Lipid-Lowering Drugs

Exogenous Pathway

In the small intestine, bile emulsifies dietary fat and cholesterol, whereas lipase excreted by the pancreas hydrolyzes triglycerides. The intestinal endothelium takes up these products by endocytosis and packages lipids into large chylomicrons, which then enter the lymphatic system. After traveling through the thoracic duct, the chylomicrons enter the bloodstream where they interact with lipoprotein lipase (LPL) in vascular endothelial cells, yielding glycerol and free fatty acids, which can be utilized by the peripheral tissues for fuel or storage. During this process, the chylomicrons shrink and become chylomicron remnants. These remnants are transported to the liver where they are taken up by hepatocytes via endocytosis and subsequently hydrolyzed.

Endogenous Pathway

In the liver, hepatocytes synthesize cholesterol, lipids, and proteins, which are assembled into VLDL and excreted into the bloodstream. Similar to the processing of chylomicrons, endothelial cell LPL hydrolyzes the fats in VLDL particles, which then shrink to form IDL and LDL. LDL particles contain most of the cholesterol in plasma and are cleared from the blood by binding to LDL receptors (LDL-R) on hepatocytes. Apoproteins C and E are essential cofactors of the hydrolysis of VLDL and are contributed by HDL particles. HDL also transfers ApoC-II to chylomicrons in the exogenous pathway and is responsible for reverse cholesterol transport, in which excess cholesterol is delivered from the peripheral tissues to the liver for excretion in the bile.¹

Lipid Disorders

A minority of lipid disorders arise from genetic defects in lipoprotein metabolism, which may present in the pediatric period or early adulthood. One such disorder, familial hypercholesterolemia, arises from a defect in the gene for LDL-R. Heterozygotes for this defect experience accelerated atherosclerosis and represent about 1 in 500 persons. Homozygotes are much more rare, have total and LDL cholesterol levels four times normal, and have an extreme propensity for atherosclerosis. Hyperlipidemia may also arise from secondary causes including obesity, diabetes, alcohol abuse, hypothyroidism, glucocorticoid excess, and hepatic or renal dysfunction.¹ Most cases of hyperlipidemia in adults arise from a combination of secondary causes, genetic predisposition, and environmental factors, including poor diet and a lack of exercise.²

It has been recognized for several decades that increased plasma concentrations of total and LDL cholesterol are associated with an increased risk of cardiovascular disease.^3,4 Conversely, higher HDL cholesterol levels appear to reduce the risk of atherosclerosis and cardiovascular events because of the critical role of HDL in reverse cholesterol transport.^5–7 Furthermore, lowering plasma concentrations of total and LDL cholesterol with pharmacologic agents decreases the risk of coronary events in patients with and without coronary artery disease.^8,9 Hypertriglyceridemia is known to cause pancreatitis, but its causal relationship to atherosclerosis is less well established.²

The safety and efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors, or statins, have been particularly well established,^9,10 as reflected in current guidelines issued by the the American College of Cardiology (ACC) and the American Heart Association (AHA). These guidelines advocate statin use in four high-risk groups (Table 23-2) for the primary or secondary prevention of atherosclerotic cardiovascular disease (ASCVD).¹¹ Based on these guidelines, about 56 million adults in the United States are eligible for statin therapy.¹² Therefore, anesthesiologists can expect to routinely encounter patients in the perioperative period taking statins for hyperlipidemia and the prevention of ASCVD. ACC/AHA guidelines no longer recommend target reductions of total or LDL cholesterol or the use of drugs other than statins for the treatment of hyperlipidemia.¹¹ However, alternative agents to statins are still used in clinical practice for the treatment of familial lipid disorders and for those who are intolerant of statins.

Drugs for Treatment of Hyperlipidemia

In the last several years, statins have become the mainstay of treatment for hyperlipidemia; however, there are multiple other agents used for patients intolerant of statins or those with genetic lipid disorders. The effects of these different classes of medications on LDL, HDL, and triglycerides are summarized in Table 23-3.

