Lipoprotein Metabolism
Lipoproteins are macromolecular lipid protein complexes responsible for the transport of lipids to and from the peripheral tissues. Lipoproteins are classified based on their relative density as (a) chylomicrons, (b) very-low-density lipoproteins (VLDLs), (c) intermediate-density lipoproteins (IDLs), (d) low-density lipoproteins (LDLs), and (e) high-density lipoproteins (HDLs) (Table 23-1). Lipoprotein metabolism can be divided into the exogenous and endogenous pathways (Fig. 23-1). The exogenous pathway refers to the processing of dietary fats, cholesterol, and lipid-soluble vitamins, whereas the endogenous pathway describes hepatic cholesterol synthesis and its distrubution to the peripheral tissues.
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.13,14Furthermore, 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
Severe muscle-related adverse events associated with statin use are often secondary to drug interactions with agents that are also metabolized by the hepatocyte cytochrome P450 (CYP) system. Myopathy appears to be most frequent in patients treated with simvastatin and lovastatin, as these are metabolized by CYP3A4 and their concentrations are increased by CYP3A4 inhibitors, including Coumadin, protease inhibitors, macrolide antibiotics, and azole antifungals. Fluvastatin and rosuvastatin are metabolized by CYP2C9 and have the lowest rate of events. Drugs likely to be administered during anesthesia, including succinylcholine, have not been shown to increase the incidence of statin-induced myopathy.21,23
Hepatic Dysfunction
Persistent increases in plasma aminotransferase concentrations occur in 0.5% to 2% of treated patients and are dose-dependent. Discontinuation of the drug is recommended if plasma aminotransferase concentrations increase to more than three times normal. Progression to hepatic failure is extremely rare.2
Bile Acid Resins
Bile acid resins are effective for the treatment of lipid disorders in which the primary abnormality is an increased plasma LDL cholesterol concentration with a normal or near normal triglyceride level. The three drugs in this class, colesevelam, cholestyramine, and colestipol, have a low potential for toxicity and are well tolerated. Both drugs are available only as powders that must be hydrated before ingestion. There is no systemic absorption of these resins. Administered as monotherapy, bile acid–binding resins decrease plasma concentrations of LDL cholesterol by 15% to 30%. Plasma concentrations of triglycerides may increase 5% to 20% in treated patients owing to increased production of VLDLs.
Bile acid resins bind bile in the intestine, interrupting enterohepatic circulation and increasing fecal excretion that increases hepatic bile acid synthesis from cholesterol stores (see Fig. 23-1). This increases the production of hepatic LDL-R and increases the uptake of LDL cholesterol from blood, lowering plasma concentrations of LDL cholesterol. HMG-CoA reductase activity also increases.
Side Effects
Palatability and constipation are common complaints in patients being treated with cholestyramine. A high fluid intake is useful in minimizing constipation. Colesevelam has fewer gastrointestinal side effects and is approved for use in adolescents with familial hypercholesterolemia. There may be transient increases in the plasma concentrations of alkaline phosphatase and transaminases.
Because cholestyramine is a chloride form of an ion exchange resin, hyperchloremic acidosis can occur, especially in younger and smaller patients in whom the relative dose is larger. Absorption of fat-soluble vitamins as well as other pharmacologic agents may be impaired. For this reason, other drugs should be given at least 1 hour before or 4 hours after administration of cholestyramine.
Niacin
Niacin (nicotinic acid) is a water-soluble B complex vitamin that inhibits synthesis of VLDLs in the liver by an unknown mechanism (see Fig. 23-1). In addition, niacin inhibits release of free fatty acids from adipose tissue and increases the activity of lipoprotein lipase. The result of these effects is a dose-related 15% to 30% decrease in plasma LDL cholesterol concentrations, a 20% to 50% decrease in triglycerides, and a 20% to 30% increase in HDL. Niacin does not produce any detectable changes in synthesis of cholesterol nor does it alter excretion of bile acids.24
Pharmacokinetics
Niacin is readily absorbed from the gastrointestinal tract and undergoes extensive hepatic first-pass metabolism. The primary route of metabolism is methylation to N-methyl-nicotinamide. Niacin also undergoes conjugation with glycine to produce nicotinuric acid. Metabolites undergo renal excretion and at high doses, niacin undergoes renal excretion unchanged.
