Pharmacotherapy of hypercholesterolemia - Continuing Education, includes test questions - Inside Pharmacy

Pharmacotherapy of hypercholesterolemia

J. Richard Thompson, Pharm. D. Assistant Professor Department of Family and Community Medicine Bowman Gray School of Medicine Wake Forest University Winston-Salem, NC.

Dec. 10, 1990, lesson 679-401-90-12

GOAL:

To review the disease of hypercholesterolemia and provide the pharmacist with a basic understanding of when and how drugs should be used in the management of this disorder.

Objectives:

After completing this lesson, the pharmacist should be able to: 1. Describe the various lipoproteins and associated disorders commonly encountered clinically. 2. Identify patient who are at high risk of developing coronary heart disease because of elevated blood cholesterol. 3. Compare and contrast the clinical efficacy of bile acid binding agents, fibric acid derivatives, niacin, probucol, and HMG-CoA reductase inhibitors in treating this disease. 4. Compare and contrast the side effects and interactions associated with the drug classes listed above. 5. Relate to patients the appropriate information to optimize the evaluation and management of this disorder.

Although cholesterol has been a household term ever since it was first suspected to be involved in the pathogenesis of coronary heart disease in the early 1950s, recent epidemiologic studies and emphasis from the National Cholesterol Education Program begun in 1987 may make hypercholesterolemia the disease of the 1990s.

With new diagnostic criteria in place, some estimate this disease may affect as many as one third of all middle-aged men. Also, the availability of more potent and, perhaps, better tolerated pharmacological agents has generated physician interest in a therapeutic area long plagued with poor patient compliance and little demonstrable benefit.

Pathophysiology

Hypercholesterolemia is one of many diseases characterized by an abnormal concentration of circulating blood lipoproteins. The lipoproteins most commonly involved in hyperlipidemias are listed in Table I. Chylomicrons are formed in the intestinal mucosa when dietary fats are solubilized by bile salts. These are triglyceride rich particles which serve to transport dietary lipids from the intestine to blood and lymph. Chylomicrons increase in the blood shortly following the ingestion of meals. The triglyceride component is released by the enzyme lipoprotein lipase and the remaining particles are removed from the blood by the liver. This is why triglyceride measurements must be made during fasting conditions.

Table : Table I. Common blood lipoproteins and their constituents.

Lipoprotein type               Major component
chylomicrons                     triglycerides
low density lipoprotein            cholesterol
very low density lipoprotein     triglycerides
high density lipoprotein           cholesterol

Aside from dietary consumption, the liver is also capable of synthesizing triglyceride which is transported in the blood by very low density lipoprotein or VLDL. This lipoprotein is typically elevated in people who have hypertriglyceridemia. This lipoprotein is also removed by lipoprotein lipase first by conversion to an intermediate density lipoprotein (IDL) and ultimately to a low density lipoprotein (LDL).

It is the LDL component that is of major concern in hypercholesterolemia. LDL is a cholesterol rich particle which is metabolized by the liver and extrahepatic tissue to release free cholesterol. This free cholesterol may then be deposited into the intima of a coronary artery in the process known as atherosclerosis. Consequently, the concentration of LDL in the blood has been directly related to the risk of developing coronary heart disease.

LDL is removed from the blood by special receptors located on the liver cells as well as by non-receptor mediated pathways peripherally. Some individuals lack one (heterozygous) or both (homozygous) genes regulating these receptors and suffer from severe coronary heart disease such as myocardial infarction even in childhood. The activity of these receptors can be regulated by the amount of cholesterol synthesized intracellularly which becomes a focal point for the action of several drugs.

High density lipoprotein (HDL) is also secreted by the liver and serves as a transport to pick up free cholesterol at the tissues and deliver it back to the liver for metabolism. Consequently, an inverse relationship has been noted between the concentration of HDL in blood and the risk of developing coronary heart disease leading some to term this lipoprotein as "good cholesterol" and LDL as "bad cholesterol."

Although preliminary evidence suggests that increasing the concentration of HDL cholesterol may be beneficial in preventing coronary heart disease, more attention is focused toward the lowering of LDL cholesterol.

Classifying hyperlipidemias

The hyperlipidemias are classified into five types as depicted in Table II although disorders in any of the lipoprotein components may occur, only three forms of the disease occur commonly. The term hypercholesterolemia generally refers to Type IIa hyperlipidemia characterized by an elevation in the total cholesterol concentration alone. Type IIb hyperlipidemia includes those who may have a mixed disorder of both cholesterol and triglyceride metabolism. Type IV hyperlipidemia includes those who may have an isolated elevation in triglyceride concentration with a normal serum cholesterol. Although triglycerides alone are not as predictive for the development of coronary heart disease, elevated concentrations may predispose to pancreatitis, particularly in diabetic individuals, and usually warrant treatment.

