Piat

Uses

Atorvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke.

Atorvastatin is indicated for the treatment of several types of dyslipidemias, including primary hyperlipidemia and mixed dyslipidemia in adults, hypertriglyceridemia, primary dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and heterozygous familial hypercholesterolemia in adolescent patients with failed dietary modifications.

Dyslipidemia describes an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis.

Atorvastatin is indicated, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and/or abnormal lipid profiles.

Atorvastatin can be used as a preventive agent for myocardial infarction, stroke, revascularization, and angina, in patients without coronary heart disease but with multiple risk factors and in patients with type 2 diabetes without coronary heart disease but multiple risk factors.

Atorvastatin may be used as a preventive agent for non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure and angina in patients with coronary heart disease.

Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.

Pioglitazone is used for an adjunct to diet and exercise to improve glycaemic control in patients with type II diabetes (NIDDM). Pioglitazone is used for monotherapy and also used for use in combination with sulphonylurea, Metformin or Insulin when diet and exercise plus the single agent does not result in adequate glycaemic control.

Piat is also used to associated treatment for these conditions: Anginal Pain, Cardiovascular Disease (CVD), Coronary Artery Disease (CAD), Coronary artery thrombosis, Dysbetalipoproteinemia, Fredrickson Type III lipidemia, Heterozygous Familial Hypercholesterolemia, High Blood Pressure (Hypertension), High Cholesterol, Homozygous Familial Hypercholesterolemia, Hospitalizations, Hypertriglyceridemias, Mixed Dyslipidemias, Mixed Hyperlipidemia, Myocardial Infarction, Non-familial hypercholesterolemia, Postoperative Thromboembolism, Primary Hypercholesterolemia, Stroke, Transient Ischemic Attack, Elevation of serum triglyceride levels, Heterozygous familial hyperlipidemia, Non-familial hyperlipidemia, Non-fatal myocardial infarction, Primary Hyperlipidemia, Revascularization procedures, Revascularization process, Thrombotic events, Cardiovascular Primary Prevention, Secondary prevention cardiovascular eventDiabetes, Diabetic Neuropathies, Type 2 Diabetes Mellitus

How Piat works

Atorvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Atorvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low-density lipoprotein (LDL) receptors, which increases hepatic uptake of LDL. Atorvastatin also reduces Very-Low-Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High-Density Lipoprotein Cholesterol (HDL-C).

In vitro and in vivo animal studies also demonstrate that atorvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. These effects include improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins were also found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an essential role in leukocyte trafficking and T cell activation.

Pioglitazone is 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 PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose and lipid production, transport, and utilization. Through this mechanism, pioglitazone both enhances tissue sensitivity to insulin and reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta cells.

Dosage

Piat dosage

Pioglitazone can be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Pioglitazone monotherapy may be initiated at 15 mg or 30 mg once daily dosages in patients not adequately controlled with diet and exercise alone. For patients who respond inadequately to the initial dose of Pioglitazone, the dose can be increased up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered.

Maximum recommended daily dose of Pioglitazone should not exceed 45 mg since doses higher than 45 mg have not been studied in placebo controlled clinical studies. Besides, no placebo controlled clinical studies of more than 30 mg once daily have been conducted in combination therapy.

Side Effects

The overall incidence and types of adverse events reported in placebo controlled clinical trials of Pioglitazone monotherapy at doses of 7.5 mg, 15 mg, 30 mg or 45 mg once daily are upper respiratory tract infection (13.2%), headache (9.1%), sinusitis (6.3%), myalgia (5.4%), tooth disorder (5.3%), and pharyngitis (5.1%).

Toxicity

The reported LD50 of oral atorvastatin in mice is higher than 5000 mg/kg. In cases of overdose with atorvastatin, there is reported symptoms of complicated breathing, jaundice, liver damage, dark urine, muscle pain, and seizures. In case of overdose, symptomatic treatment is recommended and due to the high plasma protein binding, hemodialysis is not expected to generate significant improvement.

