INSULIN AND OTHER ANTIDIABETEC DRUGS [Autosaved] [Autosaved].pptx

INSULIN AND OTHER
ANTIDIABETIC DRUGS

INSULIN
• A hormone produced in the pancreas by the islets of langerhans, which
regulates the amount of glucose in the blood.It was discovered in 1921
by banting and best.
• It was first obtained in pure crystalline form in 1926 and the chemical
structure was fully worked out in 1956 by sanger.
• Insulin isophane is used to improve blood sugar control in adults and
children with type 1 and type 2 diabetes mellitus. It is an intermediate-
acting type of insulin that helps to lower blood sugar levels and reduce
the chances of developing serious complications of diabetes.

Insulin is composed of two peptide chains referred to as the A chain and B
chain. A and B chains are linked together by two disulfide bonds, and an
additional disulfide is formed within the A chain. In most species, the A chain
consists of 21 amino acids and the B chain of 30 amino acids.
Although the amino acid sequence of insulin varies among species, certain
segments of the molecule are highly conserved, including the positions of the
three disulfide bonds, both ends of the A chain and the C-terminal residues of
the B chain. These similarities in the amino acid sequence of insulin lead to a
three dimensional conformation of insulin that is very similar among species,
and insulin from one animal is very likely biologically active in other species.
Structure of Insulin

Insulin molecules have a tendency to form dimers in solution due to
hydrogen-bonding between the C-termini of B chains. Additionally, in the
presence of zinc ions, insulin dimers associate into hexamers.
These interactions have important clinical ramifications. Monomers and
dimers readily diffuse into blood, whereas hexamers diffuse poorly. Hence,
absorption of insulin preparations containing a high proportion of
hexamers is delayed and somewhat slow. This phenomenon, among others,
has stimulated development of a number of recombinant insulin analogs.
The first of these molecules to be marketed - called insulin lispro - is
engineered such that lysine and proline residues on the C-terminal end of
the B chain are reversed; this modification does not alter receptor binding,

SYNTHESIS
• Insulin is synthesized in the BETA cells of pancreatic islets as a single chain
peptide preproinsulin ( 110 AA) from which 24 AA are first removed to produce
proinsulin. The connecting or 'C' peptide (35 AA) is split of by proteolysis in
golgi apparatus; both insulin and C peptide are stored in granules within the cell.
The C peptide is secreted in the blood along with insulin.
• Human insulin is now produced by recombinant DNA technology; structural
alterations at one or more residues are useful for modifying its physical and
pharmacologic characteristics

biologically active in another. Even today, many diabetic
patients are treated with insulin extracted from pig pancreas.
Insulin is synthesized in significant quantities only in beta cells
in the pancreas. The insulin mRNA is translated as a single chain
precursor called preproinsulin, and removal of its signal peptide
during insertion into the endoplasmic reticulum generates
proinsulin.
Proinsulin consists of three domains: an amino-terminal B
chain, a carboxy-terminal A chain and a connecting peptide in
the middle known as the C peptide. Within the endoplasmic
reticulum, proinsulin is exposed to several specific
endopeptidases which excise the C peptide, thereby generating
the mature form of insulin. Insulin and free C peptide are
packaged in the Golgi into secretory granules which accumulate
in the cytoplasm.
When the beta cell is appropriately stimulated, insulin is
secreted from the cell by exocytosis and diffuses into islet
capillary blood. C peptide is also secreted into blood, but has no

TYPE OF CHAIN
• Insulin is a two chain polypeptide having 51 amino acids.
• The A-chain has 21 amino acids while B-chain has 30 amino acids.

Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes
sense because insulin is "in charge" of facilitating glucose entry into cells. Some neural stimuli and
increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also
promote insulin secretion.
Certain features of this process have been clearly and repeatedly demonstrated, yielding the
following model:
Glucose is transported into the beta cell by facilitated diffusion through a glucose transporter;
elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose
within the beta cell.
Elevated concentrations of glucose within the beta cell ultimately leads to membrane
depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium
is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules.
The mechanisms by which elevated glucose levels within the beta cell cause depolarization is not
clearly established, but seems to result from metabolism of glucose and other fuel molecules
within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in
membrane conductance.
Increased levels of glucose within beta cells also appears to activate calcium-independent
Control of Insulin Secretion

 Stimulation of insulin release is readily observed in whole animals or
people. The normal fasting blood glucose concentration in humans
and most mammals is 80 to 90 mg per 100 ml, associated with very
low levels of insulin secretion. Clearly, elevated glucose not only
simulates insulin secretion, but also transcription of the insulin gene
and translation of its mRNA.
 Under basal condition 1U insulin is secreted per hour by human
pancreas. Much larger quantity is secreted after every meal.
Secretion of insulin from p cells is regulated by chemical, hormonal
and neural mechanisms.

1.CHEMICAL MECHANISM
• The beta cells have a glucose sensing mechanism dependent on entry of glucose into
the beta cells and its phosphorylation by glucokinase. Glucose entry and metabolism
leads to activation of the glucosensor and production of ATP which inhibits the atp-
sensitive K+ channel (K+ ATP) resulting in partial depolarization o f the beta cells . this
increases intracellular ca +2 availability
• Exocytotic release of insulin storing granules. Other nutrients that can evoke insulin
release are- amino acids, fatty acids and ketone bodies, but glucose is the principal
regulator and it stimulates the synthesis of insulin as well. Glucose induces a brief pulse
of insulin output within 2 min followed by a delayed but more sustained second phase
of insulin release. Glucose and other nutrients are 2-4 times more effective in invoking
insulin release when given orally than iv. They generate chemical signals 'incretins' from
the gut which act on beta cells in the pancreas to cause anticipatory release of insulin.
The incretins involved are glucagon-like peptide-i,glucose-dependent insulinotropic

2.HORMONAL MECHANISM
• A number of hormones, e.g. Growth hormone, corticosteroids, thyroxine
modify insulin release in response to glucose. More important are the
intra-islet paracrine interactions between the hormones produced by
different types of islet cells. The ß cells constitute the core of the islets
and are the most abundant cell type. The alfa cells, comprising 25% of the
islet cell mass, surround the core and secrete glucagon. The delta cells (5-
10%) elaborating somatostatin are interspersed between the alfa cells.
There are some pancreatic polypeptide containing cells as well.

