4. INTRODUCTION TO DRUG - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/50474/12... · 4....
Transcript of 4. INTRODUCTION TO DRUG - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/50474/12... · 4....
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4. INTRODUCTION TO DRUG
4.1 Gliclazide120
Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin-
dependent diabetes mellitus (NIDDM).
4.1.1 Description of Gliclazide
Name Gliclazide
Drug Type
Approved
Small Molecule
Standard Formula: C15H21 N3O3 S
Chemical Name: 1-[(4-methylbenzene)sulfonyl]-3-
{octahydrocyclopenta[c]pyrrol-2-yl}urea
Molecular Weight: 323.411
CAS Registry
Number 21187-98-4
Chemical Structure:
| I
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4.1.2 Physico-chemical properties of Gliclazide
Characteristics: A white or almost white powder.
Solubility: Practically insoluble in water, freely soluble in methylene
chloride, sparingly soluble in acetone, slightly soluble in
ethanol(96%).
Melting Point: 181 °C
pKa 14.13
4.1.3 Mechanism of action:
Gliclazide binds to the β cell sulfonyl urea receptor. This binding subsequently blocks the
ATP sensitive potassium channels. The binding results in closure of the channels and
leads to a resulting decrease in potassium efflux leads to depolarization of the β cells.
This opens voltage-dependent calcium channels in the β cell resulting in calmodulin
activation, which in turn leads to exocytosis of insulin containing secretorty granules.
4.1.4 Clinical Pharmacology:
Absorption: Rapidly and well absorbed but may have wide inter- and intra-individual
variability. Peak plasma concentrations occur within 4-6 hours of oral administration.
Distribution: After absorption drug bound to plasma protein and reach to site of action.
Metabolism: Extensively metabolized in the liver. Less than 1% of the orally
administered dose appears unchanged in the urine. Metabolites include oxidized and
hydroxylated derivates, as well as glucuronic acid conjugates.
Excretion: Metabolites and conjugates are eliminated primarily by the kidneys (60-70%)
and also in the feces (10-20%).
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4.1.5 Indication for usage:
For the treatment of NIDDM in conjunction with diet and exercise.
4.1.6 Drug interactions:
Drug Interaction
Acebutolol
Acebutolol may decrease symptoms of hypoglycemia and
increase the time required for the body to compensate for
hypoglycemia.
Acetylsalicylic
acid
Acetylsalicylic acid increases the effect of the sulfonylurea,
gliclazide.
Atenolol The beta-blocker, atenolol, may decrease symptoms of
hypoglycemia.
Betaxolol The beta-blocker, betaxolol, may decrease symptoms of
hypoglycemia.
Bevantolol The beta-blocker, bevantolol, may decrease symptoms of
hypoglycemia.
Bismuth
Subsalicylate
The salicylate, bismuth subsalicylate, increases the effect of
the sulfonylurea, gliclazide.
Bisoprolol The beta-blocker, bisoprolol, may decrease symptoms of
hypoglycemia.
Carteolol The beta-blocker, carteolol, may decrease symptoms of
hypoglycemia.
Carvedilol The beta-blocker, carvedilol, may decrease symptoms of
hypoglycemia.
Chloramphenicol Chloramphenicol may increase the effect of sulfonylurea,
gliclazide.
Clofibrate Clofibrate may increase the effect of sulfonylurea, gliclazide.
Dicumarol Dicumarol may increase the effect of sulfonylurea, gliclazide.
Esmolol The beta-blocker, esmolol, may decrease symptoms of
hypoglycemia.
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Glucosamine Possible hyperglycemia
Labetalol The beta-blocker, labetalol, may decrease symptoms of
hypoglycemia.
Magnesium
salicylate
The salicylate, magnesium salicylate, increases the effect of
the sulfonylurea, gliclazide.
Metoprolol The beta-blocker, metoprolol, may decrease symptoms of
hypoglycemia.
Nadolol The beta-blocker, nadolol, may decrease symptoms of
hypoglycemia.
Oxprenolol The beta-blocker, oxprenolol, may decrease symptoms of
hypoglycemia.
Penbutolol The beta-blocker, penbutolol, may decrease symptoms of
hypoglycemia.
Phenylbutazone Phenylbutazone increases the effect of the hypoglycemic agent
Pindolol The beta-blocker, pindolol, may decrease symptoms of
hypoglycemia.
Practolol The beta-blocker, practolol, may decrease symptoms of
hypoglycemia.
Propranolol The beta-blocker, propranolol, may decrease symptoms of
hypoglycemia.
Rifampin Rifampin may decrease the effect of sulfonylurea, gliclazide.
Salicylate-sodium The salicylate, salicylate-sodium, increases the effect of the
sulfonylurea, gliclazide.
Salsalate The salicylate, salsalate, increases the effect of the
sulfonylurea, gliclazide.
