Anti-Lipid Drugs

• Component of cell membrane
• Required for hormone synthesis and bile salt synthesis
• Some cholesterol comes from dietary sources.
• Most cholesterol comes from liver synthesis

• 1. Deposition of fatty plaques on arterial walls
• 2. Lipoproteins: Since cholesterol and triglycerides are not water soluble, lipoproteins are used to serve as carriers for transporting cholesterol and triglycerides in blood.

(a) VLDL (very-low-density-lipoprotein): Low percentage of protein and very high percentage of lipid. Main physiological role is to deliver triglycerides from the liver to adipose tissue and muscle. Several studies link elevated VLDL with atherosclerosis.

(b) LDL (low-density-lipoprotein): Low percentage of protein and high percentage of lipid. Accounts for the majority (60-70%) of all cholesterol in the blood. Main physiological role is to deliver cholesterol to non-hepatic tissues. LDL can also be retrieved by the liver from the plasma via LDL receptors on the surface of the hepatocytes. Makes the greatest contribution to coronary atherosclerosis. Elevated LDL increases coronary artery disease.

(c) HDL (high-density-lipoprotein) Medium percentage of protein and lower percentage of lipid. Accounts for 20 to 30% of cholesterol in the blood. HDLs remove cholesterol from peripheral tissues back to the liver. Elevated HDL lowers coronary artery disease.

• Diet modification--Limit total fat to 30% or less of caloric intake.
• Limit saturated fats to 10% or less of caloric intake.
• Limit cholesterol to 300 mg/day or less
• This method should be tried first before drug therapy
• Note: Diabetes mellitus, hypertension, smoking and obesity all increase the risk of coronary artery disease.

Lower LDL-cholesterol without lowering HDL-cholesterol

Examples: Lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), and atorvastatin (Lipitor), rosuvastation (Crestor).

First choice drugs: These are the most effective drugs for lowering LDL-cholesterol levels and cause few adverse effects.

Mechanism of Action: Statins inhibit the liver enzyme HMG CoA reductase (hydroxymethylglutaryl-Coenzyme A reductase). This enzyme controls the rate at which cholesterol is synthesized in the liver. Cholesterol levels decrease in the liver, and the liver tries to raise the cholesterol levels by increasing the number of LDL receptors present on the hepatocytes. These receptors will take up the LDL-cholesterol from the plasma and bring it into the liver. The net effect is to lower LDL-cholesterol in the plasma.

• Pharmacokinetics: Administered orally. Most of absorbed dose is extracted from the blood on its first pass through the liver.
• Lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4 and their serum concentrations can be dramatically increased by CYP3A4 inhibitors such as the antifungal drugs itraconazole, ketoconazole, and the antibiotic erythromycin or grapefruit juice.
• Crosses placenta and blood-brain barrier (contraindicated for pregnancy and nursing).
• Most effective when taken at dinner or bedtime when the liver increases its synthesis of cholesterol.
• Lovastatin, pravastatin and simvastatin must be taken with food.

• Adverse Effects:
• Minor: headache, rash or GI disturbances
• Major: Hepatotoxicity (use with extreme caution for alcoholics and those with liver damage.
• Myopathy: Highest risk with lovastatin, particularly if combines with other lipid lowering drugs such as gemfibrozil or nicotinic acid

Mechanism of action: Resins form an insoluble complex with bile acids in the intestine. This prevents the reabsorption of bile acids and accelerates their excretion. The liver must make more bile acids from cholesterol and must increase the uptake of LDL-cholesterol by increasing LDL-receptors. This decreases LDL in plasma

Pharmacokinetics: Not absorbed from the GI tract and is excreted in the feces. In general they are very safe.

Adverse Effects: (less of these effects for colesevelam) Constipation, indigestion, nausea (particularly for elderly) May decrease the uptake of fat soluble vitamins (A,D,E,K) thus must increase vitamins for pregnancy or breast-feeding clients.

Drug Interactions: (except for colesevelam) Forms complexes with drugs such as propranolol, warfarin, antibiotic.

Administration: Administer before meals by mixing powder with liquid or taking tablets with plenty of liquid. Any other medication should be given one hour prior to administration of the resin.

Mechanism of Action: Poorly understood, but appears to reduce the synthesis and transport of fatty acids from adipose tissue to the liver. Reduces LDL and VLDL and increases HDL.

Therapeutic use: Used to lower VLDL levels in patients at risk for pancreatitis.

• Side Effects: At higher pharmacological doses: Vasomotor flushing of the face, neck and ears (aspirin will prevent this by preventing the synthesis of prostaglandins which mediate the flushing response)
• Pruritus
• GI tract
• Hepatotoxicity—especially with extended-release formulations.
• Peptic ulcer

Mechanism of action: Poorly understood— Increases hydrolysis of VLDLs and produces more fatty acids for muscle. Lowers VLDL and raises HDL-cholesterol. Little effect on LDL-cholesterol.

Adverse Reactions: Rashes and GI disturbances, Risk of gallstones, Hepatotoxic, Displaces warfarin from plasma albumin.

Indications: Elevation of VLDLs

Mechanism of Action: Selectively inhibits intestinal absorption of dietary and biliary cholesterol at the brush border of the small intestine. After oral administration it is extensively converted to a pharmacologically active glucuronide in the small intestine and liver, and is excreted mostly in the stool.

In monotherapy it lowers LDL cholesterol by 17%, triglycerides by 6%, and increased HDL cholesterol by 1.3%.

Side effects: Well tolerated in contrast to bile acid binding resins but is contraindicated for patients with moderate to severe hepatoxicity. It is also contraindicated for those with gall bladder disease.

Cholestyramine and colestipol interfere with absorption of ezetimibe and so must be taken separately.