Table : Table II. Classification of hyperlipidemias

Phenotype   Abnormal lipoprotein
Type I              chylomicrons
Type IIa         LDL cholesterol
Type IIb            LDL and VLDL
Type III           VLDL remnants
Type IV        VLDL triglycerides
Type V      chylomicrons and VLDL

Rationale for intervention

Although some controversy still surrounds the concept of mass screening and aggressive treatment of this disease, several large scale epidemiological studies have suggested that asymptomatic, middle-aged men may benefit from such an approach. The Lipid Research Clinics Coronary Primary Prevention Trial, conducted over a seven year period, documented that a decrease in LDL cholesterol of 12.5 percent was associated with a 19 percent decrease in the incidence of myocardial infarction and death from coronary heart disease.

More recently, the Helsinki Heart Study showed that an 11 percent decrease in LDL cholesterol coupled with an 11 percent increase in HDL cholesterol was associated with a 34 percent decrease in myocardial infarction or death. Interestingly, neither of these studies showed a difference in overall mortality between placebo and drug treated groups because of a higher incidence of homicide and accidents in the latter.

Animal studies and some limited human data have shown by angiography that the atherosclerotic process may be halted or reversed by drugs. It is not well understood over what period of time this may be expected to occur. Also, it is important to note that most clinical data has been determined from studies using middle-aged men and may not necessarily apply to women or people of other ages.

Diagnostic Criteria

The acceptable and undersirable concentrations of both total cholesterol and LDL cholesterol as proposed by the National Cholesterol Education Program are depicted in Table III. The total cholesterol concentration should be used for screening purposes only. Upon identification, a person with a total cholesterol value exceeding 200mg/dl and definite heart disease or with two risk factors for heart disease should have another determination for fractionation of the various lipoprotein components. Risk factors for heart disease include family history, male sex, diabetes, hypertension, smoking, obesity, cerebrovascular or peripheral vascular disease or HDL 35mg/dl.

Table : Table III. Recommended serum cholesterol concentrations

Total cholesterol                                   LDL cholesterol
[is greater than]240 - high risk   [is greater than]160 - high risk
200-239 - borderline risk                 130-159 - borderline risk
[is greater than]200 - desirable   [is greater than]130 - desirable

Dietary restrictions of total fat less that 30 percent of calories, saturated fat less than 10 percent of calories, and total cholesterol intake less than 300mg/day should be instituted for patients without risk factors if LDL exceeds 160mg/dl and for patients with risk factors if LDL exceeds 130mg/dl.

After three months of dietary restriction if the LDL concentration has not decreased below these critical levels, the diet can be advanced to further restrict saturated fat intake to less than 7 percent of total calories and cholesterol intake to less than 200mg/day. If LDL concentrations remain elevated following three months of advanced diet, drug therapy should be initiated to achieve target goals of below 130 if risk factors are present or below 160 if no risk factors are present (See Table IV). [Tabular Data Omitted]

Prior to the initiation of drug therapy a careful review of the patient's medication history should be conducted. Some antihypertensives such as thiazide diuretics or beta blockers may exacerbate hyperlipidemias. Other choices such as calcium antagonists, ACE inhibitors, or prazosin do not seem to interfere. Also, decreased estrogen or increased progesterone concentrations due to changes in oral contraceptive therapy may be reflected in abnormal lipid concentrations.

Drug selection

The selection of the therapeutic agent to be utilized in the treatment of hypercholesterolemia will be determined to a large degree by the nature and magnitude of the lipid abnormality. Some agents primarily affect cholesterol whereas others have a greater impact in lowering triglyceride concentrations. Also, since the goal of therapy is to prevent morbidity and mortality from subsequent heart disease, long term compliance is an important consideration in choosing an agent.

The bile acid binding agents, cholestyramine and colestipol, have documented safety and efficacy in the treatment of hypercholesterolemia. They work by binding bile acids which are recirculated to the liver as a substrate for cholesterol synthesis. As intracellular cholesterol concentrations decline, the LDL receptors are stimulated to remove more cholesterol from the blood. At therapeutic dosages of 16-20gm/day respectively, they will usually lower LDL cholesterol 15 percent to 30 percent. They may, however, stimulate the synthesis of VLDL and thus should not be used in patients with Type IIb or Type IV hyperlipidemia.

