Oral Hypoglycemic Agents - Pharmacology

1. Prepared by:
Huzaifa Hamid Ahmad
Shanyar Kadir Hama-Karim
Shkar Dilshad Abdulkarim

2. Overview
 The pancreas is both an endocrine gland
that produces the peptide hormones
insulin, glucagon, and somatostatin and
an exocrine gland that produces digestive
enzymes. The peptide hormones are
secreted from cells located in the islets of
Langerhans (β cells produce insulin, α cells
produce glucagon, and δ cells produce
somatostatin). These hormones play an
important role in regulating the metabolic
activities of the body, particularly the
homeostasis of blood glucose.

3. Overview
 Hyperinsulinemia (due, for example, to an
insulinoma) can cause severe
hypoglycemia. More commonly, a relative
or absolute lack of insulin, such as in
diabetes mellitus, can cause serious
hyperglycemia, which, if left untreated, can
result in
retinopathy, nephropathy, neuropathy, and
cardiovascular complications.
Administration of insulin preparations or
oral hypoglycemic agents can prevent
morbidity and reduce mortality associated
with diabetes.

4. Overview
 Anti-diabetic medications treat diabetes
mellitus by lowering glucose levels in the
blood. With the exceptions of
insulin, exenatide, and pramlintide, all
are administered orally and are thus also
called oral hypoglycemic agents or oral
antihyperglycemic agents. There are
different classes of anti-diabetic drugs, and
their selection depends on:
 Nature of the diabetes
 Age and situation of the person
 Other factors.

5. Diabetes Mellitus Type I
 Type 1 diabetes most commonly afflicts individuals in
puberty or early adulthood, but some latent forms can
occur later in life. The disease is characterized by an
absolute deficiency of insulin caused by massive β-cell
necrosis. Loss of β-cell function is usually ascribed to
autoimmune-mediated processes directed against the β-
cell, and it may be triggered by an invasion of viruses or
the action of chemical toxins. As a result of the destruction
of these cells, the pancreas fails to respond to
glucose, and the Type 1 diabetic shows classic symptoms
of insulin deficiency (polydipsia, polyphagia, polyuria, and
weight loss). Type 1 diabetics require exogenous insulin
to avoid the catabolic state that results from and is
characterized by hyperglycemia and life-threatening
ketoacidosis.

6. Diabetes Mellitus Type II
 Most diabetics are Type 2. The disease is
influenced by genetic
factors, aging, obesity, and peripheral
insulin resistance rather than by
autoimmune processes or viruses. The
metabolic alterations observed are milder
than those described for Type 1 (for
example, Type 2 patients typically are not
ketotic), but the long-term clinical
consequences can be just as devastating
(for example, vascular complications and
subsequent infection can lead to
amputation of the lower limbs).

7. Types of DM
 Diabetes mellitus type 1 is a disease
caused by the lack of insulin. Insulin must
be used in Type I, which must be injected.
 Diabetes mellitus type 2 is a disease of
insulin resistance by cells. Treatments
include:
 agents that increase the amount of insulin
secreted by the pancreas
 agents that increase the sensitivity of target
organs to insulin
 agents that decrease the rate at which glucose
is absorbed from the gastrointestinal tract.

8. Types of DM
Type 1 Type 2
Age of onset Usually during childhood Frequently over age 35
or puberty
Nutritional status at Frequently Obesity usually present
time of onset undernourished
Prevalence 5 to 10 % of diagnosed 90 to 95 % of diagnosed
diabetics diabetics
Genetic predisposition Moderate Very strong
Defect or deficiency B cells are destroyed, Inability of B cells to
eliminating the produce appropriate
production of insulin quantities of insulin;
insulin resistance; other
defects

9. Insulin forms
Kinetics (in Hours) of Insulin Forms with Subcutaneous Injection
Form Onset Peak Effect Duration
Lispro* 0.3 – 0.5 1–2 3–4
Regular* 0.5 – 1 2–4 5–7
Glargine 1 No peak
* Only forms that can be used intravenously; peak action in 2 to 4 min

10. Symptoms of Hypoglycemia

11. DRUG GROUPS
OHA
Dipeptidyl
Insulin Insulin α-glucosidase
Peptidase-IV
secretagogues sensitizers inhibitors
inhibitors
Sulfonylureas Biguanides
Meglitinide Thiazolidinediones
analogue (TZD)

12. Adverse effects of OHAs
Meglitinide
Sulfonylureas Biguanides Thiazolidinediones
Hypoglycemia Nausea Risk of hepatotoxicity
Sulfonylureas
Biguanides
Meglitinides
α-Glucosidase inhibitors
Thiazolidinediones
GI disturbance Weight gain

13. 1) Insulin secretagogues
 Useful in the treatment of patients who
have Type 2 diabetes but who cannot be
managed by diet alone.
 Best response to OHA is seen in one who
develops diabetes after age 40 and has
had diabetes less than 5 years.
 Patients with long-standing disease may
require a combination of hypoglycemic
drugs with or without insulin to control their
hyperglycemia.
 Oral hypoglycemic agents should NOT be
given to patients with Type 1 diabetes.