Side Effects
Niacin, unlike the resins and statins, has many side effects, which may limit its usefulness. The most common side effect is intense prostaglandin-induced cutaneous flushing that occurs in about 10% of patients. Aspirin administered 30 minutes before ingestion of niacin decreases flushing, whereas alcohol ingestion potentiates flushing. Abdominal pain, nausea and vomiting, diarrhea, and malaise are common complaints in treated patients. Hepatic dysfunction manifesting as increased plasma transaminase activity and cholestatic jaundice may be associated with large doses of niacin. Therefore, niacin is not recommended for administration to patients with liver disease. Hyperglycemia and abnormal glucose tolerance may occur in nondiabetic patients treated with niacin. Plasma concentrations of uric acid are increased, increasing the incidence of gouty arthritis. Niacin may exaggerate the orthostatic hypotension associated with antihypertensive drugs and the myopathy associated with statins. Peptic ulcer disease may be reactivated by niacin.
Fibrates
Fibrates are derivatives of fibric acid and are the most effective drugs for decreasing plasma concentrations of triglycerides. In the postoperative period, treatment with fibrates is restarted when the patient is well hydrated and able to ingest oral medications. There are three fibric acid derivatives commonly used for the treatment of hyperlipidemia: gemfibrozil, fenofibrate, and bezafibrate. Clofibrate was the original fibric acid derivative for treatment of increased plasma triglyceride concentrations. This drug is no longer considered the drug of choice, principally because of concern that noncardiovascular adverse events may be increased in treated patients.25 Fibrates produce a dose-dependent 40% to 50% decrease in plasma triglycerides and 10% to 35% increase in HDL concentrations, whereas the effect on LDL concentrations is variable. Drug-induced increase in the activity of lipoprotein lipase is the likely mechanism for the triglyceride lowering effects of these drugs (see Fig. 23-1). This action of fibrates may reflect activation of specific transcription factors (peroxisome proliferator–activated receptors), which result in upregulation of genes for lipoprotein lipase and fatty acid oxidation. Induction of lipoprotein lipase contributes to lipolysis of triglyceride-rich lipoproteins, VLDL, and chylomicrons. When the LDL concentration increases, it is presumed to reflect improved catabolism of VLDLs and hence increased production of LDLs. Bezafibrate is also thought to improve insulin sensitivity.26
Pharmacokinetics
Gemfibrozil is well absorbed from the gastrointestinal tract following oral administration. Metabolism is by oxidation of a methyl group to form a hydroxymethyl and then a carboxyl metabolite. Protein binding is extensive. The elimination half-time of gemfibrozil is approximately 15 hours, with an estimated 70% of a single dose appearing unchanged in the urine. Fenofibrate is a prodrug that is hydrolyzed by esterases to the active metabolite, fenofibric acid. Fenofibric acid is metabolized by conjugation with glucuronic acid that undergoes extensive renal excretion. The elimination half-time of fenofibrate is about 20 hours. Absorption of fenofibrate is increased when the drug is administered with food. Protein binding is approximately 99%. Increased plasma concentrations of liver transaminase enzymes are more likely to occur with fenofibrate than with the other fibrates.
Side Effects
The most common side effects of the fibrates are gastrointestinal (abdominal pain, nausea) and headache. Gemfibrozil increases the cholesterol content of bile (lithogenicity) and may increase the formation of gallstones. The incidence of skeletal muscle myopathy and risk of rhabdomyolysis is increased when this drug is administered in combination with statins, especially lovastatin. The anticoagulant effect of warfarin is potentiated by gemfibrozil, presumably reflecting its displacement from binding sites on albumin. A mild increase in plasma transaminase enzymes may occur in treated patients. Considering the dependence on renal excretion for elimination and occasional increases in liver function tests, it may be prudent to avoid administration of this drug to patients with preexisting renal or hepatic disease. The increase in noncardiovascular mortality observed with clofibrate25 may be due to low plasma cholesterol concentrations, which predispose patients to hemorrhagic stroke, particularly when systemic hypertension is present.27 Nevertheless, much of the increased mortality at very low plasma concentrations of cholesterol may be attributable to specific diseases, which decrease cholesterol concentrations.
Ezetimibe
Ezetimibe is a relatively new agent for the treatment of hyperlipidemia that acts as a selective inhibitor of cholesterol absorption, which leads to a secondary upregulation of LDL-R (see Fig. 23-1). Cholesterol absorption is inhibited because of ezetimibe’s ability to disrupt a complex between the annexin-2 and cavolin-1 proteins in the brush border of the small intestine. Used as monotherapy, ezetimibe decreases LDL cholesterol levels by 8% to 22% and it can potentiate the effect of statins by an additionl 17%. It modestly influences triglyceride levels and has a negligible effect on HDL cholesterol levels.24 Clinical trials addressing the efficacy of ezetimibe in improving cardiovascular endpoints have been conflicting, with some showing a decreased risk of atherosclerotic events when used in conjunction with statins, whereas others have had negative results.28,29
Omega-3 Fatty Acids (Fish Oil)
One type of fat present in marine fish oils is highly unsaturated omega-3 fatty acid. The primary effect of this fatty acid is to decrease plasma concentrations of triglycerides, whereas the effect on the plasma LDL cholesterol concentrations is variable. It is not clear what dose is necessary to cause desirable effects on the plasma concentrations of triglycerides. Fish oil supplements are not regarded as drugs and thus are not regulated by the U.S. Food and Drug Administration. The long-term safety of taking fish oil capsules is not known, and there is no evidence that fish oil supplementation prevents heart disease.
