ANTI-DIABETIC DRUGS

Learning Objectives
 Explain the mechanisms by which oral anti-diabetic agents act and the
influence these mechanisms have on selection for therapy in individual
patients (e.g., obese)
 Explain the molecular mechanism of action of insulin
 Describe the relative roles of insulin and oral hypoglycemics in the treatment
of type I and type II diabetes mellitus
 Discuss the use of recombinant DNA insulin preparations that are employed
in certain patients
 List commonly used drugs with which sulfonylurea compounds are known to
interact and the postulated mechanisms for these interactions
 DIABETES

It is a chronic metabolic disorder characterized by hyperglycemia, glycosuria,

hyperlipidemia, negative nitrogen balance and sometimes ketonuria.
Blood glucose level-fasting: >7.0mmol/litre

 - P.P: >11.1mmol/litre
Both genetic and environmental factors contribute to its pathogenesis
(dysregulated glucose homeostasis)
Major sources of the morbidity are the chronic complications like retinopathy,
neuropathy, nephropathy, and cardiovascular disease
 TYPES OF DIABETES MELLITUS

Type-I diabetes mellitus Type-II diabetes mellitus

(Insulin dependent diabetes mellitus/ (Non-insulin dependent diabetes

Juvenile onset diabetes mellitus) mellitus/ maturity onset diabetes
mellitus)
- Absolute deficiency of insulin.
- accompanied both by insulin resistance
- Accounts for 5 to 10 people out of
and insulin deficiency
100 diagnosed cases of diabetes.
- Accounts for 90 to 95 out of 100
diagnosed cases of diabetes
 TYPES OF DIABETES MELLITUS

Gestational diabetes

can develop when a woman is pregnant

If the pancreas doesn’t make enough insulin during pregnancy,

a woman develops gestational diabetes.

obese women.
 SIGNS AND SYMPTOMS OF DIABETES MELLITUS

Polydipsia Loss of weight

Polyuria Slow healing wounds

Polyphagia Dry and itchy skin

Fatigue Blurry eyesight

MANAGEMENT OF DIABETES MELLITUS

The major components of the treatment of diabetes are:

A • Diet and Exercise

B • Oral hypoglycaemic therapy

C • Insulin Therapy
 DIET AND EXERCISE

Diet is a basic part of management in every case. Treatment

cannot be effective unless adequate attention is given to
ensuring appropriate nutrition.
Exercise promotes weight reduction and improves insulin
sensitivity, thus lowering blood glucose levels.
ORAL HYPOGLYCAEMIC THERAPY
Sulfonylureas- Glipizide
Biguanides- Metformin
Meglitinide- Repaglinide
Thiazolidinediones- Rosiglitazone
Alpha glucosidase inhibitors- Acarbose
Newer drugs:
DPP-IV inhibitors: Sitagliptin
SGLT-2 inhibitors: Gliflozin
 INSULIN THERAPY

Patients with type-I diabetes ,needs daily injections of

insulin to help their bodies to use glucose.
Some patients with type-II diabetes, may need to use
insulin injections if their diabetes cannot be
controlled by diet,exercise and oral hypoglycaemic
medications.
 FREDERICK BANTING AND HIS LAB PARTNER CHARLES
BEST
 THE FIRST INSULIN INJECTION

January 11, 1922.

Leonard Thompson,
14-year-old boy patient who weighed 64 lb .
Initial test failed causing only slight
reduction in blood glucose level
Second series of purified extract achieve
the desired result
Leonard lived for 13 years before dying of
pneumonia at 27
 WHAT IS INSULIN?

Insulin is a peptide hormone.

It regulates the carbohydrate and fat metabolism by

promoting the absorption of glucose from the blood
to skeletal muscles and fat tissues and stores it as
glycogen in the liver and muscles.
 Physiology of Pancreas
 Pancreas is primarily an exocrine gland,
secreting a variety of digestive enzymes like
proteases, maltase, lipase, and bicarbonate
 Endocrine pancreas is made up of islets of
Langerhans
 Alpha cells: Glucagon
 Beta cells: Insulin and Amylin
 Delta cells: Somatostatin & Gastrin
 Gamma cells (PP cells): Pancreatic
Polypeptide
 Epsilon Cells: Ghrelin
 Physiology of Insulin

 Structure : Insulin is a polypeptide

hormone with two chains A and B linked by
two disulfide bridges
 Contains 51 amino acids (chain-A having 21
AAs and B-chain have 30 AAs) with Mol wt.
5808
Regulation of Insulin
Secretion
 Insulin Secretion Process
 Hyperglycemia results in increased
intracellular ATP levels, which close the
ATP-dependent potassium channels