Somatropin
Somatropin may antagonize the hypoglycemic effect of
gliclazide. Monitor for changes in fasting and postprandial
blood sugars.
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Sotalol The beta-blocker, sotalol, may decrease symptoms of
hypoglycemia.
Timolol The beta-blocker, timolol, may decrease symptoms of
hypoglycemia.
Trisalicylate-
choline
The salicylate, trisalicylate-choline, increases the effect of the
sulfonylurea, gliclazide.
4.1.7 Dosage and administration:
Initial dose: 5 mg (immediate or sustained-release) orally once a day, 30 minutes before
breakfast.
Maintenance dose: 2.5 to 30 mg (immediate-release) orally in 1 or 2 divided doses or 5 to
20 mg (sustained-release) orally in 1 or 2 divided doses.
4.1.8 Overdosage:
Gliclazide overdose can cause life-threatening hypoglycemia.
Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating,
trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).
4.1.9 Marketed formulation129
Azukon (Torrent), Gujarat
Tablet 80mg
4.2 Glibenclamide121
:
Glibenclamide is an oral antihyperglycemic agent used for the treatment of non-insulin-
dependent diabetes mellitus (NIDDM).
4.2.1 Description of Glibenclamide
Name Glibenclamide
Drug Type
Approved
Small Molecule
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Standard Formula: C23H28ClN3O5S
Chemical Name: 5-chloro-N-[2-(4-
{[(cyclohexylcarbamoyl)amino]sulfonyl}phenyl)ethyl]-
2-methoxybenzamide .
Molecular Weight: 494.004
CAS Registry
Number 10238-21-8
Chemical Structure:
4.2.2 Physico-chemical properties of Glibenclamide
Characteristics: A white or almost white, crystalline powder.
Solubility: Practically insoluble in water, sparingly soluble in
methylene chloride, slightly soluble in alcohol and in
methanol.
Melting Point: 169 °C
pKa 4.32
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4.2.3 Mechanism of action:
Sulfonylureas such as glibenclamide bind to ATP-sensitive potassium channels on the
pancreatic cell surface, reducing potassium conductance and causing depolarization of
the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive
calcium channels, raising intracellular concentrations of calcium ions, which induces the
secretion, or exocytosis, of insulin.
4.2.4 Clinical Pharmacology:
Absorption: Gastrointestinal absorption is uniform, rapid, and essentially complete.
Distribution: after absorption drug bound to plasma protein and reach to site of action.
Metabolism: Primarily hepatic (mainly cytochrome P450 3A4). The major metabolite is
the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also
occurs. These metabolites do not contribute clinically significant hypoglycemic action in
humans as they are only weakly active; however, retention of 4-trans-hydroxyglyburide
may prolong the hypoglycemic effect of the agent in those with severe renal impairment.
Excretion: Glyburide is excreted as metabolites in the bile and urine, approximately 50%
by each route. This dual excretory pathway is qualitatively different from that of other
sulfonylureas, which are excreted primarily in the urine.
4.2.5 Indication for usage:
Indicated as an adjunct to diet to lower the blood glucose in patients with NIDDM whose
hyperglycemia cannot be satisfactorily controlled by diet alone.
4.2.6 Drug interactions:
Drug Interaction
Acebutolol
Acebutolol may decrease symptoms of hypoglycemia and
increase the time required for the body to compensate for
hypoglycemia.
Acetylsalicylic
acid
Acetylsalicylic acid increases the effect of the sulfonylurea,
glibenclamide.
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Atenolol The beta-blocker, atenolol, may decrease symptoms of
hypoglycemia.
Betaxolol The beta-blocker, betaxolol, may decrease symptoms of
hypoglycemia.
Bevantolol The beta-blocker, bevantolol, may decrease symptoms of
hypoglycemia.
Bismuth
Subsalicylate
The salicylate, bismuth subsalicylate, increases the effect of
the sulfonylurea, glibenclamide.
Bisoprolol The beta-blocker, bisoprolol, may decrease symptoms of
hypoglycemia.
Bosentan Increased risk of hepatic toxicity
Carteolol The beta-blocker, carteolol, may decrease symptoms of
hypoglycemia.
Carvedilol The beta-blocker, carvedilol, may decrease symptoms of
hypoglycemia.
Chloramphenicol Chloramphenicol may increase the effect of sulfonylurea,
glibenclamide.
Clofibrate Clofibrate may increase the effect of sulfonylurea,
glibenclamide.
Colesevelam
Colesevelam may decrease the serum concentration of
Glyburide. Glyburide should be administered at least 4 hours
before colesevelam to minimize the risk of an interaction.
Cyclosporine The sulfonylurea, glibenclamide, may increase the effect of
cyclosporine.
Diazoxide Antagonism.
