Hypolipidemic Agents

Hypolipidemic agent Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs (LLD) or agents.

Classes of hypolipidemic drugs There are several classes of hypolipidemic drugs. They may differ in both their impact on the cholesterol profile and adverse effects. For example, some may lower the "bad cholesterol" low density lipoprotein (LDL) more so than others, while others may preferentially increase high density lipoprotein (HDL), "the good cholesterol". Clinically, the choice of an agent will depend on the patient's cholesterol profile, cardiovascular risk, and the liver and kidney functions of the patient, evaluated against the balancing of risks and benefits of the medications

Statins are particularly well-suited for lowering LDL, the cholesterol with the strongest links to cardiovascular diseases

Fibrates are indicated for hypertriglyceridemia. Fibrates typically lower triglycerides by 20% to 50%. Level of the good cholesterol HDL is also increased. Fibrates may decrease LDL, though generally to a lesser degree than statins. Similar to statins, there is a risk of severe muscle damage (myopathy & rhabdomyolysis) with fibrates.

Niacin like fibrates, is also well-suited for lowering triglycerides by 20-50%. It may also lower LDL by 5-25% and increase HDL by 15-35%. Niacin may cause hyperglycemia, and may also cause liver damage.

Bile acid sequestrants (resins) are particularly effective for lowering LDL-C by sequestering the cholesterol-containing bile acids released into the gut and preventing their reabsorption from the gut. It decreases LDL by 15-30% and raises HDL by 3-5%. It has little effect on triglycerides but can cause a slight increase. Bile acid sequestrants may cause gastrointestinal problems, and may also reduce the absorption of other drugs and vitamins from the gut.

Others: Ezetimibe • Omega-3 fatty acids •

Lipid modifying agents

Statins

Atorvastatin • Cerivastatin • Fluvastatin • Lovastatin • Mevastatin • Pitavastatin • Pravastatin • Rosuvastatin • Simvastatin

Fibrates

Clofibrate • Bezafibrate • Aluminium clofibrate • Gemfibrozil • Fenofibrate • Simfibrate • Ronifibrate • Ciprofibrate • Etofibrate • Clofibride

Bile acid sequestrants

Colestyramine • Colestipol • Colextran • Colesevelam

Niacin and derivatives

Other

Niceritrol • Niacin • Nicofuranose • Aluminium nicotinate • Nicotinyl alcohol • Acipimox

Dextrothyroxine • Probucol • Tiadenol • Benfluorex • Meglutol • Omega-3-triglycerides • Magnesium pyridoxal 5phosphate glutamate • Policosanol • Ezetimibe

-1Statins

The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceutical agents to lower cholesterol levels in people with or at risk for cardiovascular disease. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.

Adverse effects Some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms

Drug interactions Combining any statin with a fibrate, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years.]Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in renal function. Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins—furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however it is a major inhibitor of only atorvastatin, lovastatin and simvastatin) and some other medications. This increases the levels of the statin, increasing the risk of dose-related adverse

effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins. This is not recommended as a result of the increased risk and potential for statin toxicity.

All statins are highly protein bound (95-98%) except for pravastatin (50%, due to carboxylate moiety). Most statins have a short half-life of about 1-3 hr except for atorvastatin which has a 1/2 of about 14 h. A 15-30 point drop in LDL could be reasonably expected with most statins after a therapy of about 1 month. A combination therapy (with bile acid sequestering agents) is helpful for particularly difficult cases. Although possible, statins typically do not affect the concentrations of steroid hormones in circulation

• Some drugs in the "statin" class have been marketed for their hypolipidemic effects: Atorvastatin calcium (LIPITOR), cerivastatin sodium (BAYCOL), fluvastatin sodium (LESCOL), lovastatin (MEVACOR), pravastatin sodium (PRAVACHOL), and simvastatin (ZOCOR). Cerivastatin sodium was withdrawn from the U.S. market by the manufacturer in August 2001 because of reports of fatal rhabdomyolysis (disintegration of muscle tissue). All statins have been associated with rhabdomylosis, but severe cases have been reported more frequently with cerivastatin sodium.

Lovastatin

Simvastatin

Pravastatin sodium

Fluvastatin sodium

Atorvastatin calcium

Cerivastatin sodium

2-Fibrates Fibrates prescribed commonly are: • • • • •

Bezafibrate (e.g. Bezalip®) Ciprofibrate (e.g. Modalim®) Clofibrate (largely obsolete due to side-effect profile, e.g. gallstones) Gemfibrozil (e.g. Lopid®) Fenofibrate (e.g. TriCor®)

Side effects Most fibrates can cause mild stomach upset and myopathy (muscle pain with CPK elevations). In combination with statin drugs, fibrates cause an increased risk of rhabdomyolysis (idiosyncratic destruction of muscle tissue, leading to renal failure). A powerful statin drug, cerivastatin (Lipobay®), was withdrawn because of this complication. The less lipophilic statins are less prone to cause this reaction, and are probably safer when combined with fibrates.

Pharmacology Although used clinically since the early 1970s, the mechanism of action of fibrates remained unelucidated until, in the 1990s, it was discovered that fibrates activate PPAR (peroxisome proliferatoractivated receptors), especially PPARα. The PPARs are a class of intracellular receptors that modulate carbohydrate, fat metabolism and adipose tissue differentiation. Activation of PPARs causes transcription of a number of genes on the DNA that facilitate lipid metabolism. Fibrates are structurally and pharmacologically related to the thiazolidinediones, a novel class of antidiabetic drugs that also act on PPARs .