In carcinogenic studies with high doses of atorvastatin, evidence of rhabdomyosarcoma, fibrosarcoma, liver adenoma, and liver carcinoma were observed.

In fertility studies with high doses of atorvastatin, there were events of aplasia, aspermia, low testis and epididymal weight, decreased sperm motility, decreased spermatid head concentration and increased abnormal sperm.

Atorvastatin was shown to not be mutagenic in diverse mutagenic assays.

The oral TDLo observed in mice is 24 mg/kg for 4 days and for rats is 3 mg/kg for 6 days.

One instance of overdose was reported during clinical trials with pioglitazone in which a patient took an oral dose of 120mg daily for four days, followed by 180mg daily for seven days - this patient did not report any adverse clinical symptoms during this time. In the event of overdosage, employ symptomatic and supportive measures according to the patient's clinical status.

Precaution

Pioglitazone exerts its antihyperglycaemic effect only in the presence of Insulin. Therefore, it should not be used in Type 1 diabetes or for the treatment of diabetic ketoacidosis. Pioglitazone should be used with caution in case of combination antidiabetic therapy and hepatic insufficiency. Liver enzyme should be monitored regularly.

Interaction

Administration of thiazolidinediones with an oral contraceptive containing ethinyl oestradiol and norethindrone reduces the plasma concentration of both hormones by approximately 30% which could result in loss of contraception.

Volume of Distribution

The reported volume of distribution of atorvastatin is of 380 L.

The average apparent volume of distribution of pioglitazone is 0.63 ± 0.41 L/kg.

Elimination Route

Atorvastatin presents a dose-dependent and non-linear pharmacokinetic profile. It is very rapidly absorbed after oral administration. After the administration of a dose of 40 mg, its peak plasma concentration of 28 ng/ml is reached 1-2 hours after initial administration with an AUC of about 200 ng∙h/ml. Atorvastatin undergoes extensive first-pass metabolism in the wall of the gut and the liver, resulting in an absolute oral bioavailability of 14%. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Administration of atorvastatin with food results in prolonged Tmax and a reduction in Cmax and AUC.

Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of atorvastatin. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 1.72-fold higher AUC for atorvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin, simvastatin, and rosuvastatin.

Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact atorvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) demonstrated that atorvastatin AUC was increased 2.45-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals.[A181493] Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, rosuvastatin, and pravastatin.

Following oral administration of pioglitazone, peak serum concentrations are observed within 2 hours (T_max) - food slightly delays the time to peak serum concentration, increasing T_max to approximately 3-4 hours, but does not alter the extent of absorption. Steady-state concentrations of both parent drug and its primary active metabolites are achieved after 7 days of once-daily administration of pioglitazone. C_max and AUC increase proportionately to administered doses.

Half Life

The half-life of atorvastatin is 14 hours while the half-life of its metabolites can reach up to 30 hours.

The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3-7 hours and 16-24 hours, respectively.

Clearance

The registered total plasma clearance of atorvastatin is of 625 ml/min.

The apparent clearance of orally administered pioglitazone is 5-7 L/h.

Elimination Route

Atorvastatin and its metabolites are mainly eliminated in the bile without enterohepatic recirculation. The renal elimination of atorvastatin is very minimal and represents less than 1% of the eliminated dose.

Approximately 15-30% of orally administered pioglitazone is recovered in the urine. The bulk of its elimination, then, is presumed to be through the excretion of unchanged drug in the bile or as metabolites in the feces.

Pregnancy & Breastfeeding use

Pregnancy: There are no adequate and well controlled studies in pregnant women. Pioglitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Lactation: It is not known whether Pioglitazone is secreted in human milk. As many drugs are excreted in human milk, it should not be administered to a lactating women.

Contraindication

Pioglitazone is contraindicated in patients with known hypersensitivity to any of its components.

Storage Condition

Store at 25° C.

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