Dicumarol Dicumarol may increase the effect of sulfonylurea,
glibenclamide.
Esmolol The beta-blocker, esmolol, may decrease symptoms of
hypoglycemia.
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Glucosamine Possible hyperglycemia
Labetalol The beta-blocker, labetalol, may decrease symptoms of
hypoglycemia.
Magnesium
salicylate
The salicylate, magnesium salicylate, increases the effect of
the sulfonylurea, glibenclamide.
Metoprolol The beta-blocker, metoprolol, may decrease symptoms of
hypoglycemia.
Nadolol The beta-blocker, nadolol, may decrease symptoms of
hypoglycemia.
Oxprenolol The beta-blocker, oxprenolol, may decrease symptoms of
hypoglycemia.
Penbutolol The beta-blocker, penbutolol, may decrease symptoms of
hypoglycemia.
Phenylbutazone Phenylbutazone increases the effect of the hypoglycemic agent
Pindolol The beta-blocker, pindolol, may decrease symptoms of
hypoglycemia.
Practolol The beta-blocker, practolol, may decrease symptoms of
hypoglycemia.
Propranolol The beta-blocker, propranolol, may decrease symptoms of
hypoglycemia.
Rifampin Rifampin may decrease the effect of sulfonylurea,
glibenclamide.
Salicylate-sodium The salicylate, salicylate-sodium, increases the effect of the
sulfonylurea, glibenclamide.
Salsalate The salicylate, salsalate, increases the effect of the
sulfonylurea, glibenclamide.
Somatropin
Somatropin may antagonize the hypoglycemic effect of
glibenclamide. Monitor for changes in fasting and postprandial
blood sugars.
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Sotalol The beta-blocker, sotalol, may decrease symptoms of
hypoglycemia.
Timolol The beta-blocker, timolol, may decrease symptoms of
hypoglycemia.
Trisalicylate-
choline
The salicylate, trisalicylate-choline, increases the effect of the
sulfonylurea, glibenclamide.
4.2.7 Dosage and administration:
The recommended starting dose is 2.5 to 5 mg daily of regular tablets or 1.5-3 mg daily
of micronized tablets. The maximum dose is 1.25 to 20 mg of regular tablets and 0.75 to
12 mg of micronized tablets. Glibenclamide usually is administered with the first main
meal of the day.
4.2.8 Overdosage:
Symptoms of overdose may include headache, sweating, shakiness, increased hunger,
changes in vision, nervousness, tiredness, seizures, and loss of consciousness.
4.2.9 Marketed formulation129
Gluconil (Bal Pharma), Karnataka
Tablet 5mg
4.3 Glipizide122
:
Glipizide is an oral hypoglycemic agent which is rapidly absorbed and completely
metabolized.
4.3.1 Description of Glipizide
Name Glipizide
Drug Type
Approved
Small Molecule
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Standard Formula: C21H27 N5O4 S
Chemical Name: N-[2-(4-
{[(cyclohexylcarbamoyl)amino]sulfonyl}phenyl)ethyl]-
5-methylpyrazine-2-carboxamide .
Molecular Weight: 445.535
CAS Registry
Number 29094-61-9
Chemical Structure:
4.3.2 Physico-chemical properties of Glipizide
Characteristics: A white or almost white, crystalline powder.
Solubility: Practically insoluble in water, very slightly soluble in
methylene chloride and in acetone, practically insoluble
in ethanol(96%). It dissolves in dilute solution of alkali
hydroxide.
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Melting Point: 208-209 °C
pKa 5.9
4.3.3 Mechanism of action:
Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic
cell surface, reducing potassium conductance and causing depolarization of the
membrane. Depolarization stimulates calcium ion influx through voltage-sensitive
calcium channels, raising intracellular concentrations of calcium ions, which induces the
secretion, or exocytosis, of insulin.
4.3.4 Clinical Pharmacology:
Absorption: Gastrointestinal absorption is uniform, rapid, and essentially complete.
Distribution: after absorption drug is bound to plasma protein and reach to site of action.
Metabolism: Hepatic. The major metabolites of Glipizide are products of aromatic
hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts
for less than 2% of a dose, an acetylaminoethyl benzine derivatives, is reported to have
1/10 to 1/3 as much hypoglycemic activity as the parent compound.
Excretion: The primary metabolites are inactive hydroxylation products and polar
conjugates and are excreted mainly in the urine.
4.3.5 Indication for usage:
Glipizide, a second-generation sulfonylurea, is used with diet to lower blood glucose in
patients with diabetes mellitus type II.
4.3.6 Drug interactions:
Interaction
Drug Interaction
Acebutolol Acebutolol may decrease symptoms of hypoglycemia and increase the
time required for the body to compensate for hypoglycemia.