 Decreased outward potassium efflux

results in depolarization of the beta cell
and opening of voltage-gated calcium
channels

 That stimulates the more Ca2+ release

from SR

 The resulting increased intracellular

calcium triggers secretion of the hormone
by stimulating the CREB (cAMP Response
Element Binding protein)
 Mode of Action of Insulin
Insulin binds to Alpha subunits
Beta subunit – activation of
Tyrosine Kinase (TK) by
Phosphorylation
Activated TK – stimulate Insulin
Receptor Substrate (IRS-1&2)
IRS - Activate Ras and Mitogen
activated protein (MAP) kinases
Translocation of glucose
transporters to cell membrane
Glucose uptake into the cells &
synthesis of glycogen
Actions of Insulin
SOURCES OF INSULIN PREPARATIONS

Conventional insulin preparations:

Bovine insulin- antigenic, differs to human insulin by 3 amino
acid residue
Procine insulin- less immunogenic, differs by only 1 amino acid

Monocomponent insulins
Human insulins- recombinant DNA technology using [Link] or
yeast
 Sources of Insulin
 Human insulin produced by recombinant DNA
techniques
 Same anino acid sequence as endogenous insulin
 Least immunogenic and insulin resistance to human
insulin is less likely (common with old animal
insulins)
 Route of Administration- Subcutaneous injection is
the most common route
 Regular insulin is the only insulin preparation that can
be administered IV
 It is particularly useful (given by IV infusion) for the
management of diabetic ketoacidosis and other
Classification of Insulin Preparations
Insulin Preparations
 Ultra-rapid onset & very short acting Insulins
Lispro, Aspart and Glulisine
 Ultra rapid acting insulins are monomeric insulins
 Because of their rapid onset, lesser the risk of early
postprandial hyperglycemia
 Because of their short duration, lesser the risk of late
postprandial hypoglycemia
 They can be taken immediately (5 minutes) before the
meal. They do not require the “injection-to-meal
interval”.
 Overall they more closely mimic normal endogenous
prandial insulin secretion than regular insulin
Insulin Analogs

Ultra
Rapid
2

1, 2, & 3 Longer
Acting
 Advantages

This transposition allows lispro to dissociates more

rapidly into monomers and the advantages are:
1. Faster absorption (ultra rapid onset of action)
2. Suitable to inject just before the meal

So both chances of early postprandial hyperglycemia

and risk of late postprandial hypoglycemia are very less
with these kind of insulin
 Regular Insulin

 Regular insulin has rapid onset, and it is short acting

 Routinely given by subcutaneous route
 In emergencies like diabetic ketoacidosis, this can be
given intravenously. In such situations this is the
insulin preparation of choice
 The SC regular insulin is given 30-45 minutes before
the meal.
 Therefore, patient has to wait up to an hour to eat
the food (This is a major drawback).
 Why wait longer to eat the meal?
 The regular insulin exists in the hexamers
form
 Are too large to be transported across
membranes
 The hexamers break down into dimers and
finally monomers which acts on target
tissues
 Therefore, shows a delayed onset and
prolongs the time to have a peak action
 If regular insulin is administered at
mealtime, the blood glucose rises faster
with resultant early postprandial
hyperglycemia and an increased risk of
late postprandial hypoglycemia
 Therefore, regular insulin should be
 Intermediate Acting Insulins
Isophane insulin: Suspension of insulin in a complex with zinc and
protamine
 Also called as NPH insulin [NPH-Neutral Protamine Hagedorn]
 Given subcutaneously, maintains the basal insulin level to control
blood glucose between the meals
 When mixing NPH with regular / ultra-short insulins precaution
should be taken. They should not be combined until it is time to
inject, otherwise they bind to each other.
 Slow Onset & Long Acting
Glargine & Detemir Insulin
 Designed to provide a constant (peak less) basal insulin
secretion throughout the day
 Slow onset of action, maintains flat level of insulin for prolong
period (>24 hrs) and then fall occurs
 Both glargine and detemir have equal efficacy
 Glargine is long acting and convenient single daily dose
compared to detemir which may require twice a day injections
Different Insulin Preparations
 Indications for Insulin

