Chapter 27: Drugs that help normalize cholesterol and Triglyceride levels

Cholesterol functions in the body

ØA component of all cell membranes and membranes of intracellular organelles, maintains stability

ØRequired precursor to cortisol, aldosterone, sex hormone, and bile salts production.

ØEssential for myelin formation and nerve signal transmission, provides energy, and transports fat.

Cholesterol 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 classes

ØSix major classes of plasma lipoproteins

ØThree relevant to coronary atherosclerosis

•Very-low-density lipoproteins (VLDLs)

†Transports endogenous triglycerides from liver to tissues

•Low-density lipoproteins (LDLs)

†Carries cholesterol in the blood and delivers to cells for use

†Greatest contributor to coronary heart disease (CHD)

•High-density lipoproteins (HDLs)

†Helps remove cholesterol from bloodstream by transporting ot liver to be excreted or recycled.

Protective against heart disease

role of LDL cholesterol in atherosclerosis

˜LDL particles contribute to the development of atherosclerosis by delivering excess cholesterol to the endothelial cells of the artery walls. Once in the subendothelial space, they are oxidized and trigger an immune response leading to the formation of foam cells.

˜This process leads to inflammation and plaque formation, arterial narrowing, and stiffening.

˜Over time, it can cause reduced blood flow and increase the risk of heart attacks and strokes.

atherogenesis

˜More than just deposit of lipids

˜Now considered primarily a chronic inflammatory process

˜Infiltration of macrophages, T lymphocytes, and other noxious chemicals

Treatment of High-LDL cholesterol

˜Therapeutic lifestyle changes (TLCs)

ØThe TLC diet

•reducing saturated fats, increasing fiber, and including healthy fats

ØExercise

ØSmoking cessation

ØWeight control

Drug therapy

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)

Secondary treatment targets

˜Metabolic syndrome (cluster of symptoms)

ØHigh blood glucose

ØHigh triglycerides

ØHigh apolipoprotein B

ØLow HDL cholesterol

ØSmall LDL particles

ØProthrombotic state

ØProinflammatory state

ØHypertension

˜High triglycerides

Levels above 150 mg/dL

What is the correlation betweenn hypercholesterolemia and Type 2 diabetes?

˜Insulin resistance in diabetes leads to increased levels of LDL cholesterol and triglycerides, while lowering HDL cholesterol.

˜This dyslipidemia, along with chronic inflammation, accelerates the development of atherosclerosis and increases cardiovascular risk.

˜Managing blood sugar, adopting a healthy diet, and using cholesterol-lowering medications are key to reducing the cardiovascular risks associated with both conditions.

Insulin resistance

Øthe body's decreased response to insulin, often a precursor to metabolic syndrome or type 2 diabetes.

Metabolic syndrome

Øa cluster of risk factors (including insulin resistance) that increases the likelihood of cardiovascular diseases and type 2 diabetes.

Diabetes (Type 2)

Øa condition where insulin resistance and/or insufficient insulin production leads to chronically high blood sugar levels.

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: Most significant contributor to cardiovascular disease

˜Also consider:

ØHigh total cholesterol

ØLow HDL cholesterol

ØHigh triglycerides

˜Drugs can improve lipid profiles, but not all improve clinical outcomes

HMG-CoA Reductase Inhibitors (Statins) NUMBER 1

˜Most effective drugs for lowering LDL

˜Beneficial actions

ØReduction of LDL cholesterol

ØElevation of HDL cholesterol

ØReduction of triglyceride levels

ØNonlipid beneficial cardiovascular actions

•Promote plaque stability

Suppress production of thrombin

HMG-CoA Reductase Inhibitors (Statins) Therapeutic uses

˜Mechanism of cholesterol reduction

˜Therapeutic uses

ØHypercholesterolemia

ØPrimary and secondary prevention of CV events

ØPost-MI therapy

ØDiabetes

ØPotential uses

HMG-CoA Reductase Inhibitors (Statins) adverse effects

ØCommon

•Headache

•Rash

•Memory loss

•GI disturbances

•Muscle pain

ØRare

•Myopathy/rhabdomyolysis

•Hepatotoxicity

New-onset diabetes

HMG-CoA Reductase Inhibitors (Statins) drug interactions

ØMost other lipid-lowering drugs (except bile-acid sequestrants)

ØDrugs that inhibit CYP3A4

•Grapefruit juice, St. John's Wort

ØUse in pregnancy

HMG-CoA Reductase Inhibitors (Statins) dosing

˜Once daily in the evening

Ø**Endogenous cholesterol synthesis increases during the night

ØStatins have greatest impact when given in the evening

Bile-acid sequestrants

˜Previously were first-line drugs

˜Now primarily used as adjuncts to statins

˜Cholestyramine

˜Colestipol

˜Colesevelam

ØNewest and better-tolerated drug

ØDoes not decrease uptake of fat-soluble vitamins (as other bile sequestrants do)

ØDoes not significantly reduce the absorption of statins, warfarin, digoxin, and most other drugs studied

Bile-acid sequestrants MOA

ØReduces LDL cholesterol and increases VLDL levels in some patients

ØMechanism of action

•*Bile acids are made from cholesterol in the liver and are essential for digesting fats.

•Bile acid sequestrants bind to bile acids in the intestines, preventing their reabsorption. As a result, the liver must use more cholesterol to produce new bile acids.

•This reduces LDL cholesterol levels in the blood.

•Reduces LDL cholesterol (in conjunction with modified diet and exercise)

Bile-acid sequestrants averse effect

constipation

Ezetimibe (Zitia) MOA

ØInhibits cholesterol absorption in the intestines.

Ezetimibe therapeutic use

ØReduces total cholesterol, LDL cholesterol, and apolipoprotein B in patients with hyperlipidemia or hypercholesterolemia.

ØApproved for monotherapy and combined use with statins*

Ezetimibe side effects

Ødiarrhea, abdominal pain, nausea, fatigue, and H/A

Ezetimibe adverse effects

ØMyopathy

ØRhabdomyolysis

ØHepatitis

ØPancreatitis

Thrombocytopenia

Ezetimibe drug interactions

ØStatins ??????

ØFibrates (increase lipolysis)

ØBile-acid sequestrants

Cyclosporine

Fibric acid derivatives (Fibrates) MOA

ØEnhances fat metabolism and lowers triglyceride levels.

ØMost effective drugs available for lowering TG levels

ØCan raise HDL cholesterol, Little or no effect on LDL cholesterol

Fibric acid derivatives (Fibrates)

˜Can increase the risk for bleeding in patients taking warfarin

Can increase the risk for rhabdomyolysis in patients taking statins

Three drugs in the US (fibrates)

ØGemfibrozil [Lopid]

ØFenofibrate [Tricor, others]

ØFenofibric acid [TriLipix]