These drugs block synthesis of cholesterol in the liver by competitively inhibiting HMG CoA (3 -hydroxy -3-methyl-glutaryl coenzyme A) reductase activity. They are capable of lowering LDL cholesterol levels by 25 to 45%. All of them are absorbed well orally, are generally extensively protein-bound, and excreted mainly in the bile.
■■The active beta-hydroxy acid form of the HMG CoA reductase inhibitors are competitive inhibitors of the enzyme (HMG CoA reductase). Atorvastatin, cerivastatin, fluvastatin and pravastatin are active drugs, whereas lovas-tatin and simvastatin are prodrugs. The liver is the primary site of action of these drugs.
■■ Inhibition of HMG CoA reductase prevents conversion of HMG CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. However, at therapeutic doses, the enzyme is not completely inhibited, thereby allowing biologically necessary amounts of mevalonate to be avail-able.
■■ When cholesterol synthesis is inhibited in the liver, an upregulation of LDL receptors and an increase in catabo-lism of LDL cholesterol occurs. Some reduction in LDL production as a result of inhibition of hepatic synthesis of very low-density lipoprotein (VLDL), the precursor of LDL, may also result. Thus, HMG CoA reductase inhibitors reduce LDL cholesterol, VLDL, cholesterol, and to a lesser extent, plasma triglyceride concentrations. They slightly increase high-density lipoprotein (HDL) concentrations.
· Myalgia, hepatic function impairment, headache, peripheral neuropathy, insomnia, behavioural changes, extrapyramidal symptoms, hyperkalaemia, flatulence, dyspepsia, diarrhoea, rash, pulmonary fibrosis, acute renal failure, and rhabdo-myolysis.
· Chronic use may cause cataract, especially with lovastatin. The manufacturer recommends slit-lamp examination as a precaution, before or shortly after starting treatment with lovastatin, and annually thereafter.
· Severe proximal muscle weakness in upper and lower extremities has been described in patients given HMG CoA reductase inhibitor therapy. Creatine phosphokinase was elevated in all cases. Histologic examinations of the skeletal muscle showed myopathic changes, such as atrophy and muscle fibre necrosis.
· In August, 2001, Bayer Pharmaceutical Division announced a voluntary withdrawal of cerivastatin (Baycol®) from the market due to several reports of fatal rhabdomy-olysis following cerivastatin therapy. Cholestin, formerly promoted as a dietary supplement to lower cholesterol levels, has been reclassified by the FDA as an unapproved drug based on the fact that cholestin contains lovastatin.
· Elevated liver enzyme levels, progressing to clinical hepa-titis, have been reported following lovastatin therapy. Minor and sporadic elevations of liver enzymes developed during clinical trials with atorvastatin.
· Pancreatitis has been reported with gemfibrozil-lovastatin combined therapy.
· Dermatitis, photosensitivity, and dermatomyositis may occur following therapy with HMG CoA reductase inhibitors.
· Case reports suggest that these agents can cause thrombo-cytopenia and haemolytic anaemia following short-term therapeutic dosing.
· Poisoning with HMG CoA reductase inhibitors is uncommon. Ingestion of up to 6 grams of lovastatin has been reported without specific effects or sequelae. Severe toxicity is not expected, unless a coingestant is present.
· Decreased plasma levels may occur if antacids or colestipol are given simultaneously.
· Decreased activity is associated with concomitant use of propranolol.
· Statins may enhance the anticoagulant effect of warfarin.
· Pectin and oat bran have been reported to reduce the absorption of lovastatin in the body, thereby decreasing lovastatin’s effect on low-density lipoprotein (LDL) cholesterol.
· Myopathy and rhabdomyolysis are rare side effects of HMG CoA reductase inhibitor monotherapy and appear to be dose-related. The risk of development of rhabdomyolysis is considerably increased with concurrent administration of all CYP3A inhibitors, such as cyclosporine with lovastatin or simvastatin, or cerivastatin with gemfibrozil.
· Alcohol use should be curbed when these drugs are being consumed regularly.
· These drugs are contraindicated in pregnancy since congen-ital anomalies may occur.
· Treatment of toxicity is symptomatic and supportive.
· Significant toxicity has not been reported after acute over-dose of these agents.
· Pre-hospital decontamination is generally not necessary unless coingestants are involved.
· Monitor serum creatinine, BUN, creatine phosphokinase, and urine myoglobin for indications of renal impairment secondary to rhabdomyolysis in symptomatic patients.
· For rhabdomyolysis: early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insuf-ficiency; diuretics such as mannitol or furosemide may be needed to maintain urine output; urinary alkalinisation is not routinely recommended.
· Haemodialysis is not expected to significantly enhance the clearance of these drugs due to extensive protein binding and large volumes of distribution.
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