 All the type-1 diabetes mellitus patients

 Type 2 patients, who are not adequately
controlled with diet & oral antidiabetic drugs
 Gestational diabetes
 Diabetic Ketoacidosis
 Hyperosmolar coma
 Circumstances in which you need to have
controlled blood sugar eg: Surgeries, infections,
trauma
 Post-pancreatectomy patients
 Adverse Effects of Insulin
Hypoglycemia- most common dangerous complication due
to delay in taking food, excess dose of insulin or too much
physical activity.
Allergic reactions
Lipodystrophy and local reactions at the site of injections
Insulin resistance
 Hypoglycemia
 Clinical features: Sweating, anxiety, palpitation,
tremor dizziness, headache, behavioral changes,
visual disturbances, fatigue and weakness
 Mental confusion, seizures and coma occur in severe
hypoglycemia
 Treatment: Oral glucose and if it is severe give IV
glucose and glucagon injection
 Hypoglycemic unawareness seen in some patients:
 Diabetic neuropathy
 Beta adrenergic blockers
 Drug Interactions with Insulin

1. ß-blockers: Masks the warning signs of hypoglycemia like

palpitation, sweating, tremor and anxiety which delays the
recognition & treatment, leads to prolong hypoglycemia
(Also, interferes with B2 mediated gluconeogenesis)

2. Alcohol: Can precipitate hypoglycemia

3. Thiazides, Frusemide, and Corticosteroids raise the blood

sugar
It was found that alcohol exerts substantial influences on pancreatic
microcirculation by evoking a massive redistribution of pancreatic blood flow
from the exocrine into the endocrine (insulin-producing) part via mechanisms
mediated by the messenger molecule nitric oxide and the vagus nerve,
augmenting late phase insulin secretion, and thereby evoking hypoglycemia.
INHALED INSULIN
Portable pen injector

Jet Injector of Insulin

Continuous Subcutaneous
Insulin Device
Classical Oral Hypoglycemic Agents

1. Sulfonylureas
2. Meglitinides
3. Biguanides
4. Thiazolidinediones (Glitazones)
5. Alpha- glucosidase inhibitors
Two newer oral hypoglycemic drugs:

1. DPP-IV inhibitors: Sitagliptin

2. SGLT-2 inhibitors: Gliflozin
 Sulfonylureas (SUs)
Chlorpropamide: 1st Generation
Prolong hypoglycemia, so not good for
elderly patients
Used to treat nephrogenic diabetes
insipidus
Glipizide: 2nd Generation
Shortest acting, less potent
Relatively less incidences of
hypoglycemia (safe in elderly pts)
Glimepiride: 2nd Generation MOA: Stimulates insulin
Long acting and most potent among other secretion by blocking ATP
sulfonylureas dependent potassium channels
Not safe in elderly of B-cells
 Sulfonylureas (SUs)
MOA: insulin release from pancreatic beta cells
 binds to sulfonylurea receptor- blocks ATP sensitive potassium
channels, resulting in depolarization, voltage gated calcium
channel open, resulting in Ca++ influx and triggering insulin
release
Pharmacokinetics:
 Well absorbed after oral administration
 Highly bound to plasma protein
 Low Vd
 Metabolised in liver
 Excreted via urine
 Sulfonylureas (SUs)
Use: Type-II DM patients,
Adverse effects: Hypoglycemia, allergic reactions, weight gain,
teratogenecity
Contraindications: Sulfa drug hypersensitivity
Drug interactions:
Sulfonylureas and salicylates- displaces sulfonylureas from plasma
protein binding sites- potentiates effects of sulfonylureas
Propranolol and sulfonylureas- propranolol masks the symptoms of
sulfonylurea induced hypoglycaemia
Rifampicin and sulfonylureas- rifampicin reduces the effect of
sulfonylureas
Warfarin and sulfonylureas- inhibits the metabolism- increases the
plasma levels of sulfonylurea
 Meglitinides
Repaglinide, Nateglinide
 Also called as Non-Sulfonylurea secretagogues
 Acts similar to sulfonylureas, stimulates insulin
secretion by blocking ATP dependent potassium
channels of B-cells
 Best use: To control post-prandial
hyperglycemia in type 2 DM
 Safe in sulfa allergic patients
 Hypoglycemia is the main side effect
 Biguanides
Metformin
 The first-line therapy for type-2 diabetes patients
 An euglycemic drug – Do not produce hypoglycemia
 Doesn’t cause weight gain, so preferred in obese patients

Mechanisms of action:
 1. ↓Hepatic gluconeogenesis (by affecting hepatic
enzymes)
 2. Slows down the glucose absorption from GIT
 3. Stimulates glucose uptake & utilization by tissues
(skeletal muscle)
 4. ↓ Plasma glucagon level
 Metformin