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Acetylsalicylic
acid Acetylsalicylic acid increases the effect of the sulfonylurea, Glipizide.
Atenolol The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
Bisoprolol The beta-blocker, bisoprolol, may decrease symptoms of
hypoglycemia.
Carvedilol The beta-blocker, carvedilol, may decrease symptoms of
hypoglycemia.
Chloramphenicol Chloramphenicol may increase the effect of sulfonylurea, Glipizide.
Clofibrate Clofibrate may increase the effect of sulfonylurea, Glipizide.
Cyclosporine The sulfonylurea, Glipizide, may increase the effect of cyclosporine.
Esmolol The beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
Labetalol The beta-blocker, labetalol, may decrease symptoms of hypoglycemia.
Metoprolol The beta-blocker, metoprolol, may decrease symptoms of
hypoglycemia.
Nadolol The beta-blocker, nadolol, may decrease symptoms of hypoglycemia.
Oxprenolol The beta-blocker, oxprenolol, may decrease symptoms of
hypoglycemia.
Phenylbutazone Phenylbutazone increases the effect of the hypoglycemic agent
Pindolol The beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
Propranolol The beta-blocker, propranolol, may decrease symptoms of
hypoglycemia.
Rifampin Rifampin may decrease the effect of sulfonylurea, Glipizide.
Somatropin Somatropin may antagonize the hypoglycemic effect of Glipizide.
Monitor for changes in fasting and postprandial blood sugars.
Timolol The beta-blocker, timolol, may decrease symptoms of hypoglycemia.
Tolbutamide Tolbutamide, a strong CYP2C9 inhibitor, may decrease the
metabolism and clearance of Glipizide..
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4.3.6 Dosage and administration:
Initial dose: 5mg orally once a day, 30 minutes before breakfast.
4.3.8 Overdosage:
A Glipizide overdose can cause life-threatening hypoglycemia.
Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating,
trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).
4.3.9 Marketed formulation129
Glez (Aristo Pharmaceuticals Ltd.), Mumbai
Tablet 5mg
4.4 Glimepiride123
:
Glimepiride is an oral hypoglycemic agent which is rapidly absorbed and completely
metabolized.
4.4.1 Description of Glimepiride
Name Glimepiride
Drug Type
Approved
Small Molecule
Standard
Formula:
C24H34N4O5S
Chemical Name: 3-ethyl-4-methyl-N-{2-[4-({[(4-
methylcyclohexyl)carbamoyl]amino}sulfonyl)phenyl]ethyl}-
2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide.
Molecular
Weight:
490.616
CAS Registry
Number 93479-97-1
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Chemical
Structure:
4.4.2 Physico-chemical properties of Glimepiride
Characteristics: A white or almost white powder.
Solubility: Practically insoluble in water, soluble in
dimethylformamide, slightly soluble in methylene
chloride, slightly soluble in methanol.
Melting Point: 207 °C
PKa 14.12
4.4.3 Mechanism of action:
The mechanism of action of glimepiride in lowering blood glucose appears to be
dependent on stimulating the release of insulin from functioning pancreatic beta cells,
and increasing sensitivity of peripheral tissues to insulin. Glimepiride likely binds to
ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing
potassium conductance and causing depolarization of the membrane. Membrane
depolarization stimulates calcium ion influx through voltage-sensitive calcium channels.
This increase in intracellular calcium ion concentration induces the secretion of insulin.
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4.4.4 Clinical Pharmacology:
Absorption: Completely (100%) absorbed following oral administration.
Distribution: Over 99.5% bound to plasma protein.
Metabolism: Hepatic. Following either an intravenous or oral dose, glimepiride is
completely metabolized by oxidative biotransformation to a major metabolite, cyclohexyl
hydroxymethyl derivative (M1), via the hepatic cytochrome P450 II C9 subsystem. M1 is
further metabolized to the carboxyl derivative (M2) by one or several cytosolic enzymes.
M1, but not M2, possessed approximately one third of the pharmacologic activity of its
parent in an animal model. However, whether the glucose-lowering effect of M1 is
clinically significant is not clear.
Excretion: The primary metabolites are inactive hydroxylation products and polar
conjugates and are excreted mainly in the urine.
4.4.5 Indication for usage:
For concomitant use with insulin for the treatment of noninsulin-dependent (type 2)
diabetes mellitus.
4.4.6 Drug interactions:
Drug Interaction
Cyclosporine The sulfonylurea, glimepiride, may increase the effect of
cyclosporine.
Gemfibrozil Gemfibrozil increases the effect and toxicity of
rosiglitazone/pioglitazone
Glucosamine Possible hyperglycemia
Ketoconazole Ketoconazole increases the effect of rosiglitazone
Rifampin Rifampin may decrease the effect of sulfonylurea, glimepiride.