• Somatostatin inhibits release of both insulin and glucagon.
• Glucagon evokes release of insulin as well as somatostatin.
• Insulin inhibits glucagon secretion. Amylin, another beta cell polypeptide released with
insulin, inhibits glucagon secretion through a central site of action in the brain.
• The three hormones released from closely situated cells influence each other's secretion
and appear to provide fine tuning of their output in response to metabolic needs.

3.NEURAL MECHANISM
• The islets are richly supplied by sympathetic and vagal nerves.
• Adrenergic alfa2 receptor activation decreases insulin release by inhibiting beta cell
adenylyl cyclase.
• Adrenergic beta2 stimulation increases insulin release by stimulating beta cell
adenylyl cyclase.
• Cholinergic-muscarinic activation by ach or vagal stimulation causes insulin
secretion through ip3/ dag-increased intracellular ca+2 in the beta cells. However,
neural influences have only modulatory effect on insulin secretion.

ACTIONS OF INSULIN
• The overall effects of insulin are to dispose meal derived glucose,
amino acids, fatty acids and favour storage of fuel. It is a major
anabolic hormone: promotes synthesis of gylcogen, lipids and
protein.The actions of insulin and the results of its deficiency can
be summarized as…..

• Insulin facilitates glucose transport across cell membrane.
• The first step in intracellular utilization of glucose is its phosphorylation to
form, glucose6-phosphate. This is enhanced by insulin through increased
production of glucokinase.
• Insulin inhibits gluconeogenesis (from protein, ffa and glycerol) in liver by
gene mediated decreased synthesis of phosphoenol pyruvate carboxykinase.
• Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis.
• Insulin enhances transcription of vascular endothelial lipoprotein lipase,
thereby accelerating clearance of vldl and chylomicrons.
• Insulin facilitates aa entry into muscles and most other cells.

PREPARATIONS OF INSULIN
• The older commercial insulin preparations were produced from beef and
pork pancreas. They contained - 1 % of other proteins (proinsulin. Other
polypeptides, pancreatic proteins. Insulin derivaties. Etc.) Which were
potentially antigenic. Such insulins are no longer produced and have been
totally replaced by highly purified pork/beef insulins. Recombinant human
insulins and insulin analogues.

HIGHLY PURIFIED INSULIN PREPARATIONS
• In the 1970 improved purification tecniques like gel filtration and ion-
exchange chromatography were applied to produce 'single peak ' and
'monocomponent' insulins which contain < 1O ppm proinsulin. The
monocomponent insulins are more stable and cause less insulin resistance
or injection site lipodystrophy. The immunogenicity of pork
monocomponent insulin is similar to that of recombinant human insulin.

TYPES OF INSULIN PREPARATIONS
THERE ARE FOUR TYPES OF INSULIN PREPARATIONS
A. RAPID ACTING
B. SHORT ACTING
C. INTERMEDIATE ACTING
D. LONG ACTING

A.RAPID ACTING
1.Insulin lispro
Produced by reversing proline and lysine at the carboxy terminus B 28 and B
29 positions, it forms very weak hexamers that dissociate rapidly after s.c.
Injection resulting in a quick and more defined peak as well as shorter
duration of action. Individual variability in absorption is minimized. Unlike
regular insulin. It is best injected s.c. 0-20 min before a meal. A better control
of meal-time glycaemia and a lower incidence of late post-prandial
hypoglycaemia have been obtained. Using a regimen of 2-3 daily meal-time
insulin lispro injections, a slightly greater reduction in HbA1c compared to
regular insulin has been reported. Fewer hypoglycaemic episodes occurred.
HUMALOG 100 U/ml, 3 ml cartridge,1O ml vial.

2.Insulin aspart
• The proline at B 28 of human insulin is replaced by
aspartic acid. This change reduces the tendency for self-
aggregation, and a time-action profile similar to insulin
lispro is obtained. It more closely mimics the
physiological insulin release pattern after a meal, with
the same advantages as above. NOVOLOG, NOVORAPID
100 U/ml inj.

•Biphasic insulin aspart
The 70:30 mixture of isophane complex or insulin aspart with
uncomplexed insulin aspart has the advantage of rapid and
predictable onset along with intermediate duration of action. It is
called 'biphasic insulin aspart', and can be injected twice daily just
before each major meal.
NOVOMIX 30 flexpen 100 U/ml in 3 ml inj., Also as PENFIL
injection.

3.Insulin glulisine
Another rapidly acting insulin analogue with lysine replacing asparagine at
B 23 and glutamic acid replacing lysine at B 29. Properties and advantages
are similar to insulin lispro. It has been particularly used for continuous
subcutaneous insulin infusion by a pump.

B. SHORT ACTING
1. REGULAR (SOLUBLE) INSULIN
• it is a buffered neutral pH solution of unmodified insulin stabilized by a small amount of zinc. At
the concentration of the injectable solution, the insulin molecules self aggregate to form
hexamers around the zinc ions. After s.c. Injection, insulin monomers are released gradually by
dilution, so that absorption occurs slowly. Peak action is produced only after 2- 3 hours and
action continues upto 6-8 hours. The absorption pattern is also affected by dose; higher doses act
longer. When injected s.c. Just before a meal, this pattern often creates a mismatch between the
need and the availability of insulin to result in early postprandial hyperglycaemia and late
postprandial hypoglycaemia. Regular insulin is optimally injected I hour before a meal.

