4. INTRODUCTION TO DRUG - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/50474/12... · 4....

Page 83

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

http://structures.wishartlab.com/molecules/DB01120/image.png


Page 84

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%).

Page 85

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.

http://www.drugbank.ca/drugs/DB01193















Page 86

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


Somatropin

Somatropin may antagonize the hypoglycemic effect of

gliclazide. Monitor for changes in fasting and postprandial

blood sugars.

















Page 87

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


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-


4.2.1 Description of Glibenclamide

Name Glibenclamide

Drug Type

Approved

Small Molecule





Page 88

Standard Formula: C23H28ClN3O5S

Chemical Name: 5-chloro-N-[2-(4-

{[(cyclohexylcarbamoyl)amino]sulfonyl}phenyl)ethyl]-

2-methoxybenzamide .


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.


pKa 4.32



Page 89


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.


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.


Indicated as an adjunct to diet to lower the blood glucose in patients with NIDDM whose

hyperglycemia cannot be satisfactorily controlled by diet alone.


Drug Interaction

Acebutolol



hypoglycemia.

Acetylsalicylic

acid

Acetylsalicylic acid increases the effect of the sulfonylurea,

glibenclamide.




Page 90


hypoglycemia.


hypoglycemia.


hypoglycemia.

Bismuth

Subsalicylate

The salicylate, bismuth subsalicylate, increases the effect of

the sulfonylurea, glibenclamide.


hypoglycemia.

Bosentan Increased risk of hepatic toxicity


hypoglycemia.


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.


hypoglycemia.

















Page 91



hypoglycemia.

Magnesium

salicylate

The salicylate, magnesium salicylate, increases the effect of

the sulfonylurea, glibenclamide.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.



hypoglycemia.


hypoglycemia.


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


Somatropin


glibenclamide. Monitor for changes in fasting and postprandial

blood sugars.

















Page 92


hypoglycemia.


hypoglycemia.

Trisalicylate-

choline

The salicylate, trisalicylate-choline, increases the effect of the



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.


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





Page 93


Chemical Name: N-[2-(4-


5-methylpyrazine-2-carboxamide .


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.

Page 94

Melting Point: 208-209 °C

pKa 5.9


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.



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.


Glipizide, a second-generation sulfonylurea, is used with diet to lower blood glucose in

patients with diabetes mellitus type II.


Interaction

Drug Interaction

Acebutolol Acebutolol may decrease symptoms of hypoglycemia and increase the

time required for the body to compensate for hypoglycemia.


Page 95

Acetylsalicylic

acid Acetylsalicylic acid increases the effect of the sulfonylurea, Glipizide.

Atenolol The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.


hypoglycemia.


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.


hypoglycemia.

Nadolol The beta-blocker, nadolol, may decrease symptoms of hypoglycemia.


hypoglycemia.


Pindolol The beta-blocker, pindolol, may decrease symptoms of hypoglycemia.


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..





















Page 96


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).


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

Page 97

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.


PKa 14.12


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.



Page 98


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.


For concomitant use with insulin for the treatment of noninsulin-dependent (type 2)

diabetes mellitus.


Drug Interaction

Cyclosporine The sulfonylurea, glimepiride, may increase the effect of

cyclosporine.

Gemfibrozil Gemfibrozil increases the effect and toxicity of

rosiglitazone/pioglitazone


Ketoconazole Ketoconazole increases the effect of rosiglitazone

Rifampin Rifampin may decrease the effect of sulfonylurea, glimepiride.

Somatropin

recombinant


glimepiride. Monitor for changes in fasting and postprandial

blood sugars.








Page 99

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.


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.


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


Page 100

Chemical Name: 1-carbamimidamido-N,N-

dimethylmethanimidamide.hydrochloride


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.


pKa 12.4


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



Page 101

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.


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.


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.

Page 102


Drug Interaction

Cimetidine

Cimetidine may increase the therapeutic and adverse effects of

metformin by increasing its serum concentration. Consider

alternate therapy.


Somatropin

recombinant


metformin. Monitor for changes in fasting and postprandial

blood sugars.


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.


Forson(Unison Pharmaceuticals Ltd.), Gujarat

Tablet 500mg

4.6 Repaglinide125

:

Repaglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-


4.6.1 Description of Repaglinide

Name Repaglinide





Page 103

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


CAS Registry

Number 135062-02-1

Chemical Structure:

4.6.2 Physico-chemical properties of Repaglinide


Solubility: soluble in methanol; slightly soluble in Alkali, practically

insoluble in water and Acid.


pKa 5.9


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



Page 104

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.


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)






Page 105


Drug Interaction

Acebutolol



hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


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.


hypoglycemia.

Gemfibrozil Gemfibrozil may increase the effect and toxicity of

repaglinide.


Josamycin The macrolide, josamycin, may increase the effect of

repaglinide.

















Page 106

hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.


hypoglycemia.

Rifampin Rifampin decreases the effect of repaglinide


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.


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


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.


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.


CAS Registry

Number 709031-78-7

Page 108

Chemical Structure:

.HCl

4.7.2 Physico-chemical properties of Saxagliptin HCl


Solubility: soluble in water; slightly soluble in ethyl acetate, soluble

in methanol, ethanol, isopropanol, acetonitrile and

acetone .

Melting Point: 205-207°C


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.




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.







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


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.


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


Chemical Name: N-[2-(4-


5-methylpyrazine-2-carboxamide .


CAS Registry

Number 274901-16-5

Chemical Structure:

4.8.2 Physico-chemical properties of Vildagliptin


Solubility: Sparingly soluble in methanol; slightly soluble in alkali,

practically insoluble in water and acid.


pKa 5.9



Page 112


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.


Absorption: Rapidly absorbed.

Distribution: Low protein binding drug.

Metabolism: Vildagliptin is metabolized by hydrolysis.

Excretion: Mainly excreted in urine and feces.


Indicated as an adjunct to diet and exercise to improve glycaemic control in patients with

type II diabetes mellitus as monotherapy.


The recommended daily dose is 50mg orally without food.

4.8.7 Overdosage:

Rare cases of hepatic dysfunction have been reported.


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


CAS Registry

Number 654671-78-0

Chemical Structure:

.H3PO4.H2O

4.9.2 Physico-chemical properties of Sitagliptin phosphate


Solubility: Soluble in water, DMF; slightly soluble in

methanol;very slightly soluble in ethanol, acetone and

acetonitrile .


pKa 7.7



Page 114


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.


Absorption: Rapidly absorbed following oral administration, with an absolute

bioavailability of 87%.


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.


Drug Interaction

Somatropin


sitagliptin. Monitor for changes in fasting and postprandial

blood sugars.


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.


Januvia (MSD Pharma),Puducherry

Tablet 50mg


Date post:	16-Apr-2020
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

4. INTRODUCTION TO DRUG - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/50474/12... · 4....

Documents