Oral hypoglycemic drugsProf. Hanan Hagar

Objectives

By the end of this lecture, students should be able to:Classify different categories of oral hypoglycemic drugs.Identify mechanism of action, pharmacokinetics and pharmacodynamics of each class of oral hypoglycemic drugs.Identify the clinical uses of hypoglycemic drugsKnow the side effects, contraindications of each class of oral hypoglycemic drugs.

Oral hypoglycemic drugs1. Sulfonylurea drugs2. Meglitinides3. Biguanides4. alpha-glucosidase inhibitors.5. Thiazolidinediones.6. Dipeptidyl peptidase-4 (DPP-4) inhibitors

Insulin secretagoguesSulfonylurea drugsMeglitinidesInsulin sensitizersBiguanidesThiazolidinedionesOral hypoglycemic drugs

OthersAlpha glucosidase inhibitorsGastrointestinal hormones

Insulin secretagoguesAre drugs which increase the amount of insulin secreted by the pancreas

Include:

Sulfonylureas Meglitinides

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:

Mechanisms of Insulin Release

Classification of sulfonylureasTolbutamide

AcetohexamideTolazamideChlorpropamide

Glipizideglibenclamide (Glyburide)GlimepirideFirst generationLongactingShort actingsecond generation

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.

Metabolized in liver excreted in urine (elderly and renal disease)Cross placenta, stimulate fetal -cells to release insulin fetal hypoglycemia at birth.Pharmacokinetics of sulfonylureas:

First generation sulfonylureas

Tolbutamid short-actingAcetohexamideintermediate-acting Tolazamide intermediate-actingChlorpropamide long- acting AbsorptionWellWellSlowWellMetabolismYesYesYesYesMetabolitesInactiveActive Active Inactive Half-life4 - 5 hrs6 8 hrs7 hrs24 40 hrsDuration of actionShort (6 8 hrs)Intermediate (12 20 hrs)Intermediate (12 18 hrs)Long( 20 60 hrs)ExcretionUrineUrineUrineUrine

Tolbutamide: safe for old diabetic patients or pts with renal impairment.First generation sulfonylureas

Glipizide - glyburide (Glibenclamide)More potent than first generationHave longer duration of action.Less frequency of administration Have fewer adverse effectsHave fewer drug interactionsSecond generation sulfonylureas

Second generation sulfonylureas

GlipizideGlibenclamide(Glyburide)Glimepiride

AbsorptionWellWellWellMetabolismYesYesYesMetabolitesInactiveInactiveInactiveHalf-life2 4 hrsLess than 3 hrs5 - 9 hrsDuration of10 16 hrs12 24 hrs12 24 hrsactionshortlonglongDosesDivided doses 30 min before meals Single doseSingle dose

ExcretionUrineUrineUrine

Unwanted Effects:1. Hyperinsulinemia & Hypoglycemia: Less in tolbutamide.More in old age, hepatic or renal diseases.2. Weight gain due to increase in appetite3. GIT upset.

CONTRAINDICATIONS:

Hepatic impairment or renal insufficiencyPregnancy & lactation Type I diabetes

Repaglinide are rapidly acting insulin secretagoguesMeglitinides

Mechanism of Action:

Stimulate insulin release from functioning cells via blocking ATP-sensitive K-channels resulting in calcium influx and insulin exocytosis.

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).

Type II diabetes: monotherapy or combined with metformin(better than monotherapy).

Specific use in patients allergic to sulfur or sulfonylureas.Uses of Meglitinides

Hypoglycemia.

Weight gain.Adverse effects of Meglitinides

Are drugs which increase the sensitivity of target organs to insulin.

Include BiguanidesThiazolidinediones (Glitazones)Insulin sensitizers

Metformin Insulin sensitizersBiguanides

Does not require 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. HDLMechanism of action of metformin

orally.NOT bound to serum protein.NOT metabolized.t 3 hours.Excreted unchanged in urinePharmacokinetics of metformin

Type II diabetes particular, in overweight and obese people (with insulin resistance).

Advantages:No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia).Uses of metformin

GIT disturbances: nausea, vomiting, diarrheaLong 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

Pregnancy.Renal disease. Liver disease.Alcoholism.Conditions predisposing to hypoxia as cardiopulmonary dysfunction.

Contraindications of metformin

Insulin sensitizersThiazolidinediones (glitazones)Pioglitazone (Actos)

Mechanism of actionActivate 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.

Pharmacokinetics of pioglitazoneOrally (once daily dose).Highly bound to plasma albumins (99%)Slow onset of activityHalf life 3-4 hMetabolized in liver .Excreted in urine 64% & bile

Type II diabetes with insulin resistance.Used either alone or combined with sulfonylurea, biguanides.No risk of hypoglycemia when used alone.Uses of pioglitazone

Hepatotoxicity ?? (liver function tests for 1st year of therapy).Fluid retention (Edema).Precipitate congestive heart failureMild weight gain.Adverse effects of pioglitazone

Contraindications of pioglitazoneCongestive heart failure.Pregnancy.Lactating womenSignificant liver disease.

-Glucosidase inhibitors

Acarbose

Are reversible inhibitors of intestinal -glucosidases in intestinal brush border that are responsible for carbohydrate digestion.

decrease carbohydrate digestion and glucose absorption in small intestine.

-Glucosidase inhibitors

Decrease postprandial hyperglycemia.Taken just before meals.No hypoglycemia if used alone. -Glucosidase inhibitors

Acarbose Given orally, poorly absorbed.Metabolized by intestinal bacteria.Excreted in stool and urine.

Kinetics of -glucosidase inhibitors

Uses effective alone in 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

GIT: Flatulence, diarrhea, abdominal pain Adverse effects of -glucosidase inhibitors

Dipeptidyl peptidase-4 inhibitorsDipeptidyl peptidase-4 inhibitors (DPP- 4 inhibitors) e.g. Sitagliptin

(DPP- 4 inhibitors) Sitagliptin

OrallyGiven once dailyhalf life 8-14 hDose is reduced in pts with renal impairment

Mechanism of action of sitagliptin

Inhibits DPP-4 enzyme, which metabolizes thenaturally occurring incretin hormonesthus increase incretin secretion (gastrointestinalhormones secreted in response to food). Incretin hormones decreases blood glucose level by :Increasing insulin secretionDecreasing glucagon secretion.

Mechanism of action of DPP-4 inhibitors

Clinical usesType 2 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.

SUMMARY

ClassMechanismSite of actionMain advantagesMain side effectsSulfonylureasTolbutamideGlipizideGlibenclamide(glyburide)Stimulating insulin production by inhibiting the KATP channelPancreatic beta cells Effective Inexpensive Hypoglycemia Weight gainMeglitinidesrepaglinideStimulates insulin secretionPancreatic beta cellsSulfa freeHypoglycemiaWeight gainBiguanidesMetforminDecreases insulin resistanceLiver mild weight loss No hypoglycemia GIT symptoms, Lactic acidosis Metallic tasteThiazolidinedionespioglitazoneDecreases insulinresistanceFat, muscleHepatoxicityEdema-Glucosidase inhibitorsAcarboseInhibits -glucosidaseGI tractLow riskGI symptoms, flatulenceDPP-4 inhibitorSitagliptinIncrease secretinGI tract