Statins

Statins are drugs that act as inhibitors of HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step of cholesterol biosynthesis in which HMG-CoA is converted to mevalonate (see Fig. 23-1). Statins are structurally related to HMG-CoA and competitive inhibition of the enzyme causes an increase in hepatic LDL-R. The combined effect of decreased cholesterol synthesis and increased LDL uptake by the liver by statins results in a decrease in LDL concentration of 20% to 60%. Statins also increase HDL by approximately 10%, possibly from increased synthesis of apolipoprotein A-I. Plasma triglyceride concentrations decrease 10% to 20% in statin-treated patients, although this is usually insufficent as the sole treatment of hypertriglyceridemia.²

The drugs in this class (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin) are considered equivalent and relatively free of side effects. Randomized clinical trials have shown that statins lower cardiac events (total mortality, death from myocardial infarction, revascularization procedures, stroke, and peripheral vascular disease) in patients with or without atherosclerosis.^13,14 Furthermore, angiographic studies have shown benefit on coronary stenosis in native vessels or grafts in patients treated with statins as well as in patients experiencing acute coronary syndromes.¹⁵ Early initiation of statin therapy following an acute myocardial infarction is recommended.^16,17

The reduction in cardiac events observed with statin use may not be only secondary to the LDL lowering effects. Statins are thought to stabilize existing atherosclerotic plaques, and there is evidence that statins have many pleiotropic effects, including antiinflammatory, antioxidant, and vasodilatory properties. Reduced cardiac morbidity and mortality has even been reported following perioperative statin administration in high-risk groups, although this is not yet widely advocated.¹⁸

Origin and Chemical Structure

Lovastatin is a naturally occurring product isolated from a strain of Aspergillus terreus. Simvastatin and pravastatin are derived synthetically from a fermentation product of the same fungus, whereas atorvastatin, fluvastatin, and rosuvastatin are entirely synthetic compounds.¹⁹

Pharmacokinetics

Statins are variably absorbed from the gastrointestinal tract following oral ingestion. Bile acid–binding resins can decrease the absorption of these drugs. Lovastatin and simvastatin are prodrugs that require metabolism to the open β-hydroxy acid form to be pharmacologically active. Atorvastatin, fluvastatin, and pravastatin are administered as the active β-hydroxy acid form. Food intake increases plasma concentrations of lovastatin but has minimal effects on the other statins. All of the statins are highly protein bound with the exception of pravastatin. Except for pravastatin, all of the statins undergo extensive metabolism by hepatic P450 enzymes. Elimination half-times are 1 to 4 hours for all the statins except atorvastatin, which has an elimination half-time of 14 hours.

Despite the short elimination half-times, the duration of pharmacodynamic effects is about 24 hours. This is a consideration in the perioperative period when patients may not be able to ingest oral medications. Atorvastatin and fluvastatin undergo minimal renal excretion and probably do not require dosage adjustments in patients with renal insufficiency. Dosages of pravastatin and to a lesser degree lovastatin and simvastatin may need to be adjusted in patients with renal insufficiency. Statins are teratogenic in animals and thus are not recommended for use during pregnancy.²⁰

Side Effects

Statins are usually well tolerated with the most common complaints being gastrointestinal upset, fatigue, and headache. In clinical trials, less than 5% of patients treated with statins experienced adverse side effects, similar to the rate in placebo-treated groups. The incidence of side effects in the general population is thought to be higher.

Muscle-Related Adverse Effects

The most common adverse side effects from statins are skeletal muscle related. These can range in severity from simple myalgias to myositis with mild creatine kinase (CK) elevation to life-threatening rhabdomyolysis characterized by a greater than 10-fold elevation in CK. Myositis and rhabdomyolysis are quite rare and in clinical trials occur with similar frequency in placebo-treated groups. Conversely, myalgias are reported in as many as a third of statin-treated patients in clinical practice and more commonly in patients with certain risk factors (Table 23-4). The mechanisms underlying statin-related myotoxicity are incompletely understood. It is possible that by inhibiting HMG-CoA reductase, statins decrease not only cholesterol synthesis but also the formation of ubiquinone (otherwise known as coenzyme Q10), which is important for mitochondrial function and cell membrane integrity.²¹ Alternatively, decreased cholesterol levels in skeletal muscle cell membranes may increase membrane fluidity, leading to unstable sarcolemma, myotonic discharges, and, in advanced but rare situations, rhabdomyolysis.²²