Somatropin
recombinant
Somatropin may antagonize the hypoglycemic effect of
glimepiride. Monitor for changes in fasting and postprandial
blood sugars.
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Tolbutamide
Tolbutamide, a strong CYP2C9 inhibitor, may decrease the
metabolism and clearance of Glimepiride. Consider alternate
therapy or monitor for changes in Glimepiride therapeutic and
adverse effects if Tolbutamide is initiated, discontinued or
dose changed.
4.4.7 Dosage and administration:
Like other medicines used to treat diabetes, the dose of glimepiride is individualized
using periodic measurements of blood sugar to determine the best dose. The
recommended dose is 1 to 8 mg once daily. The usual starting dose is 1 or 2 mg daily
4.4.8 Overdosage:
Symptoms of overdose may include: shakiness, rapid heartbeat, unexplained sweating,
loss of consciousness.
4.4.9 Marketed formulation129
Amaryl (Aventis Pharma Ltd), Maharashtra
Tablet 3mg
4.5 Metformin HCl124
:
Metformin is a biguanide antihyperglycemic agent used for treating non-insulin-
dependent diabetes mellitus (NIDDM)
4.5.1 Description of Metformin HCl
Name Metformin
Drug Type
Approved
Small Molecule
Standard Formula: C4H12 ClN5
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Chemical Name: 1-carbamimidamido-N,N-
dimethylmethanimidamide.hydrochloride
Molecular Weight: 165.66
CAS Registry
Number
1115-70-4
Chemical Structure:
.HCl
4.5.2 Physico-chemical properties of Metformin HCl
Characteristics: White crystals
Solubility: Sparingly soluble in methanol; slightly soluble in alkali,
soluble in water.
Melting Point: 223-226 °C
pKa 12.4
4.5.3 Mechanism of action:
Metformin's mechanisms of action differ from other classes of oral antihyperglycemic
agents. Metformin decreases blood glucose levels by decreasing hepatic glucose
production, decreasing intestinal absorption of glucose, and improving insulin sensitivity
by increasing peripheral glucose uptake and utilization. These effects are mediated by the
initial activation by metformin of AMP-activated protein kinase (AMPK), a liver enzyme
that plays an important role in insulin signaling, whole body energy balance, and the
metabolism of glucose and fats. Activation of AMPK is required for metformin's
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inhibitory effect on the production of glucose by liver cells. Increased peripheral
utilization of glucose may be due to improved insulin binding to insulin receptors.
Metformin administration also increases AMPK activity in skeletal muscle. AMPK is
known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-
independent glucose uptake. The rare side effect, lactic acidosis, is thought to be caused
by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis. In
those with healthy renal function, the slight excess is simply cleared. However, those
with severe renal impairment may accumulate clinically significant serum lactic acid
levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease
and acute/decompensated heart failure.
4.5.4 Clinical Pharmacology:
Absorption: Absorbed over 6 hours, bioavailability is 50 to 60% under fasting
conditions. Administration with food decreases and delays absorption. Some evidence
indicates that the level of absorption is not dose-related, suggesting that absorption occurs
through a saturable process. Limited data from animal and human cell cultures indicate
that absorption occurs through a passive, non-saturable process, possibly involving a
paracellular route. Peak action occurs 3 hours after oral administration.
Distribution: Metformin is negligibly bound to plasma proteins.
Metabolism: Metformin is not metabolized.
Excretion: Approximately 90% of the drug is eliminated in 24 hours in those with
healthy renal function. Renal clearance of metformin is approximately 3.5 times that of
creatinine clearance, indicating the tubular secretion is the primary mode of metformin
elimination.
4.5.5 Indication for usage:
For use as an adjunct to diet for the control of hyperglycemia and its associated
symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type
II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy
has proved unsatisfactory.
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4.5.6 Drug interactions:
Drug Interaction
Cimetidine
Cimetidine may increase the therapeutic and adverse effects of
metformin by increasing its serum concentration. Consider
alternate therapy.
Glucosamine Possible hyperglycemia
Somatropin
recombinant
Somatropin may antagonize the hypoglycemic effect of
metformin. Monitor for changes in fasting and postprandial
blood sugars.
4.5.7 Dosage and administration:
The recommended dose is 500mg daily.
4.5.8 Overdosage:
It would be expected that adverse reactions of a more intense character including
epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness,
dizziness, malaise and headache might be seen.
4.5.9 Marketed formulation129
Forson(Unison Pharmaceuticals Ltd.), Gujarat
Tablet 500mg
4.6 Repaglinide125
:
Repaglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-
dependent diabetes mellitus (NIDDM).
