Pharmacology of Agents Used in Hyperlipidemia

1
Pharmacology of Agents Used in Hyperlipidemia
Dr. Thomas Abraham PHAR417 Fall 2005
2
Development of Atherosclerosis
Early plaque formation
Clot formation
Advanced Plaque
3
Treatment Options in Heart Disease
Balloon Angioplasty
Stent
Coronary Artery Bypass Graft
4
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.
5
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 

6
Endogenous Lipid Transport System

•      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.

7
Bile Acid binding Resins
Cholestyramine (Questran)

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

Cholestipol HCl (Colestid)

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

• Colesevelam (Welchol)
• Anion-exchange resin in a
• tablet gel formulation

8
Bile Acid binding Resins

• 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.

9
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.

10
Fibric Acid derivatives

•     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.
•  

11
Fibric Acid derivatives

• 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 a
  (PPARa) 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.

12
HMG CoA Reductase inhibitors

•      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).

13
HMG CoA Reductase inhibitors

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

Cholesterol

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

14
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

15
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.

16
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.

17
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.
•  

18
Miscellaneous Agents

• 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.