Lecture 2 hypercholesterolemia and atherosclerosis by Marc Imhotep Cray, M.D.

DRUGS USED IN DISORDERS OF THE CARDIOVASCULAR SYSTEM Lecture 2:

Hypercholesterolemia and Atherosclerosis Marc Imhotep Cray, M.D.

Photo: Photograph of chordae tendineae attached to papillary muscles of a ventricle. Seeleyâ&#x20AC;&#x2122;s anatomy & physiology. 10th ed. New York, NY; McGraw-Hill 2010

Learning Objectives:

CVS Pharmacology Lecture 2

 To review the pathobiology of hypercholesterolemia and atherosclerosis  To understand the role elevated serum levels of LDL-C play in promoting the risk of developing cardiovascular disease.  To understand presently accepted values for desirable serum LDL-C, HDL-C and triglycerides in normal individuals and the treatment goals for those individuals with hyperlipidemia.  To understand the benefit of diet and lifestyle changes in the initial treatment of hyperlipidemia.  To understand the indications, mechanism of action, clinical effects, adverse effects and contraindications of the major drug classes used in the treatment of hyperlipidemia. Companion eNotes: Cardiovascular Pharmacology Textbook Reading: Malloy MJ & Kane JP. Ch. 35 Agents Used in Dyslipidemia. Pgs. 619-32 Marc Imhotep Cray, In: Katzung BG,M.D. ed. Basic & Clinical Pharmacology. 12th ed.

Classification Schema: Hypolipidemics with Relevant Drugs Statins Atorvastatin (Lipitor®) Fluvastatin (Lescol®) Lovastatin (Mevacor®) Simvastatin (Zocor®) Pravastatin (Pravachol®) Rosuvastatin (Crestor®) Bile Acid-binding resins Cholestyramine (Questran®) Colestipol (Colestid®) Colesevelam (Welchol®) Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Cholesterol Absorption Inhibitor Ezetimibe (Zetia®) Nicotinic Acid (Niacin) Fibrates Fenofibrate (Tricor®, Lofibra®) Gemfibrozil (Lopid®) Omega-3 fatty acids Eicosapentaenoic acid: Docosahexaenoic acid (Lorvaza®) 3

CVS Pharmacology Lecture 2

Definition  Hyperlipidemia, hypercholesterolemia or dyslipidemia is the presence of raised or abnormal levels of lipids and /or lipoproteins in the blood  Lipids are insoluble in aqueous solution  Lipids (fatty molecules) are transported in a protein capsule  the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism

Marc Imhotep Cray, M.D.

Definition(2)

Hyperlipidemia

CVS Pharmacology Lecture 2

 Lipid and lipoprotein abnormalities are extremely common in the general population, and are regarded as a highly modifiable risk factor for cardiovascular disease due to the influence of cholesterol  Cholesterol is the most clinically relevant lipid substances contributing to atherosclerosis (LDL-C)  In addition, some forms of lipid and lipoprotein abnormalities may predispose to acute pancreatitis

 E.g., Type IV Hypolipoproteinemia (Familial hypertriglyceridemia)

Learn more: http://themedicalbiochemistrypage.org/cholesterol.html Marc Imhotep Cray, M.D.

A 4-ml sample of hyperlipidemic blood with lipids separated into the top fraction

CVS Pharmacology Lecture 2

Reactions of Cholesterol Synthesis 1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). 2. HMG-CoA is converted to mevalonate. [rate-limiting reaction] catalyzed by HMG CoA reductase (HMGR) 3. Mevalonate is converted to the isoprene-based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2. 4. IPP is converted to squalene. 5. Squalene is converted to cholesterol. Cholesterol Biosynthesis http://themedicalbiochemistrypage.org/cholesterol.html Marc Imhotep Cray, M.D.