4.6.1 Description of Repaglinide
Name Repaglinide
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Drug Type
Approved
Small Molecule
Standard Formula: C27H36N2O4
Chemical Name: 2-ethoxy-4-({[(1S)-3-methyl-1-[2-(piperidin-1-
yl)phenyl]butyl]carbamoyl}methyl)benzoic acid
Molecular Weight: 452.5857
CAS Registry
Number 135062-02-1
Chemical Structure:
4.6.2 Physico-chemical properties of Repaglinide
Characteristics: White crystals
Solubility: soluble in methanol; slightly soluble in Alkali, practically
insoluble in water and Acid.
Melting Point: 130-131 °C
pKa 5.9
4.6.3 Mechanism of action:
Repaglinide activity is dependent on the presence functioning β cells and glucose. In
contrast to sulfonylurea insulin secretatogogues, repaglinide has no effect on insulin
release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose
on ATP-sensitive potassium channel and has little effect on insulin levels between meals
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and overnight. As such, repaglinide is more effective at reducing postprandial blood
glucose levels than fasting blood glucose levels and requires a longer duration of therapy
(approximately one month) before decreases in fasting blood glucose are observed. The
insulinotropic effects of repaglinide are highest at intermediate glucose levels (3 to 10
mmol/L) and it does not increase insulin release already stimulated by high glucose
concentrations (greater than 15 mmol/L). Repaglinide appears to be selective for
pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid
tissue.
4.6.4 Clinical Pharmacology:
Absorption: Rapidly absorbed following oral administration, with an absolute
bioavailability of 87%.
Distribution: The fraction of sitagliptin reversibly bound to plasma proteins is low
(38%).
Metabolism: Repaglinide is rapidly metabolized via oxidation and dealkylation by
cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2).
Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the
carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other
unidentified metabolites have been detected. Repaglinide metabolites to not possess
appreciable hypoglycemic activity.
Excretion: 90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as
unchanged drug)
4.6.5 Indication for usage:
For use as an adjunct to diet for the control of hyperglycemia and its associated
symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type
II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy
has proved unsatisfactory.
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4.6.6 Drug interactions:
Drug Interaction
Acebutolol
Acebutolol may decrease symptoms of hypoglycemia and
increase the time required for the body to compensate for
hypoglycemia.
Atenolol The beta-blocker, atenolol, may decrease symptoms of
hypoglycemia.
Betaxolol The beta-blocker, betaxolol, may decrease symptoms of
hypoglycemia.
Bevantolol The beta-blocker, bevantolol, may decrease symptoms of
hypoglycemia.
Bisoprolol The beta-blocker, bisoprolol, may decrease symptoms of
hypoglycemia.
Carteolol The beta-blocker, carteolol, may decrease symptoms of
hypoglycemia.
Carvedilol The beta-blocker, carvedilol, may decrease symptoms of
hypoglycemia.
Clarithromycin Clarithromycin may increase the effect of repaglinide.
Cyclosporine Cyclosporine may increase the therapeutic and adverse effects
of repaglinide.
Erythromycin The macrolide, erythromycin, may increase the effect of
repaglinide.
Esmolol The beta-blocker, esmolol, may decrease symptoms of
hypoglycemia.
Gemfibrozil Gemfibrozil may increase the effect and toxicity of
repaglinide.
Glucosamine Possible hyperglycemia
Josamycin The macrolide, josamycin, may increase the effect of
repaglinide.
Labetalol The beta-blocker, labetalol, may decrease symptoms of
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hypoglycemia.
Metoprolol The beta-blocker, metoprolol, may decrease symptoms of
hypoglycemia.
Nadolol The beta-blocker, nadolol, may decrease symptoms of
hypoglycemia.
Oxprenolol The beta-blocker, oxprenolol, may decrease symptoms of
hypoglycemia.
Penbutolol The beta-blocker, penbutolol, may decrease symptoms of
hypoglycemia.
Pindolol The beta-blocker, pindolol, may decrease symptoms of
hypoglycemia.
Practolol The beta-blocker, practolol, may decrease symptoms of
hypoglycemia.
Propranolol The beta-blocker, propranolol, may decrease symptoms of
hypoglycemia.
Rifampin Rifampin decreases the effect of repaglinide
Sotalol The beta-blocker, sotalol, may decrease symptoms of
hypoglycemia.
Telithromycin
Telithromycin may reduce clearance of Repaglinide. Consider
alternate therapy or monitor for changes in the
therapeutic/adverse effects of Repaglinide if Telithromycin is
initiated, discontinued or dose changed.
Timolol The beta-blocker, timolol, may decrease symptoms of
hypoglycemia.
Voriconazole
Voriconazole, a strong CYP3A4 inhibitor, may increase the
serum concentration of repaglinide by decreasing its
metabolism. Monitor for changes in the therapeutic and
adverse effects of repaglinide if voriconazole is initiated,
discontinued or dose changed.