14. A. Sulfonylureas
 These agents are classified as insulin
secretagogues, because they promote
insulin release from the β cells of the
pancreas. The primary drugs used today
are tolbutamide and the second-
generation
derivatives, glyburide, glipizide, and
glimepiride.

15. A. Sulfonylureas
 Mechanism of action:
1) stimulation of insulin release from the β
cells of the pancreas by blocking the
ATP-dependent K+ channels, resulting
in depolarization and Ca2+ influx
2) reduction in hepatic glucose production
3) increase in peripheral insulin sensitivity.

17. A. Sulfonylureas
 Pharmacokinetics:
 Given orally, these drugs bind to serum
proteins
 Metabolized by the liver
 Excreted by the liver or kidney
 Tolbutamide has the shortest duration
of action (6-12 hours), whereas the
second-generation agents last about 24
hours

18. A. Sulfonylureas
 Adverse Effects:
 Weight gain
 Hyperinsulinemia
 Hypoglycemia
 These drugs should be used with caution in patients with
hepatic or renal insufficiency, because delayed excretion of
the drug-resulting in its accumulation-may cause
hypoglycemia.
 Renal impairment is a particular problem in the case of
those agents that are metabolized to active
compounds, such as glyburide.
 Glyburide has minimal transfer across the placenta and
may be a reasonably safe alternative to insulin therapy
for diabetes in pregnancy.

19. B. Meglitinide analogs
 This class of agents includes
repaglinide and nateglinide. Although
they are not sulfonylureas, they have
common actions.

20. B. Meglitinide analogs
 Mechanism of action:
 Their action is dependent on functioning pancreatic β
cells.
 They bind to a distinct site on the sulfonylurea receptor
of ATP-sensitive potassium channels, thereby
initiating a series of reactions culminating in the release
of insulin.
 However, in contrast to the sulfonylureas, the
meglitinides have a rapid onset and a short duration
of action.
 They are are categorized as postprandial glucose
regulators.
 Meglitinides should not be used in combination with
sulfonylureas due to overlapping mechanisms of action.

21. B. Meglitinide analogs
 Pharmacokinetics:
 These drugs are well absorbed orally
after being taken 1 to 30 minutes before
meals.
 Both meglitinides are metabolized to
inactive products by CYP3A4 in the
liver.
 Excreted through the bile.

22. B. Meglitinide analogs
 Adverse Effects:
 Incidence of hypoglycemia is lower than that
of the sulfonylureas.
 Repaglinide has been reported to cause
severe hypoglycemia in patients who are
also taking the lipid-lowering drug
gemfibrozil.
 Weight gain is less of a problem with the
meglitinides than with the sulfonylureas.
 Must be used with caution in patients with
hepatic impairment.

23. 2) Insulin sensitizers
 Two classes of oral agents-the
biguanides and thiazolidinediones
improve insulin action. These agents
lower blood sugar by improving target-
cell response to insulin without
increasing pancreatic insulin secretion.
 They address the core problem in Type
II diabetes—insulin resistance.

24. A. Biguanides
 Metformin (glucophage), the only
currently available biguanide
 it increases glucose uptake and utilization
by target tissues, thereby decreasing
insulin resistance.
 Requires insulin for its action, but it does
not promote insulin secretion.
 Hyperinsulinemia is not a problem. Thus,
the risk of hypoglycemia is far less than
that with sulfonylureas

25. A. Biguanides
 Mechanism of action:
 reduction of hepatic glucose output, largely
by inhibiting hepatic gluconeogenesis.
 Slowing intestinal absorption of sugars
 Improves peripheral glucose uptake and
utilization.
 Metformin may be used alone or in
combination with one of the other
agents, as well as with insulin.
 Hypoglycemia has occurred when
metformin was taken in combination.

26. A. Biguanides
 Pharmacokinetics:
 Metformin is well absorbed orally, is not
bound to serum proteins
 It is not metabolized
 Excretion is via the urine.

27. A. Biguanides
 Adverse effects:
 These are largely gastrointestinal.
 Contraindicated in diabetics with renal and/or
hepatic disease, acute myocardial
infarction, severe infection, or diabetic
ketoacidosis.
 It should be used with caution in patients
greater than 80 years of age or in those with a
history of congestive heart failure or alcohol
abuse.
 Long-term use may interfere with vitamin B12
absorption.

28. B. Thiazolidinediones
 Another group of agents that are insulin
sensitizers are the thiazolidinediones (TZDs)
or, more familiarly the glitazones.
 Although insulin is required for their
action, these drugs do not promote its release
from the pancreatic β cells;
thus, hyperinsulinemia does not result.
 Troglitazone was the first of these to be
approved for the treatment of Type 2
diabetic, but was withdrawn after a number of
deaths due to hepatotoxicity were reported.
Presently, two members of this class are
available, pioglitazone and rosiglitazone.

