Anti-Dyslipidemic Drugs

ANTI-DYSLIPIDEMIC DRUGS

• First line drugs:
  • Statins, bile acid binding resins & intestinal cholesterol absorption inhibitors.
• Second line drugs:
  • Fibrates & niacin.

A). STATINS

MOA:

• HMG CoA reductase catalyzes in cholesterol biosynthesis, mainly conversion of HMG CoA to mevalonate.
• This is rate limiting step.
• Statins act by inhibiting HMG CoA reductase enzyme competitively.

Effect of statins:

• Decreases cholesterol synthesis in liver:
  • By inhibiting HMG CoA reductase enzyme.
• Decreases bile acids & steroid hormones synthesis:
  • Indirectly affected due to decreased cholesterol.
• Lowers plasma LDL levels:
  • Most powerful LDL lowering agents.
  • As an aftereffect of all above steps (decreasing cholesterol, bile acids & steroid synthesis).
  • All steps are compensated by, increasing LDL receptors on its surface & thus, LDL uptake from plasma.
• Also lowers TG, IDL & VLDL & increases HDL slightly.
• No effect on lipoprotein.
• Decreases plasma fibrinogen levels – Mainly Pravastatin.
• Pleotropic effects:
  • Antioxidant properties.
  • Anti-inflammatory properties.
  • Anti-proliferative properties.
  • Clinical benefits – Helps lower risk of stroke & MI.

Drugs:

• Pitavastatin, rosuvastatin, atorvastatin, fluvastatin & lovastatin
• Pravastatin approved for children ≥ 8 years.
• Other statins approved for children ≥ 10 years.

Properties of individual drugs:

1. Half-life:

• Long-acting drugs:
  • Rosuvastatin (t_1/2 – 19 hours) – Longest acting statin.
  • Atorvastatin (t_1/2 – 14 hours)
  • Hence can be administered at any time of day.

2. Drug administration & timing:

• Drugs administered at night:
  • Activity of HMG CoA reductase maximum at night – Hence, most drugs administered at night.
• Drugs administrated any time of day:
  • Long-acting drugs like Rosuvastatin & Atorvastatin – Due to longer half-life.

3. Metabolism:

• All statins absorbed orally (maximum fluvastatin).
  • Food increases absorption of all drugs, except pravastatin.
• Undergo first pass metabolism
  • Lovastatin & simvastatin – Extensive first-pass metabolism & administered as prodrugs
  • Pravastatin, fluvastatin, atorvastatin & rosuvastatin – Administered as active drugs.
• All drugs are metabolized extensively by hepatic microsomal enzymes, except pravastatin.
  • Pravastatin metabolized by sulfation (non-microsomal) –> Least chances of drug interactions.
  • Hence, Pravastatin confined to liver & is safer.

4. Drug potency:

• Pitavastatin (Most potent statin) > Rosuvastatin > fluvastatin > lovastatin (least potent statins).

B). INTESTINAL CHOLESTEROL ABSORPTION INHIBITOR

• Drug: Ezetimibe
• MOA: 
  • Inhibits transporter NPC1L1, involved in intestinal absorption of cholesterol.
  • Due to decreased absorption, liver cholesterol content decreases & in turn increases LDL receptor synthesis.
• Uses:
  • Type IIa & IIb hyperlipoproteinemia – Used alone or combined with statins.

C). BILE ACID BINDING RESINS

MOA:

• Binds to bile acids in intestinal lumen –> Decreases its reabsorption –> results in more excretion via feces.
• Depletes liver cholesterol pool, because it is utilized for bile acid formation.
• Liver acquires cholesterol from plasma, by increasing LDL receptors.
• Bile acids inhibit TG production in liver & their deficiency results in TGs elevation.

Uses:

• Only for type IIa disorder (TGs are normal in this condition).

Drugs:

• Cholestyramine, colestipol & colesevelam.
• Cholestyramine & colestipol –  
  • Available as sachets.
  • Mixed with water, kept for some time (to increase palatability) & then taken with meals.
• Colesevelam – 
  • Available as tablet.
  • Has better patient compliance.

Adverse effect:

• Constipation (Major).

D). FIBRIC ACID DERIVATIVES

MOA:

• Acts by activating LPL by activating nuclear receptor, PPARα (peroxisome proliferator-activated receptor alpha).

Major effects:

• Reduces TG (contained in VLDL).
• Increases HDL.
• Reduces plasma fibrinogen level.

Drugs:

• Clofibrate, gemfibrozil, fenofibrate, bezafibrate.
• Clofibrate – Not used now.
  • Due to increased mortality from malignancies, post-cholecystectomy complications & fatal MI. 
• Gemfibrozil, fenofibrate & bezafibrate – Currently available.

Fenofibrate:

• Prodrug with longest half-life.
• Has maximum LDL cholesterol-lowering action.
• Uricosuric

Uses:

• DOC in hypertriglyceridemia (type III & IV).
• In combination with other drugs in type IIb.
• For hyperuricemia (Fenofibrate – uricosuric)

Adverse effects:

• GI distress.
• Elevation of aminotransferases.
• Increased myopathy risk – On combining with statins, except bezafibrate.

NICOTINIC ACID

• Note: Niacin (not nicotinamide).
• An inexpensive drug (vitamin B)

MOA:

• Acts by inhibiting lipolysis in adipose tissue.

Effects:

• Decreases LDL cholesterol & VLDL triglycerides.
• Increases HDL cholesterol – Maximum HDL increasing property (Among all hypolipidemic drugs).
• Decreases lipoprotein (a) & fibrinogen.

Uses:

• Useful in patients having increased risk of CAD (due to maximum HDL increasing property).
• For type IIb, III & IV disorders.

Adverse effects:

• Cutaneous flushing & pruritis – Main compliance limiting feature.
  • Due to vasodilatory effect via PGs release.
  • Prevented by aspirin pretreatment.
• To minimize side effects, niacin should be started at low doses.

Other adverse effects:

• GI toxicity.
• Hyperuricemia.
• Hepatotoxicity (manifested by fall in both LDL & HDL).

MISCELLANEOUS DRUGS

1. Probucol:

• Useful for its antioxidant action.
• MOA: Inhibits LDL oxidation –> Reduces both HDL & LDL cholesterol levels.

2. Gugulipid: 

• Drug developed by Central Drug Research Institute, Lucknow.
• Causes modest LDL reduction & slight HDL increase.
• Diarrhea – Only adverse effect.

NEW DRUGS

1. Avasimibe:

• Inhibits ACAT-1 (acyl-coenzyme A: cholesterol acyltransferase-1) enzyme.
• ACAT-1 forms cholesterol ester from cholesterol.

2. Torcetrapib & anacetrapib:

• Increases HDL cholesterol by inhibiting enzyme CETP (cholesterol ester triglyceride transport protein).

3. Lomitapide:

• Acts by inhibiting MTP (microsomal triglyceride transfer protein).
• MTP necessary for VLDL assembly & secretion in liver.

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