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Anti-Hypercholesterolemic Agents. Biosynthesis and Metabolism of Cholesterol What is arteriosclerosis? - Link between arteriosclerosis and cholesterol Lipoproteins particles - Structure and classification of lipoprotein particles Hyperlipidemias

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Anti-Hypercholesterolemic Agents


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slide1

Anti-Hypercholesterolemic Agents

  • Biosynthesis and Metabolism of Cholesterol
  • What is arteriosclerosis?

- Link between arteriosclerosis and cholesterol

  • Lipoproteins particles

- Structure and classification of lipoprotein particles

  • Hyperlipidemias

- Types and overall strategy to control hyperlipidemias

  • Anti-hyperlipidemic Agents

- Classes

  • Statins
  • Fibrates
  • Bile Acid Sequestrants
  • Nicotinic Acid
  • Ezetimibe
slide2

O

CH3

O

CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA

OH

acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA

CH3

-OOC-CH2-C-CH2-CH2-OH

OH

mevalonate

cholesterol

Biosynthesis of Cholesterol

HMG CoA

reductase

slide4

Arteriosclerosis

Arteriosclerosis is excessive formation and deposition of endogeneous products from blood.

In 1984 a 1% drop in serum cholesterol was found to reduce the risk to coronary heart disease (CHD) by nearly 2%.

slide6

Lipoprotein Particles

Classification of lipoprotein particles

slide8

Hyperlipidemia

Types of hyperlipidemias

N = normal, = increase; = decrease; = slight increase; = slight decrease

slide9

Biosynthesis

Diet

LDL-R

Cellular Cholesterol

Serum Cholesterol

Conversion to

hormones within

cells or storage

as granules

Bile Acids

Re-absorption

Intestine

Lipoprotein

catabolism

Feces

Strategy for Controlling Hyperlipidemia

STATINS

HMG CoA reductase

Ezetimibe

BILE ACID

SEQUESTRANTS

FIBRATES

slide10

R

R

R

R

Anti-hyperlipidemic Drugs - Statins

slide11

Anti-hyperlipidemic Drugs - Statins

Atorvastatin Cerivastatin Fluvastatin

Rosuvastatin Pitavastatin

slide12

HMG CoA substrate

For example,

Mevastatin

Lovastatin

Simvastatin

For example,

Fluvastatin

Atorvastatin

Cerivastatin

Anti-hyperlipidemic Drugs - Statins

Rationale – competitive binding

slide13

Anti-hyperlipidemic Drugs - Statins

Pharmacokinetic properties of statins – case of cerivastatin

Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles.

slide14

Anti-hyperlipidemic Drugs - Statins

Metabolic properties of statins

  • Rapid first pass metabolism significantly reduces bioavailability
  • Metabolism is complex
  • Extensive conversion between the lactone and open-chain forms
  • Glucuronidated forms as well
  • Other than these three, many other lesser metabolites
  • Inhibitors of cytochrome P450 increase bioavailability of statins ….. Greater incidences of myopathy ….. E.g., cyclosporin, gemfibrozil, erythromycin, itraconazole, etc.
  • Rhabdomyolysis …. A rare complication of statin treatment …. Characterized by breakdown of muscles ….. Release of myoglobin into blood, which travels to kidneys and stops working of its tubules …. Also muscle breakdown increase K+, which induces cardiac arrythmias and death
slide15

Anti-hyperlipidemic Drugs - Fibrates

  • Older generation drugs; introduced in 1981
  • Second most useful anti-hyperlipidemic drugs
  • Primarily decrease serum triglycerides
  • Increase lipoprotein catabolism; increase TG usage by the body
  • activate PPAR-a (peroxisome proliferator-activated receptor a)
  • Most used in Type III, IV and V hyperlipidemias
slide16

Anti-hyperlipidemic Drugs - Fibrates

{No longer recommended because of an increase in overall mortality and adverse events}

{rhabdomyolysis … highest PPAR-a affinity  clinical trials stopped in the US}

slide17

Anti-hyperlipidemic Drugs – Bile Acid Sequestrants

  • Anion exchange resins
  • Water insoluble and inert to digestive enzymes
  • Not absorbed through the GI tract
  • Positively charged nitrogens sequester bile acid re-absorption
  • Lower serum LDL levels
  • Most useful in type IIa and IIb hyperlipidemias
slide19

Anti-hyperlipidemic Drugs – Nicotinic Acid

  • Administered in large doses (0.5 to 6 grams daily)
  • Reduces triglycerides and total cholesterol
  • Increases biliary secretion of cholesterol, but not bile acids
  • Useful in Type IIa, IIb, III, IV and V hyperlipidemias
slide20

Anti-hyperlipidemic Drugs – Ezetimibe

  • Approved in October 2002
  • Reduces serum LDL, TC, and TG and increases HDL
  • Prevents the absorption of cholesterol from diet
  • Useful in Type IIa, IIb, III, IV and V hyperlipidemias