Download Chapter 16 Cholinesterase Inhibitors

Prophylaxis of Coronary Heart Disease:
Drugs That Help Normalize Cholesterol
and Triglyceride Levels
Prophylaxis of Coronary Heart
Disease (CHD)





Cholesterol
Plasma lipoproteins
Role of LDL cholesterol in atherosclerosis
Detection, evaluation, and treatment of high
cholesterol: recommendations from ATP III
Drugs and other products used to improve
plasma lipid levels
ATP = Adult Treatment Panel; LDL = low-density lipoprotein.
Cholesterol






Component of all cell membranes and
membranes of intracellular organelles
Required for synthesis of certain hormones
and bile salts
Deposited in stratum corneum of the skin
Comes from dietary sources
Manufactured by cells, primarily in the liver
Increased dietary cholesterol produces only a
small increase in cholesterol in the blood
(inhibits endogenous cholesterol production)
Plasma Lipoproteins

Structure and function of lipoproteins



Function
Basic structure
Apolipoproteins
• Recognition sites for cell-surface receptors
• Activate enzymes that metabolize lipoproteins
• Increase the structural stability of lipoproteins
Plasma Lipoproteins

Classes of lipoproteins


Six major classes of plasma lipoproteins
Three relevant to coronary atherosclerosis
• Very-low-density lipoproteins (VLDLs)

Triglycerides


Cholesterol primary core lipid
Greatest contributor to coronary heart disease (CHD)

Cholesterol
• Low-density lipoproteins (LDLs)
• High-density lipoproteins (HDLs)
Role of LDL Cholesterol in
Atherosclerosis


LDLs initiate and fuel development of
atherosclerosis
Process begins with transport of LDLs from
the arterial lumen into endothelial cells, then
into the space underlying the arterial
epithelium
Atherogenesis



More than just deposit of lipids
Now considered primarily a chronic
inflammatory process
Infiltration of macrophages, T lymphocytes,
and other inflammatory mediators
Detection, Evaluation, and
Treatment of High Cholesterol

Cholesterol screening


Every 5 years for adults over the age of 20 years
Total cholesterol
• HDL cholesterol

Less than 40 mg/dL: low to undesirable

Less than 100 mg/dL: desirable
• LDL cholesterol

Triglycerides (TGs)
CHD Risk Assessment

Factors in risk assessment




Identifying CHD risk factors
Calculating 10-year CHD risk
Identifying CHD risk equivalents
• Diabetes
• Atherosclerotic disease other than CHD
• Framingham risk score greater than 20%
Identifying an individual’s CHD risk category
• Each type of dyslipidemia a patient has contributes
independently to CHD risk
Treatment of High-LDL Cholesterol

Therapeutic lifestyle changes (TLCs)



Smoking cessation
The TLC diet
Exercise
Drug Therapy: Not
First-Line Therapy





Drugs should be used only if TLCs fail
HMG-CoA reductase inhibitors
Bile-acid sequestrants
Nicotinic acid (niacin)
Fibrates (reduce levels of TGs, not LDLs)
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.
Secondary Treatment Targets

Metabolic syndrome









High blood glucose
High triglycerides
High apolipoprotein B
Low high-density lipoprotein (HDL)
Small LDL particles
Prothrombotic state
Proinflammatory state
Hypertension
High triglycerides

Levels above 150 mg/dL
Treatment Goals for
Metabolic Syndrome



Reduce the risk for atherosclerotic disease
Reduce the risk for type 2 diabetes
Increase physical activity
Drugs and Other Products to
Alter Plasma Lipid Levels


High LDL: contributes most to cardiovascular
disease
Also consider




High total cholesterol
Low HDL cholesterol
High triglycerides
Drugs can improve lipid profiles, but not all
improve clinical outcomes
HMG-CoA Reductase Inhibitors
(Statins)





Most effective drugs for lowering LDL
Reduction of LDL cholesterol
Elevation of HDL cholesterol
Reduction of triglyceride levels
Nonlipid beneficial cardiovascular actions



Promote plaque stability
Reduce the risk for cardiovascular (CV) events
Increased bone formation
HMG-CoA Reductase Inhibitors
(Statins)



