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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859 EISSN: 0972-2823
Vol. 46, Num. 3, 2000, pp. 242-243
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Journal of Postgraduate Medicine, Vol. 46, No. 3, July-September, 2000,
pp. 242-243
Drug Review
Atorvastatin: In The Management Of Hyperlipidaemia
Ray SK, Rege NN
Department of Pharmacology, Seth G. S. Medical College and K. E. M. Hospital,
Parel, Mumbai-12, India
Code Number: jp00082
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.1 Recently in India, atorvastatin calcium has
been added to the list of available HMG-CoA reductase
inhibitors (lovastatin and simvastatin).
Chemistry and Pharmacology
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.2
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.3 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.2
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.3 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.4
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.5 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.6 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).2
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.7
Pharmacokinetics
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.8
Adverse Effects
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.2
Drug Interactions
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.9 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.10
Dosage of Atorvastatin
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.
Conclusion
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.
Ray SK, Rege NN
Department of Pharmacology, Seth G. S. Medical College and
K. E. M. Hospital, Parel, Mumbai-12, India
References
- Farmer JA, Gotto AM. Choosing the right lipid-regulating agent. Drugs.
1996; 52:649-661.
- Malinowski JM. Atorvastatin: A hydroxymethylglutaryl_coenzyme A reductase
inhibitor. Am J Health-Syst Pharm. 1998; 55:2253-2267.
- Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ,
et al. Reduction of LDL-C cholesterol by 25% to 60% in patients with primary
hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler
Thromb Vasc Biol 1995; 15:678-682.
- Crouse JR 3rd, Frohlich J, Ose L, Mercuri M, Tobert JA. Effects
of high doses of simvastatin and atorvastatin on high-density lipoprotein
cholesterol and apolipoprotein A-I. Am J Cardiol 1999; 83:1476-1477, A7.
- Davidson M, McKenney J, Stein E, Schrott H, Bakker-Arkema R, Fayyad R,
et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin
in primary hypercholesterolemia. Atorvastatin Study Group I. Am J Cardiol
1997 1;79:1475-1481.
- Magnani G, Carinci V, Magelli C, Potena L, Reggiani LB, Branzi A. Role of
statins in the management of dyslipidemia after cardiac transplant: randomized
controlled trial comparing the efficacy and the safety of atorvastatin with
pravastatin. J Heart Lung Transplant 2000;19:710-715.
- Tannous M, Cheung R, Vignini A, Mutus B. Atorvastatin increases ecNOS levels
in human platelets of hyperlipidemic subjects. Thromb Haemost 1999; 82:1390-1394.
- Desager JP, Hormans Y. Clinical pharmacokinetics of 3-hydroxy-3methylglutaryl-coenzyme
A reductase inhibitors. Clin Pharmacokinet 1996; 31:348-371.
- Bakker-Arkema RG, Best J, Fayyad R, Heinonen TM, Marais AD, Nawrocki JW,
et al. A brief review paper of the efficacy and safety of atorvastatin in
early clinical trials. Atherosclerosis 1997;131:17-23.
- Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations
of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999;66:118-127.
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