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Oral anti-diabetic drugs
Supervision :Dr. Osama Othman
By:Fatima Ehsan Abduluahab
Hevi ahmed mohammed
Alaa khilil Ibrahem
• 1.what is DM?
• 2.types of oral anti diabetic drug
• 3.take home messege
• Diabetes mellitus is a clinical syndrome
characterized by an increase in plasma blood
• Diabetes has many causes but is most
commonly due to type 1 or type 2 diabetes.
• Type 1 diabetes is caused by autoimmune
destruction of insulin-producing cells (β cells)
in the pancreas, resulting in absolute insulin
• Hyperglycemia results in both acute and long-term
• Acutely, high glucose and lack of insulin can result
in marked symptoms, metabolic decompensation
• Chronic hyperglycemia is responsible for diabetes-
speciﬁc ‘microvascular’ complications affecting
the eyes (retinopathy), kidneys (nephropathy) and
• Fasting plasma glucose ≥ 7.0 mmol/L
• Glucose 2 hours after an oral glucose
challenge ≥ 11.1 mmol/L (200 mg/dL)
Diagnostic criteria for diabetes:-
Drugs to reduce hyperglycemia
• For many years, there were only a few choices of
drugs available for type 2 diabetes – the
biguanide metformin, the sulphonylureas and
insulin. Insulin is the only treatment for type 1
• Since the late 1990s, however, several new classes
of agents have been approved for use in type 2
diabetes, with more in development.
• Newer drugs include thiazolidinediones,
dipeptidyl peptidase 4 (DPP-4) inhibitors,
glucagon-like peptide 1 (GLP-1) receptor agonists,
and sodium and glucose transporter 2 (SGLT2)
• The older drugs are cheaper and have
established beneﬁts for reducing
• Use of the newer drugs is not
supported by evidence for reduction
in microvascular-lar disease (because
the trials have not yet
beencompleted) and they are much
more expensive, so are often
reserved for later therapy after failure
of metformin and sulphonylureas.
Sites of action of the most widely used oral antihyperglycemic
Management of hyperglycemia
in types 2 diabetes
• It is the first antidiabetic drug
that been discoveered at 1942
• Sulphonylureas used in
Patients with T2DM ,obese,not
respond to dietary measures
and exercise alone
Mechanism of action
• Sulphonylureas are insulin
secretagogeus that act through
specific recepter which is
linked to a k+ channel on the
surface of pancreatic Beta cells
k+ transport trigers insulin
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• First generation
• Tolbutamide: mildest one has short
duration of action usually adminstered
8 -12 hourly it useful in elderly
• Chlorpropamide: half life about 36hr
taken once daily rarely used
Gliclazide few side effects
Glibenclamide avoid in elderly
Glimepiride and modified release
form of gliclazide taken once daily
with no risk of hypoglycemia
• Sulphonylureas absorbed by intestine
after oral use.
• Hyperglycemia reduse sulphonylureas
absorption as it impaire intestinal motility
• For this reason sulphonylureas taken 30
min. before meals and dose increase every
2 wk if there is uncontrolled BS
• But the first dose is low
Side Effects of Sulphonylureas
• Signs of low blood sugar, such as sweating,
dizziness, confusion, or nervousness
• Weight gain
• Skin reactions
• Upset stomach
• Dark-colored urine
• Type1 DM
• Diabetic ketoacidosis
• Liver or kidney diseases
• Pregnancy and breast feeding
• Salicylates, phenylbutazone and antifungal
potentiate hypoglycemic effect of
sulphonylureas by displacing them from
plasma protein binding sites.
• Metformin is the only biguanide available, and it
is now widely used as first-line therapy for type 2
diabetes, irrespective of body weight.
Metformin is also used increasingly as an adjunct
to insulin therapy in obese patients with type 1
• However, it is less well tolerated than
sulphonylureas because of a higher incidence of
side-effects, particularly gastrointestinal
Mechanism of action :
• The mechanism of action of metformin has not been precisely
defined. It has no hypoglycaemic effect in non-diabetic
individuals, but in diabetes, insulin sensitivity and peripheral
glucose uptake are increased, possibly through inhibition of
mitochondrial respiration and activation of AMP-regulated
kinase (AMPK) in muscle. There is some evidence that it also
impairs glucose absorption by the gut and inhibits hepatic
• Although secretion of some endogenous insulin is mandatory for
its glucose-lowering action, it does not increase insulin secretion
and seldom causes hypoglycaemia.
• Administration of metformin is not associated with a rise in body
weight and it may be beneficial for the overweight or obese
• In addition, as the glucose lowering effect of metformin is
synergistic with that of sulphonylure as the two can be combined
when either alone has proved inadequate. It can also be given in
• combination with most other anti-diabetic medications.
