HMG-CoA Reductase Inhibitors are commonly called?

Statins

Which drugs are the most effective for lowering LDL and total cholesterol while raising HDL cholesterol and Triglycerides? 

Statins

When should statins be taken and why?

Statins should be given in the evening because cholesterol synthesis normally increases in the evening

Risk factors for CHD

• ↑ LDL
• ↑ TG
• ↓ HDL
• ↓ Activity
• ↑ Age
• Race (A.A)
• diabetes (uncontrolled)
• smoking
• excess alcohol consumption
• obesity
• family HX
• chronic untreated HTN

Total Cholesterol goal

< 200

Where is endogenous cholesterol produced?

Liver

Name enzyme catalyzes the synthesizes of hepatic cholesterol.

HMG-CoA reductase

or hydroxymethylglutaryl coenzyme

How do statins work?

Statins inhibit the HMG-CoA enzyme in the liver to prevent the production of cholesterol.

What is the primary dietary concern where cholesterol production is concerned? 

Saturated fats- because the liver uses saturated fats to make cholesterol. When lowering cholesterol, it is paramount to reduce intake of saturated fats.

What is the function of lipoproteins?

Lipoproteins solubilize lipids-cholesterol and triglycerides in the blood, as well as, transport them throughout the bloodstream.

Name the two major classes of lipoproteins that are important in coronary artherosclerosis?

1. low-density-lipoproteins (LDLs)
2. high-density lipoprotein (HDLs)

What is the goal level for LDLs?

<130

What is the primary role of LDLs in the delivery of cholesterol?

LDLs are responsible for the delivery of cholesterol to nonhepatic tissues.

The primary goal of cholesterol reducing drugs?

Reducing elevated LDL levels

What is the function of HDL?

HDLs carry cholesterol from peripheral tissues back to the liver, thus promoting cholesterol removal, the prevention of atheroschlerosis and protects against CHD.

How is atheroschlerosis formed? How are LDLs involved in 

Deposition of LDLs initiate and fuel development of atherogenosis 

• transport of LDLs to from the arterial lumen in endothelial cells 
• then into the space that underlies the arterial epithelium
• once in the subendothelial space, components of LDLs undergo oxidation
• Oxidized LDLs attract monocytes from the circulation into the subendothelial space, these monocytes are converted to macrophages
• Oxidized LDLs are cytotoxic, and hence can directly damage the vascular endothelium
• Oxidized LDLs are consumed by the macrophages and are referred to as FOAM CELLS. These large engorged macrophages lose their mobility, thereby keeping macrophages at the site of atherogenesis. Accumulation of foam cells beneath the arterial epithelium produces a fatty streak, which makes the surface of the wall lumpy
• Continued accumulation of the foam cells can eventually cause rupture of the endothelium, thereby exposing the underlying tissue to the blood
• Exposure to the blood results in platelet adhesion and formation of microthrombi.
• As this process continues, muscle cells migrate to the site, synthesis of collagen increases, and their is continued rupturing and healing of endothelium
• The end result is a mature atheroschlerosis lesion, characterized by a large lipid core and a tough fibrous cap. Less likely to cause infarction
• In less mature lesion, the fibrous cap in not strong and as a result of arterial pressure and shear forces from moving blood can cause cap to rupture; if this occurs accumulation of platelets at he site rupture can cause thrombosis and a subsequent infarction

A fasting blood draw should be done every 5 year over the age of 20 for total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides

=/>50

• Lifestyle changes- diet & exercise
• Control intake of saturated and trans fats
• ↑ fruits and vegetables
• ↑ aerobic exercise

Name the biomarker that indicates an ongoing inflammatory process such as increased CV risk

C-reactive protein (CRP)

How does smoking impact blood cholesterol levels?

Smoking raises LDL levels and and lowers HDL levels

Therapeutic Lifestyle Change are?

1. reducing LDL cholesterol
2. establishing and maintaining a healthy weight by: 

• reducing intake of cholesterol, saturated fats and trans fats
• increasing soluble fiber and plant stanols and sterols (cholesterol-reducing margarine)

When Therapeutic Lifestyle Changes (TLCs) have failed to reduce LDL levels and if the patient's risk justify it 

1. HMG-CoA reductase inhibitors (Statins)
2. Niconic Acid (Niacin)
3. Bile Acid Sequestrants (Colesevelam)
4. Fibrin Acid (Fibrates)

A group of metabolic abnormalities associated with an increased risk of CHD and type 2 diabetes. Abnormalities such as

• ↑ blood glucose
• ↑ TG
• ↑ apoliprotein B
• ↓ HDL
• small LDL particles
• a prothrombotic state
• proinflammatory state
• HTN

How is metabolic syndrome diagnosed?

