Alpha-glucosidase inhibitors(antidiabetic)

Alpha-glucosidase inhibitors
eg-Acarbose(brand name-Precose)
eg-Miglitol(brand name-Glyset)
activity-Slow the digestion of sugar
 Description
PRECOSE® (acarbose tablets) is an oral alpha-glucosidase inhibitor for use in the management of type 2 diabetes mellitus. Acarbose is an oligosaccharide which is obtained from fermentation processes of a microorganism, Actinoplanes utahensis, and is chemically known as O-4,6-dideoxy- 4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]- α-D-glucopyranosyl-(1 → 4)-O-α-D-glucopyranosyl-(1 → 4)-D-glucose. It is a white to off-white powder with a molecular weight of 645.6. Acarbose is soluble in water and has a pKa of 5.1. Its empirical formula is C25H43NO18
dosage
PRECOSE® is available as 25 mg, 50 mg and 100 mg tablets for oral use. The inactive ingredients are starch, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.
 Clinical Pharmacology
Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, PRECOSE® reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.
Mechanism of Action:
 In contrast to sulfonylureas, PRECOSE® does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.
Because its mechanism of action is different, the effect of PRECOSE® to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, PRECOSE® diminishes the insulinotropic and weight-increasing effects of sulfonylureas.
Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.
  Contraindications
PRECOSE® is contraindicated in patients with known hypersensitivity to the drug and in patients with diabetic ketoacidosis or cirrhosis. PRECOSE® is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, PRECOSE® is contraindicated in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.
  Adverse Reactions
Digestive Tract: Gastrointestinal symptoms are the most common reactions to PRECOSE®. In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 19%, 31%, and 74% respectively in 1255 patients treated with PRECOSE® 50-300 mg t.i.d., whereas the corresponding incidences were 9%, 12%, and 29% in 999 placebo-treated patients. In a one-year safety study, during which patients kept diaries of gastrointestinal symptoms, abdominal pain and diarrhea tended to return to pretreatment levels over time, and the frequency and intensity of flatulence tended to abate with time. The increased gastrointestinal tract symptoms in patients treated with PRECOSE® are a manifestation of the mechanism of action of PRECOSE® and are related to the presence of undigested carbohydrate in the lower GI tract.
If the prescribed diet is not observed, the intestinal side effects may be intensified. If strongly distressing symptoms develop in spite of adherence to the diabetic diet prescribed, the doctor must be consulted and the dose temporarily or permanently reduced.
Elevated Serum Transaminase Levels: See
Other Abnormal Laboratory Findings: Small reductions in hematocrit occurred more often in PRECOSE®-treated patients than in placebo-treated patients but were not associated with reductions in hemoglobin. Low serum calcium and low plasma vitamin B6 levels were associated with PRECOSE® therapy but are thought to be either spurious or of no clinical significance.   

Glyset (miglitol)
 Description
GLYSET Tablets contain miglitol, an oral alpha-glucosidase inhibitor for use in the management of non-insulin-dependent diabetes mellitus (NIDDM). Miglitol is a desoxynojirimycin derivative, and is chemically known as 3,4,5-piperidinetriol, 1-(2-hydroxyethyl)-2-(hydroxymethyl)-, [2R-(2α,3β,4α, 5β)]-. It is a white to pale-yellow powder with a molecular weight of 207.2. Miglitol is soluble in water and has a pKa of 5.9. Its empirical formula is C8H17NO5 
dosage
GLYSET is available as 25 mg, 50 mg and 100 mg tablets for oral use. The inactive ingredients are starch, microcrystalline cellulose, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and polysorbate 80.

