Lipid lowering drugs

Hyperiipidaemia is a high risk factor for cardiovascular disease (CVD) and enhances other risk factors such as smoking, excessive alcohol consumption, lack of exercise, diabetes, hypertension, obesity and abdominal distribution of body fat. The risk of CVD over the next 10 years is estimated for an individual using guidelines produced by the British Hypertension Society (or the Joint British Societies Cardiac Risk Assessor ), which include age, gender, smoking history, blood pressure and TC HDL ratios. This estimate is used to determine suitable treatment. 

Drugs can be used to lower lipid levels, but changes in diet and control or elimination of other risk factors play an important role in the management of hyperiipidaemia. 

A 10-year risk of CVD of over 30% would indicate treatment with lipid-lowering drugs in addition to dietary and lifestyle advice. If the 10-year risk is between 15 and 30%, changes to lifestyle and diet are recommended and followed by drug therapy if necessary. With a 10-year risk of below 15%, changes in lifestyle and diet may be sufficient. In any case, the aim is to reduce plasma TC levels to below 5 mmol 1  

Individuals with the hereditary form of hyperiipidaemia will always require drug therapy, possibly with two different types. 

Statins work by reducing the endogenous synthesis of cholesterol in the liver through the inhibition of an enzyme, HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA, if you must know). As a result, more DDLs are taken up from the circulation by the liver to provide the cholesterol needed to synthesize bile acids. An example of a statin is atorvastatin and others have similar names. 

Fatty acids and cholesterol from ingested dietary fat are le-eslcrilied in mucosal cells of the intestine and fonn the core of chyhmuTons that enter the plasma via the thoracic duct. Fatty acids are hydrolysed from 

Adverse effects are contined to the gut. because the resin.s are not absorbed, and include bloating, abdominal discomfon. diarriioea and constipation. 

Nicotinic acid reduces the release of VLDL and therefore lowers pla.sma iriglycerides (by. 50-50%), It also lowers cholesterol (by 10-20%) and increases HDL. Nicotinic acid was the first lipid-lowering drug to reduce overall mortality in patients with coronary artery disease hut its use is limited by unwanted effects that include prostaglandin-mediated flu.shing. dizzinesti and palpitations. Nicotinic acid is now alinosi never used. 

Adverse effects. All the hbrates can cause a myositis-like syndrome. Ttie incidence of myositis is increased by concurrent use of HMG CoA inhibilois and such combinations should be avoided. 

Severe hyperlipidaemia may require a combination of lipid-lowering drugs, e.g. an ion exchange resin with an HMG CoA reductase inhibitor. 

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TABLE 9-8. Effects of Lipid-Lowering Drugs on Serum Lipids at FDA-Approved Doses... 

Lipid-Lowering Drug LDL Cholesterol HDL Cholesterol Triglycerides Total Cholesterol... 

TABLE 9-9. Formulation, Dosing, and Common Adverse Effects of Lipid-Lowering Drugs... 

Lipid-Lowering Drug Dosage Forms Usual Adult Maintenance Dose Range Adverse Effects... 

Cauley JA, Zmuda JM, Lui LY et al. (2003) Lipid lowering drug use and breast cancer innolder women a prospective study. J Womens Health 12(8) 749-756... 

Neuvonen, P.J., Niemi, M. and Backman, J.T. (2006) Drug interactions with lipid-lowering drugs mechanisms and clinical relevance. Clinical Pharmacology and Therapeutics, 80, 565-581. 

Of the two subjects, Mr Leene is at the greater risk for cardiovascular disease (CVD). Despite his healthier lifestyle Mr Leene has a family history of vascular disease (brother who died of a stroke), clinical signs of lipid deposits (yellow patches in skin) and a very poor lipid profile. Lipid-lowering drug intervention is required in this subject. 

Lipitor (atorvastatin calcium) is a synthetic lipid-lowering drug. The chemical name for Lipitor is [R-(R, R )]-2-(4-fluorophenyl)-j3, 5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid, calcium salt (2 1) trihydrate. The molecular weight is 1209.42. It is a white... 

Skeletal muscle effects In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. 

Table 4. Most important lipid-lowering drugs available at present. An indication is given of the most relevant changes in the plasma lipoprotein fractions caused by these agents...