Page 107
4.6.7 Dosage and administration:
Usual initial dose: 0.5 mg, taken within 30 minutes of main meals. Initial doses of 1 or 2
mg may be used in patients who have had previous hypoglycaemic treatment. May adjust
dose at intervals of 1-2 wk, up to 4 mg before meals.
4.6.8 Overdosage:
Severe hypoglycaemic reactions with coma, seizure and other neurological impairment
may occur.
4.6.9 Marketed formulation125
Eurepa(Torrent), Gujarat
Tablet 2mg
4.7 Saxagliptin HCl126
:
Saxagliptin (rINN), previously identified as BMS-477118, is a new oral hypoglycemic
(anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.
4.7.1 Description of Saxagliptin HCl
Name Saxagliptin HCl
Drug Type
Approved
Small Molecule
Standard Formula: C18H25 N3O2.HCl
Chemical Name: (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-
yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
.hydrochloride.
Molecular Weight: 351.87
CAS Registry
Number 709031-78-7
Page 108
Chemical Structure:
.HCl
4.7.2 Physico-chemical properties of Saxagliptin HCl
Characteristics: White crystals
Solubility: soluble in water; slightly soluble in ethyl acetate, soluble
in methanol, ethanol, isopropanol, acetonitrile and
acetone .
Melting Point: 205-207°C
4.7.3 Mechanism of action:
Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic for the treatment of
Type 2 diabetes. DPP-4 inhibitors are a class of compounds that work by affecting the
action of natural hormones in the body called incretins. Incretins decrease blood sugar by
increasing consumption of sugar by the body, mainly through increasing insulin
production in the pancreas, and by reducing production of sugar by the liver. [Bristol-
Myers Squibb Press Release] DPP-4 is a membrane associated peptidase which is found
in many tissues, lymphocytes and plasma. DPP-4 has two main mechanisms of action, an
enzymatic function and another mechanism where DPP-4 binds adenosine deaminase,
which conveys intracellular signals via dimerization when activated. Saxagliptin forms a
reversible, histidine-assisted covalent bond between its nitrile group and the S630
hydroxyl oxygen on DPP4. The inhibition of DPP-4 increases levels active of glucagon
like peptide 1 (GLP-1), which inhibits glucagon production from pancreatic alpha cells
Page 109
and increases production of insulin from pancreatic beta cells.Sulfonylureas likely bind to
ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing
potassium conductance and causing depolarization of the membrane. Depolarization
stimulates calcium ion influx through voltage-sensitive calcium channels, raising
intracellular concentrations of calcium ions, which induces the secretion, or exocytosis,
of insulin.
4.7.4 Clinical Pharmacology:
Absorption: Gastrointestinal absorption is uniform, rapid, and essentially complete.
Distribution: after absorption drug bound to plasma protein and reach to site of action.
Metabolism: Hepatic. The major metabolites of saxagliptin are products of aromatic
hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts
for less than 2% of a dose, an acetylaminoethyl benzine derivatives, is reported to have
1/10 to 1/3 as much hypoglycemic activity as the parent compound.
Excretion: Approximately seventy percent of the administered human dose is excreted
in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as
unchanged Saxagliptin. Six percent of the dose is accounted for in the feces. Saxagliptin
is highly bound to plasma proteins and there is potential for displacement interactions
with other drugs.
4.7.5 Indication for usage:
For use as an adjunct to diet for the control of hyperglycemia and its associated
symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type
II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy
has proved unsatisfactory.
4.7.6 Drug interactions:
Drug Interaction
Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum
concentration of Saxagliptin. Limit saxagliptin dose to 2.5
Page 110
mg/day and monitor for increased saxagliptin levels/effects
(e.g., hypoglycemia) with concomitant administration of a
strong CYP3A4 inhibitor (e.g., ketoconazole). Monitor for
decreased saxagliptin levels/effects with discontinuation of
concomitant CYP3A4 inhibitor.
Somatropin
Somatropin may antagonize the hypoglycemic effect of
saxagliptin. Monitor for changes in fasting and postprandial
blood sugars.
Voriconazole
Voriconazole, a strong CYP3A4 inhibitor, may increase the
serum concentration of saxagliptin by decreasing its
metabolism. Monitor for changes in the therapeutic and
adverse effects of saxagliptin if voriconazole is initiated,
discontinued or dose changed.
4.7.7 DOSAGE AND ADMINISTRATION:
5mg once daily.
4.7.8 OVERDOSAGE:
The adverse reactions are mild and transient.
4.7.9 Marketed formulation129
Onglyza(Astra Zeneca), Karnataka
Tablet 5mg
4.8 Vildagliptin127
:
Vildagliptin, previously identified as LAF237, is a new oral anti-hyperglycemic agent
(anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.