 Clinical Pharmacology 

Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, GLYSET Tablets reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.
Mechanism of Action
In contrast to sulfonylureas, GLYSET does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal α-glucoside hydrolase enzymes. Membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.Because its mechanism of action is different, the effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, GLYSET diminishes the insulinotropic and weight-increasing effects of sulfonylureas.
Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance.
  Indications And Usage
GLYSET Tablets, as monotherapy, are indicated as an adjunct to diet to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) whose hyperglycemia cannot be managed with diet alone. GLYSET may also be used in combination with a sulfonylurea when diet plus either GLYSET or a sulfonylurea alone do not result in adequate glycemic control. The effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination, presumably because its mechanism of action is different.
In initiating treatment for NIDDM, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling blood glucose and symptoms of hyperglycemia. The importance of regular physical activity when appropriate should also be stressed. If this treatment program fails to result in adequate glycemic control, the use of GLYSET should be considered. The use of GLYSET must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint.
Contraindications
GLYSET Tablets are contraindicated in patients with:
Diabetic ketoacidosis
Inflammatory bowel disease, colonic ulceration, or partial intestinal obstruction, and in patients predisposed to intestinal obstruction
Chronic intestinal diseases associated with marked disorders of digestion or absorption, or with conditions that may deteriorate as a result of increased gas formation in the intestine
Hypersensitivity to the drug or any of its components.
  Adverse Reactions
Gastrointestinal:Gastrointestinal symptoms are the most common reactions to GLYSET Tablets. In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 11.7%, 28.7%, and 41.5% respectively in 962 patients treated with GLYSET 25–100 mg 3 times daily, whereas the corresponding incidences were 4.7%, 10.0%, and 12.0% in 603 placebo-treated patients. The incidence of diarrhea and abdominal pain tended to diminish considerably with continued treatment.
Dermatologic:Skin rash was reported in 4.3% of patients treated with GLYSET compared to 2.4% of placebo-treated patients. Rashes were generally transient and most were assessed as unrelated to GLYSET by physician-investigators. 

Thiazolidinediones(antidiabetic)

Thiazolidinediones
eg-Pioglitazone    (brand name-Actos)   
eg-Rosiglitazone(brand name-Avandia)
activity-Help the body use insulin better
Pioglitazone
Pioglitazone is a drug used to treat  Type 2 diabetes. It lowers blood sugar by helping the body use insulin more efficiently. As an additional health benefit, pioglitzone may also improve HDL cholesterol and triglycerides. It can be used alone or in combination with other diabetes medicines such as sulfonylureas, metformin, or insulin. Taken alone, pioglitazone does not cause hypoglycemia (low blood sugar levels).
 Other Names
Actos
Glustin
Uses
Diabetes is characterized by abnormally high concentrations of sugar in the blood. Pioglitazone is used to help lower both fasting and after-meal blood sugar levels in patients with type 2 diabetes (non-insulin dependent diabetes). It is used alone (monotherapy) or in combination with a sulfonylurea, metformin, or insulin when dietary and lifestyle modifications fail to control blood sugar adequately.
Pancreas in relation to other organs, and panceatic islet cells. Source: National Institute of Diabetes and Digestive and Kidney Diseases.
dosage
Pioglitazone is taken, in tablet form, once a day with or without food.
mechanism of action
Pioglitazone is a type of thiazolidinedione (TZD) that works by making tissues—especially muscle, fat, and liver—more responsive to insulin. The other marketed TZD, rosiglitazone (marketed as Avandia) has a similar mechanism of action. TZDs work in the nucleus of the cell by increasing the transcription of genes involved in glucose metabolism. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues, increases glucose utilization, decreases production of glucose by the liver, and reduces the amount of glucose and insulin in the bloodstream.
Side Effects
Some common side effects associated with pioglitazone use are listed below:
    Cough or cold
    Headache
    Inflammation of the sinuses or throat
    Muscle pain
    Swelling or fluid retention
    Weight gain
    Decreased triglycerides and increased HDL (good cholesterol)
Benefits
Uncontrolled diabetes increases the risk of disease in almost every organ system, notably the kidneys and eyes. Normalization of blood sugar with pioglitazone reduces those risks. Apart from benefits of improved blood sugar control, pioglitazone increases good (HDL) cholesterol, lowers bad (LDL) cholesterol and triglycerides, and may have other beneficial effects in limiting the progression of arterial plaques. [1] It also reduces the progression of carotid artery wall thickening, which is a marker of cardiovascular risk. This benefit has been reported in patients with or without cardiovascular disease.

