Chapter 10 Notes (Drug Therapy for Dyslipidemia)
Introduction
Elevated blood lipids are a major risk factor for atherosclerosis and cardiovascular disorders such
as coronary artery disease and stroke. Therapeutic lifestyle changes (including dietary
modification, physical activity, and smoking cessation) have been the cornerstone of populationbased interventions to manage dyslipidemia. Dyslipidemic drugs are used to decrease blood
lipids, prevent or delay the development of atherosclerotic plaque, promote the regression of
existing atherosclerotic plaque, and reduce morbidity and mortality from atherosclerotic
cardiovascular disease (ASCVD).
Etiology
Blood lipids, which include cholesterol , phospholipids, and triglycerides, are derived from the
diet or synthesized by the liver and intestine. Most cholesterol is found in body cells, where it is
a component of cell membranes and performs other essential functions. In cells of the adrenal
glands, ovaries, and testes, cholesterol is required for the synthesis of steroid hormones (e.g.,
cortisol, estrogen, progesterone, testosterone). In liver cells, cholesterol is used to form cholic
acid, which is conjugated with other substances to form bile salts; these salts promote absorption
and digestion of fats. In addition, a small amount of cholesterol is found in blood serum. Serum
cholesterol is the portion of total body cholesterol involved in formation of atherosclerotic
plaques.
Blood lipids are transported in plasma by specific proteins called lipoproteins .
Each lipoprotein contains cholesterol, phospholipid, and triglyceride bound to protein. The
lipoproteins vary in density and amounts of lipid and protein. The lipoproteins are differentiated
according to these properties, which can be measured in the laboratory. For example, HDL
cholesterol contains larger amounts of protein and smaller amounts of lipid; LDL cholesterol
contains less protein and larger amounts of lipid. Other plasma lipoproteins are chylomicrons and
very-low-density lipoproteins (VLDLs).
Types of lipoproteins
Chylomicrons, the largest lipoprotein molecules, are synthesized in the wall of the small
intestine. They carry recently ingested dietary cholesterol and triglycerides that have been
absorbed from the gastrointestinal tract. Hyperchylomicronemia normally occurs after a fatty
meal, reaches peak levels in 3 to 4 hours, and subsides within 12 to 14 hours. Chylomicrons
carry triglycerides to fat and muscle cells, where the enzyme lipoprotein lipase breaks down the
molecule and releases fatty acids to be used for energy or stored as fat.
Low-density lipoprotein (LDL) cholesterol, sometimes called “bad cholesterol,” transports
approximately 75% of serum cholesterol and carries it to peripheral tissues and the liver. LDL
cholesterol is removed from the circulation by receptor and nonreceptor mechanisms. The
receptor mechanism involves the binding of LDL cholesterol to receptors on cell surface
membranes.
Very-low-density lipoprotein (VLDL) contains approximately 75% triglycerides and 25%
cholesterol. It transports endogenous triglycerides (those synthesized in the liver and intestine,
not those derived exogenously, from food) to fat and muscle cells. There, as with chylomicrons,
lipoprotein lipase breaks down the molecule and releases fatty acids to be used for energy or
stored as fat. The removal of triglycerides from VLDL leaves a cholesterol-rich remnant, which
returns to the liver.
High-density lipoprotein (HDL) cholesterol, often referred to as “good cholesterol,” is a small
but very important lipoprotein. It is synthesized in the liver and intestine, and some is derived
from the enzymatic breakdown of chylomicrons and VLDL.
Pathophysiology
Abnormal lipid levels in the blood, or dyslipidemia (also called hyperlipidemia because blood
levels of lipoproteins accompany increased blood lipid levels), is associated with atherosclerosis
and its many pathophysiologic effects (e.g., myocardial ischemia and infarction, stroke,
peripheral arterial occlusive disease). Ischemic heart disease has a high rate of morbidity and
mortality. Elevated total cholesterol and LDL cholesterol and reduced HDL cholesterol are the
abnormalities that are major risk factors for coronary artery disease. Elevated triglycerides also
play a role in cardiovascular disease.
