Page 645 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 35 Agents Used in Dyslipidemia 631

LDL-C, low levels of HDL-C, and often modest hypertriglyceri-
demia. Rarely, a totally ablative form, Wolman disease, occurs in
infancy. A recombinant replacement enzyme therapy, sebelipase
alfa, effectively restores the hydrolysis of cholesteryl esters in liver,
Blood Hepatocyte Gut
normalizing plasma lipoprotein levels.
Acetyl-CoA
Other Disorders
HMG-CoA Deficiency of cholesterol 7α-hydroxylase can increase LDL in
B-100 HMG-CoA the heterozygous state. Homozygotes also can have elevated
LDL R
reductase
inhibitors triglycerides, resistance to reductase inhibitors as a single agent,
and increased risk of gallstones and coronary disease. A combi-
nation of niacin with a reductase inhibitor appears to be effec-
Ezetimibe
Cholesterol tive. Autosomal recessive hypercholesterolemia (ARH) is due to
mutations in a protein that normally assists in endocytosis of
LDL. High-dose reductase inhibitor plus ezetimibe is effective.
VLDL
The receptor chaperone PCSK9 normally conducts the receptor
B-100 Niacin Bile acids to the lysosome for degradation. Gain-of-function mutations
in PCSK9 are associated with elevated levels of LDL-C and
could be managed with a PCSK9 antibody. The ABCG5 and
ABCG8 half-transporters act together in enterocytes and hepa-
Resins tocytes to export phytosterols into the intestinal lumen and bile,
respectively. Homozygous or combined heterozygous ablative
mutations in either transporter result in elevated levels of LDL
enriched in phytosterols, tendon and tuberous xanthomas, and
FIGURE 35–2 Sites of action of HMG-CoA reductase inhibitors, accelerated atherosclerosis. Ezetimibe is a specific therapeutic for
niacin, ezetimibe, and resins used in treating hyperlipidemias. Low- this disorder.
density lipoprotein (LDL) receptors are increased by treatment with
resins and HMG-CoA reductase inhibitors. VLDL, very-low-density
lipoproteins; R, LDL receptor. HDL Deficiency
Rare genetic disorders, including Tangier disease and LCAT
Familial Combined Hyperlipoproteinemia (lecithin:cholesterol acyltransferase) deficiency, are associated
(FCH) with extremely low levels of HDL. Familial hypoalphalipo-
proteinemia is a more common disorder with levels of HDL
Some persons with familial combined hyperlipoproteinemia have cholesterol usually below 35 mg/dL in men and 45 mg/dL in
only an elevation in LDL. Serum cholesterol is often less than women. These patients tend to have premature atherosclerosis,
350 mg/dL. Dietary and drug treatment, usually with a reduc- and the low HDL may be the only identified risk factor. Man-
tase inhibitor, is indicated. It may be necessary to add niacin or agement should include special attention to avoidance or treat-
ezetimibe to normalize LDL. ment of other risk factors. Niacin increases HDL in many of
these patients but the effect on outcome is unknown. Reductase
Lp(a) Hyperlipoproteinemia inhibitors and fibric acid derivatives exert lesser effects. Aggres-
sive LDL reduction is indicated.
This familial disorder, which is associated with increased athero- In the presence of hypertriglyceridemia, HDL cholesterol is
genesis and arterial thrombus formation, is determined chiefly by low because of exchange of cholesteryl esters from HDL into
alleles that dictate increased production of the (a) protein moiety. triglyceride-rich lipoproteins. Treatment of the hypertriglyceride-
Lp(a) can be secondarily elevated in patients with severe nephro- mia increases the HDL-C level.
sis and certain other inflammatory states. Niacin reduces levels
of Lp(a) in many patients. Reduction of levels of LDL-C below
100 mg/dL decreases the risk attributable to Lp(a), as does the SECONDARY
administration of low-dose aspirin. PCSK9 monoclonal antibod- HYPERLIPOPROTEINEMIA
ies also reduce levels of Lp(a) by about 25%.
Before primary disorders can be diagnosed, secondary causes of
Cholesteryl Ester Storage Disease the phenotype must be considered. The more common conditions
are summarized in Table 35–2. The lipoprotein abnormality usu-
Individuals lacking activity of lysosomal acid lipase (LAL) accu- ally resolves if the underlying disorder can be treated successfully.
mulate cholesteryl esters in liver and certain other cell types lead- These secondary disorders can also aggravate a primary genetic
ing to hepatomegaly with subsequent fibrosis, elevated levels of disorder.