Bezafibrate 2-[4-[2-[(4-chlorobenzoyl) amino] ethyl] phenoxy]-2-methyl-propanoic acid

Side-effects The main toxicity is hepatic (abnormal liver enzymes), and myopathy and rarely rhabdomyolysis have been reported.

Other uses The Australian biotech company Giaconda combines bezafibrate with chenodeoxycholic acid in an anti-hepatitis C drug combination called Hepaconda.

Gemfibrozil 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid

Toxicities • • • •

GI distress Musculoskeletal pain Increased incidence of gallstones Hypokalemia

Drug Interactions • •

Anticoagulants. Gemfibrozil potentiates the action of coumadin and indanedione anticoagulants. Lovastatin. Risk of myopathy when gemfibrozil is given to patients receiving lovastatin.

Etofibrate

Clofibrate

Aluminium clofibrate

3-Bile Acid Sequestering (BAS) Agents Colestipol and cholestyramine are anion exchange resins that are approved in 1970s for the reduction of elevated serum cholesterol in patients with hypercholesterolemia. These resins are water insoluble, inert to digestive enzymes in the intestinal tract and are not absorbed. Both resins are quaternized at stomach pH and exchange anions for bile acids dramatically reducing the reabsorption of bile acids. The liver senses that bile acid concentrations have gone down and hence turns on cholesterol metabolism. Serum HDL and TG levels remain unchanged. LDL levels are found to decrease.

The fall in LDL concentration is apparent in 4 to 7 days. The decline in serum cholesterol is usually evident by 1 month. When the resins are discontinued, the serum cholesterol usually returns to baseline within a month. When bile acid secretion is partially blocked, serum bile acid concentration rises. For these patients, cholestyramine reduces bile acid deposits in the dermal tissues. One of greatest advantage of these polymeric agents is that they can be safely used for pregnant women. However, exercise caution for nursing women because presence of these cationic polymeric agents in the GI tract might lower the absorption of vitamin D. BAS agents may also lower the amount of anticoagulants (warfarin, coumadin) absorbed due to sequestration

Available forms Cholestyramine is available as powder form, in 4 gram packets. In the United States, it can be purchased either as a generic medicine, or as Questran® or Questran Light® (Bristol-Myers Squibb).

Dosage 4 to 8 grams once or twice daily, maximum dose 24 grams a day.

Side-effects The following side effects have been noted. •

Most frequent: Constipation

•

Seldom: tooth discoloration; tooth enamel erosion; premature tooth decay; all from prolonged oral exposure of the suspension.

Drug interactions The following interactions have been noted • • • • • • • • • •

Digitalis Estrogens and progestins Oral diabetes drugs Penicillin G Phenobarbital Spironolactone Tetracycline Thiazide Thyroid medication Warfarin

Most interactions are due to risk of decreased absorption of these drugs since Cholestyramine will prevent full absorption.

4-Nicotinic Acid& its derivatives Pharmacologic doses of nicotinic acid reduce serum cholesterol and TG levels in types II, III, IV, and V hyperlipoproteinemias. TG and VLDL are reduced by 20 to 40% in 1 to 4 days, LDL reduction may be seen in 5-7 days. The decrease in LDL is usually greater if niacin is used with a BAS resin. HDL is increased by 20%. The exact mechanism is unknown. It is known that niacin decreases lipolysis in adipose tissue, decreases TG esterification in the liver and increase LPL activity. Niacin is rapidly absorbed.

Niacin (vit B3)

Nicotinic Acid (Niacin) People taking pharmacological doses of niacin (1.5 - 6 g per day) often experience a syndrome of sideeffects that can include one or more of the following: •

• • • • •

dermatological complaints o facial flushing and itching o dry skin o skin rashes including acanthosis nigricans gastrointestinal complaints o dyspepsia (indigestion) liver toxicity o fulminant hepatic failure hyperglycemia cardiac arrhythmias birth defects

Facial flushing is the most commonly-reported side-effect. It lasts for about 15 to 30 minutes, and is sometimes accompanied by a prickly or itching sensation. This effect is mediated by prostaglandins and can be blocked by taking 300 mg of aspirin half an hour before taking niacin, or by taking one tablet of ibuprofen per day.

Niceritrol

Omega-3 fatty acids Omega-3 fatty acids which are important in human nutrition are: α-linolenic acid (18:3, ALA), eicosapentaenoic acid (20:5, EPA), and docosahexaenoic acid (22:6, DHA). These three polyunsaturates have either 3, 5 or 6 double bonds in a carbon chain of 18, 20 or 22 carbon atoms, respectively. All double bonds are in the cis-configuration, i.e. the two hydrogen atoms are on the same side of the double bond

Chemical structure of alpha-linolenic acid (ALA), an essential omega-3 fatty acid, (18:3Δ9c,12c,15c). Although chemists count from the carbonyl carbon, physiologists count from the omega (ω) carbon (red numbering). Note that from the omega end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "omega-3"

In a study published in the American Journal of Health System Pharmacy March 2007, patients with high triglycerides and poor coronary artery health were given 4 grams a day of a combination of EPA and DHA along with some monounsaturated fatty acids. Those patients with very unhealthy triglyceride levels (above 500 mg/dl) reduced their triglycerides on average 45% and their VLDL cholesterol by more than 50%. VLDL is a bad type of cholesterol and elevated triglycerides can also be deleterious for cardiovascular health

Ezetimibe It acts by decreasing cholesterol absorption in the intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with statins (e.g. ezetimibe/simvastatin) when cholesterol levels are unable to be controlled on statins alone. It is marketed by Schering-Plough and Merck under the trade names Ezetrol, Zetia and Ezemibe.

Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea. Infrequent adverse effects (0.1–1% of patients) include: myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.