746
P A R T 8
Drugs acting on the cardiovascular system
triglycerides and to increase HDL levels in individuals
with primary hyperlipidaemia or mixed lipid disorders.
Fenofibric acid is slowly absorbed from the GI tract,
with peak levels occurring in 4 to 5 hours; metabo-
lised in the liver, it has a half-life of 20 hours and is
excreted in the urine. Caution should be used in people
with renal impairment, and the drug should be avoided
in individuals with severe renal impairment. The most
common adverse effects that have been reported are
headache, back pain, nausea, diarrhoea, muscle pain,
runny nose and respiratory infections. Gallstones have
also been reported with this drug. Individuals complain-
ing of gallstone-type pain should be screened carefully.
There is an increased risk of muscle breakdown and
rhabdomyolysis if taken with a statin, and people using
this combination need to be monitored closely. Caution
must be used with warfarin anticoagulants; increased
bleeding can occur. The person should be monitored
closely and the dose of the anticoagulant regulated to
achieve therapeutic anticoagulation.
COMBINATION THERAPY
Frequently, if the person shows no response to strict
dietary modification, exercise, and lifestyle changes and
the use of one lipid-lowering agent, combination therapy
may be initiated to achieve desirable serum LDL and
cholesterol levels. For example, a bile acid sequestrant
might be combined with niacin; the combination would
decrease the synthesis of LDLs while lowering the serum
levels of LDLs. This combination is thought to help slow
the progression of CAD. Numerous fixed-combination
therapies are available (see Box 47.6). However, care
must be taken not to combine agents that increase the
risk of rhabdomyolysis. For example, HMG-CoA reduc-
tase inhibitors are not usually combined with nicotinic
acid or gemfibrozil.
FUTURE THERAPIES
Despite advances in treatment, CAD remains the
number one killer of adults in Australia. New drugs
are being investigated that would address multiple risk
factors simultaneously with hopes of cutting risk suc-
cessfully. The
endocannabinoids
are substances present
in the body that activate various neurological receptors
that seem to be very important in the body’s regulation
of appetite, satiety and lipid metabolism. With blocking
of the endocannabinoid system, a series of changes
occur that would seem to have a very profound effect
on many components of the metabolic syndrome.
Blocking the endocannabinoid system results in feelings
of satiety and decreased appetite, leading to weight loss;
decreased release of growth hormone, increased oxygen
and glucose use in the muscle, decreased fat synthesis in
the liver, decreased levels of triglycerides and LDLs and
increased levels of HDLs, improving the lipid profile;
increased sensitivity of insulin receptor sites, leading
to decreased blood glucose levels; decreased fat pro-
duction and storage; increased levels of adiponectin;
and decreased activity of tumour necrosis factor, a pro
inflammatory agent, and decreased activity of C-reactive
protein, which is associated with proinflammatory and
prothrombotic states.
Rimonabant is an endocannabinoid blocker that
has been used in Europe as a weight loss agent. In early
studies in the US, it was shown to significantly reduce
weight and abdominal adiposity and improve lipid
profiles while increasing insulin sensitivity and reducing
the proinflammatory and prothrombotic markers. US
approval of the drug was denied at one point because
of some significant CNS changes that occur, leading to
questions of safety. It has since been removed from the
market.
■■
Other agents used to lower cholesterol include
fibrates, peroxisome proliferator receptor alpha
activator and niacin. Often lipid-lowering agents
are used in combination to lower the cholesterol at
different sites.
■■
Research is being done on the effects of blocking
the endocannabinoid system, resulting in weight
loss, improved lipid profiles and decreased
proinflammatory and prothrombotic states.
Questions have not been answered about the safety
or effectiveness of drugs that block this system.
CHAPTER SUMMARY
■■
CAD is the leading cause of death in the Western
world. It is associated with the development of
atheromas or plaques in arterial linings that lead to
narrowing of the lumen of the artery and hardening
of the artery wall, with loss of distensibility and
responsiveness to stimuli for contraction or dilation.
■■
The cause of CAD is not known, but many
contributing risk factors have been identified,
including increasing age, male gender, genetic
predisposition, high-fat diet, sedentary lifestyle,
smoking, obesity, high stress levels, bacterial
infections, diabetes, hypertension, gout and
menopause. The presence of many of these factors
constitutes metabolic syndrome.
■■
Treatment and prevention of CAD is aimed at
manipulating the known risk factors to decrease
CAD development and progression.
KEY POINTS