• Regular insulin injected s.c. is also not suitable for providing a low constant
basal level of action in the inter digestive period. However, the slow onset of
action is not applicable to i.v. Injection, because the insulin hexamer
dissociates rapidly to produce prompt action. Regular insulin is the only
insulin used for i.v. injection. To overcome the above problems, some long-
acting ' modified' or ' retard ' preparations of insulin were developed.
Recently, both rapidly acting as well as peakless and longacting insulin
analogues have available. For obtaining retard preparations, insulin is
rendered insoluble either by complexing it with protamine or by
precipitating it with excess zinc and increasing the particle size.

C. INTERMEDIATE ACTING
1.LENTE INSULIN
• Also known as insulin-zinc suspension there are two types of insulin-zinc
suspensions have been produced. The one with large particles is crystalline
and practically insoluble in water. It is long-acting. The other has smaller
particles and is amorphous, is short-acting. Their 7:3 ratio mixture is called '
lente insulin' and is intermediate-acting.

2. ISOPHANE (NEUTRAL PROTAMINE
HAGEDORN) INSULIN
• Protamine is added in a quantity just sufficient to complex all insulin molecules; neither insulin nor
protamine is present in free form and pH is neutral. On s.c. Injection, the complex dissociates slowly to
yield an intermediate duration of action. However, the time course of absorption and intensity of
action of NPH [neutral protamine hagedorn] insulin is relatively inconsistent. It is mostly combined
with regular insulin (70:30 or 50:50) and injected s.c. Twice daily before breakfast and before dinner
(split-mixed regimen).
I. Highly purified (monocomponent) pork regular insulin: ACTRAPID MC. RAPIDICA 40 U/ml inj.
II. Highly purified (MC) pork lente insulin: LETARD, M01JOTARD MC, LENTINSULIN-HPI, zinulin 40
U/ml
III. Highly purified (MC) pork isophane ( PH) insulin: INSULATARD 40 U/ml inj.
IV. Mixture or highly purified pork regular insulin (30%) and isophane insulin (70%): RAPIMIX,
MIXTARD 40 U/ml inj.

D. LONG ACTING
1. INSULIN GLARGINE
• This long-acting biosynthetic insulin has 2 additional arginine residues at
the carboxy terminus of B chain and glycine replaces asparagine at A 21.
This analogue remains soluble at pH4 of the formulation. But precipitates at
neutral pH encountered on s.c.Injection. A depot is created from which
monomeric insulin dissociates slowly to enter the circulation. Onset of
action is delayed, but relatively low blood levels o f insulin are maintained
for upto 24 hours. A smooth 'peakless' effect is obtained. Thus, it is suitable
for once daily injection to provide background insulin action.

• Fasting and inter digestive blood glucose levels are effectively
lowered irrespective of time of the day when injected or the site
of s.c. Injection. It is mostly injected at bed time. Lower incidence
of night-time hypoglycaemic episodes compared to isophane
insulin has been reported. However, it does not control meal-time
glycaemia, for which a rapid acting insulin or an oral
hypoglycaemic is used concurrently. Because of acidic pH, it
cannot be mixed with any other insulin preparation; must be
injected separately. LANTUS OPTISET 100 U/ml in 5 ml vial and 3
ml prefilled pen injector.

2. Insulin detemir
• Myristoyl (a fatty acid) radical is attached to the amino group of lysine at
B29 of insulin chain. As a result, it binds to albumin after s.c. Injection from
which the free form becomes available slowly. A pattern of insulin action
almost similar to that of insulin glargine is obtained, but twice daily dosing
may be needed. LEVEMIR flexpen 100 U/ml in 3 ml prefilled pen injector.

• This is the most frequent and potentially the most serious reaction. Hypoglycaemic episodes are more
common in patients of ' labile' diabetes in whom insulin requirement fluctuates unpredictably.
Hypoglycaemia can occur in any diabetic following inadvertent injection of large dose, by missing a
meal after injection or by performing vigorous exercise. The symptoms can be divided into those due
to counter-regulatory sympathetic stimulation, viz. Sweating, anxiety, palpitation, tremor; and those
due to deprivation of the brain of its essential nutrient glucose (neuroglucopenic symptoms)-
dizziness, headache, behavioural changes, visual disturbances, hunger, fatigue, weakness, muscular
incoordination and sometimes fall in BP. Generally, the reflex sympathetic symptoms occur, before the
neuroglucopenic, but the warning symptoms of hypoglycaem ia differ from patient to patient and also
depend on the rate of fall in blood glucose level.
1. Hypoglycaemia

• Diabetic neuropathy can abolish the autonomic symptoms. Hypoglycaemic
unawareness tends to develop in patients who experience frequent episodes
of hypoglycaemia. Finally, when blood glucose fall further (to < 40 mg/dl)
mental confusion, abnormal behaviour, seizures and coma occur. Irreversible
neurological deficits are the sequelae of prolonged hypoglycaemia.
Treatment glucose (or glucose yielding carbohydrate, e.g. Sugar) 15- 20 g
orally reverses the symptoms rapidly in most cases. if no improvement
occurs, the same amount may be repeated after 15- 20 min. In severe cases
30- 50 ml of 50% glucose may be injected i.v. Over 10 min. Glucagon 0.5- 1
mg i.v. or 0.2 mg s.c. (Less desirable) may be given as an expedient measure
in patients who are not able to take sugar orally and injectable glucose is not
available.

