1. Drugs used in the treatment of hyperlipidemiasBy
S.Bohlooli, PhD

2. Introduction Introduction Cholesterol
Used to prevent or slow progression of atherosclerosis to reduce the risk of coronary artery disease and prolong life
Cholesterol
Advantages
Serves as a component of cell membranes and intracellular organelle membranes
Is involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroids
Needed for the synthesis of bile salts which are needed for digestion and absorption of fats.

3. Introduction Cholesterol Advantages Origin
Is deposited in the stratum corneum of the skin to help ↓ evaporation of water and create impermeability to water soluble compounds (helps keep moisture in skin)
Origin
Is synthesized in the liver. Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase.

4. Introduction Cholesterol Origin
Endogenous synthesis of cholesterol increases at night
An increase in dietary cholesterol produces only a small ↑ in blood levels of cholesterol because ingestion inhibits endogenous synthesis
Dietary saturated fats ↑ blood cholesterol levels because they are converted to cholesterol in the body.

5. Introduction Lipoproteins
Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood.
Apolipoproteins
Embedded in the lipoprotein shell
Three functions
1. Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein.
2. Activate enzymes that will metabolize the lipoprotein
3. ↑ structural stability of the lipoprotein

6. Introduction Lipoproteins Apolipoproteins
All lipoproteins that deliver lipids to peripheral tissues (nonhepatic tissues) contain apolipoprotein B-100 (Ex: VLDL, LDL)
All lipoproteins that transport lipids from peripheral tissues back to the liver contain apolipoprotein A-I (Ex: HDL)

7. Introduction Lipoproteins Lipoproteins of importance
VLDL (very low density lipoprotein)
Contain triglycerides (TGs) and some cholesterol
Account for nearly all TGs in the blood
Contain B-100
Deliver triglycerides from the liver to adipose tissues and muscles.

8. Introduction Lipoproteins Lipoproteins of importance
VLDL (very low density lipoprotein)
Remnants of hydrolysis are IDL (intermediate density lipoproteins), which can be transported to liver or converted to LDL

9. Introduction Lipoproteins Lipoproteins of importance
LDL (low density lipoprotein)
“Bad cholesterol”
Contain cholesterol
Account for 60-70% of cholesterol in the blood
Contains B-100
Delivers cholesterol to peripheral tissues

10. Introduction Lipoproteins Lipoproteins of importance
LDL (low density lipoprotein)
Formed from IDL, the remnants of VLDL
Makes the greatest contribution to coronary atherosclerosis
Oxidized LDL contributes to atherosclerotic plaque
Removed from plasma via endocytosis by liver converting it to bile acids excreted in GI

11. Introduction Lipoproteins Lipoproteins of importance
HDL (high density lipoprotein)
“Good cholesterol”
Contain cholesterol
Account for 20-30% of cholesterol in the blood
Some contain Apo A-I and Apo A-II
Apo A-I is cardioprotective
Transports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removal
Antiatherogenic

12. Characteristics of Plasma Lipoproteins
LIPOPROTEIN CLASS
DENSITY OF FLOTATION, g/ml
SIGNIFICANT APOPROTEINS
SITE OF SYNTHESIS
MECHANISM(S) OF CATABOLISM
Chylomicrons and remnants
<<1.006
B-48, E, A-I, A-IV, C-I, C-II, C-III
Intestine
Triglyceride hydrolysis by LPL
ApoE-mediated remnant uptake by liver
VLDL
<1.006
B-100, E, C-I, C-II, C-III
Liver
IDL
B-100, E, C-II, C-III
Product of VLDL catabolism
50% converted to LDL mediated by HL, 50% apoE-mediated uptake by liver
50% apoE-mediated uptake by liver
LDL
B-100
ApoB-100-mediated uptake by LDL receptor (~75% in liver)
HDL
A-I, A-II, E, C-I, C-II, C-III
Intestine, liver, plasma
Complex:
Transfer of cholesteryl ester to VLDL and LDL
Uptake of HDL cholesterol by hepatocytes
Abbreviations: apo, apolipoprotein; CHOL, cholesterol; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; Lp(a), lipoprotein(a); LDL, low-density lipoproteins; NS, not significant (triglyceride is less than 5% of LDL and HDL); TG, triglyceride; VLDL, very-low-density lipoproteins; HL, hepatic lipase; LPL, lipoprotein lipase.

13. The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver
Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apoC lipoproteins and apolipoprotein E (apoE) from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apoE are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apoE. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum.
(Modified and redrawn, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological Disease. Butterworth-Heinemann, 1993.)

