Chemistry:

Chemically it is [( + )- 5 – [[ 4 – [ 2 – ( 5 – ethyl – 2 – pyridinyl) ethoxy]phenyl]methyl-2,4-]thiazolidinedione monohydrochloride . The empirical formula is c19H20N2O3S.HCl and a molecular weight of 392.90 .

Pharmacokinetics:

• Absorption : Rapid
• Distribution:0.63 L/kg
• Protein binding : Very high (>99%)
• Biotransformation:Pioglitazone is extensively metabolized in the liver to several active metabolites. Cytochrome (CYP ) P450 iso forms involved in the hepatic metabolism of pioglitazone are cyP2C8 and cyP3A4 .
• Half – life :3-7 hours
• Time to peak concentration :2 hours .
• Elimination:It is assumed that most of a dose is excreted into bile as active drug or metabolites and is eliminated in the feces. Renal : 5 –30%

Mechanism of actions :

Pioglitazone is a thiazolidinedione antidiabetic agent that is effective only in the presence of insulin. Its primary action is to decrease insulin resistance at peripheral sites and in the liver , resulting in increased insulin – dependent glucose disposal and decreased hepatic glucose output.
These effects are accomplished through selective binding at the peroxisome proliferator – activated receptor – gamma, which is found in adipose tissue ,skeletal muscle, and the liver. Activation of these receptors modulates transcription of several insulin – responsive genes that control glucose and lipid metabolism . Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. (USP DI 2007)

Indications and usage :

Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Pioglitazone is indicated for monotherapy. Pioglitazone is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control . Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

Contraindication :

Pioglitazone is indicated in patients with known hypersensitivity to this product or any of its components.

Pregnancy :

FDA Pregnancy Category C.
It is recommended that insulin alone be used during pregnancy for maintenance of blood glucose concentrations that are as close to normal as possible.Abnoraml maternal blood glucose concentrations have been associated with a higher incidence of congenital anomalies and increased neonatal morbidity and mortality. (USP DI 2007)
Nursing mothers: Pioglitazone is not recommended for use by nursing mothers. (USP DI 2007)

Precaution:

• Precaution: – Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore pioglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
• Hypoglycemia: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.
• Ovulation: Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women . Then ,these patients may be at an increased risk for pregnancy .
• Hematologic: Pioglitazone may cause decreses in hemoglobin and hematocrit.
• Edema: Pioglitazone should be used with caution in patients with edema.
• Cardiac: In preclinical studies pioglitazone cause plasma volme expansion and pre- load – induced cardiac hypertrophy .
• Hepatic effects: Therapy with pioglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal .

Drug interactions :

1 – Oral contraceptives
2 – Glipizide
3 – Digoxin
4 – Warfarin
5 – Ketoconazole

Adverse effects :

Those indicating need for medical attention :

• Incidence more frequent : Tooth disorders (5.3%)
• Incidence less frequent : Peripheral edema (4.8%)

Those indicating need for medical attention only if they continue or are bothersome .

• Incidence more frequent : Headache (9.1%) , myalgia (5.4%) pharyngitis ( 5.1%) , sinusitis ( 6.3%) , upper respiratory tract infection (13.2%)

Over dose:

دFor more information on the management of over dose or unintentional ingestion, contact a poison control center .

Dosage and administration :

Usual adult dose :

• – As monotherapy : Oral initially 15 or 30 mg once a day the dose may be increased in increments up to 45 mg once daily.
• – In combination with insulin . Oral , initially 15 or 30 mg once daily.
• – In combination with metformin: Oral , initially 15 or 30 mg once dialy.
• – In combination with sulfonylurea : Oral, initially 15 or 30 mg once daily.

Usual adult prescribing limits :
45 mg daily .
Usual pediatric dose :
Safety and efficacy have not been established.

Packaging and storage :

• Store below 30ºC in a tightly closed container. Protect from moisture and humidity .
• Keep out of children .