• 2. Local reactions
Swelling, erythema and stinging sometimes occur at the injected site, especially in the
beginning. Lipodystrophy of the subcutaneous fat around the injection site occurred
occasionally with the older pork/beef insulin preparations. This is rare with the newer
preparations.
• 3. Allergy
This is due to contaminating proteins, and is , very rare with human/highly purified insulins.
Urticaria, angioedema and anaphylaxis are the manifestations.
• 4. Edema
Some patients develop short-lived dependent edema when insulin therapy is started.

NEWER INSULIN DELIVERY DEVICES
• A number of innovations have been made to improve ease and accuracy of insulin
administration as well as to achieve tightglycacmia control. These are
A.Insulin syringes
Prefilled disposable syringes contain specific types or mixtures of regular and modified
insulins. These are in common use now. And avoid the need for carrying insulin vials and
syringes.
B.Pen devices
Fountain pen like: they use insulin cartridges for s.c. Injection through a needle. Preset
amounts (in 2 U increments) are propelled by pushing a plunger. They are convenient in
carrying and injecting.

C.Inhaled insulin
The early inhaled insulin formulations were found to be unsatisfactory for clinical use due to
risk of pulmonary complications. A new dry powder formulation (AFREZZA) of recombinant
human insulin called technosphere insulin' has been found satisfactory for use in bo1h type l
and 2 diabetics. Administered by a breath-powered inhaler, it is absorbed from the alveoli and
acts rapidly within 10-15 min. The action is terminated by 3 hours. Thus. It is suitable for use
just before a meal 10 control prandial glycaemia. Combined with basal insulin injection
(insulin glargine, etc.). It has been found equi-effective in lowering blood glucose and HbA1c
levels as prandial insulin aspart injected s.c. (Along with basal insulin). Weight gain and risk of
hypoglycaemic episodes is claimed to be lower compared to rapid acting s.c. Insulin. Cough is
the most common adverse effect reponed by >25% patients. It is not to be used in smokers
and COPD patients.

D.Insulin pumps
Portable infusion devices connected to a subcutaneously placed cannula- provide'continuous
subcutaneous insulin infusion'. Only regular insulin or a fast acting insulin analogue is used. The
pump can be programmed to deliver insulin at a low basal rate (approx. I U/hr) and premeal
boluses (4-15 times the basal rate) 10 control post-prandial glycaemia. Though, theoretically more
appealing, no definite advantage of CSII over multidose s.c. Injection has been demonstrated.
Moreover, cost, strict adherence to diet, exercise, care of the device and cannula, risk of pump
failure, infusion site infection, are 100 demanding on the patient. The CSI I may be appropriate for
sellected type 2 DM cases only.
E.Implantable pumps
These consist of an electromechanical mechanism which regulates insulin delivery from a
percutaneously refillable reservoir. Mechanical pumps, propellant driven and osmotic pumps have
been utilized.

DRUG INTERACTIONS
I. Beta adrenergic blockers prolong hypoglycaemia by inhibiting compensatory
mechanisms operating through p2 receptors (P1 selective blockers are less liable).
Warning signs of hypoglycaemia like palpitation, tremor and anxiety are marked.
II. Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to
raise blood sugar and reduce effectiveness of insulin.
III. Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic glycogen.
IV. Lithium, high dose aspirin and theophylline may also accentuate hypoglycaemia by
enhancing insulin secretion, as well as peripheral glucose utilization.

USES OF INSULIN
• Diabetes mellitus
The purpose of therapy in diabetes mellitus is to restore metabolism to
normal, avoid symptoms due to hyperglycaemia and glucosuria, prevent short-
term complications (infection, ketoacidosis, etc.) And long-term sequelae
(cardiovascular, retinal. Neurological, renal, etc.)
• The generally accepted criteria for adequate glycaemia control in an adult
diabetic treated with insulin or oral antidiabetics are:
• Fasting (morning) blood glucose levels 90-130 mg/dl
• Blood glucose levels < 150 mg/dl 2 hours after meals
• HbAIC levels < 7%.

• Insulin is effective in all forms of diabetes mellitus and is a must for type I cases, as well as
for post pancrcatectomy diabetes and gestational diabetes. Many type 2 cases can be
controlled by lifestyle measures like diet, reduction in body weight and appropriate exercise
supplemented, if required, by oral antidiabetics. Insulin is needed by such patients when:
• Not controlled by diet and exercise or when these are not practicable.
• Primary or secondary failure of oral antidiabetics or when these drugs are not tolerated.
• Under weight patients.
• Temporarily to tide over infections, trauma, surgery, pregnancy. In the perioperative period
and during labour, monitored i.v. Insulin in fusion is preferable.
• Any complication of diabetes, e.g. Ketoacidosis, nonketotic hyperosmolar coma, gangrene of
extremities.

DIABETIC KETOACIDOSIS
• (Diabetic coma) ketoacidosis of different grades generally occurs in insulin dependent
diabetics, and is due to inadequate/no insulin replacement. It is infrequent in type 2 DM.
The most common precipitating cause is infection; others are trauma, stroke, pancreatitis,
stressful conditions and inadequate doses of insulin.
• Patients may present with varying severity. Typically they are dehydrated, hyperventilating
and have impaired consciousness. The principles of treatment remain the same, irrespective
of severity, only the vigour with which therapy is instituted is varied. Close monitoring of
vital signs, plasma glucose, blood pH, electrolytes, plasma acetone, etc. Is needed.