Fedder DO, Koro CE, L ltaUen GJ. Primary prevention lipid-lowering drug therapy. Circulation 2002 106 e35-6. 

Shepherd J. Combined lipid lowering drug therapy for the effective treatment of hypercholesterolaemia. Eur Heart J 2003 24 685-9. 

Drug interactions InsuUn requirements may be increased by medications with hyperglycemic activity such as corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, and thyroid... 

Rodriguez EG et al Use of lipid-lowering drugs in older adults with and without dementia A community-based epidemiological study. J Am GeriatrSoc 2002 50 1852. [PMID 12410906]... 

Asberg A Interactions between cyclosporin and lipid-lowering drugs Implications for organ transplant recipients. Drugs 2003 63 367. [PMID 12558459]... 

Various chemicals, such as the fibrate (e.g., clofibrate, bezafibrate, and ciprofibrate) and other lipid-lowering drugs (e.g., Wy-14643) and phthalate plasticizers (e.g., diethylhexyl phthalate), bind to and activate PPARa and are also hepa to carcinogenic in rodents. However, different compounds bind with different affinities, from strong (e.g., Wy-14643) to weak (e.g., phthalates). Thus, it is believed that peroxisomal proliferators act via the receptor (PPARa) to cause some of the effects seen. 

One major question is whether humans are at risk from these chemicals. Although they clearly have the receptor for the lipid-lowering drugs to work, there is no evidence of increased risk of hepatic cancer from epidemiological studies. However, fibrates are relatively weak PPARa agonists. 

Recent research using NMR has revealed novel noninvasive biomarkers for peroxisomal proliferation. These are two breakdown products of NAD detectable in plasma by HPLC. These reflect the increased demand and production of NAD for oxidation metabolism such as (3-oxidation of fatty acids. This biomarker will be useful in studies in humans, especially clinical trials of more potent lipid-lowering drugs. 

Rhabdomyolysis is a problem with several lipid-lowering drugs (SEDA-13, 1325 SEDA-13, 1328 SEDA-13, 1330 ... 

Cattley RC. Carcinogenicity of lipid-lowering drugs. JAMA... 

In a series of seven cases of neuropathy, all were axonal peripheral neuropathies and both thick and thin nerve fibers were affected (10). No cause of peripheral neuropathy other than statin treatment could be identified. In this series at least four of the cases were irreversible, probably due to long exposure to statins (4—7 years versus 1-2 years in previous reports). Besides an effect on ubiquinone, interference with cholesterol synthesis may alter nerve membrane function, since cholesterol is a ubiquitous component of human cell membranes. Neuropathy has not been observed in extensive long-term trials of lipid-lowering drugs. It could be due to patient selection, a low frequency of the adverse effect, or lack of attention to symptoms of peripheral neuropathy. The observed association may also not be causal. 

Rhabdomyolysis is a problem with several lipid-lowering drugs (SEDA-13, 1325 SEDA-13, 1328 SEDA-13, 1330 SEDA-19, 409), especially when they are used in combination (37). In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis (38). All statins can cause myopathy and rhabdomyolysis, but not all statins are alike. For example, the evidence to date, based on almost 2 decades of experience, points to an extremely low risk of myopathy and rhabdomyolysis with lovastatin, and lovastatin 20 mg tablets are being considered for non-prescription availability in several countries (39). Furthermore, muscle adverse effects do not necessarily occur after a change from one statin to another (40). Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyolysis (SEDA-18, 426). For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination (41). 

Physicians should check for lipid-lowering drugs before treating elderly individuals with itraconazole (73). Susceptibility to this interaction varies from statin to statin, in that simvastatin is more affected than pravastatin (74). Concomitant use of simvastatin with itraconazole should be avoided, and the same holds true for atorvastatin (75). In another study, the blood concentration of fluvastatin was not significantly increased, whereas that of lovastatin was (76). 

Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, Grenade LL, Gurwitz JH, Chan K A, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004 292(21) 2585-90. 

Nicotinic acid has been associated with the development of myopathy with nocturnal leg aching and cramps, symptoms that can be exacerbated by simultaneous use of other lipid lowering drugs associated with similar adverse effects, or alcohol, which also has myopathic effects (SEDA-15, 413 38). 

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