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Pioglitazone; Uses, Contra indications, Dosage, Side Effects, Drug Interactions

Pioglitazone is an orally-active thiazolidinedione with antidiabetic properties and potential antineoplastic activity. Pioglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation.

Pioglitazone is a medication belonging to the thiazolidinedione class of drugs that are used as adjuncts to diet, exercise, and other diabetes medications to manage type 2 diabetes mellitus. The thiazolidinedione class of medications exerts its pharmacological effect primarily by promoting insulin sensitivity and the improved uptake of blood glucose. Following entry into fat cell nuclei, pioglitazone selectively binds to the Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)

Mechanism of action of Pioglitazone

Pioglitazone acts as a selective agonist at Peroxisome Proliferator Activated Receptor Gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors increases the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, pioglitazone both enhances tissue sensitivity to insulin and reduces the production of glucose via the liver (hepatic gluconeogenesis). Thus, insulin resistance associated with type 2 diabetes mellitus is improved without an increase in insulin secretion by pancreatic β cells.

Thiazolidinediones reduce insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity. The mechanism of action involves binding to the peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also in other tissues. It is likely that thiazolidinediones primarily act in adipose tissue where PPARgamma is predominantly expressed. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g. free fatty acids, adipocytokines such as tumor necrosis factor alpha, resistin, adiponectin) in a way that results in net improvement of insulin sensitivity (i.e. in muscle and liver). Nevertheless, a direct molecular effect in skeletal muscle cannot be excluded.

Pioglitazone, a full peroxisome proliferator-activated receptor (PPAR)-gamma agonist, improves insulin sensitivity by increasing circulating adiponectin levels. However, the molecular mechanisms by which pioglitazone induces insulin sensitization are not fully understood. In this study, we investigated whether pioglitazone improves insulin resistance via upregulation of either 2 distinct receptors for adiponectin (AdipoR1 or AdipoR2) expression in 3T3-L1 adipocytes. Glucose uptake was evaluated by 2-[(3)H] deoxy-glucose uptake assay in 3T3-L1 adipocytes with pioglitazone treatment. AdipoR1 and AdipoR2 mRNA expressions were analyzed by qRT-PCR. /The investigators/ first confirmed that pioglitazone significantly increased insulin-induced 2-deoxyglucose (2-DOG) uptake in 3T3-L1 adipocytes. Next, we investigated the mRNA expression and regulation of AdipoR1 and AdipoR2 after treatment with pioglitazone. Interestingly, pioglitazonesignificantly induced AdipoR2 expression but it did not affect AdipoR1 expression. In addition, adenovirus-mediated PPARgamma expression significantly enhanced the effects of pioglitazone on insulin-stimulated 2-DOG uptake and AdipoR2 expression in 3T3-L1 adipocytes. These data suggest that pioglitazone enhances adiponectin’s autocrine and paracrine actions in 3T3-L1 adipocytes via upregulation of PPARgamma-mediated AdipoR2 expression. Furthermore, we found that pioglitazone significantly increased AMP-activated protein kinase (AMPK) phosphorylation in insulin-stimulated 3T3-L1 adipocytes, but it did not lead to the phosphorylation of IRS-1, Akt, or protein kinase C?/?. … Pioglitazone increases insulin sensitivity, at least partly, by PPARgamma-AdipoR2-mediated AMPK phosphorylation in 3T3-L1 adipocytes. In conclusion, the upregulation of AdipoR2 expression may be one of the mechanisms by which pioglitazone improves insulin resistance in 3T3-L1 adipocytes.