When three or more of the following are present:

• Abdominal obesity- waist circumference 40 in or more for men and 35 inches or more for most women
• High TG levels- 150 mg/dl or higher or undergoing drug therapy for high TGs
• Low HDL cholesterol- below 40 mg/dl for men and 50 mg/dl for women
• Hyperglycemia- fasting BG 110 mg.dl or higher
• High BP 130/85 mm Hg or higher

Which is the most effective drug for lowering LDLs and why?

HMG-CoA reductase inhibitors (Statins) are the most effective drug because they are

• most effective for ↓ LDLs, ↓ total cholesterol, ↓ TGs, and ↑HDLs
• cause fewer adverse effects
• better tolerated
• more likely to improve clinical outcomes ↓ risk of heart failure and sudden death (morbidity and mortality)

What is the primary mechanism by which HMG-CoA reductase (Statins) inhibitors work?

What are Statins therapeutic uses?

• Hypercholesterolemia
• Prevention MI, angina, stroke
• Post MI therapy, if patient was not on Statins pre MI
• Diabetes

Pharmacokinetic of Statins 

• administered orally
• 30-90% absorbed
• most absorbed in the first pass through the liver, where it acts
• excreted in bile
• rosuvastatin(Crestor) reached abnormally high levels in Asians. At therapuetic doses, it is twice those in whites, therefore dosage should be reduced in Asians.

Adverse Effects of Statins

Statins are generally well tolerated and side effects are rare and if occur are usually mild and transient

Mild effects

• headaches
• rash
• GI disruption (dyspepsia, cramps, flatulence, constipation, abdominal pain)

Contraindications for Statins

• pregnancy - risk category X
• not to be combined w/ other lipid lowering drugs (except bile acid sequestrants) as increase in the incidence of and severity of the serious statin-related side effects
• with drugs that inhibit CYP3A4
• grapefruit juice, as little as 8 oz can inhibit effectiveness

Statin dosing considerations

Which LDL Reducing Drug also lowers TGs and increases levels of HDL levels better than any other drug?

Nicotinic Acid (Niacin)

What does nicotinic acid (Niacin) reduce and how does it work?

Nicotinic acid (Niacin) reduces risk of major coronary events and may also reduce total mortality by reducing production of LDLs by reducing production of VLDLs (LDLs are a by-product of VLDLs)

Name adverse effects of nicotinic acid

• intense skin flushing of the face, neck and ears - this reaction diminishes in several weeks and can be attenuated by aspirin
• irritation of GI tract (gastric upset, nausea, vomiting, diarrhea)
• Severe liver damage can occur (most likely with Slo-Niacin
• hyperglycemia
• gouty arthritis

Name the LDL reducer that is used primarily as adjunct to statins

Name the Bile-Acid Sequestrant that is the drug of choice 

Colesevelam (Welchol)

What is the mechanism in Colesevelam?

What is the main response on colesevelam on plasma lipoproteins?

The main response to bile-acid sequestrants is a reduction in LDL cholesterol

Pharmacokinetics of bile-acid sequestrants

• biologically inert
• insoluble in water and cannot be absorbed in GI tract and cannot be attacked by digestive enzymes
• following oral administration, they pass through the intestines and are excreted in feces

• adjunct therapy to diet and exercise for reducing LDL cholesterol in patients with primary hypercholesterolemia 
• often used with a statin

• constipation
• bloating
• indigestion
• nausea

Drug interaction of bile acid sequestrants and other drugs

• can form insoluble complexes with drugs that undergo binding- cannot be absorbed and then are not available for systemic effect. Drugs such as:  thiazide diuretics, digoxin, warfarin, and some antibiotics
• know drugs that interact should be given 1 hour before sequestrant or 4 hours after

Which drug is most effective for lowering TG levels, raising HDLs, but having no effect on LDLs

Fibric Acid Derivatives (Fibrates)

What is the main Fibric Acid Derivative and what is it primarily used for?

Gemfibrozil (Lopid)

used to reduce high levels of TGs in patients who have not responded to weight loss and diet modiication

Adverse effects of gemfibrozil

gemfibrozil is generally well tolerated however, the most common reactions are

• rash
• Gi upset (nausea, abdominal pain, diarrhea)
• increases risk of gallstones
• Myopathy
• Liver injury

Drug interaction with gemfibrozil

• gemfibrozil displaces warfarin from plasma albumin, thereby increasing anticoagulant effects- warfarin may need to be reduces
• in combination with a statin increases risk of statin-induces myopathy- use great caution, if at all

Dosing of gemfibrozil (Lopid)

• available in 600 mg tablets
• adult dosage is 600 mg twice a day
• given 30 minutes before morning and evening meals 

What do lipoproteins consist of?

Lipoproteins consist of a hydrophobic core, a hydrophilic shell, plus at least one apolipoprtein, which serves as a recognition site for receptors on cells