14. Classification of Plasma Lipid Levels
Total cholesterol
<200 mg/dl
Desirable
mg/dl
Borderline high
≥240 mg/dl
High
HDL-C
<40 mg/dl
Low (consider <50 mg/dl as low for women)
>60 mg/dl
LDL-C
<70 mg/dl
Optimal for very high risk (minimal goal for CHD equivalent patients)
<100 mg/dl
Optimal
mg/dl
Near optimal
mg/dl
mg/dl
≥190 mg/dl
Very high
Triglycerides
<150 mg/dl
Normal
mg/dl
mg/dl
≥500 mg/dl

15. Secondary Causes of Dyslipidemia
DISORDER
MAJOR LIPID EFFECT
Diabetes mellitus
Triglycerides > cholesterol; low HDL-C
Nephrotic syndrome
Triglycerides usually > cholesterol
Alcohol use
Triglycerides > cholesterol
Contraceptive use
Estrogen use
Glucocorticoid excess
Hypothyroidism
Cholesterol > triglycerides
Obstructive liver disease

16. Treatment of hyperlipidemia
Treatment (tx)
Non-Pharmacological Therapy – 1st line tx
1. Diet modification
Decrease intake of total fat and especially saturated fat
Increase fiber intake
Increase Omega-3-fatty acids (found in fish)
↑ fruits and vegetables (antioxidants)
↓ simple sugars (sucrose)

17. Sites of action of drugs used for treatment of dislypidemia
Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.

18. Treatment of hyperlipidemia
Non-Pharmacological Therapy – 1st line tx
2. Exercise (will ↑ HDL levels)
3. Reduce risk factors if possible
Drug Therapy
Niacin (vitamin B3)
Decreases VLDL and LDL and significantly ↑ HDL
MOA
1. Inhibits VLDL secretion into the blood thereby preventing production of LDL
2. Increases clearance of VLDL via lipoprotein lipase pathway

19. Niacin: chmeistry

20. Antilipemic agents Niacin MOA
3. Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system
4. Reduces circulating fibrinogen (contributes to clot formation) and ↑ tissue plasminogen activator (clot dissolver)
5. HDL catabolic rate is decreased
6. Reduces the plasma level of Lp(a) lipoprotein, which can increase risk of CAD

21. Antilipemic agents Niacin Indications
Drug of choice for ↓ levels of TG (VLDL) in pts at risk for pancreatitis
Mixed elevation of LDL and VLDL (alone or in combination with reductase inh.)
Elevation of TG (VLDL) and low levels of HDL (Niaspan® - approved for elevating HDL levels)
Start with low dose and gradually increase
Given 1-3g/day in divided doses or once daily with extended release. Give at night with food.

22. Antilipemic agents Niacin - Adverse effects Flushing
Harmless cutaneous vasodilation
Uncomfortable sensation of warmth
Occurs after drug is started or ↑ dose
Lasts for the first several weeks
Can give 325mg aspirin 30 minutes before each dose (prevents prostaglandin synthesis). Can also take ibuprofen QD in place of ASA

23. Antilipemic agents Niacin - Adverse effects Pruritis, rashes, dry skin
acanthosis nigricans (eruption of velvet warty benign growths and hyperpigmentation)
Associated with insulin resistance
Will have to d/c drug if occurs
Nausea and abdominal discomfort
Reduce dosage and may need to use inhibitors of gastric acid secretion or antacids (not containing aluminum)
Avoid in pts with severe peptic disease

24. Antilipemic agents Niacin - Adverse effects Hepatotoxicity
Severe is rare, and reversible
Occurs mostly with older sustained release forms
Monitor liver fx regularly
Liver injury is less likely with Niaspan® (given once daily) the new extended release formulation
Carbohydrate tolerance may be moderately impaired (hyperglycemia)
Reversible
Can still be given to diabetics receiving insulin

25. Antilipemic agents Niacin - Adverse effects Hyperuricemia Hypotension
Occurs in about 1/5 of pts
Occasionally precipitates gout
Hypotension
Especially seen in pts on antihypertensive meds
Can ↑ homocysteine levels which ↑ risk of CAD (give folic acid to ↓ homocysteine levels)

26. Fibrates: chemistry

27. Hepatic and peripheral effects of fibrates
Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

28. Antilipemic agents
Fibrates (gemfibrozil, fenofibrate, clofibrate, bezafibrate)
Little or no effect on LDL
↓ VLDL (TG)
moderate ↑ of HDL
MOA
Ligand for the nuclear transcription regulator, peroxisome proliferator-activated receptor-α (PPAR- α)
MOA mostly unknown

29. Antilipemic agents Fibrates MOA
↑ activity of lipoprotein lipase for lipolysis of triglyceride (↑ clearance)
↓ lipolysis in adipose tissue, ↓ FFA release
↓ secretion of VLDL by liver
↓ uptake of FFA by liver
↑ HDL levels moderately

30. Antilipemic agents Fibrates Indication: Hypertriglyceridemia
Gemfibrozil – 600mg QD-BID (half life 1.5hrs)
Fenofibrate – mg tablets QD (half life 20hrs)
Taken with food - ↑ absorption
Max reduction of VLDL is achieved within 3-4 weeks of treatment
Adverse Effects
Rashes
GI disturbances (nausea, abdominal pain, diarrhea)

31. Antilipemic agents Fibrates - Adverse Effects
Gallstones (upper abdominal discomfort, intolerance of fried food, bloating)
Gemfibrozil ↑ biliary cholesterol saturation
Use with caution in pts with biliary tract ds, women, obese pts, and Native Americans
Myopathy (muscle injury)
Tenderness, weakness, or unusual muscle pain
Will increase risk of statin-induced myopathy when used together (rhabdomyolysis has occurred rarely)