29. B. Thiazolidinediones
 Mechanism of action:
 Exact mechanism by which the TZDs lower
insulin resistance remains to be elucidated
 They are known to target the peroxisome
proliferator-activated receptor-γ (PPARγ)-α
nuclear hormone receptor. Ligands for
PPARγ regulate adipocyte production and
secretion of fatty acids as well as glucose
metabolism, resulting in increased insulin
sensitivity in adipose tissue, liver, and
skeletal muscle.

30. B. Thiazolidinediones
 Pharmacokinetics:
 Both pioglitazone and rosiglitazone are absorbed
very well after oral administration and are extensively
bound to serum albumin.
 Both undergo extensive metabolism by different
cytochrome P450 isozymes.
 Pioglitazone:
 Renal elimination is negligible, with the majority of
the active drug and metabolites excreted in the bile
and eliminated in the feces.
 Rosiglitazone:
 The metabolites are primarily excreted in the urine.

31. B. Thiazolidinediones
 Adverse Effects:
 Very few cases of liver toxicity have been
reported with rosiglitazone or pioglitazone.
 Weight increase can occur, possibly through the
ability of TZDs to increase subcutaneous fat or
due to fluid retention.
 Glitazones have been associated with
osteopenia and increased fracture risk.
 Other adverse effects include headache and
anemia.

32. 3) α-glucosidase inhibitors
 Alpha-glucosidase inhibitors are oral anti-
diabetic drugs used for diabetes mellitus
type 2 that work by preventing the
digestion of carbohydrates (such as
starch and table sugar). Carbohydrates are
normally converted into simple sugars
(monosaccharides), which can be
absorbed through the intestine.
Hence, alpha-glucosidase inhibitors reduce
the impact of carbohydrates on blood
sugar.

33. α-glucosidase inhibitors
 Acarbose and miglitol are orally active
drugs used for the treatment of patients
with Type 2 diabetes.

34. α-glucosidase inhibitors
 Mechanism of action:
 These drugs are taken at the beginning of meals. They
act by delaying the digestion of carbohydrates, thereby
resulting in lower postprandial glucose levels. Both drugs
exert their effects by reversibly inhibiting membrane-
bound α-glucosidase in the intestinal brush border. This
enzyme is responsible for the hydrolysis of
oligosaccharides to glucose and other sugars.
Consequently, the postprandial rise of blood glucose is
blunted. Unlike the other oral hypoglycemic agents, these
drugs do not stimulate insulin release, nor do they
increase insulin action in target tissues. Thus, as
monotherapy, they do not cause hypoglycemia.
However, when used in combination with the
sulfonylureas or with insulin, hypoglycemia may develop.

35. α-glucosidase inhibitors
 Pharmacokinetics:
 Acarbose is poorly absorbed. It is
metabolized primarily by intestinal
bacteria, and some of the metabolites
are absorbed and excreted into the
urine. On the other hand, miglitol is very
well absorbed but has no systemic
effects. It is excreted unchanged by the
kidney.

36. α-glucosidase inhibitors
 Adverse effects:
 The major side effects are
flatulence, diarrhea, and abdominal
cramping. Patients with inflammatory
bowel disease, colonic ulceration, or
intestinal obstruction should not use
these drugs.

37. 4) Dipeptidyl peptidase-4
inhibitor
 DPP-4 inhibitors or gliptins, are a class of oral
hypoglycemics that block DPP-4. They can be used
to treat diabetes mellitus type 2.
 The first agent of the class - sitagliptin - was
approved by the FDA in 2006.
 Glucagon increases blood glucose levels, and DPP-
4 inhibitors reduce glucagon and blood glucose
levels. The mechanism of DPP-4 inhibitors is to
increase incretin levels (GLP-1 and GIP), which
inhibit glucagon release, which in turn increases
insulin secretion, decreases gastric emptying, and
decreases blood glucose levels.

38. Dipeptidyl peptidase-4
inhibitor
 Sitagliptin is an orally active dipeptidyl
peptidase-IV (DPP-IV) inhibitor used for
the treatment of patients with Type 2
diabetes. Other agents in this category
are currently in development.

39. Sitagliptin
 Mechanism of action:
 Sitagliptin inhibits the enzyme DPP-
IV, which is responsible for the inactivation
of incretin hormones, such as glucagon-like
peptide-1 (GLP-1). Prolonging the activity
of incretin hormones results in increased
insulin release in response to meals and a
reduction in inappropriate secretion of
glucagon. Sitagliptin may be used as
monotherapy or in combination with a
sulfonylurea, metformin or a glitazone.

40. Sitagliptin
 Pharmacokinetics:
 Sitagliptin is well absorbed after oral
administration. Food does not affect the
extent of absorption. The majority of
sitagliptin is excreted unchanged in the
urine. Dosage adjustments are
recommended for patients with renal
dysfunction.

41. Sitagliptin
 Adverse Effects:
 In general, sitagliptin is well
tolerated, with the most common
adverse effects being nasopharyngitis
and headache. Rates of hypoglycemia
are comparable to those with placebo
when sitagliptin is used as monotherapy
or in combination with metformin or
pioglitazone.