Atorvastatin is one of the best selling drugs in the world if not the best seller. Therefore this class of drugs is very important for Oriental medical practitioners to know and understand. This excerpt from the book Integrated Pharmacology, Combining Modern Pharmacology with Chinese Medicine will examine them, how they work, and what we need to know about their adverse effects and herbal interactions.

ATORVASTATIN (a TORE va sta tin) (Caduet®,[i] Lipitor®)

FLUVASTATIN (FLOO va sta tin) (Lescol® XL, Lescol®)

LOVASTATIN (LOE va sta tin) (Advicor®, Altoprev™, Mevacor®)

PRAVASTATIN (PRA va stat in) (Pravachol®)

ROSUVASTATIN (roe SOO va sta tin) (Crestor®)

SIMVASTATIN (SIM va stat in) (Vytorin™, Zocor®)

The drugs in this class are commonly known as statins, as that is the last part in each agent’s name. The herb Hong Qu (red yeast rice) has been found to include several of the statins as natural constituents. It is an excellent whole food alternative to a statin drug. Be advised, however, that dosing is critical, with most current studies showing beneficial effects at 2.4g a day.

Function

These drugs are used to treat hyperlipidemia including hypertriglyceridemia and hypercholesterolemia.

Mechanisms of Action

The agents in this class have two major mechanisms for reducing LDL and VLDL cholesterol. The first mechanism is by inhibiting 3-hydroxy- 3-methylglutarate (HMG) coenzyme A (CoA) reductase which is an enzyme necessary to produce cholesterol. Some of these agents do this directly and others need to be metabolized to the active agent.

The second mechanism of action for these drugs is due to a reduction of LDL cholesterol in the cell due to the inhibition of HMG-CoA reductase. The cell starts to produce more LDL receptors on the cell surface which bind and reduce LDL that is in the blood. These effects are summarized in the figure 1.

Besides these effects, HMG-CoA reductase inhibitors also tend to raise HDL (the “good” cholesterol) cholesterol, stabilize plaques, so that they don’t break off and form an emboli, improve cardiac endothelial function, inhibit platelet thrombus synthesis, and have some anti-inflammatory effects. All of these are very beneficial in preventing or minimizing coronary heart disease, even though the exact mechanisms of these actions are not completely understood.

Figure 1: Effects of HMG CoA reductase inhibitors (statins). 1: HMG CoA reductase is inhibited and reduces the amount of cholesterol produced in the cell. 2: Reduced cholesterol initiates LDL receptor synthesis. 3: An increased number of LDL receptors on the cell membrane increases the amount of cholesterol removed from the blood and hence lowers circulating LDL. 4: Low intracellular VLDL lowers secretion into the blood.

Dosages

ATORVASTATIN, adjustments should be made at intervals of 2-4 weeks. For children 10-17 years: 10 mg once daily; may increase to 20 mg once daily, doses >20 mg have not been studied. For adolescents >17 years and adults, initiate at 10-20 mg once daily, patients who require a reduction of >45% in LDL-C may be started at 40 mg once daily, recommended dosage range is 10-80 mg/day.

FLUVASTATIN, for adolescents 10-16 years, initiate at 20 mg once daily, may increase every 6 weeks based on tolerability and response to a maximum recommended dose of 80 mg/day, given in 2 divided doses (immediate release capsule) or as a single daily dose (extended-release tablet). For adults, for patients requiring ≥25% decrease in LDL, 40 mg capsule once daily in the evening or 80 mg extended release tablet once daily (anytime), or 40 mg capsule bid; for patients requiring less than 25% decrease in LDL, initiate at: 20 mg capsule once daily in the evening; may increase based on tolerability and response to a maximum recommended dose of 80 mg/day, given in 2 divided doses (immediate release capsule) or as a single daily dose (extended release tablet).

