BENGAL SCHOOL OF TECHNOLOGY

SUGANDHA, DELHI ROAD, CHINSURAH,

HOOGHLY, WEST BENGAL-712102.

REPORT WRITING

ON

TITLE OF THE TOPIC: ORAL HYPOGLYCEMIC DRUGS

PATHOPHYSIOLOGICAL BASIS OF THEIR MECHANISM OF

ACTION

SUBMITTED BY:

NAME: Debkantha Gope

COURSE: M.pharm YEAR/SEMESTER: 1st Year 2st Semester

ROLL NO: 19320222008 REGISTRATION NO: : 221932310020 OF

2022-23 SUBJECT: ADVANCE PHARMACOLOGY II

SUBJECTCODE: MPT2081

ACADEMIC SESSION: 2022-23

DATE OF SUBMISSION:8.3.23
Introduction
Diabetes mellitus is a chronic metabolic disorder characterised by hyperglycaemia and altered
metabolism of carbohydrates, lipids and proteins. It is a common condition affecting 1-2% of
population with a strong hereditary tendency.

Diabetes mellitus (DM) was earlier grouped into two types but most researchers now classify
them into four types.

Type I previously called insulin-dependent diabetes mellitus (IDDM) is an autoimmune

disorder where antibodies destroy the ß cells of the islets of Langerhans leading to absolute
insulin deficiency. It usually occurs in the young children and adolescents (hence called
juvenile onset diabetes mellitus). The incidence of this type of DM is fortunately low.

Type II was earlier called non-insulin- dependent diabetes mellitus (NIDDM). Most patients
are obese. There is both reduced sensitivity of tissues to insulin and impaired regulation of
insulin secretion.

Type III or secondary diabetes is due to causes like pancreatectomy, drugs and nonpancreatic
diseases.

Type IV is gestational diabetes which manifests around 20-24 weeks of pregnancy during
which rising placental hormones are responsible for insulin resistance.

Prolonged exposure of tissues to hyper- glycaemia results in various complications including

premature atherosclerosis, retino- pathy, nephropathy and gangrene of the limbs. It is thought
to be due to reduced blood supply to these structures-because of thickening of the capillary
walls. Accumulation of glycosylated products in the vessel walls may be responsible for the
thickening. Moreover, intracellular glucose is converted to sorbitol by the enzyme aldose
reductase. This sorbitol exerts osmotic effect resulting in - tissue damage particularly in the
retina and peripheral nerves. Hence, it is necessary to maintain normal blood glucose levels
though diabetes mellitus as such does not cause significant troublesome symptoms. It helps to
prevent or delay the onset of complications of diabetes. The haemoglobin becomes glycosy
lated and forms HBA1c and its concentration indicates the severity and duration of
thehyperglycaemic state. Administration of glucose by oral route stimulates insulin secretion
better than by IV route because orally given glucose evokes the release of gastrointestinal
hormones and also stimulates vagal activity.
ORAL ANTIDIABETIC DRUGS

The main disadvantage of insulin Classification

is the need for injection. The 1. Insulin secretagogues
advent of oral antidiabetics came A. Sulfonylureas (K ATPchannel blockers)
as a boon to millions of NIDDM I generation
patients with early and mild Tolbutamide
diabetes. Sulfonylureas were the
II generation
first oral antidiabetics (OAD) to
Glibenclamide, glipizide gliclazide, glimepiride
be made available in 1950s. We
B. Meglitinides
now have several groups of oral
Repaglinide, nateglinide
antidiabetics. Many newer drugs
C. GLP-1 analogs (subcutaneous)
are also being introduced.
Exenatide, Liraglutide, albiglutide dulaglutide
Though all orally active
D. DPP-4 inhibitors
antidiabetic drugs are often
Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin,
called oral hypoglycaemics, all
alogliptin
of them do not cause
2. Biguanide :Metformin
hypoglycaemia. Therefore, 'oral
3. Thiazolidinediones:Troglitazone, pioglitazone
antidiabetic drugs' is a more
4. Alpha glucosidase inhibitors:Acarbose, miglitol,
appropriate terminology for voglibose
them . 5. Amylin analog :Pramlintide (subcutaneous)
6. SGLT-2 inhibitors:Dapagliflozin, remogliflozin

1. INSULIN SECRETAGOGUES

A. Sulfonylureas:

A sulfonamide derivative used for its anti- bacterial effects in typhoid patients produced
hypoglycaemia. This observation led to the development of sulfonylureas. These drugs enhance
insulin release-insulin secreto gogues.