HYPEROSMOLAR (NONKETOTIC
HYPERGLYCAEMIC) COMA
• This is characterized by high blood glucose (>600 mg/di) and serum osmolality (>320 mosm/L) along with
deteriorating mental status. It generally occurs in elderly type 2 patients. The cause is obscure, but appears to be
precipitated by the same factors as ketoacidosis, especially those resulting in dehydration. Uncontrolled glycosuria
of DM produces diuresis resulting in dehydration and haemoconcentration over several days. Urine output is finally
reduced and glucose accumulates in blood rapidly raising blood osmolality leading to coma. Death can occur if not
vigorously treated. The general principles of treatment are the same as for ketoacidotic coma, except that faster
fluid replacement is to be instituted, insulin requirement is lower, less potassium replacement is generally needed
and alkali is usually not required. These patients are prone to thrombosis (due to hyperviscosity and sluggish
circulation), prophylactic heparin therapy is recommended. Despite intensive therapy, mortality in hyperosmolar
coma remains high. Treatment of precipitating factor and associated illness is vital.

ORAL ANTIDIABETIC DRUGS
• These drugs lower blood glucose levels in diabetics and
are effective orally. The chief drawback of insulin is it
must be given by injection. Orally active drugs have
always been saught.

1.SULFONYLUREAS (KATP CHANNEL BLOCKERS)
• All SU have similar pharmacological profile, their sole significant
action being lowering of blood glucose level in normal subjects and in
type 2 diabetics, but not in type I diabetics. Being more potent and
clinically superior, only the second generation SU are employed now.
All first generation compounds have been discontinued except
tolbutamide which is infrequently used.

MECHANISMOF ACTION
• Sulfonylureas bind to a specific 'sulfonylurea receptor’ located on the
pancreatic beta cell membrane and provoke a brisk release of insulin.
• The rate of insulin secretion at any glucose concentration is increased, i.e.
Insulin release is provoked even at low-glucose concentration risking
production o f severe and unpredictable hypoglycaemia.
• In type 2 DM the kinetics of insulin release in response to glucose or meals is
delayed and subdued.

The SU primarily augment the 2nd phase insulin secretion with
little effect on the Ist phase. That they do not cause
hypoglycaeamia in pancreatectomised animals and in type I
diabetics , confirms their indirect action through pancreas. A minor
action reducing glucagon secretion. Probably by increasing insulin
and somatostatin release has been demonstrated. Hepatic
degradation of insulin is also slowed.

PHARMACOKINETICS
• All SU are well absorbed orally, and are 90% or more bound to plasma
proteins have low volumes of distribution (0.2- 0.4 L/kg). They are primarily
metabolized may produce active metabolite. The metabolites
(active/inactive) are excreted in urine. As such, they should be used
cautiously in patients with liver or kidney dysfunction.

ADVERSE EFFECTS
• Hypoglycaemia
It is the commonest problem, may occasionally be severe and rarely fatal. It is more common in elderly,
liver and kidney disease patients and when potentiating drugs are added.
• Nonspecific side effects
Majority of diabetics started on sus tend lo gain 1- 3 kg weight. This may be a consequence of
insulinaemic action of sus. Nausea, vomiting, flatulence, diarrhoea or contipation, headache and
paresthesias are generally mild and infrequent.
• Hypersensitivity
Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis. Flushing and disulfiram-
like reaction after alcohol is reported to occur in some individuals taking sus.

2. MEGLITINIDE/D-PHENYLALANINE ANALOGUES
(KATP CHANNEL BLOCKERS)
• These are KATP channel blockers with a quick and short lasting insulinemic action.

REPAGLINIDE
• This meglitinide analogue oral hypoglycaemic is designed to normalise meal-time glucose excursions. Though not a
sulfonylurea, it acts in an analogous manner by binding to SUs closure of ATP sensitive K+ channels
depolarization insulin release.
Repaglinide is quickly absorbed and rapidly metabolized. It induces fast onset short-lasting insulin release. Because of
this characteristic its pallcrn of use is different from that of sus. It is adminis1ered before each major meal to control
postprandial hyperglycaemia; the dose should be omitted if a meal is missed. Because of short lasting action it may
have a lower risk of serious hypoglycaemia. Side effects are mild headache, dyspepsia, arthralgia and weight gain.
• Repaglinide is indicated only in selected type 2 diabetics who suffer pronounced postprandial hyperglycaemia, or
to supplement metformin/ long-acting insulin. It should be avoided in liver disease.

NATEGLINIDE
• It is a D-phenylalanine derivative which principally stimulates the 1st phase insulin secretion by
closing ~ cell KATP channels resulting in faster onset and shorter lasting hypoglycaemia than
repaglinide. Ingested 10 min before meal, it limits postprandial hyperglycaemia in type 2 diabetics
without producing late phase hypoglycaemia. There is little effect on fasting blood glucose level.
Episodes of hypoglycaemia are less frequent than with SUs.
• Side effects are dizziness, nausea, flu-like symptoms and joint pain. It is used in type 2 DM along with
other antidiabetics, to control postprandial rise in blood glucose.

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
• Realizing the key role of the enzyme DPP-4 in rapid degradation of
endogenous GLP-1, orally active inhibitors of this enzyme have been
developed as indirectly acting insulin secretagogues. In the past few years,
DPP-4 inhibitors have emerged as important adjunctive drugs in type 2 DM,
but their blood sugar lowering efficacy is moderate compared to that of SUs.

SITAGLIPTIN
• This is the first DPP-4 inhibitor introduced in 2006. It is a competitive
and selective DPP-4 inhibitor which potentiates the action of GLP- 1
and GIP, boosts postprandial insulin release, decreases glucagon
secretion and lowers meal-time as well as fasting blood glucose in type
2 diabetics. No effect on gastric emptying and appetite have been
noted. It carries low risk of hypoglycaemia unless combined with sus
or insulin, because GLP- 1 evokes little insulin release al normal
plasma glucose levels. The HbA1c lowering achieved by sitagliptin is
almost equivalent to that with metformin.

