Drugs used in Hyperlipoproteinemias

Lipid-Lowering Agents

Triglycerides and cholesterol are essential
constituents of the organism.
Among other things, triglycerides represent
a form of energy store and cholesterol
is a basic building block of biological
membranes. Both lipids are water
insoluble and require appropriate transport
vehicles in the aqueous media of
lymph and blood. To this end, small
amounts of lipid are coated with a layer
of phospholipids, embedded in which
are additional proteins—the apolipoproteins
(A). According to the amount and
the composition of stored lipids, as well
as the type of apolipoprotein, one distinguishes
4 transport forms:

Lipoprotein metabolism. Enterocytes
release absorbed lipids in the form
of triglyceride-rich chylomicrons. Bypassing
the liver, these enter the circulation
mainly via the lymph and are hydrolyzed
by extrahepatic endothelial
lipoprotein lipases to liberate fatty acids.
The remnant particles move on into
liver cells and supply these with cholesterol
of dietary origin.
The liver meets the larger part
(60%) of its requirement for cholesterol
by de novo synthesis from acetylcoenzyme-
A. Synthesis rate is regulated at
the step leading from hydroxymethylglutaryl
CoA (HMG CoA) to mevalonic
acid, with HMG CoA reductase
as the rate-limiting enzyme.
The liver requires cholesterol for
synthesizing VLDL particles and bile acids.
Triglyceride-rich VLDL particles are
released into the blood and, like the
chylomicrons, supply other tissues with
fatty acids. Left behind are LDL particles
that either return into the liver or supply
extrahepatic tissues with cholesterol.
LDL particles carry apolipoprotein B
100, by which they are bound to receptors
that mediate uptake of LDL into the
cells, including the hepatocytes (receptor-
mediated endocytosis).
HDL particles are able to transfer
cholesterol from tissue cells to LDL particles.
In this way, cholesterol is transported
from tissues to the liver.
Hyperlipoproteinemias can be
caused genetically (primary h.) or can
occur in obesity and metabolic disorders
(secondary h). Elevated LDL-cholesterol
serum concentrations are associated
with an increased risk of atherosclerosis,
especially when there is a concomitant
decline in HDL concentration
(increase in LDL:HDL quotient).
Treatment. Various drugs are available
that have different mechanisms of
action and effects on LDL (cholesterol)
and VLDL (triglycerides). Their use is
indicated in the therapy of primary hyperlipoproteinemias.
In secondary hyperlipoproteinemias,
the immediate
goal should be to lower lipoprotein levels
by dietary restriction, treatment of
the primary disease, or both.
Drugs. Colestyramine and colestipol
are nonabsorbable anion-exchange
resins. By virtue of binding bile acids,
they promote consumption of cholesterol
for the synthesis of bile acids; the

liver meets its increased cholesterol demand
by enhancing the expression of
HMG CoA reductase and LDL receptors
(negative feedback).
At the required dosage, the resins
cause diverse gastrointestinal disturbances.
In addition, they interfere with
the absorption of fats and fat-soluble vitamins
(A, D, E, K). They also adsorb and
decrease the absorption of such drugs as
digitoxin, vitamin K antagonists, and
diuretics. Their gritty texture and bulk
make ingestion an unpleasant experience.
The statins, lovastati= L , simvastatin = s,
pravastatin =p , fluvastatin = F,
cerivastatin, and atorvastatin, inhibit
HMG CoA reductase. The active group of
L, S, P, and F (or their metabolites) resembles
that of the physiological substrate
of the enzyme. L and S are lactones
that are rapidly absorbed by the
enteral route, subjected to extensive
first-pass extraction in the liver, and
there hydrolyzed into active metabolites.
P and F represent the active form
and, as acids, are actively transported by
a specific anion carrier that moves bile
acids from blood into liver and also mediates
the selective hepatic uptake of
the mycotoxin, amanitin (A). Atorvastatin
has the longest duration of action.
Normally viewed as presystemic elimination,
efficient hepatic extraction
serves to confine the action of the statins
to the liver. Despite the inhibition of
HMG CoA reductase, hepatic cholesterol
content does not fall, because hepatocytes
compensate any drop in cholesterol
levels by increasing the synthesis of
LDL receptor protein (along with the reductase).
Because the newly formed reductase
is inhibited, too, the hepatocyte
must meet its cholesterol demand by
uptake of LDL from the blood (B). Accordingly,
the concentration of circulating
LDL decreases, while its hepatic
clearance from plasma increases. There
is also a decreased likelihood of LDL being
oxidized into its proatheroslerotic
degradation product. The combination
of a statin with an ion-exchange resin
intensifies the decrease in LDL levels. A
rare, but dangerous, side effect of the
statins is damage to skeletal musculature.
This risk is increased by combined
use of fibric acid agents (see below).
Nicotinic acid and its derivatives
(pyridylcarbinol, xanthinol nicotinate,
acipimox) activate endothelial lipoprotein
lipase and thereby lower triglyceride
levels. At the start of therapy, a
prostaglandin-mediated vasodilation
occurs (flushing and hypotension) that
can be prevented by low doses of acetylsalicylic
acid.
Clofibrate and derivatives (bezafibrate,
etofibrate, gemfibrozil) lower plasma
lipids by an unknown mechanism.
They may damage the liver and skeletal
muscle (myalgia, myopathy, rhabdomyolysis).
Probucol lowers HDL more than
LDL; nonetheless, it appears effective in
reducing atherogenesis, possibly by reducing
LDL oxidation.
3-Polyunsaturated fatty acids (eicosapentaenoate,
docosahexaenoate)
are abundant in fish oils. Dietary supplementation
results in lowered levels
of triglycerides, decreased synthesis of
VLDL and apolipoprotein B, and improved
clearance of remnant particles,
although total and LDL cholesterol are
not decreased or are even increased.
High dietary intake may correlate with a
reduced incidence of coronary heart
disease.