Uses of Metformin:
 Type-2 diabetes mellitus
 Especially in obese T2DM pts
 Polycystic Ovary Syndrome (PCOS)
Advantages over other drugs:
 Metformin promotes mild weight loss
 Improves the lipid profile
 Lowers cancer risk
 No hypoglycemia when used as monotherapy
 Metformin
Adverse Effects: Nausea and
vomiting, Metallic taste, Lactic
acidosis, Vit B12 deficiency, weight
loss

Contraindications:
Renal failure: monitor creatinine
All other conditions that predispose
to acidosis
Liver dysfunction
Alcoholism
Sepsis
 Thiazolidinediones
 Thiazolidinediones are ligands of PPAR-γ receptors that
are found in muscle, fat, and liver

 The endogenous ligands for these receptors are free fatty

acids (FFAs) and eicosanoids. When activated, the
receptor binds to DNA in complex, modulating the
expression of the genes involved in lipid and glucose
metabolism, insulin signal transduction, and adipocyte
differentiation

 Two thiazolidinediones are currently available:

pioglitazone and rosiglitazone. Troglitazone, was
withdrawn from the market because of hepatic toxicity
 Thiazolidinediones
Pioglitazone , Rosiglitazone
MOA: Increase the target tissue sensitivity to
insulin & reduce insulin resistance
 They binds to nulcear Peroxisome Proliferator
Activated Receptor Gamma (PPARG),
 Activates the transcription of several insulin
responsive “genes” involved in carbohydrate
and lipid metabolism
 Sensitizes the peripheral tissues to insulin
 Reduces blood glucose levels by:
 Increasing glucose transport into muscle and
adipose tissue
 Inhibiting hepatic gluconeogenesis
 Promoting lipogenesis
 Thiazolidinediones

 No hypoglycemia
 Delayed effect (Gene transcription)
 Hepatotoxicity, fluid retention, CCF are major
side effects
 Precipitation of congestive heart failure from
fluid retention
 Try avoiding TZDs in CCF patients
 TZDs are very useful medications in the
treatment of metabolic syndrome, nonalcoholic
fatty liver disease (also called “NASH”), and
polycystic ovarian disease (PCOD)
 Alpha-Glucosidase Inhibitors

Acarbose & Miglitol

 MOA: The drugs are competitive inhibitors of the
intestinal brush border enzyme alpha-
glucosidase involved in the breakdown of
starches into simple sugars
 This leads to a decreased monosaccharide
formation from carbohydrates in the upper small
intestine and therefore the absorption of
monosaccharides from duodenum and upper
jejunum is reduced
 Miglitol is more potent
 Alpha-Glucosidase Inhibitors
Use:
 In type 2 DM, administered just before ingestion of first
portion of each meal. Most suitable in patients with
predominantly postprandial hyperglycemia

Adverse effects:
 Flatulence (up to 40%)
 Diarrhea (up to 20%), abdominal pain (7%)
 Contraindicated in Inflammatory bowel disease
 Amylin analogues
Pramlintide
 Amylin is a polypeptide stored and secreted by beta cells of the
pancreas
 Present abnormally low in patients with diabetes
 Pramlintide- reduces postprandial glucose by:
 Decreasing glucagon secretion
 Delays gastric emptying
 Suppresses appetite and decrease body weight
 Indication- administered s.c in type 2 diabetes(in combination with
insulin)
 Incretins
 Incretins are gut hormones that are secreted from
enteroendocrine cells into the blood within
minutes after eating and stimulate a decrease in
blood glucose levels by increasing the insulin
release.
 In addition, they inhibit glucagon release
 There are two types of incretins:
 Glucagon Like Peptide-1 (GLP-1)
 Gastric Inhibitory Peptide (GIP)
 Glucagon like peptide-1(GLP-1) agonists
Exenatide, Liraglutide, Albiglutide,
Dulaglutide
 Analogs of hormone incretin(GLP-1)
 Increase glucose dependent insulin secretion
 Decrease glucagon secretion
 Slow gastric emptying
 Injected s.c 1 hour before breakfast and
dinner
 Indication- type 2 DM
 A/E- GI distress, acute pancreatitis
 Dipeptidyl peptidase 4(DPP-4) inhibitors
Sitagliptin, Saxagliptin, Linagliptin
DPP-4- rapid degradation of endogenous GLP-1
These agents inhibits DPP-4 , prevents
inactivation of GLP-1:
 Increase glucose dependent insulin secretion
 Decrease glucagon secretion
 Improves control of fasting and postprandial
hyperglycemia
 Indication- type 2 DM
 A/E- allergic reaction, hepatotoxicity
 SGLT-2 Inhibitors
Canaglifozin, Dapaglifozin
 Sodium/Glucose cotransporter 2 (SGLT2)are
responsible for at least 90% of the glucose
reabsorption in PCT
 Blocking this transporter mechanism causes
reduced reasbsorption of filtered glucose-
increase urinary excretion of glucose and
decrease blood glucose levels
 Indication- type 2 DM
 Side effects: UTIs, Hypotension
 Diabetic Ketoacidosis (Common in T1DM)
 Symptoms: Nausea/vomiting, Thirst/polyuria, Abdominal pain, Shortness
of breath
 Physical Findings: Tachycardia, Dehydration/hypotension,
Tachypnea/respiratory distress, Abdominal tenderness, Lethargy/cerebral
edema/possibly coma
 Precipitating events: Inadequate insulin administration, Infection,
Infarction, Drugs (cocaine), Pregnancy
 Treatment :
 1. Insulin – Regular insulin bolus dose of 0.1–0.2 U/kg i.v. is followed by
0.1 U/kg/hr infusion
 2. Fluid replacement- I.V normal saline
 3. Potassium chloride
 4. Sodium bicarbonate
 5. Antibiotics
JC is a slender 17-year-old young man who arrives in your clinic with
complaints of chronic fatigue, excessive thirst, frequent urination (5-6
times per night), and an unexpected 20 lb weight loss over the past two
months. His prior medical history is unremarkable. His family history is
negative for diabetes, and JC takes no other medications except for an
antibiotic for acne. Lab results indicate: FPG 270 mg/dL (normal <110),
HbA1c 13% (normal 4-6%). Your presumptive diagnosis is Type 1 diabetes
mellitus. What is the most appropriate therapy for controlling JC's
hyperglycemia?