• Further lowering of HbA1c by 0.5- 1.2% occurs when it is added to
pioglitazone/SUs/ insulin with or without metformin. However, sitagliptin
monotherapy is recommended only when metformin cannot be used. Most
professional guidelines recommend DPP-4 inhibitors primarily as adjuvant drugs in
type 2 diabetics not well controlled by metformin/SUs/pioglitazone or insulin.
Though clinical efficacy of all DPP-4 inhibitors is comparable, one meta analysis has
found sitagliptin to cause greater reduction of fasting blood glucose than
vildagliptin. Sitagliptin is well absorbed orally, is little metabolized and is largely
excreted unchanged in urine with a t½ averaging 12 hours.

VILDAGLIPTIN
• This DPP-4 inhibitor binds to the enzyme covalently. The complex dissociates very slowly
resulting in persistent DPP-4 inhibition even after the free drug has been cleared from
circulation. This explains the longer duration of action ( 12- 24 hours) despite short plasma t½
(2-4 hours). The major route of elimination is by hepatic metabolism; only 20- 25% is excreted
unchanged in urine. Dose reduction is needed in moderately severe liver and kidney disease. No
significant drug interactions have been reported. Vildagliptin is less selective than sitagliptin for
DPP-4; causes some inhibition of DPP-8, DPP-9 as well, but the clinical significance of this feature
is not known. The tolerability of vildagliptin is similar to that of sitagliptin, but hepatotoxicity has
been reported. Vildagliptin may require twice daily dosing; though single daily dose suffices in
most cases when combined with another hypoglycaemic.

SAXAGLIPTIN
• Like vildagliptin, saxagliptin binds covalently with DPP-4 and acts for 24 hours
despite a plasma t½ of 2-4 hours. Added to metformin/SU ± pioglitazone it causes
HbA1c reduction similar to that caused by sitagliptin or vildagliptin. It is
metabolized by CYP3A4 and generates an active metabolite that has a t½ of 3-7
hours. Drug interactions with CYP3A4 inhibitor are posible.
• Dose: 5 mg OD; reduce by half in moderately severe renal failure, but not in liver
disease.
• Onglyza 2.5, 5 mg tabs

TENELIGLIPTIN
• It is a new DPP-4 inhibitor developed in japan which exerts long-lasting (>24 hours) DPP-4
inhibition and antiglycaemic effect. Following a single morning dose, postprandial
hyperglycaemia is suppressed at all 3 meals of the day. Therapeutic efficacy both as monotherapy
as well as in combination with metformin ± SUs or a thiazolidinedione is comparable to other
gliptins. Metabolites of teneligliptin are excreted by both liver and kidney; no dose reduction is
needed in patients with renal impairment. Though no cardiovascular adverse effects have been
noted, caution is to be exercised in patients prone to QT prolongation.
Dose: 20 mg/before breakfast daily, increase to 40 mg/ day if needed.
TENEFIT-20, TENLIMAX 20 mg tab.

• BIGUANIDE
Two biguanide antidiabetics, phenformin and metformin were introduced in the 1950.
Because of higher risk of lactic acidosis, phenformin has been banned in india since 2003.

METFORMIN
• It differs markedly from SUs: causes little or no hypoglycaemia in
nondiabetic subjects and even in diabetics, hypoglycaemia is rare. Thus, it is
'euglycaemic', rather than hypoglycaemic'.1st does not stimulate pancreatic
beta cells. Metformin is reported to improve lipid profile as well in type 2
diabetics.

MECHANISM OF ACTION
Biguanides do not cause insulin release, but presence of insulin is essential for their action. Metformin is not
effective in pancreatectomized animals and in type I diabetics. Though the details are not clear, recent studies
have recognized activation of AMP-dependent protein kinase to play a crucial role in mediating the actions of
metformin, the key features of which are
I. Suppresses hepatic gluconeogenesis and glucose output from liver. This is the major action responsible for
lowering of blood glucose in diabetics.
II. Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat. Insulin resistance
exhibited by type-2 diabetics is thus overcome. This translates into- - glycogen storage in skeletal muscle -
reduced lipogenesis in adipose tissue and enhanced fatty acid oxidation.
III. Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization through
anaerobic glycolysis. AMPK activation by metformin appears to be an indirect consequence of interference
with cellular respiration and lowering of intracellular ATP and other energy sources. Metformin also
retards intestinal absorption of glucose, other hexoses, amino acids and vit B12•

PHARMACOKINETICS
• Metformin is well absorbed orally, not metabolized, but excreted unchanged by kidney.
• It accumulates in renal failure and increases the risk of lactic acidosis.

ADVERSE EFFECTS
• Abdominal pain
• Anorexia
• Bloating
• Nausea
• Metallic taste
• Mild diarrhoea and tiredness
• Lactic acidosis

• Uses metformin is now established as a first choice drug for all type 2 DM patients, except when
not tolerated or contraindicated.
Advantages of metformin are,
Antihyperglycaemic but not hypoglycaemic
Weight loss promoting
Has potential to prevent macrovascular as well as microvascular complications of diabetes
No acceleration of beta cell exhaustion/ failure in type 2 DM.
Antihyperglycaemic efficacy (HbA1, reduction by 0.8- 1.2%) equivalent to other oral drugs.
Can be combined with any other oral or injectable antidiabetic.
Can prevent new onset type 2 DM in obese, middle aged subjects with impaired glucose tolerance
(but not in non obese older subjects) as shown by the diabetes prevention programme.

PIOGLITAZONE
• Pioglitazone should not be used during pregnancy.