Drug therapy
PROTOTYPE
:
ATORVASTATIN (HMG-COA REDUCTASE
INHIBITORS)
i or statins. By decreasing production of cholesterol, the statins decrease total serum cholesterol,
LDL cholesterol, VLDL cholesterol, and triglycerides. They reduce LDL cholesterol within 2 weeks
and reach maximal effects in approximately 4 to 6 weeks. HDL cholesterol levels remain unchanged
or may increase.
PHARMICOKENETICS:
Metabolism occurs in the liver, with 80% to 85% of drug metabolites excreted in feces and the
remaining products excreted in urine.
ACTION:
inhibit an enzyme (HMG-CoA reductase) required for hepatic synthesis of cholesterol. In part,
metabolism involves one or more hepatic cytochrome P450 enzymes (including CYP2D6), leading to
an increased risk of drug interactions and problems with certain foods (e.g., grapefruit juice).
Additionally, some of the variability in the response to statins and associated adverse effects statins
may relate to genetic differences in the rate of drug metabolism.
USE:



Atorvastatin and the other statins are indicated for the treatment of hypercholesterolemia
reducing cardiovascular events in people with multiple risk factors.
the most powerful drug class for reduction of LDL cholesterol.
MED ADMIN:
of statins normally takes place in the evening or at bedtime. However, atorvastatin has a long halflife, and evidence suggests that the drug can be given without regard to time of day. There is no
definitive global recommendation for the entire class; thus, the timing of administration of statins
should be based on manufacturer recommendations.
ADVERSE EFFECTS:
Statins are usually well tolerated; the most common adverse effects (nausea, constipation,
diarrhea, abdominal cramps or pain, headache, skin rash) are usually mild and transient.
Myopathies are important adverse effects and can range from discreet muscle pain to
rhabdomyolysis. Statins can injure muscle tissue, resulting in muscle ache, pain, or weakness.
CONTRAINDICATIONS:
Statins are potentially teratogenic (pregnancy category X). Careful consideration is necessary if
potential benefits warrant use of these drugs in pregnant women. Additional contraindications
include lactation, because the drugs are secreted in breast milk, and hypersensitivity to statins.
BLACK BOX: NO Black Box Warning in book
INTERVENTIONS:
The statins are the most effective dyslipidemic agents for improving clinical outcomes when used
for primary and secondary prevention of cardiovascular disease.
PT TEACHING:
Women of childbearing age should receive contraceptive counseling to enhance awareness of the
risks associated with statin use. In addition, education should focus on the importance of
monitoring liver function on a regular basis. Liver function tests are recommended before starting
a statin, at 12 weeks after starting the drug, at every increase in dose, and then periodically. The
nurse monitors patients with increased serum aminotransferases until the abnormal values resolve.
If the increases are more than three times the upper limit of normal levels and persist, it is
necessary to reduce the dose or change the drug.
PROTOTYPE: Cholestyramine (BILE ACID SEQUESTRANTS)
BILE ACID SEQUESTRANTS:
Cholestyramine (Prevalite, Questran),
the prototype bile acid sequestrant, has the ability to reduce LDL cholesterol. It has little or no
effect on HDL cholesterol and either no effect or an increased effect on triglyceride levels
PHARMICOKENETICS:
Cholestyramine is not absorbed when taken orally. Therefore, the drug is excreted in feces
essentially unchanged.
ACTION:
Cholestyramine binds bile acids in the intestinal lumen, causing the bile acids to be excreted in
feces, preventing recirculation to the liver. Loss of bile acids stimulates hepatic synthesis of more
bile acids from cholesterol. As more hepatic cholesterol is used to produce bile acids, more serum
cholesterol moves into the liver to replenish the supply, thereby lowering serum cholesterol
(primarily LDL). LDL cholesterol levels decrease within a week of starting cholestyramine and
other bile acid sequestrants and reach maximal reductions within a month. When the drugs are
stopped, pretreatment LDL cholesterol levels return within a month.
USE:
Cholestyramine reduces LDL cholesterol levels (15%–30%) and also produces a minimal elevation
in HDL cholesterol (3%–5%).