Hypercholesterolemia: Causes

CVS Pharmacology Lecture 2

 Cholesterol, a simple lipid found in cell membranes, is a precursor of steroids, bile acids, and vitamin D and a major part of atherosclerotic plaques  Most circulating blood cholesterol is synthesized from liver acetyl CoA and is excreted as bile salts  Only 25% of blood cholesterol is from the diet, but high-fat diets increase liver cholesterol production and blood cholesterol levels

 HMG-CoA formation from HMG-CoA reductase, the rate determining step in cholesterol synthesis, is regulated via feedback inhibition  When cholesterol uptake is low, the liver and small intestine increase cholesterol synthesis Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Hypercholesterolemia: Causes (cont.) The plaque forming ability of cholesterol is related to LDLs, which promote plaque formation HDLs remove cholesterol from arteries and transport it to the liver HDLs remove cholesterol from plaques and slow atherosclerosis Control of cholesterol and LDL levels is a major goal in heart disease therapy Marc Imhotep Cray, M.D.

Risk Factors for Hyperlipidemia

CVS Pharmacology Lecture 2

 High fat intake  Obesity  Type 2 diabetes mellitus  Advanced age  Hypothyroidism  Obstructive liver disease  Genetics = Familial hypercholesterolemia (FH) or primary hypercholesterolemia  Drug induced: glucocorticoids, thiazide diuretics, beta blockers, protease inhibitors, cyclosporine, progestins, alcohol Marc Imhotep Cray, M.D.

Arteriosclerosis

 Atherosclerosis is patchy intimal plaques (atheromas) in medium-sized and large arteries  The plaques contain lipids, inflammatory cells, smooth muscle cells, and connective tissue

Marc Imhotep Cray, M.D.

Normal coronary artery, microscopic

From: Webpath Cardiovascular Pathology image plates

 Arteriosclerosis is a general term for several disorders that cause thickening and loss of elasticity in the arterial wall  Atherosclerosis, the most common form, is also the most serious because it causes coronary artery disease and cerebrovascular disease

CVS Pharmacology Lecture 2

Coronary artery with atherosclerotic narrowing, microscopic 10

Atherosclerosis

CVS Pharmacology Lecture 2

 Atherosclerosis can affect all large and medium sized arteries, including the coronary, carotid, and cerebral arteries; the aorta; its branches; Aortas demonstrating various degrees of atherosclerosis, gross and major arteries of the extremities  It is the leading cause of morbidity and mortality in the US and in most developed countries  Atherosclerosis is rapidly increasing in prevalence in developing countries, and as people in developed countries live longer, incidence will increase  By 2020, atherosclerosis is expected to be the leading cause of death worldwide The Merck Manual of Diagnosis and Therapy 19th Ed. (2011) Marc Imhotep Cray, M.D.

From: Webpath Cardiovascular Pathology image plates 11

CVS Pharmacology Lecture 2

Risk Factors for Atherosclerosis* Risk factors atherosclerosis include:  dyslipidemia  diabetes  cigarette smoking  family history  sedentary lifestyle  obesity  hypertension *Note the commonalities to the Risk Factors for Hyperlipidemia in Slide 9 Marc Imhotep Cray, M.D.

Pathobiology of Atherosclerosis

CVS Pharmacology Lecture 2

 When excess cholesterol deposits on cells and on the inside walls of blood vessels it forms an atherosclerotic plaque  The first step of atherosclerosis is injury to the endothelium which results in atherosclerotic lesion formation  When the plaque ruptures, blood clots form which lead to decreased blood flow, resulting in cardiovascular events Marc Imhotep Cray, M.D.

Pathobiology of Atherosclerosis (2)  Symptoms develop when growth or rupture of the plaque reduces or obstructs blood flow; symptoms vary by artery affected  Diagnosis is clinical and confirmed by angiography, ultrasonography, or other imaging tests  Treatment includes risk factor and dietary , modification, physical activity, antiplatelet drugs, and antiatherogenic drugs Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Heart and LAD coronary artery with recent thrombus, gross  The anterior surface of the heart demonstrates an opened left anterior descending coronary artery.  Within the lumen of the coronary can be seen a dark red recent coronary thrombosis.  The dull red color to the myocardium as seen below the glistening epicardium to the lower right of the thrombus is consistent with underlying myocardial infarction From: Webpath Cardiovascular Pathology image plates 14

Complications of Hyperlipidemia

CVS Pharmacology Lecture 2

 Macrovascular complications:  Unstable Angina (chest pain)  Myocardial Infarction (heart attack)  Ischemic Cerebrovascular Disease (stroke)  Coronary Artery Disease (heart disease)  Microvascular complications:  Retinopathy (vision loss)  Nephropathy (kidney disease)  Neuropathy (loss of sensation in the feet and legs)

Marc Imhotep Cray, M.D.