LOVASTATIN, for children and adolescents 10-17 years, initiate at, using immediate release formulation, 10 mg once daily, increase to 20 mg once daily after 8 weeks and 40 mg once daily after 16 weeks as needed. Girls must be at least 1-year post-menarche. For adults, using immediate release tablet, initiate at 20 mg once daily and adjust dosage at 4-week intervals to a usual range of 10-80 mg/day in a single or 2 divided doses; for extended-release tablet, initiate at 20mg once daily and adjust dosage at 4-week intervals up to a maximum dose of 60 mg/day.

PRAVASTATIN, for children, 8-13 years, 20 mg/ day, 14-18 years, 40 mg/day. For adults, initiate at 40 mg once daily, usual dose range is 10-80 mg with a maximum dose of 80 mg once daily.

ROSUVASTATIN, for adults, initiate at 10 mg once daily (20 mg in patients with severe hypercholesterolemia or 5 mg in patients requiring less aggressive treatment or predisposed to myopathy), after 2 weeks, may be increased by 5-10 mg once daily, usual dosing range is 5-40 mg/day up to a maximum dose of 40 mg once daily.

SIMVASTATIN, adjustments should be made at intervals of 4 weeks or more. For children 10- 17 years (females >1 year post menarche), 10 mg once daily in the evening increasing to a usual dose range of 10-40 mg/day and a daily maximum of 40 mg. For adults, 20-40 mg once daily in the evening, changing to a usual range of 5-80 mg/day.

Adverse Effects

In general, these drugs are quite safe and the incidence of adverse effects is minimal. With that said, there are some serious, if rare, adverse effects. These include liver failure, muscle abnormalities, and rhabdomyolysis. These last two effects are more prominent in patients who have renal issues, or were taking other drugs with the statin. The drugs showing this increased risk include cyclosporine, itraconazole, erythromycin, gemfibrozil, and niacin. These drugs should not be used during pregnancy or breast feeding, and only under specific conditions should they be used in children and teenagers. 

Rosuvastatin has been implicated by several FDA scientists as having more adverse effects than other statins and they have gone public with suggestions to take it off the market.

"Rhabdomyolysis: An acute, potentially fatal disease of destruction of skeletal muscle; signs include myoglobinemia and myoglobinuria"

Red Flags

None noted.

Interactions

Drug

Taking a statin with cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin may increase the risk of myopathies and rhabdomyolysis. These agents also increase warfarin levels and increased observation of prothrombin times is warranted.

Herb

The letters after the herb names indicate the level of evidence of the interaction. “A” level is highest and “D” level lowest.

Anticholesterol Agents

• Da Suan (Garlic) (D)–may potentiate cholesterol lowering agents as shown in metaanalysis of human clinical trials (Silagy, Neil, 1994) Level 5 evidence.

• Hu Lu Ba (Fenugreek) (D)–may potentiate cholesterol lowering agents as shown in several small human studies and one dog study (Mills & Bone, 2000) Level 5 evidence.

Lovastatin

• Hong Qu (Red yeast rice) (D)–should not be used with gemfibrozil or lovastatin as severe rhabdomyolysis and myopathy have been reported, expert opinion (Chen & Chen, 2004) Level 5 evidence.

Other Supplements

• CoQ-10 is an excellent supplement to administer with statins. It has been found to reduce the amount of adverse effects.

Provisional Chinese Medical Description

HMG-COA reductase inhibitors are used to treat high serum cholesterol. The side effects of these drugs include:

• Muscle cramps

• Liver failure

• Acute kidney failure

In Chinese medicine, the clinical symptoms of high cholesterol are all associated with blood stasis, such as chest impediment and angina pectoris, while muscle cramps are mainly due to blood vacuity.

We have seen that excessive or inappropriate use of blood-quickening medicinals can damage the blood. The signs and symptoms of acute renal failure include peripheral edema, weight gain, anorexia, lack of strength, nausea and vomiting and other such symptoms of qi vacuity. The signs and symptoms of liver failure also indicate spleen qi vacuity, such as jaundice. Fatigue, somnolence, lack of strength, and orthostatic hypotension. Therefore, we believe that these drugs should also be classified as blood-quickening medicinals (huo xue yao).