32. Antilipemic agents Fibrates - Adverse Effects Hepatoxicity Arrythmias
Hypokalemia
Displaces warfarin from plasma albumin since drug is highly protein bound. Need to ↓ warfarin dose

33. Bile Acid-Binding Resins :chemistry

34. Antilipemic agents
Bile Acid-Binding Resins (colestipol and cholestyramine)
Will ↓ LDL, may ↑ VLDL (would require niacin combo if ↑ TG prior to tx)
MOA
Bile acids, the metabolites of cholesterol, are normally reabsorbed in the jejunum and ileum. When resins are given, they bind to bile acids in the intestinal lumen, prevent their reabsorption and increase their excretion.

35. Antilipemic agents Bile Acid-Binding Resins MOA Indication
↑ excretion creates a demand for ↑ synthesis of bile acid. Liver cells must have an ↑ cholesterol supply (provided by LDL) to synthesize bile acid. Liver cells will ↑ their LDL receptors, ↑ing uptake of LDL from plasma.
Indication
Used alone to ↓ LDL (by 15-20%)
Normally used as adjuncts to the statins to ↓ LDL (by 50%)

36. Antilipemic agents Bile Acid-Binding Resins Indication Adverse Effects
Can be used to relieve pruitis in pts who have cholestasis
Can be used for severe digitalis toxicity
Dispensed in powder form (must be mixed with fluid). Cholestyramine 4-12g BID. Colestipol 5-30g/day in divided doses and also in 1g tablets (2-16g/day) taken w/ fluid
Adverse Effects
Max reductions of LDL occur in one month
Must be taken with meals

37. Antilipemic agents Bile Acid-Binding Resins Adverse Effects
Constipation
Bloating, indigestion, nausea
Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K)
Drug Interactions
Resins bind digoxin, warfarin, thiazide diuretics, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, ascorbic acid (these agents should be given 1 hour before the resin or 4 hours after)

38. chemistry

39. Antilipemic agents
HMG COA Reductase Inhibitors (“statins”) (lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, cerivastatin)
Most Effective for ↓ LDL
Will ↑ HDL and ↓ VLDL
Fewest adverse effects and tolerated best

40. Inhibition of HMG-CoA reductase
Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas).

41. Antilipemic agents (“statins”) MOA Inhibits hepatic HMG CoA reductase
Inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptors
Hepatocytes are able to remove more LDLs from the blood
Decrease production of apolipoprotein B-100, thereby ↓ production of VLDL
↓ plaque cholesterol content

42. Antilipemic agents (“statins”) MOA ↓ inflammation at the plaque site
Improve abnormal endothelial function
Enhance the ability of blood vessels to dilate
↓ risk of thrombosis (inhibits platelet aggregation and blocks thrombin synthesis)
Statins have high first pass extraction by liver (only a small fraction of each dose reaches the general circulation)
Prodrugs – lovastatin and simvastatin

43. Antilipemic agents (“statins”) – Indications Used alone to ↓ LDL
Used with bile acid – binding resins to ↓ LDL
Used with niacin to ↓ LDL, ↓ VLDL, and ↑ HDL
Enhanced if taken with food (except for pravastatin – taken without food)
Give in the evening
Half life is 1-3 hours (except atorvastatin – 14 hours)

44. Antilipemic agents (“statins”) – Indications
Atorvastatin is most efficacious agent for use in severe hypercholesterolemia
High potency (>40-50% LDL lowering) – atorvastatin, simvastatin, cerivastatin
Low potency (20-40% LDL lowering) – lovastatin, fluvastatin, pravastatin
↓ LDL within 2 weeks; max reduction in 4-6 weeks

45. Antilipemic agents (“statins”) – Indications New Drug: Altocor®
Extended release lovastatin
Slightly more effective than regular lovastatin
Take without food

46. Antilipemic agents (“statins”) – Adverse Effects
Since LDL cholesterol levels will return to pretreatment values if drugs are withdrawn, treatment must continue lifelong
Statins are pregnancy category X
rash, GI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain)

47. Antilipemic agents (“statins”) – Adverse Effects Hepatotoxicity
Myopathy (0.5% of pts)
Risk highest with lovastatin and especially in combination with Fibrates
Cyp3A4 drug interactions with all statins excepts for pravastatin and fluvastatin

48. Ezetimibe:chemistry

49. Antilipemic agents Ezetimibe
ezetimibe reduced cholesterol absorption by 54%
Cholesterol lowering agent
Will challenge the statins
Approved for monotherapy or in combo with statins
reduction of 60% with simvastatin for LDL-C

50. Inhibitors of Cholesteryl Ester Transfer Protein
a plasma glycoprotein synthesized by the liver
mediates the transfer of cholesteryl esters
In animal models
inhibition of CETP result in:
higher HDL levels
decreased LDL levels
resistance to developing atherosclerosis
JTT-705 and torcetrapib