  Increase sensitivity of target tissues to insulin.  Increase glucose uptake and utilization in muscle and adipose tissue.
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  Pharmacokinetics of pioglitazone Orally (once daily dose).  Highly bound to plasma albumins (99%)  Slow onset of activity  Half life 3-4 h  Metabolized in liver .  Excreted in urine 64% & bile
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   Type IIdiabetes with insulin resistance.  Used either alone or combined with sulfonylurea, biguanides.  No risk of hypoglycemia when used alone. Uses of pioglitazone
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   Hepatotoxicity ??(liver function tests for 1st year of therapy).  Fluid retention (Edema).  Precipitate congestive heart failure  Mild weight gain.  Potential weight gain (2-4 kg)  LDL elevation (Mainly over 1st 2 months)  Oedema  Worsens Osteoporosis  Containdicated in Grave’s Ophthalmopathy, Macular Oedema  Occasional fluid overload (therefore avoid in Ischemic heart Disease) Adverse effects of pioglitazone
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  Contraindications of pioglitazone Congestive heart failure.  Pregnancy.  Lactating women  Significant liver disease.
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  -Glucosidase inhibitors  Acarbose
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   Are reversibleinhibitors of intestinal -glucosidases in intestinal brush border that are responsible for carbohydrate digestion.  decrease carbohydrate digestion and glucose absorption in small intestine.  Acarbose (Precose) and miglitol (Glyset)  Contraindicated in cirrhosis, malabsorption, severe renal impairment -Glucosidase inhibitors
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   Decrease postprandialhyperglycemia.  Taken just before meals.  No hypoglycemia if used alone. -Glucosidase inhibitors
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  Acarbose  Given orally,poorly absorbed.  Metabolized by intestinal bacteria.  Excreted in stool and urine. Kinetics of -glucosidase inhibitors
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   Acarbose- 25mg to 50mg thrice a day  Miglitol- 25mg to 100mg thrice a day  Voglibose- 0.2 to 0.3 mg thrice a day
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  Uses  effective alonein the earliest stages of impaired glucose tolerance.  Combined with sulfonylurea in treatment of Type 2 diabetes to improve blood glucose control. Uses of -glucosidase inhibitors
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   GIT: Flatulence,diarrhea, abdominal pain Adverse effects of -glucosidase inhibitors
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  Contraindications  an inflammatorybowel disease, such as ulcerative colitis or Crohn's disease; or any other disease of the stomach or intestines  ulcers of the colon  Intestinal Obstruction
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  Incretin concept  Insulinsecretion dynamics is dependent on the method of administration of glucose  Intravenous glucose gives a marked first and second phase response  Oral glucose gives less marked first and second phase insulin response, but a prolonged and higher insulin
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  What are theincretins?  GIP: Glucose-dependent insulinotrophic polypeptide Small effect in Type 2 diabetes.  GLP-1(glucagon-like peptide 1) augmented in the presence of hyperglycaemia. Action less at euglycaemia and in normal subjects.  Pituitary Adenylate Cyclase Activating Peptide (PACAP)
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  GLP-1 localisation  Cleavedfrom proglucagon in intestinal L-cells (and neurons in hindbrain/hypothalamus)  Secreted in response to meal ingestion  Cleared via the kidneys
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  GLP-1 Modes ofAction in Humans GLP-1 is secreted from the L-cells in the intestine This in turn… • Stimulates glucose-dependent insulin secretion • Suppresses glucagon secretion • Slows gastric emptying Long term effects demonstrated in animals… • Increases beta-cell mass and maintains beta-cell efficiency • Reduces food intake Upon ingestion of food…
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  Native GLP-1 israpidly degraded by DPP- IV Human ileum, GLP-1producing L-cells Capillaries, DiPeptidyl Peptidase-IV (DPP-IV) Adaptedfrom:Hansenetal.Endocrinology1999:140(11):5356-5363
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  Dipeptyl- peptidase inhibitors Sitagliptin Vildagliptin Saxagliptin Septagliptin Allogliptin
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  Mechanism of Actionof Sitagliptin Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the actions of these hormones. Release of active incretins GLP-1 and GIP  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon (GLP-1)  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X Sitagliptin (DPP-4 inhibitor)  Insulin (GLP-1 and GIP) Glucose- dependent Glucose dependen t Pancreas Inactive GIP β cells α cells  Glucose uptake by peripheral tissues 30
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  Dipeptidyl peptidase-4 inhibitors Dipeptidylpeptidase-4 inhibitors (DPP- 4 inhibitors) e.g. Sitagliptin, Vildagliptin
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  (DPP- 4 inhibitors) Sitagliptin Orally  Given once daily  half life 8-14 h  Dose is reduced in pts with renal impairment
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  Mechanism of actionof sitagliptin Inhibits DPP-4 enzyme, which metabolizes the naturally occurring incretin hormones thus increase incretin secretion (gastrointestinal hormones secreted in response to food). Incretin hormones decreases blood glucose level by :  Increasing insulin secretion  Decreasing glucagon secretion.