Experimental and Emerging Agents
Lomitapide is an experimental inhibitor of microsomal triglyceride transfer protein, an intracellular lipid transport protein that is thought to be important for the production of chylomicrons in the intestine and VLDL by hepatocytes. Trials in patients with genetic lipid disorders have shown favorable reductions in LDL and triglycerides. The incidence of gastrointestinal side effects with lomitapide appears to be high, and elevation of liver enzymes has also been observed.
Mipomersen is an antisense oligopeptide that has been recently approved for the treatment of patients with homozygous familial hyperlipidemia. The antisense oligopeptide binds to mRNA molecules for apolipoprotein B-100, an important component of atherogenic lipoproteins. This binding interferes with translation of the mRNA and decreases apolipoprotein B-100 levels. Mipomersen is adminitered via weekly subcutaneous injection and leads to substantial decreases in non–HDL cholesterol and triglycerides. Like lomitapide, mipomersen frequently causes elevations in liver enzymes as well as steatosis.23
References
1. Longo DL, Harrison TR. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill; 2012.
2. Brenner GM, Stevens CW. Pharmacology. Philadelphia, PA: Saunders/Elsevier; 2013.
3. Kannel WB, Castelli WP, Gordon T, et al. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study. Ann Intern Med. 1971;74(1):1–12.
4. Keys A, Aravanis C, Blackburn H, et al. Probability of middle-aged men developing coronary heart disease in five years. Circulation. 1972;45(4):815–828.
5. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham study. Am J Med. 1977;62(5):707–714.
6. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham study. JAMA. 1986;256(20):2835–2838.
7. Franceschini G. Epidemiologic evidence for high-density lipoprotein cholesterol as a risk factor for coronary artery disease. Am J Cardiol. 2001;88(12A):9N–13N.
8. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–1622.
9. Mihaylova B, Emberson J, Blackwell L, et al; Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581–590.
10. Baigent C, Blackwell L, Emberson J, et al; Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–1681.
11. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;63(25, pt B):2889–2934.
12. Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370(15):1422–1431.
13. Genser B, Marz W. Low density lipoprotein cholesterol, statins and cardiovascular events: a meta-analysis. Clin Res Cardiol. 2006;95(8):393–404.
14. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816.
15. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Atorvastatin for acute coronary syndromes. JAMA. 2001;286(5):533–535.
16. Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA. 2001;285(4):430–436.
17. Bavry AA, Mood GR, Kumbhani DJ, et al. Long-term benefit of statin therapy initiated during hospitalization for an acute coronary syndrome: a systematic review of randomized trials. Am J Cardiovasc Drugs. 2007;7(2):135–141.
18. Chan WW, Wong GT, Irwin MG. Perioperative statin therapy. Expert Opin Pharmacother. 2013;14(7):831–842.
19. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117–125.
20. Chong PH, Seeger JD, Franklin C, et al. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med. 2001;111(5):390–400.
21. Tompkins R, Schwartzbard A, Gianos E, et al. A current approach to statin intolerance. Clin Pharmacol Ther. 2014;96(1):74–80.
22. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292(21):2585–2590.
23. Turan A, Mendoza ML, Gupta S, et al. Consequences of succinylcholine administration to patients using statins. Anesthesiology. 2011;115(1):28–35.
24. Gotto AM Jr, Moon JE. Pharmacotherapies for lipid modification: beyond the statins. Nat Rev Cardiol. 2013;10(10):560–570.
25. Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit. A new look at old data. Circulation. 1995;91(8):2274–2282.
26. Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovasc Diabetol. 2012;11:125.
27. Law MR, Thompson SG, Wald NJ, et al. Assessing possible hazards of reducing serum cholesterol. BMJ. 1994;308(6925):373–379.
28. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343–1356.
29. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–2192.
30. Jackson RL, Morrisett JD, Gotto AM Jr, et al. Lipoprotein structure and metabolism. Physiol Rev. 1976;56(2):259–316.
31. Mahley RW, Innerarity TL, Rall SC Jr, et al. Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res. 1984;25(12):1277–1294.