Rosiglitazone (roh-sig-LIH-tuh-zone)

The active ingredient in a drug that helps control the amount of glucose (sugar) in the blood and is being studied in the prevention and treatment of some types of cancer. Rosiglitazone stops cells from growing and may prevent the growth of new blood vessels that tumors need to grow. It is a type of thiazolidinedione and a type of antiangiogenesis agent.

Meglitinides(antidiabetic drug)

 Meglitinides
eg-Repaglinide (brand name-Prandin)   
eg-Nateglinide    (brand name-Starlix)
activity-Raise the amount of insulin in the body
Nateglinide is a prescription drug used to lower blood sugar levels in people with type 2 diabetes. It belongs to a family of drugs called oral antidiabetics because, unlike insulin, it is taken by mouth (orally).
MeglitinidesNateglinide itself does not lower blood sugar, but rather it acts by stimulating release of insulin—i.e., it acts as an insulin secretagogue. Other insulin secretagogues such as repaglinide (Prandin), glyburide (Amaryl), and tolbutamide (Orinase) have been approved for use in type 2 diabetes and have slightly different properties.
The Food and Drug Administration approved nateglinide on December 26, 2000.
Uses
Nateglinide is used to control glucose levels in people with type 2 diabetes. It is used when diet and exercise are unable to reduce blood sugar levels.
dosage
Nateglinide is available in 60-mg and 120-mg tablets. The recommended dosage is 120 mg taken three times daily within 30 minutes before a meal. Nateglinide is taken alone or with other antidiabetic medications taken by mouth, such as metformin (Glucophage).The 60-mg dose of nateglinide, either alone or in combination with metformin, may be used in people who have achieved their blood sugar level goal.
mechanism of action
Nateglinide lowers blood sugar levels by stimulating insulin secretion from the pancreas. It blocks protein channels on the surface of beta cells, which are the insulin-secreting cells of the pancreas. This opens calcium channels and allows calcium to flood into the cells. The calcium sets off a series of reactions that ultimately stimulate the beta cells to secrete insulin. Insulin reduces blood sugar by causing body tissues to take in the sugar, which then reduces the amount of sugar in the blood.
Compared to other insulin secretagogues, nateglinide gives a more rapid, but less sustained, secretion of insulin.[1] Thus, the drug's major therapeutic effect is reducing after-meal blood glucose elevations, rather than maintaining steady levels throughout the day.Following administration, nateglinide reaches peak blood concentrations in approximately one hour. Nateglinide is metabolized in the liver by enzymes called CYP2C9 and CYP3A4. Most nateglinide and the products of metabolism are excreted in the urine, and a minor amount is excreted in the feces.
Side Effects
The most common side effects (occurring in more than 2% of patients in clinical trials) are the following:
    upper respiratory infection (e.g., a cold)
    back pain
    flu symptoms
    dizziness
    joint inflammation or pain
    diarrhea
    accidental trauma
    bronchitis
    cough
    hypoglycemia (low blood sugar levels)