How to Diagnose Patients with Hyperlipidemia

CVS Pharmacology Lecture 2

 The fasting lipid profile (TC, LDL-C, HDL-C, TG) is analyzed  The following individuals are recommended for screening:  All adults 20 years and older should be screened at least once every 5 years  Individuals with family history of premature cardiovascular disease should be screened more frequently

Marc Imhotep Cray, M.D.

How to Diagnose Patients with Hyperlipidemia (2)

CVS Pharmacology Lecture 2

 History and physical examination:  Presence of cardiovascular risk factors or cardiovascular disease  Family history of premature cardiovascular disease, hyperlipidemia, or diabetes mellitus  Diabetes mellitus or glucose intolerance  Central obesity  High blood pressure  Presence or absence of kidney or liver disease, peripheral vascular disease, abdominal aortic aneurysm, cerebral vascular disease An individual with a combination of lipid profile with history and physical exam, will be treated according to the ATP III guideline See: Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program Slide Shows Marc Imhotep Cray, M.D.

Lipoprotein Level Classification

CVS Pharmacology Lecture 2

Standard fasting blood tests for cholesterol will include values for total cholesterol, triglycerides, HDL cholesterol (so-called “good” cholesterol), and LDL cholesterol (so-called “bad” cholesterol).

Marc Imhotep Cray, M.D.

• LDL-C < 100 mg/dL-----------------------------Optimal • 100-129 mg/dL --------------------------Near or above optimal • 130-159 mg/dL---------------------------Borderline high • 160-189 mg/dL --------------------------High • > or = 190 mg/dL -----------------------Very high • Total -C • <200 mg/dL------------------------------ Desirable • 200-239 mg/dL---------------------------Borderline high • > or= 240 mg/dL-------------------------High • TG-C: • <150 mg/dL------------------------------Optimal • 150-199 mg/dL --------------------------Borderline high • 200-499 mg/dL --------------------------High • > or = 500 mg/dL -----------------------Very high • HDL cholesterol: • <40 mg/dL -------------------------------Low • >60 or = 60 mg/dL --------------------- High

Treatment Goals

CVS Pharmacology Lecture 2

1. Reduce total cholesterol and LDL (bad) cholesterol and increase HDL 2. Prevent the formation of atherosclerotic plaques and stop the progression of established plaques 3. Prevent heart disease 4. Prevent morbidity and mortality The best drugs for such therapy are statins, however prior to instituting pharmacotherapy non-pharmacological management (lifestyle modification ) should be implemented. Marc Imhotep Cray, M.D.

Non-Pharmacological Treatment Lipid lowering therapy should be started with lifestyle modification for at least 12 weeks 1.Increase physical activity 2.Weight reduction

CVS Pharmacology Lecture 2

3.Diet modification:  Total fat 25-35% of total calories  Saturated fat <7% of total calories  Polyunsaturated fat up to 10% total calories  Monounsaturated fat up to 20% total calories  Carbohydrates 50-60% total calories  Fiber 20-30 g/ day total calories  Protein 15% total calories  Cholesterol <200 mg/day  Achieve and maintain desirable body weight

See: Treatment of Diabetic Dyslipidemia / Medscape (Med Student Section) Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Pharmacological Treatment  If non-pharmacological treatment is not successful, a lipid-lowering drug should be started, especially in high risk populations  1st step:  Initiate LDL-lowering drug therapy  Start with statins, bile acid sequestrants, or nicotinic acid  Evaluate after 6 weeks  2nd step:  If goal was not reached, intensive lipidlowering treatment should be started  Increase dose of statins  Bile acid sequestrants or nicotinic acid should be added  Evaluate after 6 weeks Marc Imhotep Cray, M.D.