MED ADMIN:
It is necessary to mix cholestyramine powder with water or other fluids, soups, cereals, or fruits
such as applesauce and to follow with more fluid. The nurse ensures that the drug is not taken in a
dry form. It is essential that cholestyramine not be given with other drugs; to minimize altered
absorption, people should take the other drugs 1 hour before or 4 to 6 hours after cholestyramine.
ADVERSE EFFECTS:
Cholestyramine is not absorbed systemically, so the main adverse effects are GI ones (abdominal
fullness, flatulence, diarrhea, and constipation). Constipation is especially common, and a bowel
program may be necessary to control this problem.
CONTRAINDICATIONS:
Cholestyramine is contraindicated in people with complete biliary obstruction, because bile is not
secreted into the intestine. The drug can bind with vitamin K; thus, use in individuals with any
coagulopathy requires caution.
BLACK BOX: No Black Box Warning in book
INTERVENTIONS:
Cholestyramine may decrease absorption of many oral medications (e.g., digoxin, folic acid,
glipizide, propranolol, tetracyclines, thiazide diuretics, thyroid hormones, fat-soluble vitamins, and
warfarin). Apparently, no drugs significantly affect cholestyramine. Herbs and foods that increase
the effects of cholestyramine include fibers such as oat bran and pectin. No herbs and foods seem to
decrease the effects of cholestyramine.
PT TEACHING:
The nurse assesses the adequacy of levels of fat-soluble vitamins A, D, E, and K; supplementation
may be required. Good dental hygiene is important because holding the mixture in the mouth can
damage the teeth. Some products may contain aspartame or sugar, so caution is necessary in
patients with phenylketonuria or diabetes mellitus.
PROTOTYPE: Fenofibrate ( FIBRATES) \
Fibrates are derivatives of fibric acid and are similar to endogenous fatty acids.
PHARMICOKENETICS:
Fenofibrate is administered orally and is highly protein bound, primarily to albumin. Time to peak
effect is 6 to 8 hours. Metabolism occurs in the liver and excretion is by urinary elimination.
ACTION:
Fenofibrate and other fibrates increase the oxidation of fatty acids in liver and muscle tissue. Thus,
they decrease hepatic production of triglycerides, decrease VLDL cholesterol, and increase HDL
cholesterol.
USE:
Fibrates are the most effective drugs for reducing serum triglyceride values, and their main
indication for use is high serum triglycerides
MED ADMIN:
It is necessary to give fenofibrate with food to increase drug absorption.
ADVERSE EFFECTS:
The main adverse effects are GI discomfort and diarrhea, which may occur less often with
fenofibrate than with other fibrates. Fibrates may also increase cholesterol concentration in the
biliary tract and formation of gallstones.
CONTRAINDICATIONS:
Contraindications include a hypersensitivity to fibrates, hepatic or (severe) renal impairment,
preexisting gallbladder disease, primary biliary cirrhosis, or persistent liver function abnormalities
of unknown origin.
BLACK BOX: No Black Box Warning
INTERVENTIONS:
Fenofibrate and other fibric acid derivatives may enhance the hypoprothrombinemic effect of
warfarin-type oral anticoagulants, increasing the risk of bleeding. Patients receiving warfarin
concurrently require a substantially decreased dosage of warfarin because fibrates displace
warfarin from binding sites on serum albumin.
PT TEACHING:
The nurse instructs patients to report signs and symptoms of adverse effects to the health care
provider. Throughout drug therapy, patients should have periodic blood tests.
Ezetimibe (CHOLESTEROL ABSORPTION
INHIBITOR)
CHOLESTEROL ABSORPTION INHIBITOR: Ezetimibe (Zetia) is the prototype of the newest
class of dyslipidemic drugs, which act in the small intestine to inhibit absorption of cholesterol and
decrease the delivery of intestinal cholesterol to the liver, resulting in reduced hepatic cholesterol
stores and increased clearance of cholesterol from the blood.
PHARMICOKENETICS:
Ezetimibe is significantly protein bound, is metabolized in the small intestine and liver, and is
excreted predominately in feces. The time to peak effect is 4 to 12 hours.
