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The plaques in the arterial walls of patients with atherosclerosis contain large amounts of cholesterol The higher the level of low-density lipoproteins (LDL) cholesterol, the greater the risk of atherosclerotic heart disease; conversely, the higher the high-density lipoproteins (HDL) cholesterol, the lower the risk of coronary heart disease (CHD) This is true in men and women, in different racial and ethnic groups, and at all ages up to age 75 years Because most cholesterol in serum is LDL, high total cholesterol levels are also associated with an increased risk of CHD Middle-aged men whose serum cholesterol levels are in the highest quintile for age (above about 230 mg/dL) have a risk of coronary death before age 65 years of about 10%; men in the lowest quintile (below about 170 mg/dL) have a 3% risk Death from CHD before age 65 years is less common in women, with equivalent risks one-third those of men In men, each 10-mg/dL increase in cholesterol (or LDL cholesterol) increases the risk of CHD by about 10%; each 5-mg/dL increase in HDL reduces the risk by about 10% The effect of HDL cholesterol is greater in women, whereas the effects of total and LDL cholesterol are smaller All of these relationships diminish with age There are several genetic disorders that provide insight into the pathogenesis of lipid-related diseases Familial hypercholesterolemia, rare in the homozygous state (about one per million) is a condition in which the cell-surface receptors for the LDL molecule are absent or defective, resulting in unregulated synthesis of LDL Patients with two abnormal genes (homozygotes) have extremely high levels up to eight times normal and present with athero-

sclerotic disease in childhood Homozygotes may require liver transplantation to correct their severe lipid abnormalities Those with one defective gene (heterozygotes) have LDL concentrations twice normal; persons with this condition may develop CHD in their 30s or 40s Another rare condition is caused by an abnormality of lipoprotein lipase, the enzyme that enables peripheral tissues to take up triglyceride from chylomicrons and verylow-density lipoproteins (VLDL) particles Patients with this condition, one cause of familial hyperchylomicronemia, have marked hypertriglyceridemia with recurrent pancreatitis and hepatosplenomegaly in childhood Numerous other genetic abnormalities of lipid metabolism are named for the abnormality noted when serum is electrophoresed (eg, dysbetalipoproteinemia) or from combinations of lipid abnormalities in families (eg, familial combined hyperlipidemia) Thus, family members of patients with severe lipid disorders are appropriately studied Other patients have abnormalities in the production of apoproteins, such as increased apoprotein B and its affiliated lipoproteins, LDL and VLDL; reduced apoprotein AII and its affiliated particle; or excess lipoprotein(a) Other mutations occur in lipoprotein lipase and in the gene encoding for cholesterol efflux regulatory protein

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Ansell BJ et al High-density lipoprotein function recent advances J Am Coll Cardiol 2005 Nov 15;46(10):1792 8 [PMID: 16286161] Berneis K et al Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes Metabolism 2005 Feb;54(2):227 34 [PMID: 15690318] Drexel H et al Is atherosclerosis in diabetes and impaired fasting glucose driven by elevated LDL cholesterol or by decreased HDL cholesterol Diabetes Care 2005 Jan;28(1):101 7 [PMID: 15616241] Nam BH et al Search for the optimal atherogenic lipid risk profile: from the Framingham study Am J Cardiol 2006 Feb 1;97(3):372 5 [PMID: 16442398]

ACE inhibitors are being increasingly used as the initial medication in mild to moderate hypertension (Table 11 8)

1:

Cost of 30 Days Treatment (Based on Average Dosage)1 $4020 Special Properties 2 Selectivity 2 + Lipid Solubility + Renal vs Hepatic Elimination H>R

Comments5 Positive ANA; rare LE syndrome; also indicated for arrhythmias Doses > 800 mg have 1 and 2 effects Also indicated for angina pectoris and post-MI Doses > 100 mg have 1 and 2 effects

$2490

H>R R=H Low-dose combination approved for initial therapy Bisoprolol also effective for heart failure : -Blocking activity 1:9; may cause orthostatic symptoms; effective for congestive heart failure : -Blocking activity 1:3; more orthostatic hypotension, fever, hepatotoxicity

$12600 (25 mg twice a day)

$4680

$3300

FIGURE 1-7

Also indicated for angina pectoris and post-MI Approved for heart failure Doses > 100 mg have 1 and 2 effects

50 200 mg once daily 20 160 mg once daily 20 80 mg once daily 10 60 mg in 2 doses 40 320 mg in 2 doses

$4350 $3150 $6060 $4200 $3060 0 0 0 0 0 + ++ 0 0 0 + ++ 0 ++ + +++ R R>H H>R H In adults, 35% renal clearance Once-daily SR preparation also available Also indicated for angina pectoris and post-MI Also indicated for post-MI 80% hepatic clearance

$ 2280

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