Mechanism of Action

Sulfonylureas reduce the blood glucose level by:

1. Stimulating the release of insulin from the pancreatic ẞ cells.

2. Increasing the sensitivity of peripheral tissues to insulin.
3. Increasing the number of insulin
receptors.
4. Suppressing hepatic gluconeogenesis.
5. Prolonged administration of
sulfonylureas in Type II DM patients
reduces the glucagon levels probably due to
negative feedback from raised insulin
levels.
Sulfonylureas bind to the sulfonylurea
receptors (SUR) which are nothing but the
ATP sensitive K+ channels (KATP) present
on the cell membrane of the pancreatic beta
cells. Sulfonylureas bind to the SUR1
subunit on the KATP and bring about closure
of these K+ channels (prevent K+ efflux)
causing depolarisation of the membrane. This inturn opens the voltage-dependent calcium
channels, thereby leading to calcium influx. This calcium brings about release of insulin that
is stored in the granules of the beta cells.
Pharmacokinetics
Sulfonylureas are well-absorbed orally, extensively bound to plasma proteins (>90%),
metabolised in the liver and some are excreted in the urine. Hence they should be avoided in
patients with renal or liver dysfunction.
First Generation Agents

First generation agents include tolbutamide and chlorpropamide but after the synthesis of
second generation agents which have certain advantages, first generation agents are not
preferred.

Tolbutamide is short acting as it is rapidly metabolised in the liver, t½ 4-5 hr and is therefore,
associated with lesser risk of hypoglycaemia but is rarely used now.

Dose: 500 mg BD-TDS. RASTINON 500 mg tab

Second Generation Agents

Second generation agents are more potent, have fewer side effects and drug interactions as
compared to first generation agents. They can cause hypoglycaemia because of which they
should be used cautiously particularly in the elderly. Utmost caution is also required in patients
with cardiovascular diseases. They are all contraindicated in renal and hepatic impairment.

Glibenclamide (gliburide) is a commonly used sulfonylurea. It is longer acting-can be given

once a day It can cause hypoglycaemia and rarely, flushing after alcohol consumption. It may
be started with a low dose of 2.5 mg in the morning and increased to 5-10 mg once daily.
Different formulations are available for controlled release and extended release.

Dose: 2.5-5 mg OD. DAONIL, EUGLUCON 2.5,5 mg tab

Glipizide has a short t½; food delays its absorption, hence should be taken 30 min before
breakfast. It is less likely to cause hypoglycaemia because of its short t½. Started with 5 mg/day
the dose may be increased to 15 mg/day. It is metabolized in the liver; contraindicated in renal
and hepatic dys- function.

Dose: 5-15 mg OD-BD. GLYNASE, GLIBETIC. D-GLIP 5 mg tab

Gliclazide can be used in diabetes with renal dysfunction. It is found to delay the onset of
retinopathy in diabetics.

Dose: 40-240 mg OD. D-GLIC, GLIX

Glimepiride is longer acting and can be given as a single morning dose-started with 1 mg, the
dose may be increased to 4 mg daily but a maximum of 8 mg has also been given.

Dose:1-4 mg OD. GLYPRIDE, GLIMZ, AMARYL-1, 2 mg tab.

B. Meglitinides

Repaglinide and nateglinide are insulin secretogogues and like sulphonylureas, meglitinides
enhance the release of insulin by blocking the ATP-dependent K+ channels (sulfonylurea
receptors) in the pancreatic  cells.

Repaglinide is rapidly absorbed, has a rapid onset of action, peak effect in 1 hr and a t½ of 1
hour. It is metabolised in the liver by microsomal enzymes. Gastrointestinal disturbances are
common with repaglinide. Both drugs can cause hypersensitivity reactions and
hypoglycaemia—but the incidence is relatively lower with nateglinide. Dose: 0.5–4 mg. TDS-
QID 30 min before food. RAPLEN 0.5, 1, 2 mg tab. EUREPA 0.5, 2, 4 mg.

Nateglinide is a D-phenylalanine derivative. It is rapidly absorbed with peak effect in 60 min

and a duration of action of 3–4 hr. It is metabolised by microsomal enzymes in the liver. It can
be given even in patients with renal dysfunction and hypoglycaemia is least with it. Nausea,
dizziness, joints pain can occur. Nateglinide is administered just before meals in the dose 60–
120 mg two-three times a day.

GLINATE 60, 120 mg tab.

Uses: Meglitinides can be used in type II diabetes mellitus either alone or with biguanides.
They can also be used as alternatives to sulfonylureas—a dose before each major meal.May be
useful in patients allergic to sulfonylureas, they do not have sulfur in their structure.
Meglitinides enhance insulin release in presence of glucose—therefore, the incidence of
hypoglycaemia is least with their use.In patients who have significant postprandial
hyperglycaemia (fast action and less hypoglycaemia) but the basal insulin secretion is not
altered by meglitinides.