• can also be used in polcystic ovarian syndrome.
• Metformin is given with food, usually starting
with 500 mg 12-hourly, gradually increased as
required to a maximum of 1 g 8-hourly.
• Excretion of the drug is through the kidneys
• Its use is contraindicated in patients with
impaired renal or hepatic function and in
those who drink alcohol in excess in whom the
risk of lactic acidosis is significantly increased.
• It should be discontinued, at least
temporarily, if any other serious medical
condition develops, especially one
causing severe shock or hypoxaemia. In
such circumstances,treatment with
insulin should be substituted.
• history of congestive heart failure
• acute myocardial infarction
• use of IV contrast media: This can affect
kidneys function and put patient at risk for
• major surgical procedures
• people with diabetic ketoacidosis
Metformin during pregnancy :
• Metformin is safe and effective treatment option for
women with type 2 diabetes in pregnancy with or without
add-on insulin who require pharmacological treatment for
glycemic control .
• Metformin has advantages over insulin such as less
maternal weight gain, no maternal hypoglycemia, being
cheap, being oral therapy, and requiring no vigorous
monitoring and frequent hospital admissions with good
compliance and acceptability.
• Metformin treatment when compared with insulin
treatment showed less maternal hypertensive
complications and less risk of neonatal hypoglycemia with
few neonatal intensive care admissions.
• Metformin treatment is suitable for non
obese type 2 diabetes patients in
pregnancy without complications.
• Metformin treatment in type 2 diabetes in
pregnancy required lower dose of add-on
insulin, at a later gestational age for
maintaining glycemic control when
compared with insulin treatment.
Serious side effects
• lactic acidosis. Symptoms include:
• unusual muscle pain
• trouble breathing
• unusual sleepiness
• Abdominal pain , nausea, or vomiting
• dizziness or lightheadedness
• slow or irregular heart rate
• Metformin does not usually cause low blood sugar (hypoglycemia). Low blood
sugar may occur if this drug is prescribed with other diabetes medications.
low blood sugar. Symptoms include:
• shaking or feeling jittery
• fast heart rate
• These act, like the sulfonylureas, but they
don’t have sulfonylurea moiety.
• These include repaglinide and nateglinide
• MOA : Same as sulfonylureas .
• Short duration of action and a low risk of
• Given orally, rapidly metabolized by liver
enzymes and excreated in the bile .
Thiazolidinediones (TZDs) reduce insulin resistance, act as insulin
sensitizers; thus, they require the presence of insulin to work. They must be
taken for 12-16 weeks to achieve maximal effect.
These agents are used as monotherapy or in combination with
sulfonylurea, metformin, meglitinide, DPP-4 inhibitors, GLP-1 receptor
agonists, or insulin. They are the only antidiabetic agents that have been
shown to slow the progression of diabetes (particularly in early disease).
most likely through activation of PPAR-γ, a nuclear receptor that regulates
the transcription of several insulin-responsive genes that regulate
carbohydrate and lipid metabolism.
The biologic effect of TZDs is principally mediated by stimulation
of peripheral glucose metabolism.
PPAR-γ activation also attenuates lipolysis and stimulates
peripheral adipocyte differentiation, thereby redistributing fat
stores from the liver and muscle to subcutaneous depots.
This effect may be largely responsible for the “insulin-sensitizing”
effects of the TZDs.
There is a concomitant modulation in the circulating levels of
adipocytokines, particularly in adiponectin, which is increased
two- to three-fold after TZDherapy.
In 1997, troglitazone was the first TZD approved for
use in the United States; although effective, the
drug was withdrawn from the market 2 years later
because of concerns about idiosyncratic
Rosiglitazone and pioglitazone were later approved;
these agents have no significant hepatotoxicity.
Both pioglitazone and rosiglitazone are absorbed very
well after oral adminstration and are extensively bound
to serum albumin
both undergo extensive metabolism bt different
cytochrome p450 isozymes
the therapeutic range for pioglitazone is
15–45 mg/d in a single daily dose, the
majority of the active drug and metabolite
are excreated in the bile and eliminated in
and for rosiglitazone the total daily dose is
2–8 mg/d administered either once daily or
twice daily in divided doses.the metabolite
are excreated in the urine.
Adverse effects: A few cases of liver toxicity have been reported
with these drugs, and periodic monitoring of liver function is
Weight gain can occur because TZDs may increase
subcutaneous fat and cause fluid retention. [Note: Fluid retention
can worsen heart failure. These drugs should be avoided in
patients with severe heart failure.] TZDs have been associated
with osteopenia and increased fracture risk. Pioglitazone may also
increase the risk of bladder cancer. Several meta-analyses identified
a potential increased risk of myocardial infarction and death
from cardiovascular causes with rosiglitazone. As a result, use of
rosiglitazone was limited to patients enrolled in a special restricted
access program. After a further review of safety data, the restrictions
on rosiglitazone use were subsequently lifted.