MECHANISM OF ACTION
• Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated
receptor gamma and to a lesser extent ppar-α. It modulates the transcription of the genes
involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and
the liver. As a result, pioglitazone reduces insulin resistance in the liver and peripheral
tissues, decreases gluconeogenesis in the liver, and reduces quantity of glucose and glycated
hemoglobin in the bloodstream.

PHARMACOKINETICS
• Pioglitazone is metabolized by both CYP2C8 and CYP3A4. Ketoconazole inhibits and
rifampin induces its metabolism. Failure of oral contraception may occur during
pioglitazone therapy. Pioglitazone is indicated in ty pe 2 DM, but not in type I DM. It reduces
blood glucose and HbAc without increasing circulating insulin . about 25% patients may not
respond , probably due to low baseline insulin levels. It should be stopped if HbA1c ,
reduction is < 0.5% at 6 months. Pioglitazone is primarily used to supplement
SUs/metformin and in case of insulin resistance. However, it is not likely to be effective
when cell failure has set in, which may be responsible for loss of efficacy of combination of
SUs + metfomin. It may also be used as monotherapy (along with diet and exercise) in mild
cases.

ADVERSE EFFECTS
• Weight gain
• Blurred vision
• Headache
• Respiratory tract infection
• Numbness
• Increase risk of bone fracture especially in elderly women
• Peripheral oedema
• Myalgia and mild anaemia.

C.RETARD CARBOHYDRATE ABSORPTION

• Retard carbohydrate absorption
means it decrease as well as slow
down the carbohydrate absorption,
that cause indirectly decrease the
glucose synthesis.

ALFA GLUCOSIDASE INHIBITORS
1.Acarbose
• Acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates,
specifically, alphaglucosidase enzymes in the brush border of the small intestines, and
pancreatic alpha-amylase. However, bacterial alpha-amylases from gut microbiome are able
to degrade acarbose.

MECHANISM OF ACTION
• Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of
the small intestine, whereas the membrane-bound intestinal alpha-glucosidases
hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and
other monosaccharides in the small intestine. Inhibition of these enzyme systems reduces
the rate of digestion of complex carbohydrates. Less glucose is absorbed because the
carbohydrates are not broken down into glucose molecules.

PHARMACOKINETICS
It is a complex oligosaccharide which reversibly inhibits alfa-glucosidases, the final enzymes for the
digestion of carbohydrates in the brush border of small intestine mucosa. It slows down and decreases
digestion and absorption of polysaccharides (starch, etc.) and sucrose. Postprandial glycaemia is
reduced without significant increase in insulin levels. Regular use lowers HbA1c modestly (by 0.4-
0.8%), but change in body weight and lipid levels is minimal. Acarbose is a mild antihyperglycaemic and
not a hypoglycaemic may be used as an adjuvant to diet (with or without metformin/SU) in obese
diabetics. Acarbose 50- 100 mg TDS is taken at the beginning of each major meal. Only a small fraction of
the dose is absorbed.
Brand name : GLUCOBAY 50, 100 mg tabs, ASUCROSE, GLUCAR 50 mg labs

ADVERSE EFFECTS
• Abdominal pain
• Diarrhea
• Flatulence

2. MIGLITOL
That acts by inhibiting the ability of the patient to break down complex carbohydrates into
glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic
control by preventing the digestion of carbohydrates (such as disaccharides, oligosaccharides,
and polysaccharides) into monosaccharides which can be absorbed by the body.
It has a smaller molecule than acarbose, and it is a stronger inhibitor of sucrase. Potency for
other alfa-glucosidases is equivalent to acarbose. No systemic toxicity is known.
Dose: 25-100 mg tds at beginning of each meal. MIGTOR, DIAMIG, ELITOX 25, 50 mg tabs

MECHANISOM OF ACTION
• Since miglitol works by preventing digestion of carbohydrates, it lowers the
degree of postprandial hyperglycemia. It must be taken at the start of main
meals to have maximal effect. its effect will depend on the amount of non-
monosaccharide carbohydrates in a person's diet.

PHARMACOKINETICS
• In contrast to acarbose(another alpha-glucosidase inhibitor), miglitol is systemically
absorbed; however, it is not metabolized and is excreted by the kidneys

ADVERSE EFFECTS
• Skin rash
• Flatulence
• Abdominal pain
• Diarrhea

3. VOGLIBOSE
VOGLIBOSE belongs to the group of anti-diabetic medicines called alpha-glucosidase
inhibitors used to treat type-2 diabetes mellitus. VOGLIBOSE is prescribed for the condition of
type 2 diabetes when diet and exercise alone cannot control their blood sugar levels.
Dose: 200- 300 microgram tds just before meals.
Brand name : voglitor, volix, volibo 0.2, 0.3 mg tabs

• Complex carbohydrates are normally converted into simple sugars (monosaccharides)
which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce
the impact of complex carbohydrates on blood sugar.
• VOGLIBOSE works by inhibiting the intestinal enzymes responsible for breaking complex
sugars into simple sugars like glucose. Thereby, it helps in preventing blood glucose levels
from rising immediately after meals.

PHARMACOKINETICS
• Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes needed to digest
carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines. The
membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and
disaccharides to glucose and other monosaccharides in the small intestine. Acarbose also blocks pancreatic
alpha-amylase in addition to inhibiting membrane-bound alpha-glucosidases. Pancreatic alpha-amylase
hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine. Inhibition of these
enzyme systems reduces the rate of digestion of complex carbohydrates.