Sulfonylureas (second-generation)-Glyburide

Brand name
Diabeta   Micronase
class-Sulfonylureas (second-generation)-Raise the amount of insulin in the body 
Description
Glyburide tablets (micronized) contain smaller particle size, glyburide. Glyburide is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide is a white, crystalline compound.Each tablet, for oral administration, contains 1.5 mg, 3 mg or 6 mg of micronized glyburide. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, pregelatinized starch, and sodium lauryl sulfate. In addition, the 3 mg tablets contain the following ingredient: D&C Yellow #10 Aluminum Lake and the 6 mg tablets contain the following ingredients: D&C Yellow #10 Aluminum Lake and FD&C Blue #1 Aluminum Lake.The chemical name for glyburide is 1-[[p-[2-(5-Chloro-o-anisamido) ethyl]phenyl]-sulfonyl]-3-cyclohexylurea and the molecular weight is 494.01.  
 Clinical Pharmacology
 mechanism of Actions
Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complimentary mechanisms.In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide.
Pharmacokinetics
Single dose studies with glyburide tablets (micronized) in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about two to three hours, and low but detectable levels at twenty-four hours.Bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from non-micronized glyburide tablets 5 mg. Therefore, the patient should be retitrated.It has been reported that in a single-dose bioavailability study  in which subjects received micronized glyburide tablets 3 mg and non-micronized glyburide tablets 5 mg with breakfast, the peak of the mean serum glyburide concentration-time curve was 97.2 ng/mL for the micronized glyburide tablets 3 mg and 87.5 ng/mL for non-micronized glyburide tablets 5 mg. The mean of the individual maximum serum concentration values of glyburide (Cmax) from micronized glyburide tablets 3 mg was 106 ng/mL and that from non-micronized glyburide tablets was 104 ng/mL. The mean glyburide area under the serum concentration-time curve (AUC) for this study was 568 ng × hr/mL for micronized glyburide tablets 3 mg and 746 ng × hr/mL for non-micronized glyburide tablets 5 mg.
  Indications And Usage
Glyburide tablets (micronized) are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone.Glyburide may be used concomitantly with metformin when diet and glyburide or diet and metformin alone do not result in adequate glycemic control (see metformin).In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of glyburide must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glyburide. 
Contraindications
Glyburide is contraindicated in patients with:
 Known hypersensitivity or allergy to the drug.
Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
 Type I diabetes mellitus, as sole therapy.
 Adverse Reactions
Gastrointestinal ReactionsCholestatic jaundice and hepatitis may occur rarely; glyburide should be discontinued if this occurs.Liver function abnormalities, including isolated transaminase elevations, have been reported.Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced.
Dermatologic ReactionsAllergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of glyburide. If skin reactions persist, the drug should be discontinued.Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic ReactionsLeukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.
Metabolic ReactionsHepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with glyburide and disulfiram-like reactions have been reported very rarely.Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.
Other ReactionsChanges in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported.
Dosage And Administration
Patients should be retitrated when transferred from non-micronized glyburide tablets or other oral hypoglycemic agents.There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets (micronized) or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.Short-term administration of glyburide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

GPAT 2010 Syllabus for pharmacy

GPAT Examination is conducted for admission into M. Pharm and for awarding fellowships and scholarships to Pharama Students. The syllabus of the exam is given below:
Natural Products:
Pharmacognosy & Phytochemistry – Chemistry, tests, isolation, characterization and estimation of phytopharmaceuticals belonging to the group of Alkaloids, Glycosides, Terpenoids, Steroids, Bioflavanoids, Purines, Guggul lipids. Pharmacognosy of crude drugs that contain the above constituents. Standardization of raw materials and herbal products. WHO guidelines. Quantitative microscopy including modern techniques used for evaluation. Biotechnological principles and techniques for plant development, Tissue culture.
Pharmacology:
General pharmacological principles including Toxicology. Drug interaction. Pharmacology of drugs acting on Central nervous system, Cardiovascular system, Autonomic nervous system, Gastro intestinal system and Respiratory system. Pharmacology of Autocoids, Hormones, Hormone antagonists, chemotherapeutic agents including anticancer drugs. Bioassays, Immuno Pharmacology. Drugs acting on the blood & blood forming organs. Drugs acting on the renal system.
Medicinal Chemistry:
Structure, nomenclature, classification, synthesis, SAR and metabolism of the following category of drugs, which are official in Indian Pharmacopoeia and British Pharmacopoeia. Introduction to drug design. Stereochemistry of drug molecules. Hypnotics and Sedatives, Analgesics, NSAIDS, Neuroleptics, Antidepressants, Anxiolytics, Anticonvulsants, Antihistaminics, Local Anaesthetics, Cardio Vascular drugs – Antianginal agents Vasodilators, Adrenergic & Cholinergic drugs, Cardiotonic agents, Diuretics, Anti-hypertensive drugs, Hypoglycemic agents, Antilipedmic agents, Coagulants, Anticoagulants, Antiplatelet agents. Chemotherapeutic agents – Antibiotics, Antibacterials, Sulphadrugs. Antiprotozoal drugs, Antiviral, Antitubercular, Antimalarial, Anticancer, Antiamoebic drugs. Diagnostic agents. Preparation and storage and uses of official Radiopharmaceuticals, Vitamins and Hormones. Eicosanoids and their application.
Pharmaceutics:
Development, manufacturing standards Q.C. limits, labeling, as per the pharmacopoeial requirements. Storage of different dosage forms and new drug delivery systems. Biopharmaceutics and Pharmacokinetics and their importance in formulation. Formulation and preparation of cosmetics – lipstick, shampoo, creams, nail preparations and dentifrices. Pharmaceutical calculations.
Pharmaceutical Jurisprudence:
Drugs and cosmetics Act and rules with respect to manufacture, sales and storage. Pharmacy Act. Pharmaceutical ethics.
Pharmaceutical Analysis:
Principles, instrumentation and applications of the following: Absorption spectroscopy (UV, visible & IR). Fluorimetry, Flame photometry, Potentiometry. Conductometry and Polarography. Pharmacopoeial assays. Principles of NMR, ESR, Mass spectroscopy. X-ray diffraction analysis and different chromatographic methods.
Biochemistry:
 Biochemical role of hormones, Vitamins, Enzymes, Nucleic acids, Bioenergetics. General principles of immunology. Immunological. Metabolism of carbohydrate, lipids, proteins. Methods to determine, kidney & liver function. Lipid profiles.
Microbiology
:Principles and methods of microbiological assays of the Pharmacopoeia. Methods of preparation of official sera and vaccines. Serological and diagnostics tests. Applications of microorganisms in Bio Conversions and in Pharmaceutical industry.
Clinical Pharmacy:
Therapeutic Drug Monitoring Dosage regimen in Pregnancy and Lactation, Paediatrics and Geriatrics. Renal and hepatic impairment. Drug – Drug interactions and Drug – food interactions, Adverse Drug reactions. Medication History, interview and Patient counselling.