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  Mechanism of actionof DPP-4 inhibitors
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  Clinical uses  Type2 diabetes mellitus as a monotherapy or in combination with other oral antidiabetic drugs when diet and exercise are not enough. Adverse effects Nausea, abdominal pain, diarrhea.
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  . Glucagon-like peptide-1(GLP-1) agonists (in type 2 DM): increase pancreatic secretion of insulin: Exenatide Bydureon (s.c./7 days): $323/4 doses, resp. $4200 per year
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  Liraglutid Liraglutid is a GLP-1 agonist, whichreduces, , HbA1C, and systolic blood pressure, and improves beta cell function of the pancreas (s.c. once a day)
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  Inhibitors of reabsorption ofglucose (SGLT2 inhibitors): p.o. •Canagliflozin blocks in renal proximal tubule sodium / glucose co-transporter protein 2 (SGLT2), which re-absorbed 90% of the filtrated glucose. The result is increased glucosuria and plasma glucose levels are lowered. ADRs: Hypoglycaemia, vulvovaginal candidiasis urinary tract infections, polyuria, frequent urination.
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  SUMMARY Class Mechanism Siteof action Main advantages Main side effects Sulfonylureas Tolbutamide Glipizide Glibenclamide (glyburide) Stimulating insulin production by inhibiting the KATP channel Pancreatic beta cells • Effective • Inexpensive • Hypoglycemia • Weight gain Meglitinides repaglinide Stimulates insulin secretion Pancreatic beta cells Sulfa free •Hypoglycemia •Weight gain Biguanides Metformin Decreases insulin resistance Liver • mild weight loss • No hypoglycemia • GIT symptoms, • Lactic acidosis • Metallic taste Thiazolidinedio nes pioglitazone Decreases insulin resistance Fat, muscle Hepatoxicity Edema ccf -Glucosidase inhibitors Acarbose Inhibits α- glucosidase GI tract Low risk •GI symptoms, flatulence DPP-4 inhibitor Sitagliptin Increase secretin GI tract
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  Which is theappropriate oral hypoglycaemic agent to use and when?
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  Determinants of OADusage 1)Body Mass Index : Metformin, Gliptins BMI> 22kg/m2 2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones 3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpha (variable) 4) Aging Meglitinides, Gliptins(?) 5) Hepatic Dysfunction Nateglinide, Saxagliptin(?) 6) Compliance Gliptins, Glitazones, 7) Cost Metformin, Sulphas, Glitazones
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  Therapeutic Algorithm for OralHypoglycaemic Drugs…….Today. Metformin Secretagogue Thiazolidinediones DPPV-4 inhibitor 1. Metformin+ Secretagogue 2. DPPV-4 inhibitor+ Secretagogue Triple Therapy: A) M +Sec +DPPV B) M+Thia+DPPV Metformin 3. DPPV-4 inhibitor + Metformin 4.Thiazolidinedione + Metformin Quadruple Therapy!!
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  ADA guidelines, 2008recommend…
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  Thank You
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  References  Harrisons principleof internal medicine 19th Ed.  Kumar & Clarks clinical medicine 7th Ed.  Davidson's principles and practice of medicine 22nd Ed.  Emergency Medicine Board Review Series. L Stead, Lippincott Williams & Wilkins, 2000.  Emergency Medicine, A comprehensive study guide. Tintinalli, 6th edition, McGraw Hill, 2004.  Medscape