The bile acid binding agents are probably most noted for their problems with palatability and side effects. They can be mixed with fruit juice as a beverage or eaten as a candy bar. Neither vehicle completely disguises the gritty texture or odor. They should not be baked into cookies as heat may affect the stability of the resin. Side effects of these agents include bloating, constipation, heartburn, gas, abdominal pain, nausea, and belching. They have also been reported to bind other drugs such as warfarin, digitoxin, iron, thyroxine, and thiazides. This can be avoided by taking the other medication at least one hour before or four hours after taking the resins. These agents may also decrease the absorption of fat soluble vitamins and folic acid at dosages greater than 24gm/day.

Niacin, or nicotinic acid, is also an effective agent in treating hypercholesterolemia. Niacin inhibits the synthesis and secretion of VLDL by the liver, therefore it has a potent triglyceride lowering effect and a more modest cholesterol lowering effect. Niacin may lower triglycerides by up to 80 percent but usually only lowers LDL 15 percent to 30 percent. It also appears to increase the concentration of HDL cholesterol.

Niacin, unfortunately, has a number of dose related side effects. Many patients require dosages of as much as four to six grams per day. Lower dosages are usually started and titrated until effective. As the dose is escalated, many patients complain of intense flushing with niacin. This is a prostaglandin-mediated process and may be ameliorated somewhat by premedicating with either aspirin or a nonsteroidal antiinflammatory agent. Alternatively, a sustained-release form of niacin may be administered, however these are often associated with an increase in gastrointestinal side effects.

Other side effects associated with niacin include hyperuricemia, hyperglycemia, aggravation of peptic ulcer disease, skin rash, pruritis, and chemical hepatitis. It is important to advise consumers to use niacin only under the direction of a physician to lower cholesterol. At these dosages it should not be considered a vitamin supplement.

Probucol reduces the concentration of LDL cholesterol in a non-receptor dependent method. This is apparent because the drug works in patients who are homozygous and have no functioning LDL receptors. The fall in LDL cholesterol usually approaches 10 percent to 15 percent. Unfortunately, the HDL concentration is lowered also and often to a greater degree. The importance of this concomitant effect is not well understood.

Probucol also possesses antioxidant properties which may prevent the deposition of cholesterol in the intima. Cholesterol deposits in the skin known as xanthomas usually resolve when therapy with probucol is instituted. Because of these questions, probucol is usually reserved as a second line agent and seldom used in the initial treatment of the disease.

Probucol is a generally well tolerated drug from the standpoint of side effects. Diarrhea may occur in up to 10 percent of patients but few other effects occur. Probucol prolongs the Q-T interval on the electrocardiogram and probably should not be used in conjunction with Type Ia antiarrhythmics such as guinidine, procainamide or disopyramide. The usual dosage is 250-500mg twice daily.

Fibric acid derivitives available for the treatment of this disorder include clofibrate and gemfibrozil. Although clofibrate was the first agent specifically marketed for the treatment of hyperlipidemia, it has virtually been replaced by gemfibrozil due to greater efficacy and better tolerance to side effects. Both of these agents work by stimulating the enzyme lipoprotein lipase to enhance the clearance of VLDL. Since VLDL is metabolized to LDL the concentration of this lipoprotein will also decrease somewhat over time although an increase may be seen initially. These agents lower triglyceride concentrations by 30 percent to 40 percent but usually only lower LDL concentrations 10 percent or less. They may increase HDL concentrations by 10 percent or more.

In the Coronary Drug Project and World Health Organization trials, clofibrate was found to be associated with increased mortality. This was due to increases in pulmonary embolism, angina, and arrhythmia as well as noncardiovascular causes such as increased gallbladder disease. Other side effects reported with clofibrate include breast tenderness, loss of libido, thromboembolism, myositis, and elevated liver enzymes. Both clofibrate and gemfibrozil potentiate the action of warfarin resulting in a clinically significant drug interaction.

The side effects seen with gemfibrozil are similar to those occurring with clofibrate but lower in incidence. Most frequently reported are rash and abdominal discomfort. Gemfibrozil may exacerbate hyperglycemia in diabetic individuals or predispose to the development of gallstones. Rarely, myositis manifested as muscle tenderness may result from gemfibrozil therapy and patients may seek relief by way of over-the-counter salicylate lotions or liniments.

The most recent cholesterol lowering drugs to become available are the hydroxymethylglutaryl coenzyme A reductase inhibitors. Lovastatin was the first of these agents to be approved by the Food and Drug Administration and two others, pravastatin and simvastatin, are currently under review. These agents work by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase which is the rate-limiting step in the intracellular synthesis of cholesterol. Because of this specific pharmacologic mechanism, these agents are very potent and usually reduce LDL cholesterol by 20 percent to 40 percent in the usual dosage range which is 20-80mg/day for lovastatin. They also decrease triglycerides and may increase HDL cholesterol.

