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Atorvatatin


Category:

Antihyperlipidemic.

Composition:

Each film coated tablet contains atorvastatin calcium trihydrate, equivalent to 10 or 20 or 40 mg atorvastatin. (PDR 2007

Chemistry :

(Electronic Martindale 35)
Chemical name: Calcium (βR,δR)-2-(p-fluorophenyl)-β,δ-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoic acid (1:2) trihydrate Molecular formula: C66H68CaF2N4O10,3H2O =1209.4 CAS: 134523-00-5 (atorvastatin); 134523-03-8 (atorvastatin calcium)

Mechanism of action:

3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors competitively inhibit the anzyme that catalyzes the conversion of HMG-COA to mevalonate, the rate-limiting step in cholesterol biosynthesis. The primary site of action of HMG-COA reductase inhibitors is the liver , which is the principal site of cholesterol synthesis and low density lipoprotein clearance . Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. These complexes are composed of high-density lipoprotein (HDL) , intermediate-density lipoprotein (IDL) , low –density lipoprotein (LDL) , and very – low – density lipoprotein (VLDL). In the liver, triglycerides (TG) and cholesterol are incorporated into VLDL , Which is released into the plasma for transport to the peripheral tissues. LDL is formed from VLDL and is catabolized primarity through the LDL receptor . Elevated plasma concentrations of total cholesterol (total-C) , LDL – cholesterol (LDL-C) , and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease. Increased plasma concentrations of HDL-C are associated with decreased cardiovascular risk . Atorvastatin lowers plasma cholesterol and lipoprotein concentrations by inhibiting HMG-COA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL. Atorvastatin also reduces total – C, LDL-C , and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH) , nonfamilial forms of hypercholesterolemia , and mixed dyslipidemia . atorvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1 .

Pharmacokinetics:

Absorption:Rapidly .
Protein binding: Very high (≥98%)

Biotransformation:

Administered in active (open acid )form.Biotransformation by ortho-and parahydroxy lation and various beta-oxidation.
Ortho-and parahydroxylated metabolites are pharmacologically active. The active metabolites are responsible for approximately 70% of the inhibition of HMG-COA reductase . Studies in vitro suggest that atorvastatin is metabolized by the cytochrome P 450 3A4 isozyme.

Elimination half life:

Approximately 14 hours .

Time to peak concentration:

About 1-2 hours.

Elimination:

Fecal(biliary):Primary route of elimination
Renal:Less than 2%

Indications:

Atorvastatin is indicated:
1- As an adjunct to diet to reduce elevated total –C,LDL-C apo B ,and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial ) and mixed dyslipidemia (Fredrickson types II a and IIb).
2- As an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson type IV) .
3- For the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson type III) who did not respond adequately to diet.
4- To reduce total–C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid–lowering treatments (eg,LDL apheresis ) or if such treatments are unavailable.

Contraindications:

1 – Active liver disease or unexplained persistent elevations of serum transaminases.
2 – Hypersensitiviy to any component of this medication .
3 – Pregnancy and lactation.
4 – Hepatic disease, active , including
5- Alcoholic liver disease, chronic or
6- Childs-Pugh Index grade A disease or
7- Childs-Pugh Index gradeB disease or
8- Elevations of transaminase values, unexplained, persistent ( The presence of hepatic disease may increase atorvastatin plasma concentrations . Plasma concentrations are significantly increased in patients with chronic alcoholic liver disease . In patients with Childs-Pugh Index grade A disease, Cmax and AUC are each 4-fold greater. In patients with Childs-Pugh Index grade B disease, Cmax and AUC are approximately 16- and 11 – fold greater, respectively) .
9- Hypersensitivity to atorvastatin

Warnings:

1–Liver dysfunction: Atorvastatin has been associated with biochemical abnormalities of liver function.
2 – Skeletal muscle: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. Uncomplicated myalgia has been reported in atorvastatin treated patients .
Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdo- myolysis (eg,severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, uncontrolled seizures) .

