Adverse effects and contraindications
Mild and infrequent side effects include nausea, constipation,
diarrhoea, flatulence, fatigue, insomnia and rash. More serious
adverse events are rare, but include rhabdomyolysis, hepatitis
and angioedema. Liver function tests should be performed
before starting treatment and at intervals thereafter, and
patients should be warned to stop the drug and report at once
for determination of creatine kinase if they develop muscle
aches. HMG CoA reductase inhibitors should be avoided in
alcoholics and patients with active liver disease, and are
contraindicated during pregnancy.
Pharmacokinetics
Statins are well absorbed, extracted by the liver (their site of
action) and are subject to extensive presystemic metabolism
by CYP3A4 or CYP2D6. Simvastatinis an inactive lactone
prodrug which is metabolized in the liver to its active form,
the corresponding β-hydroxy fatty acid.
Drug interactions
The risk of rhabdomyolysis is increased by concurrent use of a
fibrate or inhibitors of statin metabolism, e.g. azoles (Chapter 45),
macrolides (Chapter 43). Their potency is increased by concur-
rent use of a drug that interferes with cholesterol absorption
(see below).
DRUGS THAT REDUCE CHOLESTEROL
ABSORPTIONEZETIMIBE
Use
Ezetimibeis most often used in combination with diet and
statins for severe hypercholesterolaemia; also in occasional
patients who cannot tolerate statins or where statins are con-
traindicated, and in (rare) cases of homozygous sitosterolaemia.
Mechanism of action
It blocks the NPLC1L sterol transporter in the brush border
of enterocytes, preventing cholesterol and plant sterols
(phytosterols) transport from the intestinal lumen. This mech-
anism is distinct from that of phytosterol and phytostanol
esters (present in ‘health’ foods such as Benecol™) which inter-
fere with the micellar presentation of sterols to the cell surface,
or of resins (see below) which bind bile acids in the gut lumen.
Pharmacokinetics
Ezetimibeis administered by mouth and is absorbed into
intestinal epithelial cells, where it localizes to the brush bor-
der. It is metabolized, followed by enterohepatic recycling and
slow elimination. It enters breast milk.
Adverse effects and contraindications
Diarrhoea, abdominal pain or headaches are occasional prob-
lems; rash and angioedema have been reported. It is con-
traindicated in breast-feeding.
ANION-EXCHANGE RESINS
Use
Colestyramineorcolestipolwere used for hypercholesterol-
aemia, but have been almost completely superseded by statins.
Resins retained an important niche as add-in treatment in
severe disease (e.g. heterozygous familial hypercholestero-
laemia (FH)) which was inadequately responsive to statin
monotherapy. This role has now been taken by ezetimibe(see
above) which is effective and well tolerated in milligram doses
in contrast to resins which are administered in doses of several
grams, are unpalatable and commonly cause abdominal bloat-
ing and diarrhoea. They retain a highly limited usefulness in
children and in breast-feeding women. Completely separate
indications include bile salt diarrhoea and pruritus in incom-
plete biliary obstruction. (They are ineffective in patients with
complete biliary obstruction, in whom there are no bile salts to
bind in the gut lumen.) They cause malabsorption of fat solu-
ble vitamins and interfere with the absorption of many drugs
(Chapter 13).FIBRATES
Use
Bezafibrate,gemfibrozilandfenofibrateare available in the
UK and are used mainly for patients with mixed dyslipidaemia
with severely raised triglycerides especially if they are poorly
responsive to statins. Clofibrate, which was used in a World
Health Organization (WHO) trial, is less often used because it
increases biliary cholesterol secretion and predisposes to gall-
stones. Its use is therefore limited to patients who have had a
cholecystectomy. Furthermore, while it reduced the number of
myocardial infarctions in the WHO trial, this was offset by an
increased number of cancers of various kinds. The meaning of
this has been extensively debated, but remains obscure. This
issue is clouded by an effect of malignancy of lowering serum
cholesterol. The original observations with clofibrate may
have been a statistical accident and there is no excess of cancers
in patients treated with gemfibrozilin other trials (e.g. the
Helsinki Heart Study). These studies have shown that fibrates
have a marked effect in lowering plasma triglycerides (TG), with
a modest (approximately 10%) reduction in LDL and increase in
HDL.Fenofibratehas an additional uricosuric effect.Mechanism of action
Fibrates are agonists at a nuclear receptor (peroxisome
proliferator-activated receptor α(PPARα)) which is present in
many tissues including fat. The ensuing effects are incom-
pletely understood. They stimulate lipoprotein lipase (hence
their marked effect on TG) and increase LDL uptake by the
liver. In addition to their effects on plasma lipids, fibrates
lower fibrinogen.Adverse effects
Fibrates can cause myositis (in severe cases rhabdomyolysis
with acute renal failure), especially in alcoholics (in whom they
should not be used) and in patients with impaired renal func-
tion (in whom elimination is prolonged and protein binding182 PREVENTION OF ATHEROMA:LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES