Oral hypoglycemic drugs

Prof. Hanan Hagar

Objectives

By the end of this lecture, students should be able to:

1. Classify different categories of oral hypoglycemic drugs.

2. Identify mechanism of action, pharmacokinetics and pharmacodynamics of each class of oral hypoglycemic drugs.

3. Identify the clinical uses of hypoglycemic drugs

4. Know the side effects, contraindications of each class of oral hypoglycemic drugs.

Oral hypoglycemic drugs

1. Sulfonylurea drugs

2. Meglitinides

3. Biguanides

4. alpha-glucosidase inhibitors.

5. Thiazolidinediones.

6. Dipeptidyl peptidase-4 (DPP-4) inhibitors

Insulin secretagoguesSulfonylurea drugsMeglitinides

Insulin sensitizersBiguanidesThiazolidinediones

Oral hypoglycemic drugs

Others Alpha glucosidase inhibitors Gastrointestinal hormones

Insulin secretagogues

Are drugs which increase the amount of insulin secreted by the pancreas

Include:

• Sulfonylureas• Meglitinides

Stimulate insulin release from functioning B cells by blocking ATP-sensitive K+ channels which causes depolarization and opening of voltage- dependent Ca 2+ channels, which causes an increase in intracellular calcium in the beta cells and stimulates insulin release.

Mechanism of action of sulfonylureas:

Mechanism of action of sulfonylureas:

Mechanisms of Insulin Release

Classification of sulfonylureasClassification of sulfonylureas

TolbutamideTolbutamide AcetohexamideAcetohexamide

TolazamideTolazamide

ChlorpropamideChlorpropamide Glipizide

GlibenclamideGlibenclamide

(Glyburide)(Glyburide)

GlimepirideGlimepiride

First generationFirst generation second generationsecond generation

Short acting

Intermediateacting

Longacting Long

actingShort

acting

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 β-cells to

release insulin → fetal hypoglycemia

Pharmacokinetics of sulfonylureas:

Tolbutamide short-acting

Acetohexamide

intermediate-acting

Tolazamide intermediate

-acting

Chlorpropamide

long- acting

Absorption Well Well 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

Tolbutamide:

safe for old diabetic patients or patients

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 interactions

Second generation sulfonylureas

Glipizide Glibenclamide

(Glyburide)

Glimepiride

Absorption Well Well Well

Metabolism Yes Yes Yes

Metabolites Inactive Inactive Inactive

Half-life 2 – 4 hrs Less than 3 hrs 5 - 9 hrs

Duration of

action

10 – 16 hrs 12 – 24 hrs 12 – 24 hrs

short long long

Doses Divided doses

30 min before meals

Single dose Single dose

Excretion Urine Urine Urine

Second generation sulfonylureas

Unwanted Effects:

Hyperinsulinemia & Hypoglycemia: Less in tolbutamide. More in old age, hepatic or renal diseases.

Weight gain due to increase in appetite

GIT upset.

Allergic reactions in pts sensitive to sulfa drugs

CONTRAINDICATIONS:

Hepatic impairment or renal insufficiencyPregnancy & lactation

e.g. Repaglinide

are rapidly acting insulin secretagogues

Meglitinides

Mechanism of Action:

Stimulate insulin release from functioning

β 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 Specific use in patients allergic to sulfur

containing drugs e.g. sulfonylureas. Can be used as monotherapy or combined

with metformin

Uses of Meglitinides

Hypoglycemia.

Weight gain.

Adverse effects of Meglitinides

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

Include Biguanides Thiazolidinediones (Glitazones)

Insulin sensitizers

e.g. Metformin

Does not require functioning B cells.

Does not stimulate insulin release.

Insulin sensitizersBiguanides

Decrease insulin resistance. Increases peripheral glucose utilization

(tissue glycolysis). Inhibits hepatic gluconeogenesis. Impairs glucose absorption from GIT. LDL , VLDL & HDL

Mechanism of action of metformin

orally. Not bound to serum protein. Not metabolized. t ½ 3 hours. Excreted unchanged in urine

Pharmacokinetics of metformin

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

Advantages: No risk of hypoglycemia Mild weight loss (anorexia).

Uses of metformin

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

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

cardiopulmonary dysfunction.

Contraindications of metformin

Insulin sensitizersThiazolidinediones (glitazones)

Pioglitazone (Actos)

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.

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

Type II diabetes with insulin resistance.

Used either alone or combined with

sulfonylureas, 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 failure

Mild weight gain.

Adverse effects of pioglitazone

Contraindications of pioglitazone

Congestive heart failure.

Pregnancy.

Lactating women

Significant 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

Effective alone in the earliest stages of impaired glucose tolerance.

Can be combined with sulfonylurea in the 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 inhibitors

DPP- 4 inhibitors e.g. Sitagliptin

(DPP- 4 inhibitors) Sitagliptin

Orally

Given once daily

half life 8-14 h

Dose is reduced in pts with renal impairment

Mechanism of action of sitagliptin 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.

mechanism of action of Sitagliptin

Clinical uses

Type II 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.

SUMMARYClass Mechanism Site of

actionMain advantages Main side

effects

SulfonylureasTolbutamideGlipizideGlibenclamide(glyburide)

Stimulating insulin production by inhibiting the KATP channel

Pancreatic beta cells

• Effective• Inexpensive

• Hypoglycemia• Weight gain• Allergy

Meglitinidesrepaglinide

Stimulates insulin secretion

Pancreatic beta cells

Sulfa free •Hypoglycemia•Weight gain

BiguanidesMetformin

Decreases insulin resistance

Liver

• mild weight loss• No hypoglycemia

• GIT symptoms, • Lactic acidosis• Metallic taste

Thiazolidinedionespioglitazone

Decreases insulinresistance

Fat, muscle

HepatoxicityEdema

-Glucosidase inhibitorsAcarbose

Inhibits α-glucosidase

GI tract Low risk•GI symptoms, flatulence

DPP-4 inhibitorSitagliptin

Increase secretin

GI tract