Pharmacology of Agents Used in Hyperlipidemia

Dr. Thomas AbrahamPHAR417: Fall 2005

Development of Atherosclerosis

Early plaqueformation

Advanced Plaque

Clot formation

Treatment Options in Heart Disease

Balloon Angioplasty

StentCoronary Artery Bypass Graft

Potential Role of Cholesterol in Heart disease

Normal Coronary Artery Atherosclerotic Coronary Artery

Cholesterol contributes to atherosclerosis and may make the disease worse by the development of unstable or fragile atheromas.

Atherosclerotic plaques promote thrombotic events that can lead to cardiac tissue ischemia and death.

Endogenous Lipid Transport System

    Very low density lipoproteins (VLDL) composed of mostly triglycerides, cholesterol ester and ApoB-100. Formed in the liver and metabolized in the peripheral circulation by lipoprotein lipase to Intermediate density lipoprotein (IDL, VLDL remnant).

     IDL returns to liver where it is metabolized to LDL (released into general circulation) or taken up into liver cells. LDL removed from plasma by cells (hepatic and non-hepatic) that express the LDL receptor.

High circulating LDL may be due to increased metabolism of IDL to LDL (by liver) or due to decreased LDL receptors on peripheral tissues 

     High density lipoproteins (HDL) carries lipids from the peripheral cells to the liver and transfers lipids between lipoproteins. Anti-atherogenic actions due to ability to carry cholesterol away from vasculature.

Dietary triglycerides and cholesterol incorporated into chylomicrons which carry lipids via the lymphatic system and the blood to the liver.

Endogenous Lipid Transport System

Bile Acid binding Resins

Cholestyramine (Questran®)

     Basic anion exchange resin of trimethylbenzylammonium in large copolymer of styrene and divinylbenzene.       Water-insoluble, hygroscopic.

CH2 CH2 CH

CHCH2 CH2 N+

CH3

CH3

CH3

Cl

nCholestipol HCl (Colestid®)

Copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane; water insoluble and very hygroscopic.

NH CH2CH2

CH2

COHH

CH2

NCH2CH2 NCH2 CH2

NCH2CH2CH2CH2

CH2

COHH

CH2

N

CH2

COHH

CH2

NCH2 CH2H N

N

CH2

COHH

CH2

CH2CH2NH

CH2

COHH

CH2

NH CH2 CH2 n

Colesevelam (Welchol®)

Anion-exchange resin in atablet gel formulation

97% of bile acids reabsorbed via enterohepatic circulation.

    Anion exchange resins bind negatively charged bile acids in place of Cl- to decrease bile acid reabsorption.  

Decreased bile acid reabsorption …… Increased cholesterol conversion to bile acid ……. Increased LDL uptake……..Decreased Plasma cholesterol.

Bile Acid binding Resins

     Also increased hepatic LDL receptors enhance LDL uptake; and increased HMG CoA reductase activity increases cholesterol biosynthesis. 

     VLDL levels not significantly altered by resin therapy; LDL cholesterol decreases by 10-35%, mostly in first 2 weeks of therapy.

       Adverse effects: bloating, abdominal cramps, constipation. Can interfere with absorption of anions; decreases absorption of thyroxine, digitalis, anticoagulants.

Bile Acid binding Resins

Fibric Acid derivatives

Cl O C

CH3

CH3

C

O

O C2H5

Clofibrate (Atromid-SR)

CH3

CH3

O(CH2 )3 C

CH3

CH3

C

O

OH

Gemfibrozil (LopidR)

O C

CH3

CH3

C

O

OHClCl

Ciprofibrate

Cl C

O

O C

CH3

C

O

O CH

CH3

CH3Fenofibrate (TricorR)

CH3

    Gemfibrozil: non-halogenated derivative.    Well absorbed from GI tract esp. with meal; ester derivatives are metabolized to acid form in liver.

      Highly protein bound in plasma. Up to 90% metabolized to glucuronide conjugate and excreted in urine.

 

Mechanism of action to decrease VLDL and increase HDL may be related to increased lipoprotein lipase activity; has variable effects on LDL levels

May increase gene transcription of apolipoprotein AI and AII via activation of peroxisome proliferator-activated receptor (PPAR): Apo AI and AII are components of HDL-C

May decrease VLDL by up to 50% and increase HDL by 10-30% and indirectly decrease LDL by 10-20%

Adverse effects: skin rash, GI disturbances, myopathy (increased risk when combined with high dose HMG CoA reductase inhibitors), arryhthmias, hypokalemia, impotence and liver toxicity.