? diet & exercise

? glucagon
? GLP-agonists
? insulin
? sulfonylureas
insulin
JC begins a rigorous treatment regimen for type 1 diabetes that includes a
nightly dose of insulin glargine, and doses of rapid-acting insulin aspart
with each meal. Nine months later his HbA1c has fallen from 13% to 6-7%.
During a family vacation his parents note that JC is sweating on a
temporate day, and he seems both irritable and confused, as well as slow
to respond to questions. JC also complains of being warm and having chest
palpitations. What would be best treatment for JC's s condition?

? chicken soup
? coffee
? insulin
? orange juice

orange juice
Unfortunately, JC's condition continues to spiral downhill, and he becomes
unconscious. What drug would be the best choice for treating his current
condition?

? glucacon s.c.
? insulin aspart s.c.
? metformin, po
? rosiglitazone, po

glucacon s.c.
A chronic reduction of insulin levels in patients with type 1 diabetes can
have serious consequences. Which of the following conditions is relatively
common, and is typically treated by giving i.v. "regular" insulin along with
other supportive measures?

? hypoglycemia
? ketoacidosis
? metabolic alkalosis
? hyperkalemia

ketoacidosis
Before consuming a meal, a patient with type 1 diabetes estimates the
meal's approximate carbohydrate load and administers a rapid-acting
"prandial" insulin to control postprandial glucose levels. Which of the
following types of insulin would be most appropriate to accomplish this
goal?

? aspart
? glargine
? lente
? NPH

aspart
Forms of insulin that have very long durations of action are most
commonly used to control fasting "basal" glucose levels that are present
in-between meals. Which of the following insulin formulations has this
pharmacokinetic characteristic?

? lispro
? detemir
? glulisine
? regular

detemir
A patient with type 1 diabetes who is suffering from diabetic ketoacidosis
requires insulin therapy with a form of insulin that is both soluble and will
have a short (vs delayed) onset of action. Which of the following types of
insulin has these properties?

? insulin detemir
? insulin glargine
? NPH insulin
? regular insulin

regular insulin
A 40-year- old hypertensive man, who was taking hydrochlorothiazide and propranolol,
was brought to hospital in a state of confusion with bizarre behaviour. He was profusely
sweating. His pulse rate was high. His skin was cold. History revealed that he is also an
established case of Diabetes Mellitus for which he was receiving regular insulin 15 units in
the morning. On the day of above mentioned attack he was fasting for a religious
ceremony in his house, though he received the insulin shot.

1. What is the probable cause of symptoms of attack? Give the underlying mechanism of
development of symptoms?
2. How will you manage the case and how could this condition have been prevented?
3. Do you think his antihypertensive therapy was suitable? Comment.
4. List the Insulin preparations.
5. Write the therapeutic uses and adverse effects of Insulin.