Indications of Pioglitazone

Type 2 Diabetes Mellitus
Diabetes, Type 2
Nonalcoholic Fatty Liver Disease

Drug Indication FDA Level

Diabetes, Type 2
Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below, asmonotherapy in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance asdual oral therapyin combination with
metformin, in adult patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea.
astriple oral therapyin combination with metformin and a sulphonylurea, in adult patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy.
Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained.
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below:as monotherapy in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance as dual oral therapy in combination with metformin, in adult patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea.
As triple oral therapy in combination with metformin and a sulphonylurea, in adult patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy.
Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance .
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained.
Pioglitazone is indicated in the treatment of type 2 diabetes mellitus: asmonotherapy
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below: as monotherapy in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications o intolerance as dual oral therapy in combination with metformin, in adult patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy witha sulphonylurea. as triple oral therapy in combination with metformin and a sulphonylurea, in adult patients (particularly overweight patients) with insufficienglycaemic control despite dual oral therapy.
Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance.
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assessadequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy,prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained.
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below asmonotherapy
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below:as monotherapy in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance as dual oral therapy in combination with metformin, in adult patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea.
Pioglitazone is indicated as second or third line in the treatment of type 2 diabetes mellitus as described below , asmonotherapy
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below: as monotherapy in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance as dual oral therapy in combination with metformin, in adult patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea as triple oral therapy in combination with metformin and a sulphonylurea, in adult patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy.
Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance.After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below: as monotherapy in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance
Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance.After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained.
Treatment of adrenoleukodystrophy

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Contra Indications of Pioglitazone

Dilated neck veins
Hypersensitivity to the active substance or to any of the excipients
Cardiac failure or history of cardiac failure (NYHA stages I to IV)
Hepatic impairment
Diabetic ketoacidosis
Current bladder cancer or a history of bladder cancer,
Uninvestigated macroscopic haematuria.

Dosage of Pioglitazone

Diabetes Type 2

gas (flatulence)
Patients without congestive heart failure:
Initial dose: 15 mg or 30 mg orally once a day

Patients with congestive heart failure (New York Heart Association [NYHA] Class I or II)

15 mg ,30 mg ,45 mg
Initial dose: 15 mg orally once a day
Maintenance dose: 15 mg to 45 mg orally once a day based on glycemic response as determined by HbA1c
Maximum dose: 45 mg orally once a day

Side Effects of Pioglitazone

Most common

Chest pain
decreased urine output
dilated neck veins
extreme fatigue
abdominal pain,
physical weakness (asthenia)
diarrhea
gas (flatulence)
symptoms of weakness, muscle pain (myalgia)
upper respiratory tract infection
low blood sugar (hypoglycemia)
abdominal pain (GI complaints), lactic acidosis (rare)
low blood levels of vitamin B-12
nausea,vomiting
chest discomfort
chills, dizziness
bloating/abdominal distention
constipation
heartburn

More common

Abdominal or stomach discomfort
cough or hoarseness
decreased appetite
diarrhea
fast or shallow breathing
fever or chills
general feeling of discomfort
lower back or side pain
muscle pain or cramping
painful or difficult urination

Less common

Abnormal stools
bad, unusual, or unpleasant (after) taste
change in taste
difficulty with moving
discoloration of the fingernails or toenails
flu-like symptoms
joint pain
rash
runny nose
sneezing
stuffy nose
swollen joints

Drug Interactions of Pioglitazone

Pioglitazone may interact with following drugs ,suppliments & may decrease the efficacy of drug

angiotensin converting enzyme inhibitors (ACEIs; captopril, enarapril,ramipril)
alcohol
antipsychotic medications (e.g., chlorpromazine, haloperidol, olanzapine,
atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, risperidone)
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
barbiturates (e.g., pentobarbital, phenobarbital)
cyclosporine
diabetes medications (e.g., chlorpropamide, glipizide, glyburide, insulin, metformin, nateglinide, pioglitazone)
diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene)
phenytoin
pregabalin
irbesartan
lapatinib
losartan
mifepristone
corticosteroids (e.g., dexamethasone, prednisone)
diabetic drugs (e.g., glyburide, insulin, repaglinide, sitagliptin)
diuretics (e.g., furosemide, hydrochlorothiazide)
HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
phenytoin
quinolone antibiotics (e.g., levofloxacin, moxifloxacin)
selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, sertraline paroxetine,
trimethoprim
vancomycin
verapamil
warfarin

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Pregnancy & Lactation of Pioglitazone

FDA Pregnancy Category : Not catagorised

Pregnancy

Pioglitazone has not been studied for use by pregnant women. This medication should not be used during pregnancy. In general, blood sugar should be controlled during pregnancy by using insulin injections. If you become pregnant while taking this medication, contact your doctor immediately.

Breast-feeding

It is not known if pioglitazone passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding . The safety and effectiveness of using this medication have not been established for children.

References