GPAT Exam Structure:
The GPAT question paper is a multiple choice objective-type test. Each question has four choices for the answer with only one correct answer. The other details are:
Maximum Time: 3 hours
Number of Questions: 100
Maximum Marks: 100
Negative Marking: 1/3 mark will be deducted for each incorrect answer

Sulfonylureas -glipizide (antidiabetic drug)

Brand name

glucotrol

Description
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.The Chemical Abstracts name of glipizide is 1-Cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)-ethyl]phenyl]sulfonyl]urea. The molecular formula is C21H27N5O4S; the molecular weight is 445.54; the structural formula is shown below:

Clinical Pharmacology
Mechanism of Action  

The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.Blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that timeSome patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas.
Other Effects  

It has been shown that glipizide therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for NIDDM.In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity, and, in fact, led to a slight increase in free water clearance.
Pharmacokinetics  

Gastrointestinal absorption of glipizide in man is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98 to 99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug.The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine.
Indications And Usage  

Glipizide tablets are indicated 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.

In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified, and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of glipizide must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone also may be transient, thus requiring only short-term administration of glipizide.

During maintenance programs, glipizide should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgements should be based on regular clinical and laboratory evaluations.In considering the use of glipizide in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.
Contraindications 

Glipizide tablets are contraindicated in patients with:
 1. Known hypersensitivity to the drug.
   2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. 

Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and administer insulin.The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given.
Adverse reaction
Gastrointestinal: Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or reduction of dosage. Cholestatic jaundice may occur rarely with sulfonylureas: Glipizide should be discontinued if this occurs.

Dermatologic: Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients. These may be transient and may disappear despite continued use of glipizide; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
 Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic: Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide has an extremely low incidence of disulfiram-like alcohol reactions.

Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.

Miscellaneous: Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with glipizide. They are usually transient and seldom require discontinuance of therapy.
Dosage And Administration  

There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of any adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy.Short-term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.In general, glipizide should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia.Initial Dose: The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg.