Fibric Acid derivatives

HMG CoA Reductase inhibitors

O

OH

CH3H

O

O

HCH3

H3C

Lovastatin (MevacorR)

O

OH

CH3H

O

O

CH3

H3C

CH3

Simvastatin (ZocorR)

OH

OH

CH3H

O

O

HCH3

OH

COOH

Pravastatin (PravacolR)

OH

OH

COOH

CH (CH3)2

F

N

Fluvastatin (LescolR)

     Mevastatin isolated from Penicillium cultures (1976); Lovastatin isolated from Aspergillus species.        Lovastatin and simvastatin administered in lactone ring form which is hydrolyzed to acid (active) form. Pravastatin and fluvastatin already in acid form; fluvastatin supplied as sodium salt.        Oral bioavailability of 30-80%; high first-pass metabolism – only about 5% of ingested dose reaches blood. Predominant liver metabolism and excretion for statins but some urine excretion occurs (esp. pravastatin).

     Inhibits cholesterol synthesis by competing with hydroxymethylglutaryl (HMG)-CoA for the reductase enzyme.

O

OH COO-H3C

SCoA

HMG CoA

NADPH + H+ OH

H3C

SCoA

COO-

OHNADPH + H+

OH

H3C

OH

COO-

Mevalonate

Catalyzed by HMG CoA reductase

Cholesterol

      Decreases cholesterol biosynthesis to decrease LDL levels (25-55%); atorvastatin appears more efficacious than other statins.

HMG CoA Reductase inhibitors

     Inhibition of HMG CoA reductase causes increased reductase protein synthesis, which tends to restore cholesterol biosynthesis toward pretreatment levels. Also increases LDL receptor expression which increases plasma clearance of LDL, IDL and VLDL.

     Adverse effects (relatively rare): increases heptic transaminase levels in serum; myopathies (with increases in creatine phosphokinase).

Rhabdomyolysis occurs more often when combined with gemfibrozil, cyclosporine or azole fungal drugs

HMG CoA Reductase inhibitors

Miscellaneous Agents

Ezetimibe (Zetia®)

    Is rapidly absorbed into intestinal cells where it is metabolized to the glucuronide conjugate. Glucuronide form is eliminated from liver by the biliary route into small intestines.

Glucuronide form of the drug binds the cholesterol transport protein to prevent absorption of dietary cholesterol into the intestinal cells.

Ezetimibe can lower LDL-C by up to 20% after about 2 week treatment and has some effect to increased HDL-C and lower triglycerides.

Combination with statins or fenofibrate results in additive lowering in LDL-C.

Miscellaneous Agents

Ezetimibe (Zetia®)

 Chronic therapy with ezetimibe alone results in enhanced cholesterol biosynthesis in the liver.

Cholestyramine decreases absorption of ezetimibe; cyclosporine and renal failure may elevated ezetimibe blood levels.

Adverse effects are generally minor or rare: chest pains, arthralgia, diarrhea, dizziness, headache, sinusitis, pharyngitis, upper respiratory infection.

Miscellaneous Agents

Nicotinic acid (Niacin, Niaspan ®)     Pyridine 3-carboxylic acid; water-soluble vitamin B.      Lipid-lowering activity is unrelated to vitamin function.       Good oral bioavailability; excreted unchanged in urine.       Decreases VLDL production by: (a) decreased lipolysis and delivery of FFA to liver; (b) decreased triglyceride synthesis; (c) increased VLDL clearance by liver.        LDL is lowered secondary to VLDL lowering; HDL levels increased (perhaps by decreasing HDL metabolism). Decreases LDL by 20-30% (3-5 wks.) and VLDL by 35-45%.

 

N

COOH

Nicotinic Acid (Niaspan®)

     Adverse effects: flushing, pruritis (face, upper body), dyspepsia, vomiting, diarrhea, peptic ulcers, dry skin, increased AST/ALT (liver enzymes), jaundice, hepatic failure, increased plasma glucose, increased uric acid levels (gout).

Cutaneous flush may be decreased by aspirin or ibuprofen since this a prostaglandin-mediated event.

Miscellaneous Agents