Hypolipidemic Drugs

Hypolipidemic Drugs
Binding resins: cholestyramine, colestipol
Nicotinic acid: Nicotnicotinic acid
Fibric acid derivatives: gemfibrozil
Statins: lovastatin, atorvastatin, pravastatin, ezetimibe
Let’s start with some basics:
 Dyslipidemia is the name give to high cholesterol or triglycerides. When both
are elevetated, we call this combined dyslipidemia. The major sequlae of
hyperlipidemia are acute pancreatitis and atherosclerosis.
 Atherosclerosis is the deposit of cholesterol an d pilids into the intima of
vessels.
 Chylomicrons are formed in the intestines and carry absorbed dietary
triglycerides
 Very low density lipoprotein (vLDL) are secreted by the liver, and they
facilitate the transport of triglycerides from the liver to peripheral tissues
 Low density lipoprotein (LDL) transports triglycerides from the liver to the
blood; high levels of LDL in the blood are associated with atherosclerosis and
coronary heart disease
 High density lipoprotein (HDL) acquire cholesterol from peripheral tissues
 LP(a) lipoprotein is basically part LDL and part LP(a) protein; high levels are not
good
Here are some diseases. They can be classified into primary or secondary dyslipedmic
disorders:
 Primary dyslipidemias
1. Familial hypercholesterolemia is an AD disease that results in a defect
in the high affinity LDL receptor, which means LDL never gets taken-up by
the liver, so it deposists in tissue and vessels. As a result, individuals
develop coronary heart disease in childhood. Treat with Niacin or
Atorvastatin; binding resins have no effect because they increase
the expression of mutated receptors.
2. Familial ligand-defective apolipoprotein B is a less severe form of
familial of hypercholesterolemia due to a mutation is a less important
receptor protein (the exact details are not important). Statins have
variable effects, but Niacin will be greatly benefitial.
3. Primary triglyceridemias are due to a defective lipoprotein lipase. If TG
levels become too high, patients will suffer from pancreatitis . Treat with
fibric acid derivatives and Niacin.
 Secondary dyslpipidemias
1. Diabetes
2. Hypothyroidism
3. Birth control pills
4. Drug induced dyslopidemias, such as HIV drugs and thiazide diuretics
How do you treat dyslipidemia? Well, you have to modify your lifestyle: decrease
alcohol, increase your exercise, and change to a healthier diet. However, if, you’re like
me, just give a statin so I can gorge myself.
1. Explain the mechanisms of action of binding resins (cholestyramine, colestipol) in the
treatment of hypercholesterolemia.
 Cholestyramine and colestipol are both binding resins that decrease LDL and
increase HDL by binding to bile acids in the feces, causing them to be excreted.
This net loss of bile acid means that the body will oxidize cholesterol to make new bile
acids, and in the process, the body upregulates LDL receptors on the liver, thereby
reducing serum LDL levels.
 The side effects include constipation.
 Binding resins will not work in familial hypercholesteremia due to lack of LDL
receptors.
2. Describe the mechanism of action of nicotinic acid and fibric acid derivatives
(gemfibrozil) in the treatment of hypercholesterolemia and hypertriglyceridemia.
 Nicotinic acid = Niacin. Niacin decreses LDL, vLDL, TG, and Lp(a) levels while
increasing HDL. How does it do this? It inhibits vLDL secretion which prevents LDL
from even leaving the liver. Niacin’s side effects include flushing, hepatic function,
and hyperuricemia (i.e. do not give niacin to patients with liver disease or gout).
 Fibric acid derivatives are Gemfibrozil and Fenofibrate, and they work by increasing
the activity of lipoprotein lipase, which will cause a reduction in vLDL and TG
while increasing HDL. Their major side effects are myopathy, arrhythmias,
hypokalemia, elevated risk of cholesterol gallstones, and high levels of
aminotransferases. The fibric acid derivatives increase the activity of warfarin, and
do not give them to patient with renal of hepatic failure.
3. Explain the mechanism of action of HMG-CoA reductase inhibitors in the treatment of
hypercholesterolemia.
 Statins are HMG-CoA reducatse inhibitors. Specifically, they are analogs of hydroxylmethyl-glutaryl coenzyme A, and thus they are competitive inhibitors of HMG-CoA
reductase! This means that statins cause a reduction in LDL and CRP by inhibiting
the first step in sterol biosynthesis. Just remember that statins will cause a decrease
in LDL.
 Statins have a high first-pass rate, so graprefruit juice will inhibit CYT p-450, causing
statins to have an elevated effect (to be fair, you’d have to drink a quart of grapefruit a
day).
 Most statins have a shalf-life of 1 to 3 hours, except for atorvastatin which has a half life
of 14 hours.
 The major side effects of statins are:
1. Hepatotoxicity, which can be avoided by not giving statins to heavy drinkers
2. Rhabdomyolysis is the destruction of muscle which results in muscle pain
4. Explain the mechanism of action of ezetimibe.
 Exetimibe is used in hypercholesteremia, and it causes a decrease in serum LDL and
triglycerides. It does this by decreasing the GI uptake of cholesterol, and by
increasing the synthesis of high-affinity LDL receptors in the liver.
 Mixing Ezetimibe with a statin can cause liver toxicity, so watch patients closely
5. Describe the common side-effects related to hypolipidemic drugs.
 See above
Practice questions:
Answers: a, b, c, c, a, a, a-e, a

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