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|Year : 2000 | Volume
| Issue : 3 | Page : 242-3
Atorvastatin: in the management of hyperlipidaemia.
SK Ray, NN Rege
Department Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai-400 012, India., India
S K Ray
Department Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai-400 012, India.
Source of Support: None, Conflict of Interest: None
Keywords: Anticholesteremic Agents, pharmacology,therapeutic use,Heptanoic Acids, pharmacology,therapeutic use,Human, Hyperlipidemia, drug therapy,India, Pyrroles, pharmacology,therapeutic use,Sensitivity and Specificity, Treatment Outcome,
|How to cite this article:|
Ray S K, Rege N N. Atorvastatin: in the management of hyperlipidaemia. J Postgrad Med 2000;46:242
The proved association between hypercholesterolaemia with development of atherosclerosis and coronary heart disease warrants reduction in high levels of serum cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C). Since the discovery, HMG-CoA reductase inhibitors are considered as one of the most effective classes of drugs for reducing LDL-C and TC. Recently in India, atorvastatin calcium has been added to the list of available HMG-CoA reductase inhibitors (lovastatin and simvastatin).
Atorvastatin calcium is a synthetic stereo isomer of a pentasubstituted pyrrole. Unlike the previously introduced prodrugs , lovastatin and simvastatin, which are inactive till get metabolised, atorvastatin is an active compound. The statins inhibit competitively an enzyme (HMG-CoA reductase) in the liver that converts HMG-CoA to mevalonic acid, an early precursor of cholesterol. Animal models have shown that by reducing cholesterol supply, statins increase expression of LDL-receptor in liver. These LDL receptors increase uptake and subsequent removal of LDL, very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) and thus restore cholesterol homeostasis.
The primary lipid fraction targeted in pharmacotherapy of hyperlipidaemia is LDL-C. However, triglycerides in high concentrations also have atherogenic potential. Compared to other statins, Atorvastatin appears to reduce triglyceride levels to a greater extent. Two possible mechanisms for the triglyceride-lowering effect of atorvastatin have been postulated. First mechanism involves increased triglyceride clearance. The increased LDL-receptor expression by atorvastatin promotes uptake of VLDL and LDL particles. It may be possible that these LDL receptors have more affinity for VLDL particles (contain apoB and apo E) than for LDL particles, which contain only apoB. The second mechanism is reduction in the synthesis of triglycerides during therapy with atorvastatin. This reduction is secondary to reduced synthesis of cholesterol. Cholesterol is needed to form VLDL particles. Thus, secretion and formation of VLDL particles is reduced, which reflects in decreased triglyceride levels. The time taken for maximum reduction in triglycerides varies from four weeks to more than six months. Atorvastatin also increases high-density-lipoprotein cholesterol (HDL-C) levels approximately 5–15%. However, mechanism responsible is still unknown.
Various studies have been reported in the literature during last 4 years, which have compared atorvastatin with other statins. In a clinical study conducted by Nawrocki, et al, atorvastatin was found to increase HDL-C in a dose-independent fashion by 12% and cause about 90% of maximum reduction in LDL-C as compared to placebo within the first two weeks of treatment. As compared to lovastatin, the changes induced in all the lipid fractions except HDL-C are significantly greater with atorvastatin at the end of 52 weeks of therapy. Comparison with simvastatin has revealed that atorvastatin shows greater reduction in levels of triglycerides, TC, LDL-C, & apoB at both 16 and 52 weeks of therapy. The same study reported that simvastatin raises HDL-C and apoA-I more than atorvastatin. Thus metabolic effects of these 2 statins on plasma lipids and lipoproteins differ. In patients with cardiac transplant, atorvastatin even in lower doses was significantly more effective than pravastatin in reducing TC, LDL-C and triglycerides. Tolerability and safety of these 2 agents was comparable. In the curves trial (atorvastatin vs four other statins) atorvastatin (10 mg) reduced LDL-C significantly more than simvastatin (10 mg), lovastatin (20 mg & 40 mg), pravastatin (20 mg), and fluvastatin (20 mg & 40 mg). At a higher dose of 20-mg, atorvastatin produced significant reduction in LDL-C than simvastatin (20 mg or 40 mg), and pravastatin (40 mg).
Atorvastatin has also been shown to elevate of nitrous oxide production. It was found to reduce the size of atherosclerotic lesion and decrease vascular smooth muscle cell proliferation in in-vitro model. These effects raise a hope that atorvastatin may promote platelet deaggregation and vasodilatation in patients of dyslipidaemia.
Atorvastatin is rapidly absorbed when given orally and peak plasma level occurs at nearly 2.5 hours. The absorption of atorvastatin is non-linear and dose dependent. Due to extensive first-pass metabolism, the bioavailability of atorvastatin is approximately 12% and is not significantly affected by food. It is about 98% bound to plasma proteins and metabolised extensively by cytochrome P4503A4 to active metabolites, which account for about 70% of the circulating HMG-CoA reductase inhibitory activity. Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however the drug does not appear to undergo enterohepatic re-circulation. Mean plasma elimination half-life is 14 hours, but because of active metabolites, the half-life of HMG-CoA reductase inhibitory activity is nearly 24 hrs.
Atorvastatin is generally well tolerated and adverse reactions have been mild and transient. Frequently encountered adverse effects are constipation, flatulence, dyspepsia and abdominal pain. Headache, rash and sleep disturbances have also been reported. Atorvastatin, like other HMG-CoA reductase inhibitors, have been associated with abnormal liver function values. Persistent elevations (>3 x upper limit of normal value) in serum transaminases have been noticed in 0.7% of patients receiving atorvastatin. Hence, it is recommended that liver function tests should be performed before initiation of treatment and after 6 and 12 weeks of therapy or whenever dose escalation is carried out. For patients on chronic therapy periodic (semi-annually) assessment of liver function is necessary. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve.
Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class but not so far with atorvastatin. Uncomplicated myalgia has been reported in atorvastatin-treated patients. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Although atorvastatin lacks teratogenicity in animal studies, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.
Concurrent use of atorvastatin with drugs like erythromycin, azole antifungals (e.g. ketoconazole or fluconazole), cyclosporine, gemfibrozil, or niacin that may interfere with its metabolism or its protein binding may increase serum concentrations of atorvastatin and the risk of myopathy. Concurrent use of atorvastatin may increase digoxin serum concentrations. Grape fruit juice has been found to elevate bioavailability of atorvastatin, lovastatin and simvastatin probably by decreasing CYP3A4-mediated first-pass metabolism of atorvastatin in the small intestine but no effect on the pharmacokinetics of pravastatin.
Atorvastatin is available as white, film-coated 10, 20 and 40 mg tablets. Recommended initial dosage of atovastatin calcium is 10 mg/day; upper limit being 80 mg/day. If additional lipid reduction is required, the dosage can be doubled every four weeks based on the patient’s risk status.
Atorvastatin reduces TC, LDL-C and triglycerides in patients with hypercholesterolaemia more efficiently than other HMG-CoA reductase inhibitors. However, post-marketing surveillance for this newly introduced agent is necessary to confirm its benefit over other statins used in the management of hyperlipidaemia.
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