Lovastatin is also generally well tolerated acutely with few side effects in excess of 6 percent incidence. One exception to this is headache which may occur in up to 10 percent of patients. Typical side effects include constipation, diarrhea, dyspepsia, flatus, abdominal pain, nausea, heartburn, myalgia, muscle cramps, dizziness, headache, rash, dysguesia, blurred vision, and increases in liver enzymes or creatine kinase. The myositis seen with lovastatin may be exacerbated by concurrent administration of gemfibrozil possibly resulting in acute rhabdomyolysis and death. Therefore the simultaneous use of these drugs should be discouraged. Also, drug interactions have been noted with erythromycin and cyclosporine resulting in a similar syndrome.

The long-term toxicity concerns with lovastatin primarily involve the liver and the eyes. Although approximately 5 percent of patients will develop mild increases in liver enzymes which are transient in nature and do not require discontinuation of therapy, approximately 2 percent of patients may develop a direct hepatocellular toxicity with liver enzymes greater than three times normal which necessitates that therapy be discontinued. This reaction usually occurs between three and 15 months of beginning therapy thus it has been suggested that liver function studies be performed monthly for the first year of therapy.

In animal models lovastatin has caused cataract formation suggesting long-term toxicity to the eyes. In early clinical trials with lovastatin some patients did indeed develop opacities when given lovastatin, however other patients had fewer opacaties after the drug was administered. Obviously, methodological problems flawed the studies. Newer ongoing studies are in progress to better assess the risk of ocular toxicity with lovastatin, however, in clinical use only one case report has appeared of a visual deficit temporally related to the administration of lovastatin. It therefore seems unlikely that this toxicity will be widespread.

Animal studies with very high dosages of lovastatin were also correlated with the development of hepatocellular carcinoma. When these studies were repeated at one tenth the original dose but still 60 times the maximum human dose on a kilogram basis, no carcinogenesis was noted. There have been no reports to date of any form of cancer occurring in relationship to lovastatin administration.

Pharmacist involvement

Hypercholesterolemia offers many opportunities for pharmacists to be involved directly in patient management. Screening programs using fingerstick technology can be very helpful in identifying patients who may be at risk of developing heart disease and directing them to appropriate medical therapy. Since the disease is lifelong and compliance is imperative to achieve the goals of long term cholesterol control, patient education and counselling can have a major impact upon the successfulness of any therapeutic program.

As has been noted, many of the cholesterol lowering medications have the potential for severe and possibly life-threatening drug interaction problems with other medications the patient may receive. Patients will benefit greatly by the knowledge and expertise pharmacists can render in dealing with this disorder.

BIBLIOGRAPHY

1. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Int Med 1988;148:36-69.

2. Blum CB, Levy RI. Current Therapy for Hypercholesterolemia. JAMA 1989;261:3582-3587.

3. Perry RS. Contempory Recommendations for Evaluating and Treating Hyperlipidemia. Clin Pharm 1986;5:113-127.

4. Illingworth DR. Lipid-Lowering Drugs. Drugs 1987;33:259-279.

5. Labreche DG. Reassessment of the Value of Lowering Serum Cholesterol. Clin Pharm 1988;7:592-607.

6. Choice of Cholesterol-Lowering Drugs. The Medical Letter 1988;30:81-84.

7. Knodel LC, Talbert RL. Adverse Effects of Hypolipidaemic Drugs. Medical Toxicology 1987;2:10-32.

8. Lipid Research Clinics Program. The Lipid Research Clinics Primary Coronary Prevention Trial Results I. JAMA 1984;251:351-374.

9. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et l. Helsinki Heart Study: Primary Prevention Trial With Gemfibrozil in Middle-Aged Men With Dyslipidemia. NEJM 1987;317:1237-1245.

10. McKenney JM. Lovastatin: A New Cholesterol-Lowering Agent. Clin Pharm 1988;7:21-36.

Table : Table V. Comparison of agents that lower cholesterol

Drug                  Effect on LDL         Other effects
Cholestyramine   15-30 percent decrease     increases VLDL

Colestipol

Niacin           15-30 percent decrease     decreases VLDL
                 increases HDL
Probucol         10-15 percent decrease     decreases HDL
Clofibrate       [is less than]10 percent   decreases VLDL
Gemfibrozil      decrease                   increases HDL
Lovastatin       20-40 percent decrease     decreases VLDL
                                            increases HDL

COPYRIGHT 1990 Reproduced with permission of the copyright holder. Further reproduction or distribution is prohibited without permission.
COPYRIGHT 2004 Gale Group