ADVERSE EFFECTS
• Abdominal pain
• Diarrhea
• Flatulence (wind)
• Skin reactions
• Heart burn
• Nausea
• Vomiting

1.SODIUM-GLUCOSE CO-TRANSPORT-2
(SGLT-2) INHIBITOR
• Practically all the glucose filtered at the glomerulus is reabsorbed in the proximal tubules.
• SGLT-2 inhibitors are a class of medicine used to lower high blood glucose levels in people with type 2 diabetes.
They may also be called gliflozins.
• SGLT-2 inhibitors inhibit SGLT-2 proteins located in the renal tubules of the kidneys which are responsible for
reabsorbing glucose back into the blood. As a result, more glucose is excreted in the urine. SGLT-2 inhibitors have
been shown to be effective at lowering HbA1c levels, improving weight loss and lowering blood pressure. They
carry a low risk of hypoglycemia.
• They are usually well tolerated. SGLT-2 inhibitors may be used in the treatment of type 2 diabetes and act
independently of beta-cell function in the pancreas.

A.DAPAGLIFLOZIN
• Dapagliflozin is used by itself or in combination with other medicines to treat type 2
diabetes mellitus. It helps control the high blood sugar levels seen in diabetes. This reduces
the chances of serious complications of diabetes and also helps prevent heart disease.
• Dapagliflozin may be unsafe to use during pregnancy.

• Dapagliflozin inhibits subtype 2 of the SGLT2 which are responsible for at least 90% of the
glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood
glucose to be eliminated through the urine.in clinical trials, dapagliflozin lowered HbA1c by
0.6 versus placebo percentage points when added to metformin.
• Regarding its protective effects in heart failure, this is attributed primarily to haemodynamic
effects, where SGLT2 inhibitors potently reduce intravascular volume through osmotic
diuresis and natriuresis. This consequently may lead to a reduction in preload and afterload,
thereby alleviating cardiac workload and improving left ventricular function.

PHARMACOKINETICS
• Oral dapagliflozin reaches a maximum concentration within 1 hour of administration when
patients have been fasting. When patients have consumed a high fat meal, the time to maximum
concentration increases to 2 hours and the maximum concentration decreases by half though a
dose adjustment is not necessary dapagliflozin inhibits the sodium-glucose contransporter 2
which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of
glucose resorption in the kidneys and so its inhibition allows for glucose to be excreted in the
urine. This excretion allows for better glycemic control and potentially weight loss in patients
with type 2 diabetes mellitus

ADVERSE EFFECTS
Glycosuria
Weight loss
Tiredness
Dehydration
Urinary tract infections
Candidiasis
Fournier gangrene
Risk of diabetic ketoacidosis
Genital yeast infections

B.CANAGLIFLOZIN
• Canagliflozin is used by itself or in combination with other medicines to treat type 2
diabetes mellitus. It helps control the high blood sugar levels seen in diabetes. This reduces
the chances of serious complications of diabetes and also helps prevent heart disease. It is
a third-line medication to be tried after metformin, a first-line medication for type 2
diabetes.it is used together with exercise and diet.it is not recommended in type 1 diabetes.

• Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which is
responsible for at least 90% of renal glucose reabsorption (the remaining 10% is done
by SGLT1). Blocking this transporter causes up to 119 grams of blood glucose per day to be
eliminated through the urine,[34] corresponding to 476 kilocalories. Additional water is
eliminated by osmotic diuresis, resulting in a lowering of blood pressure.
• This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose)
compared to other types of anti-diabetic drugs such as sulfonylurea derivatives and insulin.

PHARMACOKINETICS
• When taken by mouth, canagliflozin reaches highest blood plasma concentrations after one
to two hours and has an absolute bioavailability of 65%, independently of food intake. When
in the bloodstream, 99% of the substance are bound to plasma proteins, mainly albumin. It
is metabolized mainly by o-glucuronidation via the enzymes UGT1A9 and UGT2B4, and
by hydroxylation to a lesser extent. The terminal half life is 10.6 hours for a 100 mg dose
and 13.1 hours for a 300 mg dose, with 43% being excreted in the faeces (mostly in
unchanged form) and 33% in the urine (mostly as glucuronide).

ADVERSE EFFECTS
• Frequent urge to urinate
• Genital infection
• Urinary tract infection
• Increased thirst
• Nausea

2.DOPAMINE D2 AGONIST
• A dopamine agonist is a compound that activates dopamine receptors. There are two
families of dopamine receptors, d₂-like and d₁-like, and they are all G protein-coupled
receptors. D₁- and d₅-receptors belong to the d₁-like family and the d₂-like family includes
D₂, D₃ and D₄ receptors. Dopamine agonists are used in parkinson’s disease and, to a lesser
extent, to treat depression, hyperprolactinemia and restless legs syndrome.

BROMOCRIPTINE
• IT is an ergoline derivative and dopamine agonist that is used in the treatment
of pituitary tumors, parkinson's disease, hyperprolactinaemia, neuroleptic malignant
syndrome, IT IS ALSO used to treat type 2 diabetes mellitus, female infertility and
acromegaly.

MECHANISM OF ACTION
• When administered within 2 hours of awakening, it increases hypothalamic dopamine level
and as a result decreases hepatic glucose production. It therefore acts as an adjunct to diet
and exercise to improve glycemic control.

PHARMACOKINETICS
• Bromocriptine is a partial agonist of the dopamine D2 receptor. it also interacts with
other dopamine receptors and with various serotonin and adrenergic
receptors. bromocriptine has additionally been found to inhibit
the release of glutamate by reversing the GLT1 glutamate transporter

ADVERSE EFFECTS
• Nausea
• Orthostatic hypotension
• Headaches
• Vomiting
• Pulmonary fibrosis

QUESTION
1. Plain insulin is indicated in
(a) Diabetic coma
(b) Obese diabetic undergoing surgery
(c) Juvenile unstable diabetic
(d) All of the above

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