Cholesterol

Outline

• What is cholesterol?– Synthesis– Functions– Lipoproteins

• Drugs to reduce cholesterol– Statins– Bile-Acid Sequestrants– Niacin (Nicotinic Acid)– Fibric Acid Derivatives– Ezetimibe and the Inhibition of Dietary Cholesterol

What is cholesterol?

• Waxy, fat-like substance• Steroid alcohol (sterol)• Found in all cells of the body• 75% of cholesterol is synthesized – 25% comes from diet

Cholesterol synthesis

• Synthesized primarily in the liver• Occurs in the cytoplasm and ER• The HMG-CoA Reductase reaction is rate-

limiting– Highly regulated– Target of pharmaceutical intervention

• Very complex process involving over 30 enzymes

Functions of Cholesterol

• Cell membranes• Sex hormones• Hormones released by the adrenal glands• Production of bile acids• Vitamin D

Dangers of High Cholesterol Levels

• Atherosclerosis– Increased coronary heart disease risk– Heart attack– Angina– Stroke

Lipoproteins

• Chylomicrons• Very low density lipoproteins (VLDL)• Intermediate-density lipoproteins (IDL)• Low density lipoproteins (LDL)• High density lipoproteins (HDL)

Class % Protein % Cholesterol % Phospholipid % Triglyceride

Chylomicrons <2 8 7 84

VLDL 10 22 18 50

IDL 18 29 22 31

LDL 25 50 21 8

HDL 33 30 29 4

Apolipoproteins• Six major classes– A, B, C, D, E and H

Apolipoprotein Site of Synthesis Function(s)

ApoA-I Liver, intestine Structural in HDL; reverse cholesterol transport

ApoA-V Liver Modulates triglyceride incorporation into hepatic

VLDLApoB-100 Liver Structural protein of VLDL,

IDL, LDLApoB-48 Intestine Structural protein of

chylomicronsApoE Liver, brain, skin, gonads,

spleenStructural in HDL; reverse

cholesterol transport

Chylomicron

Triglyceride, LDL and HDL Metabolism

Atherosclerosis

Risk Factors

• Diet• Medical conditions– Diabetes– Hypertension

• Genetics• Sex• Age• Smoking• Inactivity & obesity

Drugs Therapy of Hyperlipidemia

1. Statins2. Bile-Acid Sequestrants3. Niacin (Nicotinic Acid)4. Fibric Acid Derivatives5. Ezetimibe and the Inhibition of Dietary

Cholesterol

Statins• Competitive inhibitors of HMG-CoA reductase– Decreased cholesterol synthesis– Increased expression of the LDL receptor gene

• Reduce LDL levels• Documented in reducing fatal and nonfatal

CHD events, strokes, and total mortality– Adverse effects were similar in placebo and drug

groups

Statins

Lipitor

Zocor

Crestor

Effects on Triglycerides & Lipoprotein Levels

• Decrease triglycerides in hypertriglyceridemic– 35-45%

• Increase HDL-C– Normal patients: 5-10%– Low patients: 15-20%

• Decrease LDL-C– 20-55%

• Non-lipid lowering effects– Endothelial function (Enhances

production of nitric oxide)– Anti-inflammatory– Reduce venous thromboembolic

events• 43%

• Adverse Effects– Hepatotoxicity

• Elevated hepatic transaminase values

• One case of liver failure per million person-years of use

– Myopathy• One death per million

prescriptions caused by rhabdomyolysis

Bile-Acid Sequestrants

• Highly positively charged– Bind negatively charged bile acids

• Large size keeps them from being absorbed– Secreted in stool

• Hepatic bile-acid synthesis increases– Hepatic cholesterol declines stimulating the production of

LDL receptors and lowers LDL levels– Partially offset by the enhanced cholesterol synthesis

caused by upregulation of HMG-CoA reductase• Combining these with a statin substantially increases their effect