Sulfonylureas -Glimepiride (antidiabetic drug)

Brand name
amaryl
AMARYL(glimepiride tablets) is an oral blood-glucose-lowering drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder formulated into tablets of 1-mg, 2-mg, and 4-mg strengths for oral administration. AMARYL Tablets contain the active ingredient glimepiride and the following inactive ingredients: lactose (hydrous), sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. In addition, AMARYL 1-mg tablets contain Ferric Oxide Red, AMARYL 2-mg tablets contain Ferric Oxide Yellow and FD&C Blue #2 Aluminum Lake, and AMARYL 4-mg tablets contain FD&C Blue #2 Aluminum Lake.
Mechanism of Action
The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which AMARYL therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.
AMARYL is effective as initial drug therapy. In patients where monotherapy with AMARYL or metformin has not produced adequate glycemic control, the combination of AMARYL and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different primary mechanisms of action. This complementary effect has been observed with metformin and other sulfonylureas, in multiple studies.
Pharmacodynamics
A mild glucose-lowering effect first appeared following single oral doses as low as 0.5–0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin]) was about 2 to 3 hours. In noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.
In larger dose-ranging studies, blood glucose and HbA1c were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of AMARYL. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of AMARYL up to 8 mg once daily. No difference in response was found when AMARYL was administered once or twice daily.
  Pharmacokinetics
Absorption
After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively).
Distribution
After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
Metabolism
Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.
Excretion
When 14C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80–90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.
  Adverse Reactions
The incidence of hypoglycemia with AMARYL, as documented by blood glucose values <60 mg/dL, ranged from 0.9–1.7% in two large, well controlled, 1-year studies.
AMARYL has been evaluated for safety in 2,013 patients in US controlled trials, and in 1,551 patients in foreign controlled trials. More than 1,650 of these patients were treated for at least 1 year. Adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with AMARYL are shown below.
Adverse Events Occurring in ≥1% AMARYL Patients 
Gastrointestinal ReactionsVomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas, including AMARYL.
Dermatologic Reactions
Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of AMARYL. If those hypersensitivity reactions persist or worsen, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylureas, including AMARYL.
Hematologic Reactions
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas, including AMARYL.
Metabolic Reactions
Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas, including AMARYL. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with sulfonylureas, including AMARYL, and it has been suggested that certain sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Other Reactions

Changes in accommodation and/or blurred vision may occur with the use of AMARYL. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment. In placebo-controlled trials of AMARYL, the incidence of blurred vision was placebo, 0.7%, and AMARYL, 0.4%.  Dosage and Dosage & Administration
There is no fixed dosage regimen for the management of diabetes mellitus with AMARYL or any other hypoglycemic agent. The patient's fasting blood glucose and HbA1c must be measured periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels should be performed to monitor the patients response to therapy.Short-term administration of AMARYL may be sufficient during periods of transient loss of control in patients usually controlled well on diet and exercise.

Metformin -Antidiabetic drugs

Antidiabetic drugs
Antidiabetic drugs are medications that work to lower blood glucose concentrations, or the amount of sugar in the blood. They are an important way of treating  gestational,  type 1 and  type 2 diabetes mellitus.
 There are many types of antidiabetic drugs. Herbal remedies and other forms of alternative medicine are also used for diabetes treatment, especially in areas where modern drugs are not easily available.Antidiabetic drugs exert their useful effects through: (1) increasing insulin levels in the body or (2) increasing the body's sensitivity (or decreasing its resistance) to insulin, or (3) decreasing glucose absorption in the intestines.
 Antidiabetic Drugs That Increase Insulin
Metformin
Metformin is one of the oldest, most widely used, and least-expensive antidiabetic drugs for treatment of type 2 diabetes (T2DM). It is one of several orally-available medicines for this disease, but is very different structurally from the other compounds.  