Mechanism of cholesterol reduction
Clinical trials
Therapeutic uses





Hypercholesterolemia
Primary and secondary prevention of CV events
Post-MI therapy
Diabetes
Potential uses
HMG-CoA Reductase Inhibitors
(Statins)

Adverse effects


Common
• Headache
• Rash
• GI disturbances
Rare
• Myopathy/rhabdomyolysis
• Hepatotoxicity
HMG-CoA Reductase Inhibitor
(Statins)

Drug interactions






Most other lipid-lowering drugs (except bile acid
sequestrants)
Drugs that inhibit CYP3A4
Use in pregnancy
Dosing should be once daily in the evening
Endogenous cholesterol synthesis increases
during the night
Statins have greatest impact when given in
the evening
Nicotinic Acid (Niacin)



Reduces LDL and TG levels
Increases HDL levels more effectively than
any other drug
Effect on plasma lipoproteins


Lowering TG levels
Raising HDL cholesterol
Nicotinic Acid (Niacin)

Adverse effects

Skin (flushing, itching)
• Intense flushing initially; can pretreat with aspirin
• Decreased with SR version of niacin
 Gastrointestinal
 Hepatotoxicity
 Hyperglycemia
 Gouty arthritis
 Can raise blood levels of uric acid
Bile-Acid Sequestrants





Previously were first-line drugs
Now primarily used as adjuncts to statins
Cholestyramine
Colestipol
Colesevelam


Newest and better-tolerated drug
Does not decrease uptake of fat-soluble vitamins
(as other bile sequestrants do)
 Does not significantly reduce the absorption of
statins, warfarin, digoxin, and most other drugs
studied
Bile-Acid Sequestrants

Colesevelam (cont’d)




Reduction in LDL cholesterol
Increased VLDL levels in some patients
Mechanism of action
• Increases LDL receptors on hepatocytes
• Prevents reabsorption of bile acids
Therapeutic use
• Reduces LDL cholesterol (in conjunction with modified
diet and exercise)

Adverse effects
• Constipation
Ezetimibe

Mechanism of action and impact on plasma
lipids


Inhibits cholesterol absorption
Therapeutic use


Reduces total cholesterol, LDL cholesterol, and
apolipoprotein B
Approved for monotherapy and combined use with
statins
Ezetimibe

Adverse effects






Myopathy
Rhabdomyolysis
Hepatitis
Pancreatitis
Thrombocytopenia
Drug interactions




Statins
Fibrates
Bile-acid sequestrants
Cyclosporine
Fibric Acid Derivatives (Fibrates)






Most effective drugs available for lowering TG levels
Can raise HDL cholesterol
Little or no effect on LDL cholesterol
Can increase the risk for bleeding in patients on
warfarin
Can increase the risk for rhabdomyolysis in patients
taking statins
Three drugs in the United States



Gemfibrozil (Lopid)
Fenofibrate (Tricor, others)
Fenofibric acid (TriLipix)
Gemfibrozil

Effects on plasma lipoproteins




Mechanism


Decreases plasma TG content
Lowers VLDL levels
Can raise HDL cholesterol
Appears to interact with a specific receptor
subtype (PPAR alpha)
Drug interactions


Displaces warfarin from plasma albumin
Measure INR frequently
Gemfibrozil

Therapeutic uses





Reduces high levels of plasma triglycerides (VLDLs)
Treatment reserved for patients who have not responded to
diet modification
Less effective than statins in reducing LDL
Can raise HDL (not approved for this use)
Adverse effects





Rashes
Gastrointestinal disturbances
Gallstones
Myopathy
Liver injury (hepatotoxic)
Other Products Used to Alter
Plasma Lipid Levels



Fenofibrate
Fenofibric acid
Drug combinations




Niacin/lovastatin
Simvastatin/niacin, simvastatin/ezetimibe
Pravastatin/aspirin
Atorvastatin/amlodipine
Other Products Used to Alter
Plasma Lipid Levels





Lovaza
Fish oil
Plant stanol and sterol esters
Estrogen
Cholestin