C.Glucagon Like Peptide-1 (GLP-1) Analogs/Incretin Analogs

Glucagon like peptides (also called incretins) are released from the gut following oral glucose
administration and GLP-1 inturn enhances insulin secretion. However, GLP-1 cannot be used
therapeutically due to its rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4).
Exenatide is a synthetic GLP-1 analog which acts on the GLP-1 receptors. It enhances the
glucose-1-mediated insulin secretion, suppresses glucagon release, delays gastric emptying and
reduces appetite. Studies have shown it to increase the beta cell mass and reduce HbA1c levels

Exenatide is given SC 30–60 min before food in the dose of 5–10 g twice daily in type II
DM. Long-acting preparations are available for once weekly injection.

Liraglutide a longer-acting analog, is given once daily. Started with a low dose of 0.6 mg and
doubled after a week, liraglutide may be used as an add-on drug. Albiglutide is GLP-1 fused
to human albumin and dulaglutide is another GLP-1 analog and both have a longer t½ for once
weekly injection. Semaglutide and lixisenatide are other GLP-1 analogs. GLP-1 analogs can
cause nausea, vomiting (self-limiting), diarrhoea and weight loss. One adverse effect of
concern though rare is the haemorrhagic pancreatitis which can be fatal. Should be avoided in
patients with renal impairment as it can be worsened.

D. Dipeptidyl Peptidase 4 (DPP-4) Inhibitors

Dipeptidyl peptidase is an enzyme which degrades incretins. Sitagliptin is a DPP-4 inhibitor

and thereby enhances incretin levels. It enhances insulin secretion and decreases glucagon
levels. Sitagliptin is orally effective (dose: 100 mg OD) and may be used alone or along with
other antidiabetic drugs. Adverse effects include headache, increased susceptibility to upper
respiratory infections and allergic reactions. Saxagliptin (2.5–5 mg OD) and linagliptin (5 mg
OD) are longer acting DPP-4 inhibitors.

Biguanides:

Biguanides lower blood glucose level by insulin-like effects on the tissues

Mechanism of action is not clear but could act as follows:

• Suppress hepatic gluconeogenesis by activation of an enzyme (AMP-activated protein

kinase or AMPK)—this is the principal effect.
• Inhibit glucose absorption from the intestines.
• Stimulate peripheral uptake of glucose in tissues in the presence of insulin.
• Stimulate glycolysis in the tissues.
• Reduce plasma glucagon levels.
• Decrease appetit

Pharmacokinetics: Metformin is wellabsorbed from the gut, has a duration of action of 6–8
hr, is not metabolised but excreted unchanged in the urine.

Dose: 500 mg OD-BD. GLYCIPHAGE, DIAFORMIN 500 mg tab.

Uses: Other than in diabetes, metformin is tried in a variety of conditions (off-label uses) like
obesity, hirsutism and infertility in PCOD patients. Metformin reduces androgen levels and
increases chances of ovulation.

Thiazolidinediones (TZDs):

Thiazolidinediones (TZDs) or glitazones are agonists

at the PPAR- receptors (gamma subtype of
peroxisome proliferator-activated receptors). These
are nuclear receptors present mostly in adipose tissue
and also in muscle, liver and other tissues. TZDs
activate the PPAR- receptors and modulate the
expression of insulin-sensitive genes, i.e. they induce the synthesis of genes which enhance
insulin action. TZDs increase insulin-mediated glucose transport into muscle and adipose
tissue. They also promote glucose utilization.
Pioglitazone is an agonist at PPAR- and PPAR- receptors. It lowers plasma triglyceride
levels and raises HDL cholesterol—could be due to its action on PPAR- receptors. It is
absorbed over 2 hr after oral administration and absorption is further delayed by food. It is
metabolised by hepatic microsomal enzymes and the metabolites are also active.

Dose: 15–45 mg once daily. PIONORM, PIOREST 15, 30 mg tab..

Uses: TZDs are used as adjuvants to sulfonyl ureas/biguanides/insulin in Type II diabetes

mellitus. Though they can also be used as monotherapy in mild cases of type II diabetes, further
studies are needed to prove their long term benefits. However, rosiglitazone is now withdrawn
by many countries including India due to increased risk of cardiac problems.

4. -GLUCOSIDASE INHIBITORS:

Acarbose, an oligosaccharide, voglibose and miglitol competitively inhibit the enzymes -

glucosidases present in the intestinal brush border and thereby prevent the absorption and delay
the digestion of carbohydrates. Monosaccharides like glucose and fructose are absorbed from
the intestines while disaccharides and oligosaccharides are broken down into monosaccharides
before being absorbed. This ‘breaking down’ is done by the enzymes -glucosidases (e.g.
sucrase, maltase, glycoamylase) and -amylase present in the intestinal wall. Alpha
glucosidase inhibitors inhibit the hydrolysis of disaccharides and decrease carbohydrate
absorption.