Page 111
4.8.1 Description of Vildagliptin
Name Vildagliptin
Drug Type
Approved
Small Molecule
Standard Formula: C21H27 N5O4 S
Chemical Name: N-[2-(4-
{[(cyclohexylcarbamoyl)amino]sulfonyl}phenyl)ethyl]-
5-methylpyrazine-2-carboxamide .
Molecular Weight: 445.535
CAS Registry
Number 274901-16-5
Chemical Structure:
4.8.2 Physico-chemical properties of Vildagliptin
Characteristics: White crystals
Solubility: Sparingly soluble in methanol; slightly soluble in alkali,
practically insoluble in water and acid.
Melting Point: 153-155 °C
pKa 5.9
Page 112
4.8.3 Mechanism of action:
Vildagliptin inhibits dipeptidyl peptidase-4 (DPP-4). This in turn inhibits the inactivation
of GLP-1 by DPP-4, allowing GLP-1 to potentiate the secretion of insulin in the beta
cells. Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through
degradation of GIP and the degradation of GLP-1.
4.8.4 Clinical Pharmacology:
Absorption: Rapidly absorbed.
Distribution: Low protein binding drug.
Metabolism: Vildagliptin is metabolized by hydrolysis.
Excretion: Mainly excreted in urine and feces.
4.8.5 Indication for usage:
Indicated as an adjunct to diet and exercise to improve glycaemic control in patients with
type II diabetes mellitus as monotherapy.
4.8.6 Dosage and administration:
The recommended daily dose is 50mg orally without food.
4.8.7 Overdosage:
Rare cases of hepatic dysfunction have been reported.
4.8.8 Marketed formulation129
Jalra (USV Ltd), Maharashtra
Tablet 50mg
4.9 Sitagliptin phosphate 128
:
Sitagliptin is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl
peptidase-4 (DPP-4) inhibitor class of drugs.
Page 113
4.9.1 Description of Sitagliptin phosphate
Name Sitagliptin phosphate
Drug Type
Approved
Small Molecule
Standard Formula: C16H15 F6 N5 O.H3PO4.H2O
Chemical Name: (3R)-3-amino-1-[3-(trifluoromethyl)-5H,6H,7H,8H-
[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-
trifluorophenyl)butan-1-one,phosphate monohydrate
Molecular Weight: 523.32
CAS Registry
Number 654671-78-0
Chemical Structure:
.H3PO4.H2O
4.9.2 Physico-chemical properties of Sitagliptin phosphate
Characteristics: White crystals
Solubility: Soluble in water, DMF; slightly soluble in
methanol;very slightly soluble in ethanol, acetone and
acetonitrile .
Melting Point: 202-204 °C
pKa 7.7
Page 114
4.9.3 Mechanism of action:
Sitagliptin is a highly selective DPP-4 inhibitor, which is believed to exert its actions in
patients with type 2 diabetes by slowing the inactivation of incretin hormones, thereby
increasing the concentration and prolonging the action of these hormones. Incretin
hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and
levels are increased in response to a meal. These hormones are rapidly inactivated by the
enzyme, DPP-4. The incretins are part of an endogenous system involved in the
physiologic regulation of glucose homeostasis. When blood glucose concentrations are
normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic
beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers
glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose
production. By increasing and prolonging active incretin levels, sitagliptin increases
insulin release and decreases glucagon levels in the circulation in a glucose-dependent
manner. These changes lead to a decrease in hemoglobin A1c (HbA1c)levels, as well as a
lower fasting and postprandial glucose concentration. Sitagliptin demonstrates selectivity
for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations
approximating those from therapeutic doses.
4.9.4 Clinical Pharmacology:
Absorption: Rapidly absorbed following oral administration, with an absolute
bioavailability of 87%.
Distribution: after absorption drug bound to plasma protein and reach to site of action.
Metabolism: Sitagliptin does not undergo extensive metabolism. In vitro studies indicate
that the primary enzyme responsible for the limited metabolism of sitagliptin was
CYP3A4 (oxidation), with contribution from CYP2C8.
Excretion: Approximately 79% of sitagliptin is excreted unchanged in the urine with
metabolism being a minor pathway of elimination. Following administration of an oral
[14C]sitagliptin dose to healthy subjects, approximately 100% of the administered
radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing.
Page 115
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular
secretion.
4.9.5 Indication for usage.
Recommended dose is 100mg once daily,with or without food for the treatment of
diabetes.
4.9.6 Drug interactions:
Drug Interaction
Somatropin
Somatropin may antagonize the hypoglycemic effect of
sitagliptin. Monitor for changes in fasting and postprandial
blood sugars.
4.9.7 Dosage and administration:
100mg orally once daily. It can be taken with or without food.
4.9.8 Overdosage:
No dose related clinical adverse reactions observed upto 600mg per day.
4.9.9 Marketed formulation129
Januvia (MSD Pharma),Puducherry
Tablet 50mg