Anti-Dyslipidemic Drugs

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.

Adverse effects:

  • Myopathy & hepatotoxicity (Major).
    • Myopathy chances increase on co-administration with fibrates (maximum with gemfibrozil) or niacin.
    • Myopathy proceeds to rhabdomyolysis & then, renal shutdown.
    • Pravastatin is safer in this regard.
  • Be avoided in pregnancy & lactation.

Uses:

  • First line drugs for type IIa, type IIb & secondary hyperlipoproteinemia.
    • Because these conditions, cholesterol level is raised more than TG.
  • In children with heterozygous familial hypercholesterolemia.

Properties of individual drugs:

1. Half-life:

  • Long-acting drugs:
    • Rosuvastatin (t1/2 – 19 hours) – Longest acting statin.
    • Atorvastatin (t1/2 – 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 cholesterolMaximum 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.

Exam Important

ANTI-DYSLIPIDEMIC DRUGS

  • First line anti-dyslipidemic drugs are statins, bile acid binding resins & intestinal cholesterol absorption inhibitors.
  • Second line anti-dyslipidemic drugs are fibrates & niacin.
  • Statins act by inhibiting HMG CoA reductase enzyme competitively.
  • HMG CoA reductase catalyzes in cholesterol biosynthesis, mainly conversion of HMG CoA to mevalonate.
  • Rate-limiting step in cholesterol biosynthesis is conversion of HMG CoA to mevalonate, catalyzed by HMG CoA reductase.
  • Statins decrease cholesterol synthesis in liver, by inhibiting HMG CoA reductase enzyme.
  • Statins decrease bile acids & steroid hormones synthesis.
  • Statins are most powerful LDL lowering agents.
  • Statins decrease TG, IDL & VLDL & increases HDL slightly.
  • Statins have no effect on lipoprotein.
  • Statins mainly pravastatin decreases plasma fibrinogen levels.
  • Statins exhibit pleiotropic effects like antioxidant, anti-inflammatory & anti-proliferative properties.
  • Pitavastatin, rosuvastatin, atorvastatin, fluvastatin & lovastatin are drugs included under statins.
  • Pravastatin approved for children ≥ 8 years.
  • Major adverse effect of statins includes Myopathy & hepatotoxicity.
  • Pravastatin is safer with regard to causing myopathy.
  • Statins are first-line drugs for type IIa, type IIb & secondary hyperlipoproteinemia.
  • Long-acting statins are Rosuvastatin (t1/2 – 19 hours) & Atorvastatin (t1/2 – 14 hours).
  • Rosuvastatin with t1/2 19 hours is the longest acting statin.
  • Activity of HMG CoA reductase maximum at night, hence most statins are administered at night.
  • Long-acting drugs like Rosuvastatin & Atorvastatin are administrated any time of day, due to their longer half-life.
  • All statins absorbed orally, maximum with fluvastatin.
  • Lovastatin & simvastatin are administered as prodrugs & have extensive first-pass metabolism.
  • Pravastatin, fluvastatin, atorvastatin & rosuvastatin are administered as active drugs.
  • All statins are metabolized extensively by hepatic microsomal enzymes, except pravastatin.
  • Pravastatin metabolized by sulfation (non-microsomal).
  • Most potent statin is Pravastatin; Least potent statin is lovastatin.
  • Ezetimibe is an intestinal cholesterol absorption inhibitor.
  • Ezetimibe acts by inhibiting NPC1L1 transporter, involved in intestinal absorption of cholesterol. 
  • Intestinal cholesterol absorption inhibitor like Ezetimibe indicated in type IIa & IIb hyperlipoproteinemia.
  • Bile acid binding resins bind to bile acids in intestinal lumen –> Decreases its reabsorption –> results in more excretion via feces.
  • Bile acid binding resins are indicated only for type IIa disorder.
  • Drugs included under bile acid binding resins cholestyramine, colestipol & colesevelam.
  • Fibric acid derivatives act by activating LPL by activating nuclear receptor, PPARα (peroxisome proliferator-activated receptor alpha).
  • Fibric acid derivatives reduces TG (contained in VLDL), increases HDL & reduces plasma fibrinogen level.
  • Drugs included under fibric acid derivatives are Clofibrate, gemfibrozil, fenofibrate, bezafibrate.
  • Fenofibrate is prodrug with longest half-life.
  • Fenofibrate has maximum LDL cholesterol-lowering action & are uricosuric.
  • DOC in hypertriglyceridemia (type III & IV) is Fenofibrate.
  • Nicotinic acid acts by inhibiting lipolysis in adipose tissue.
  • Main effects of nicotinic acid increase HDL cholesterol, decrease LDL cholesterol, VLDL triglycerides, lipoprotein (a) & fibrinogen.
  • Among all hypolipidemic drugs, nicotinic acid is maximum HDL increasing property.
  • Due to maximum HDL increasing property, Nicotinic acid is useful in patients having increased risk of CAD.
  • Except for type-I disorders, nicotinic acid is useful in type IIb, III & IV disorders.
  • Main limiting feature of nicotinic acid is cutaneous flushing & pruritis.
  • Probucol is an anti-dyslipidemic drug useful for its antioxidant action.
  • Probucol inhibits LDL oxidation resulting in reducing both HDL & LDL cholesterol levels.
  • Gugulipid causes modest reduction of LDL & slight increase of HDL.
  • Avasimibe is a new anti-dyslipidemic drug that acts by inhibiting ACAT-1 (acyl-coenzyme A: cholesterol acyltransferase-1) enzyme.
  • Torcetrapib & anacetrapib is an anti-dyslipidemic drug, which increases HDL cholesterol, by inhibiting enzyme CETP (cholesterol ester triglyceride transport protein).
  • Anti-dyslipidemic drug, Lomitapide acts by inhibiting MTP (microsomal triglyceride transfer protein).
Don’t Forget to Solve all the previous Year Question asked on ANTI-DYSLIPIDEMIC DRUGS

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