08&09 oral hypoglycemics-level 11
TRANSCRIPT
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
1/48
Oral hypoglycemic drugs
Prof. Mohammad Alhumayyd
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
2/48
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.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
3/48
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
4/48
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.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
5/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
6/48
Insulin
secretagogues
Sulfonylurea drugs
Meglitinide analogues
Insulinsensitizers
Biguanides
Thiazolidinediones
Oral hypoglycemic drugs
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
7/48
Others
Alpha glucosidase inhibitors
Dipeptidyl peptidase-4(DPP-4)
inhibitors
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
8/48
Insulin secretagogues
Are drugs which increase the amount of
insulin secreted by the pancreas
Include:
SulfonylureasMeglitinides
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
9/48
Classification of sulfonylureas
Tolbutamide AcetohexamideTolazamide
Chlorpropamide Glipizide
Glyburide
(Glibenclamide)
Glimepiride
First generation
Long
acting
Short
acting
second generation
Shortacting
Intermediateacting
Long
acting
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
10/48
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:
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
11/48
Mechan ism s o f Insu l in Release
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
12/48
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.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
13/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
14/48
Tolbutamide:
safe for old diabetic patients or pts withrenal impairment.
First generation sulfonylureas
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
15/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
16/48
Type II diabetes:
monotherapy or in combination with otherantidiabetic drugs.
Uses of sulfonylureas
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
17/48
Unwanted Effects:
1. Hyperinsulinemia & Hypoglycemia:
2. Weight gaindue to increase in appetite
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
18/48
e.g. Repaglinide
Rapidly acting insulin secretagogues
Meglitinide analogues
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
19/48
Mechanism of Action:
Insulin secretagogue as sulfonylureas.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
20/48
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.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
21/48
Type II diabetes:
monotherapy or combined with otherantidiabetic drugs.
Patients allergic to sulfonylurea
Uses of Meglitinides
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
22/48
Hypoglycemia Weight gain.
Adverse effects of Meglitinides
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
23/48
1. Biguanides, e.g. Metformin
2. Thiazolidinediones, e.g. pioglitazone
Insulin sensitizers
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
24/48
BIGUANIDES
E.g. Metformin
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
25/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
26/48
orally.
Not bound to serum protein. Not metabolized.
t 3 hours.
Excreted unchanged in urine
Pharmacokinetics of metformin
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
27/48
Obese patients with type II diabetes
Monotherapy or in combination.
Advantages:
No risk of hyperinsulinemia or hypoglycemia
or weight gain (anorexia).
Uses of metformin
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
28/48
Metallic taste in the mouth
GIT disturbances: nausea, vomiting, diarrhea Lactic acidosis
Long term use interferes with vitamin B12
absorption.
Adverse effects of metformin
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
29/48
Pregnancy.
Renal disease. Liver disease.
Alcoholism.
Heart failure
Contraindications of metformin
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
30/48
Insulin sensitizers
Thiazolidinediones (glitazones)
Pioglitazone
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
31/48
Mechanism of action
Increase sensitivity of target tissues to insulin.
Increase glucose uptake and utilization inmuscle and adipose tissue.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
32/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
33/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
34/48
Hepatotoxicity ?? (liver function tests for1st year of therapy).
Fluid retention (Edema).
Precipitate congestive heart failure
Mild weight gain.
Adverse effects of pioglitazone
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
35/48
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
36/48
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 )
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
37/48
37
-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
38/48
Acarbose
Given orally, poorly absorbed.
Metabolized by intestinal bacteria.
Excreted in stool and urine.
Kinetics of -glucosidase inhibitors
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
39/48
GIT: Flatulence, diarrhea, abdominal
pain. No hypoglycemia if used alone.
Adverse effects of -glucosidase
inhibitors
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
40/48
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.
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
41/48
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
42/48
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
43/48
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).
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
44/48
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)
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
45/48
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
-
8/11/2019 08&09 Oral Hypoglycemics-level 11
46/48
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
http://upload.wikimedia.org/wikipedia/commons/6/64/Incretins_and_DPP_4_inhibitors.svghttp://upload.wikimedia.org/wikipedia/commons/6/64/Incretins_and_DPP_4_inhibitors.svg -
8/11/2019 08&09 Oral Hypoglycemics-level 11
47/48
ec s oaction
http://upload.wikimedia.org/wikipedia/commons/6/64/Incretins_and_DPP_4_inhibitors.svghttp://upload.wikimedia.org/wikipedia/commons/6/64/Incretins_and_DPP_4_inhibitors.svghttp://upload.wikimedia.org/wikipedia/commons/6/64/Incretins_and_DPP_4_inhibitors.svg -
8/11/2019 08&09 Oral Hypoglycemics-level 11
48/48