brand name

Glucophage 
Chemical structure of metformin 

uses
Metformin is used to help control blood glucose levels in persons with type 2 diabetes by reducing glucose production in the liver and increasing sensitivity to existing insulin. It is not a replacement for injected insulin and is not used in treating type 1 diabetes. It is often used in combination with other medications as part of regimen that includes recommendations for weight loss and decreased caloric intake.Metformin is also used in treating polycystic ovary syndrome
dosage
Metformin is provided as tablets to take by mouth; the tablets may contain metformin as the only active ingredient or may also contain other medicines. The regular tablet is usually taken with meals two or three times a day. The extended-release tablet is usually taken once daily with the evening meal. Tablets are usually taken at the same time each day and should be swallowed whole. The dose of metformin is adjusted gradually in response to how well it is tolerated and how well the patient's blood sugar levels respond to the drug.
mechanism of action
In contrast to some other medications, the precise (molecular) mechanism of metformin is not known. However, it is well-established that metformin acts as an insulin sensitizer in that it increases the blood glucose-lowering activity of insulin. The beneficial glycemic effects of metformin are mainly attributed to lowering the amount of glucose produced by the liver (hepatic gluconeogenesis), and increased peripheral tissue insulin sensitivity. Metformin probably works by interrupting mitochondrial oxidation in the liver and by correcting intracellular calcium abnormalities in tissues such as the liver, fat, and skeletal muscle.[2]
Metformin is excreted unchanged in the urine. The body does not seem to modify metformin, as no metabolites have been identified in humans, and the drug is not excreted in the bile. After oral administration, about 90% of the absorbed drug is eliminated via the kidneys in the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the drug may enter and leave red blood cells.
Benefits
Blood glucose control; tendency to lose weight; improved lipid levels...
Side Effects
Metformin alone does not lead to low blood sugar levels; however, it is often taken in combination with other medications that can cause this. Symptoms of low blood sugar (hypoglycemia) include shakiness, dizziness or lightheadedness, sweating, nervousness or irritability, sudden changes in behavior or mood, headache, numbness or tingling around the mouth, weakness, pale skin, hunger, and clumsy or jerky movements.Metformin itself may cause may cause side effects. In most patients, the effects are not troublesome enough to mandate discontinuation. Commonly-reported side effects of metformin include: diarrhea, bloating, stomach pain, gas, constipation, unpleasant metallic taste in mouth, heartburn, headache, sneezing, cough, runny nose, flushing of the skin, nail changes, and muscle pain.Chest pain or rash are serious side effects that require immediate discontinuation of metformin and medical evaluation.
Risks and Precautions
Metformin carries a very small risk of causing lactic acidosis; the risk is about 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, and electrolyte disturbances. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.[3]

Glycemil - Anti Diabetic Drugs

Drug Name  

Glycemil

Drug Uses

Glycemil is specifically formulated to help prevent the health problems associated wsith high blood sugar levels by:

• Helping blunt the insulin spike caused by high glycemic index foods;
• Helping regulate blood sugar levels;
• Helping lower insulin resistance;
• Helping regulate insulin production.

How Taken

As a dietary supplement, take one (1) capsule before each meal. Do not exceed three (3) capsules per day.

Drug Class and Mechanism

High Blood Sugar Levels can be bad news, leading to a number of serious health problems including excess weight gain (obesity), insulin resistance syndrome, diabetes and heart disease. Typically, controlling blood sugar levels has been done through diet, exercise, insulin injections for diabetics, and other prescription medications, some of which can have side effects that include nausea, diarrhea, weight gain, liver damage and respiratory infections.

The good news is that Lazarus Labs has just released Glycemil, the pharmaceutical quality, non-prescription product clinically proven to help control blood sugar levels - without dangerous side effects.

Missed Dose

If you miss a dose of Glycemil, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Storage

Store Glycemil at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Keep Glycemil out of the reach of children and away from pets.

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Warnings/Precautions

No absolute contraindications.

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Possible Side Effects

This product contains only 100% pure pharmaceutical grade ingredients and is regularly tested to ensure the safety and quality. Each ingredient has been approved as safe by the FDA and all appear on the FDAs GRAS (Generally Recognized As Safe) list.

More Information

High blood sugar (glucose) levels are associated with a number of serious health problems including obesity, heart disease and diabetes. Diabetes is a disease characterized by the body inability to properly regulate levels of blood sugar by producing or adequately utilizing insulin. It affects over 20,000,000 people in the U.S. alone and is associated with an increased risk of life-threatening complications such as a heart attack, stroke, and/or kidney disease. At present, diabetes is the third leading cause of death in the United States.