Precautions:

Before instituting therapy with atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients and to treat other underlying medical problems . Endocrine Function : Atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. Caution should be exercised if an HMG –CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine . CNS toxicity, carcinogenicity, mutagenicity and impairment of fertility.
Regular visits to physician to check progress .
Notifying physician immediately if pregnancy is suspected because of possible harm to the fetus . Caution if any kind of surgery (including dental surgery) or emergency treatment is required .
Not taking over-the-counter niacin preparations without consulting physician because of increased risk of rhabdomyolysis . Not using alcohol excessively because elevations of liver enzymes mayoccur .
Notifying physician immediately if unexplained muscle pain , tenderness , or weakness occurs. Especially if accompanied by unusual tiredness or fever . (USP DI 2007)

Pregnancy:

Atorvastain therapy is contraindicated in pregnant women because it decreases cholesterol synthesis and possibly the synthesis of other biologically active substances. Such as steroids and cell membranes , that are derived from cholesterol and are essential for fetal development .

Breast – feeding:

While it is not known whether atorvastatin is distributed into breast milk, atorvastatin is contraindicated in women who are breast-feeding because inhibition of cholesterol synthesis may cause serious adverse effects in the nursing infant. Atorvastatin is distributed into the milk of lactating rats. Plasma and liver atorvastatin concentrations in nursing rat pups have reached 50% and 40% , respectively , of that in the mother's milk .

Drug interactions:


1- Alcohol
2- Antacids
3- Azole antifungals
4- Cyclosporine
5- Erythromycin
6- Fibric acid derivatives
7- Niacin (nicotinic acid)
8- Cimetidine
9- Detoconazole
10- Spironolactone
11- Colestipol
12- Digoxin
13- Grapefruit juice in large amounts
14- Oral contraceptives

Adverse reactions:

Those indicating need for medical attention :
Incidence less frequent or rare
Allergic reaction; muscle disorders, such as leg cramps ; myalgia , uncomplicated (muscle pain) ; myopathy and / or rhabdomyolysis (fever ; muscle cramps , pain , stiffness , or weakness ; unusual tiredness) ; and myositis (inflammation of muscle) Anaphylaxis; angioneurotic edema ; bullous rashes; erythema multiforme; toxic epidermal necrolysis ; stevens- Johnson syndrome .
Those indicating need for medical attention only if they continue or are bothersome .
Incidence more frequent:
Headache ; infection (fever or chills; cough or hoarseness ; lower back or side pain ; painful or difficult urination ) ; sinusitis (pain or tenderness around eyes and cheekbones ; fever ; stuffy or runny nose ; headache ; cough ; shortness of breath or troubled breathing ; tightness of chest or wheezing) .
Dosage and administration: (USP DI 2007)
Usual adult and adolescent dose:
Coronary heart disease (prophylaxis) – Oral , 10 mg once per day .
Heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipedemia
(Fredrickson Types 11a and 11b) –
Oral , initially 10 mg once a day . The dosage range is 10 to 80 mg once a day , to be administered at any time of the day , with or without food . After initiation or titration of atorvastatin , lipid concentrations should be measured within 2 to 4 weeks and the dosage adjusted accordingly .
Homozygous familial hypercholesterolemia –
Oral , 10 to 80 mg a day .
Usual adult prescribing limits
80 mg a day .
Usual pediatric dose
Heterozygous familial hypercholesterolemia –
Oral , 10 mg per day in boys and postmenarchal girls 10 to 17 years of age.
Adjustments should be made at intervals of 4 weeks or more .
Not : Atorvastatin has not been studied in prepubertal patients or patients younger than 10 years of age .
Dosage adjustment in patients with renal dysfunction is not necessary .
Usual pediatric prescribing limit
Doses greater than 20 mg per day have not been studied in this patient population .

Packaging and storage:

Store at controlled room temperature below 30 ºC .

References :

USP DI 2007
PDR 2007
Electronic Martindale 35
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