ACTION:
Ezetimibe blocks biliary and dietary cholesterol absorption at the brush border of the intestine
without affecting absorption of fat-soluble vitamins and triglycerides.
USE:
Ezetimibe is used together with dietary management for treatment of primary dyslipidemia. The
drug may result in a 14% to 17% decrease in LDL levels. It can be used as monotherapy on in
combination with a statin. When given as monotherapy (without a statin), ezetimibe does not
require dosage reduction in geriatric patients.
MED ADMIN:
Ezetimibe may be administered with or without food. The patient takes the drug:

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At the same time each day
At night if used in combination with a statin (ezetimibe may be given at the same time as a
statin)
Either 2 hours before or 4 hours after bile sequestrants to prevent altered absorption
ADVERSE EFFECTS:
The most common adverse effects of ezetimibe include headache, diarrhea, hypersensitivity
reactions such as rash, and nausea.
CONTRAINDICATIONS:
Contraindications include pregnancy and lactation. Additional contraindications are
hypersensitivity to ezetimibe or concomitant use with a statin in people with active hepatic disease.
BLACK BOX: No Black Box Warning
INTERVENTIONS:
The nurse instructs patients to maintain a low-cholesterol diet during ezetimibe therapy. Patients
should report side effects to their health care providers.
PT TEACHING:
The nurse instructs patients to report signs and symptoms of adverse effects to the health
care provider. Throughout drug therapy, patients should have periodic blood tests.
Alirocumab (PCSK9 INHIBITORS)
PCSK9 INHIBITORS: PCSK9 inhibitors are fully humanized monoclonal antibodies that
inactivate a protein in the liver called proprotein convertase subtilisin/kexin 9 (PCSK9)
that regulates the life span of the cholesterol clearing receptors on the liver. The inhibition
of PCSK9 significantly lowers LDL cholesterol levels.
PHARMICOKENETICS:
Alirocumab is administered subcutaneously every 2 to 4 weeks, and at recommended
dosages, median times to maximum serum concentrations are 3 to 7 days. Following
subcutaneous injection, the drug is distributed primarily in the circulatory system. As a
protein, the drug degrades to small peptides and individual amino acids. At low
concentrations, the drug is eliminated through binding to the PCSK9 receptors; at higher
concentrations, it is eliminated principally through nonsaturable proteolysis.
ACTION:
Unlike statins that lower cholesterol by inhibiting the synthesis of cholesterol, the PCSK9 inhibitors
promote modulation of the receptor that clears cholesterol, thereby prolonging the receptor activity
and promoting the clearance of cholesterol.
USE:
Alirocumab is indicated in adults with ASCVD or familial hypercholesterolemia who require
additional lowering of LDL cholesterol when diet and maximally tolerated statin therapy have not
produced the desired therapeutic response.
MED ADMIN:
The drug should be administered by subcutaneous injection into the upper arm, abdomen,
or thigh. The injection site should be rotated with each injection, and other drugs should
not be given at the same injection site at the same time. The prefilled syringe or pen should
be warmed to room temperature for 30 to 40 minutes before use. Note that it may take 20
seconds to inject the drug subcutaneously.
ADVERSE EFFECTS:
Alirocumab appears to be well tolerated, with injection site reactions the most common adverse
effect. In addition, nasopharyngitis, itching, influenza, muscle pain, diarrhea, and serious allergic
reactions have been reported with use of the drug.
CONTRAINDICATIONS:
Contraindications include known hypersensitivity to the drug or a component to the formulation.
Limited information is available regarding additional contraindications.
BLACK BOX: No Black Box Warning
PT TEACHING:
Patients (and providers) need to read patient information and instructions each time the patient
administers alirocumab in case new information is available. The nurse provides guidance to
patients and caregivers regarding the proper subcutaneous injection technique, including aseptic
technique and how to use the prefilled syringe or pen correctly. Patient instruction regarding
discarding needles and syringes in a puncture-resistant disposal container is necessary. Women
should notify their health care provider if they become pregnant while taking alirocumab.