Mechanism of action :
• Alpha-glucosidase inhibitors work on two different enzymes in
the small intestine:
– Intestinal enzymes (acarbose and miglitol)
• Intestinal cells contain an enzyme called alpha-glucosidase that
metabolizes carbohydrates so that they can be absorbed into the
• Alpha-glucosidase inhibitors block alpha-glucosidase thereby
inhibiting the metabolism of carbohydrates and slowing their
absorption into the bloodstream
– Pancreatic enzymes (acarbose only)
• When a person consumes food, the pancreas secretes enzymes that
help digest the food so that it can be absorbed into the bloodstream
• Alpha-amylase is a pancreatic enzyme that metabolizes
• Acarbose blocks alpha-amylase thereby inhibiting the metabolism of
carbohydrates and slowing their absorption into the bloodstream
• Acarbose and miglitol are available and are taken with
• Both lower post-prandial blood glucose and modestly
improve overall glycaemic control. They can be combined
with a sulphonylurea. they must be taken at the start of
main meals to have maximal effect. Their effects on blood
sugar levels following meals will depend on the amount of
complex carbohydrates in the meal.
• The main side-effects are flatulence,
abdominal bloating and diarrhoea.
• Patients with inflammatory bowel disease,
colonic ulceration, or intestinal obstruction
should not use these drugs.
• The drug is not recommended in pregnancy
Incretin-based therapies: Dipeptidyl peptidase-4 inhibitors
and GLP-1 analogues
DPP4 # inhibit the enzyme DPP-4, which is responsible for the
degredation of incretin hormones such as GLP-1.
The incretin effect is the augmentation of insulin secretion
seen when a glucose stimulus is given orally rather
than intravenously, and reflects the release of incretin
peptides from the gut .
The incretin hormones are primarily glucagon-like
peptide 1 (GLP-1) and gastric inhibitory
polypeptide (GIP),which act to potentiate insulin
These are rapidly broken down by the peptidase
DPP-4 (dipeptidyl peptidase 4).
The incretin effect is diminished in type 2 diabetes,
and this has stimulated the development of two
incretin-based therapeutic approaches.
The ‘gliptins’, or DPP-4 inhibitors, prevent
breakdown and therefore enhance
concentrations of endogenous GLP-1 and
GIP. The first DPP-4 inhibitor to market was
sitagliptin; others now available include
vildagliptin, saxagliptin and linagliptin.
These drugs are very well tolerated and are
The GLP-1 receptor agonists have a similar
structure to GLP-1 but have been modified
to resist breakdown by DPP-4. These agents
are not orally active and have to be given by
. Recently, GLP-1 receptor agonists and long-acting insulin
analogue have been combined, enabling co-
administration of insulin and GLP-1 receptor agonists
with one injection.
However, they have a key advantage over the DPP-4
inhibitors: because the GLP-1 activity achieved is
supra-physiological, it delays gastric emptying and, at
the level of the hypothalamus, decreases appetite.
Thus, injectable GLP-1 analogues lower blood glucose
and result in weight loss – an appealing therapy, as the
majority of patients with type 2 diabetes are obese.
•Currently available GLP-1 receptor agonists include exenatide
(twice daily), exenatide MR (once weekly) and liraglutide (once
• All the incretin-acting drugs have been reported to
be associated with an increased risk of
pancreatitis, although this risk is small: between 1
and 10 cases per 1000 patients treated.
• Unlike sulphonylureas, both incretin-based
therapies only promote insulin secretion when
there is a glucose ‘trigger’ for insulin secretion.
Thus, when the blood glucose is normal, the
insulin secretion is not augmented and so these
agents do not cause hypoglycaemia.
sodium and glucose transporter 2 (SGLT2)
The sodium and glucose transporter 2 (SGLT2) inhibitor,
dapagliﬂozin, was licensed for use in 2012. Glucose is ﬁltered
freely in the renal glomeruli and reabsorbed in the proximal
tubules. SGLT2 is involved in reabsorption of glucose.
• Inhibition results in approximately 25% of the
ﬁltered glucose not being reabsorbed, with
consequent glycosuria. Although this helps to
lower blood glucose and results in calorie loss and
subsequent weight loss, the glycosuria does result
in increased urinary tract and genital fungal
• Euglycaemic diabetic ketoacidosis (i.e. DKA not
associated with marked hyperglycaemia) has been
recognised as a rare complication of this class of