• Alpha-glucosidase inhibitors reduce the glucose

absorption from upper intestines, thereby reducing
postprandial blood glucose levels.
• Miglitol also inhibits isomaltase and beta
glucosidases
• Alpha-glucosidase inhibitors do not cause
hypoglycaemia. When used with other
antidiabetics—if hypoglycaemia occurs, glucose
should be given and not sucrose because sucrase is
also inhibited.
• They may cause gastrointestinal disturbances including abdominal distention and pain,
flatulence and diarrhoea because of undigested carbohydrates reaching the colon and
then getting fermented to fatty acids and in the process gas is released.
 • They can be used alone in patients with predominantly postprandial hyperglycaemia or
in combination with other oral anti diabetics or insulin.
• They are contraindicated in patients with inflammatory bowel disease and in renal
failure.

AMYLIN ANALOGS

Amylin is a polypeptide produced by the pancreatic beta cells. It inhibits glucagon secretion,
delays gastric emptying and suppresses appetite.
Pramlintide, a synthetic amylin analog,
modulates postprandial glucose levels like
amylin. Pramlintide has beneficial effects on
HbA1C levels. Given subcutaneously it is
rapidly absorbed and has a duration of action
around 2–3 hr. Started with a low dose of 15 g
just before meals; dose may be increased to 60– 120 g but the concurrent dose of insulin or
other antidiabetics may be reduced to avoid hypoglycaemia. It should not be mixed with other
drugs in the syringe. It can cause nausea, vomiting and anorexia. Pramlintide can be used in
both type I and type II DM.

6. SGLT-2 INHIBITORS :

A large amount of glucose is reabsorbed from the proximal tubule by sodium-glucose

cotransporter-2 (SGLT-2). Inhibition of SGLT-2 reduces the absorption of glucose and sodium
and causes glycosuria. Dapagliflozin, remogliflozin, canagliflozin, empagliflozin and
sergliflozin are SGLT-2 inhibitors found to be useful in patients with diabetes. They are
particularly useful when the patients also have hypertension. They do not cause hypoglycaemia
but could cause hypotension and increase the risk of urinary infection due to the presence of
glucose in the urine. They should be avoided in presence of low GFR.

TREATMENT OF DIABETES MELLITUS:

The aim of treatment is to keep the blood sugar within normal limits and prevent complications
of diabetes. For patients with type I, insulin is the only treatment as there is insulin deficiency
due to destruction of pancreatic  cells. Sulfonylureas need functional  cells for their action
and, therefore, are not useful in them. Mild type II may be controlled by diet, exercise and
weight reduction. When not controlled, an oral hypoglycaemic should be given. Most patients
may require insulin sometime later in life.

Status of Oral Antidiabetics

Uncomplicated type 2 diabetes mellitus patients not controlled by diet and exercise are given
oral anti-diabetics, patients with recent onset diabetes, age above 40 years at the onset of
diabetes, obese with fasting blood sugar <200 mg/dl are candidates for OAD. They are
convenient to use. Sulfonylureas are preferred, but when not adequately controlled, metformin
can be added. Metformin has the advantages of

• Reducing appetite
• Being euglycaemic
• Suitable for combination with other drugs.

Therefore, can be considered first-line drug in mild diabetics. If uncontrolled or if metformin

not tolerated, sulfonylurea may be added. In conditions like stress, surgery or complications of
diabetes, insulin should be used. TZDs, meglitinides, alpha-glucosidase inhibitors or SGLT-2
inhibitors may be used as monotherapy in mild diabetes patients or as adjuvants along with
sulfonylureas or biguanides.

Mechanism of action and adverse effects of all oral antidiabetics.

REFERENCE:
• Ungar G, Freedman L, Shapiro SL. Pharmacological studies of a new oral
hypoglycemic drug. Proceedings of the Society for Experimental Biology and
Medicine. 1957 May;95(1):190-2.
• Rowden AK, Fasano CJ. Emergency management of oral hypoglycemic drug toxicity.
Emergency medicine clinics of North America. 2007 May 1;25(2):347-56.
• Greene MF. Oral hypoglycemic drugs for gestational diabetes. New England Journal
of Medicine. 2000 Oct 19;343(16):1178-9.
• Ferner RE. Oral hypoglycemic agents. Medical Clinics of North America. 1988 Nov
1;72(6):1323-35.