08&09 Oral Hypoglycemics-level 11

8/11/2019 08&09 Oral Hypoglycemics-level 11

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Oral hypoglycemic drugs

Prof. Mohammad Alhumayyd


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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 oral hypoglycemic drugs.

Identify the clinical uses of hypoglycemic drugs

Know the side effects contraindications of each class of

oral hypoglycemic drugs.


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Pts with Type 11 diabetes havetwo physiological defects:

1. Abnormal insulin secretion.

2. Resistance to insulin action in target

tissues associated with decreased

number of insulin receptors.


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Drugs used for treatment of

Type-2 diabetes

1. Sulfonylurea drugs

2. Meglitinide analogues

3. Biguanides

4. Thiazolidinediones.

5.Alpha-glucosidase inhibitors.

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


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Insulin

secretagogues

Sulfonylurea drugs

Meglitinide analogues

Insulinsensitizers

Biguanides

Thiazolidinediones

Oral hypoglycemic drugs


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Others

Alpha glucosidase inhibitors

Dipeptidyl peptidase-4(DPP-4)

inhibitors


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Insulin secretagogues

Are drugs which increase the amount of

insulin secreted by the pancreas

Include:

SulfonylureasMeglitinides


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Classification of sulfonylureas

Tolbutamide AcetohexamideTolazamide

Chlorpropamide Glipizide

Glyburide

(Glibenclamide)

Glimepiride

First generation

Long

acting

Short

acting

second generation

Shortacting

Intermediateacting

Long

acting


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Stimulate insulin release from functioning B cells

by blocking of ATP-sensitive K channels resultingin depolarization and calcium influx(Hence, not

effective in totally insulin-deficient pts type-1).

Potentiation of insulin action on target tissues.

Reduction of serum glucagon concentration.

Mechanism of action of sulfonylureas:


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Mechan ism s o f Insu l in Release


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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. Metabolized in liver

excreted in urine

Cross placenta, stimulate fetal B cells to release

insulin hypoglycemia at birth.


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Tolbutamid

short-acting

Acetohexamide

intermediate-acting

Tolazamide

intermediate-acting

Chlorpropa

midelong- acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes YesMetabolites Inactive Active Active Inactive

Half-life 4 - 5 hrs 6 8 hrs 7 hrs 24 40 hrs

Duration of

actionShort

(6

8 hrs)

Intermediate

(12

20 hrs)

Intermediate

(12

18 hrs)

Long

( 20

60hrs)

Excretion Urine Urine Urine Urine

First generation sulfonylurea


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Tolbutamide:

safe for old diabetic patients or pts withrenal impairment.

First generation sulfonylureas


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Glipizide Glibenclamide

(Glyburide)

Glimepiride

Absorption Well Well Well

Metabolism Yes Yes YesMetabolites Inactive Moderate activity Moderate activity

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 longDoses Divided doses

30 min before

meals

Single dose Single dose

1 mg

Excretion Urine Urine Urine

SECOND GENERATION SULPHONYLUREA


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Type II diabetes:

monotherapy or in combination with otherantidiabetic drugs.

Uses of sulfonylureas


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Unwanted Effects:

1. Hyperinsulinemia & Hypoglycemia:

2. Weight gaindue to increase in appetite


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e.g. Repaglinide

Rapidly acting insulin secretagogues

Meglitinide analogues


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Mechanism of Action:

Insulin secretagogue as sulfonylureas.


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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 the liver & excreted in

bile.


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Type II diabetes:

monotherapy or combined with otherantidiabetic drugs.

Patients allergic to sulfonylurea

Uses of Meglitinides


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Hypoglycemia Weight gain.

Adverse effects of Meglitinides


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1. Biguanides, e.g. Metformin

2. Thiazolidinediones, e.g. pioglitazone

Insulin sensitizers


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BIGUANIDES

E.g. Metformin


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Does not stimulate insulin release. Increases liver ,muscle &adipose tissues

sensitivity to insulin & increase peripheralglucose utilization.

Inhibits gluconeogenesis.

Impairs glucose absorption from GIT.

Mechanism of action of metformin


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orally.

Not bound to serum protein. Not metabolized.

t 3 hours.

Excreted unchanged in urine

Pharmacokinetics of metformin


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Obese patients with type II diabetes

Monotherapy or in combination.

Advantages:

No risk of hyperinsulinemia or hypoglycemia

or weight gain (anorexia).

Uses of metformin


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Metallic taste in the mouth

GIT disturbances: nausea, vomiting, diarrhea Lactic acidosis

Long term use interferes with vitamin B12

absorption.

Adverse effects of metformin


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Pregnancy.

Renal disease. Liver disease.

Alcoholism.

Heart failure

Contraindications of metformin


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Insulin sensitizers

Thiazolidinediones (glitazones)

Pioglitazone


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Mechanism of action

Increase sensitivity of target tissues to insulin.

Increase glucose uptake and utilization inmuscle 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 the liver

Excreted in urine 64% & bile


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Type II diabetes with insulin resistance.

Used either alone or combined withsulfonylurea, biguanides or insulin.

No risk of hypoglycemia when used alone

Uses of pioglitazone


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Hepatotoxicity ?? (liver function tests for1st year of therapy).

Fluid retention (Edema).

Precipitate congestive heart failure

Mild weight gain.

Adverse effects of pioglitazone


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decrease carbohydrate digestion and

absorption in small intestine. Decrease postprandial hyperglycemia.

Taken just before meals.

No hypoglycemia if used alone.

-Glucosidase inhibitors

GLUCOSIDASE INHIBITORS (Contd )


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-GLUCOSIDASE INHIBITORS (Contd.)

MECHANISM OF ACTION


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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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GIT: Flatulence, diarrhea, abdominal

pain. No hypoglycemia if used alone.

Adverse effects of -glucosidase

inhibitors


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Incretin mimetics

e.g. Exenatide(GLP-1)

Incretins are GI hormones secreted inresponse to food, carried through circulationto the beta cells to stimulate insulin secretion& decrease glucagon secretion.


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Incretins

Two main Incretin hormones:

GLP-1(glucagon-like peptide-1) GIP(gastric inhibitory peptide or glucose-

dependent insulinotropic peptide)

Both are inactivated by dipeptidyl peptidase-4(DPP-4).


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Incretin mimetics

Exenatide

is glucagon-like peptide-1 (GLP-1) agonist. given s.c. once or twice daily

Therapy of patients with type 2 diabetes

who are not controlled with oral medicine.Adverse efects

Nausea & vomiting(most common)


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Dipeptidyl peptidase-4 (DPP- 4 )

inhibitors

e.g. Sitagliptin

Orally Given once daily

half life 8-14 h

Dose is reduced in pts with renalimpairment


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Mechanism of action of sitagliptin

Inhibit DPP-4 enzyme and leads to an

increase in incretin hormones level.This results in an increase in insulin

secretion & decrease in glucagon secretion.

Mechanism of
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ec s oaction
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08&09 Oral Hypoglycemics-level 11