Bile-Acid Sequestrants

Effects on Lipoprotein Levels & Adverse Effects

• Dose dependent decrease in LDL-C– Normal dose: 12-18%

reduction– Maximal dose (2x

normal): Up to 25% reduction• GI side effects

• HDL-C: Increase 4-5%• Combined with statins or

niacin: 40-60% reduction

• Adverse Effects– Generally safe– Hyperchloremic acidosis– Are not used in patients

with hypertriglyceridemia • May increase

triglycerides

Niacin (Nicotinic Acid)• Inhibits the lipolysis by hormone-sensitive lipase– Reduces transport of free fatty acids to the liver– Decreases hepatic triglyceride synthesis

• May inhibit diacylglycerol acyltransferase-2– Rate-limiting in triglyceride synthesis– Reducing triglyceride synthesis reduces hepatic

VLDL production• Raises HDL levels by decreasing the fractional

clearance of apoA-I in HDL

Effects on Lipoprotein Levels & Adverse Effects

• Increases HDL: 30-40%• Lowers triglycerides by

35-45%• Reduces LDL: 20-30%• Half-life: 60 minutes– Requires 2-3 doses/day

• Therapeutic Use– Hypertriglyceridemia

and low HDL levels

• Adverse Effects– Flushing– Dyspepsia– Hepatotoxicity– Hyperglycemia

Fibric Acid Derivatives: PPAR Activators

• Mechanism of action still remains unclear– Thought to interact with peroxisome proliferator-

activated receptors (PPARs)• Bind to PPARα

– Increase LPL synthesis – Reduce expression of apoC-III– Stimulate apoA-I and apoA-II

Fibric Acid Derivatives: PPAR Activators

Effects on Lipoprotein Levels & Adverse Effects

• Decreases triglycerides• Increases HDL-C• LDL-C can decrease,

increase or be unchanged

• Should not be used in patients with renal failure or hepatic dysfunction

• Therapeutic Use– Type III

hyperlipoproteinemia– Hypertriglyceridemia– Chylomicronemia

syndrome

• Adverse Effects– Rash– Hair loss– Fatigue

Ezetimibe and the Inhibition of Dietary Cholesterol Uptake

• Inhibits cholesterol absorption by enterocytes in the small intestine– 54% in humans

• Inhibits the transport protein NPC1L1

Combination Therapy & Adverse Effects

• Reduces LDL by 15-20% alone

• Reduces LDL by 60% in combination with simvastatin

• Should not be given with bile-acid sequestrants

• Adverse Effects– Rare allergic reactions

Videos

• http://www.youtube.com/watch?v=9Tbo-0GfDcg

• Cholesterol

• Atherosclerosis

Mechanism of Action Statins

• Inhibit an early and rate limiting step in cholesterol biosynthesis

• Inhibiting hepatic cholesterol synthesis results in increased expression of the LDL receptor gene– Decreased free cholesterol causes membrane-bound

SREBPs to be cleaved and translocated to the nucleus to bind the sterol responsive element of the LDL receptor gene. This enhancnes transcription and increases the synthesis of LDL receptors

• It also reduces the degradation of LDL receptors

Adverse Effects

• Hepatotoxicity– Elevated hepatic transaminase values– One case of liver failure per million person-years

of use• Myopathy– One death per million prescriptions caused by

rhabdomyolysis

Bile-Acid Sequestrants

• One of the oldest hypolipidemic drugs• Safest– Not absorbed from the intestine

• Used as a second agent if statins are not sufficient

• Maximal dose can reduce LDL-C by up to 25%– Cause bloating and constipation so compliance is

low

Mechanism of Action

• Inhibits the lipolysis by hormone-sensitive lipase– Reduces transport of free fatty acids to the liver– Decreases hepatic triglyceride synthesis

• May inhibit diacylglycerol acyltransferase-2– Rate-limiting in triglyceride synthesis– Reducing triglyceride synthesis reduces hepatic

VLDL production• Raises HDL-C levels by decreasing the fractional

clearance of apoA-I in HDL

Mechanism of Action

• Still remain unclear• Thought to interact with peroxisome

proliferator-activated receptors (PPARs)– Bind to PPARα and stimulate fatty acid oxidation,

increase LPL synthesis and reduce expression of apoC-III to reduce triglycerides

– Bind to PPARα to stimulate apoA-I and apoA-II expression to increase HDL-C levels

Mechanism of Action

• Inhibits the transport protein NPC1L1• Inhibits absorption by 54% in humans