 3rd step:  If goal is not reached, intensive lipid lowering should be continued or individual should be referred to a lipid specialist  If goal was reached, other lipid risk factors should be treated  4th step:  Monitor response and compliance

Pharmacological Treatment

CVS Pharmacology Lecture 2

Statins (HMG CoA Reductase Inhibitors) (Case 13 in MedPharm Clinical Cases)

 Used as first-line agents in the management of hyperlipidemia  Statins are designed to reduce low-density–lipoprotein (LDL) cholesterol and raise HDL cholesterol  Agents  Atorvastatin(Prototype)  Simvastatin  Lovastatin  Pravastatin  Fluvastatin  Rosuvastatin Marc Imhotep Cray, M.D.

Statins (HMGR Inhibitors)(2)

CVS Pharmacology Lecture 2

 Effectiveness of statins:  Reduce Total Cholesterol up to 30%  Reduce LDL cholesterol by 18-50%  Decrease TG by 7-30%  Raise HDL cholesterol by 5-15%  Statins are the most effective in lowering LDL cholesterol  Statins are the most effective in the patient who has low HDL and high LDL

Marc Imhotep Cray, M.D.

Statins (HMGR Inhibitors)(3)

CVS Pharmacology Lecture 2

MOA (Mechanism of action)  Statins competitively inhibit HMG-CoA reductase (enzyme involved in cholesterol synthesis) thus decreasing mevalonic acid production and stimulating LDL breakdown  Reduced biosynthesis of cholesterol causes an increase in the number of LDL receptors, through the actions of sterol regulatory element binding proteins (SREBPs) >>> additional LDL receptors increase the catabolic rate of LDL, and the liver’s extraction of LDL precursors>>> these actions reduce the plasma pool of LDL Marc Imhotep Cray, M.D.

Statins (HMGR Inhibitors)(4)

CVS Pharmacology Lecture 2

Pharmacokinetics: ď&#x201A;§ Atorvastatin, simvastatin, and lovastatin are metabolized by CYP3A4; thus drug interactions are of concern with these agents ď&#x201A;§ Pravastatin is the only statin that is not metabolized by the CYP450 enzyme pathways

Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Statins (HMGR Inhibitors)(4) Side effects:  Statins are generally well tolerated  Myalgia: muscle pain and associated weakness (about 10% of patients)  Increased liver enzymes and hepatotoxicity  Fatigue, sleep disturbances, anxiety, stomach disturbances, headache, rash

Marc Imhotep Cray, M.D.

Statins (HMGR Inhibitors)(5)

CVS Pharmacology Lecture 2

Rare, Serious Side Effects  Myositis and rhabdomyolysis are rare (1% for myositis) but serious adverse effects  Tend to occur at higher doses or when a drug interaction is present  Myositis is inflammation of muscle cells and is associated with increase in creatine kinase (CK) levels in the blood  Rhabdomyolysis is an extreme form of myositis and results in lysis of skeletal muscle cells and release of myoglobin in high quantities, which results in damage to renal glomeruli and acute renal failure  Usually occurs in the presence of other risk factors in addition to statin administration  E.g., coadministration with cyclosporine or gemfibrozil (another lipid-lowering agent) Marc Imhotep Cray, M.D.

Statins (HMG CoA Reductase Inhibitors)(6)

CVS Pharmacology Lecture 2

Contraindications: Avoid use in:  Active or chronic liver disease and pregnancy (birth defects) Use with caution with:  Concomitant use of cyclosporine, macrolide antibiotics, antifungal agents (CYP450 enzyme inhibitors)  For example: Itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporine, nefazodone, HIV antiretrovirals

 When statins are used with fibric acids and niacin, appropriate caution should be taken because of increasing incidence of muscle breakdown Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Statins (HMG CoA Reductase Inhibitors)(7) Drug- food interaction:  Grapefruit juice increases concentration of some statins (A CYP450 enzyme inhibitor)  Pravastatin, rosuvastatin & fluvastatin concentrations are not affected by grapefruit juice

Monitoring:  Muscle soreness, tenderness, or pain  Liver function tests : baseline, 4-6 weeks after starting therapy, and then annually  Muscle enzyme levels when individual has muscle pain

Marc Imhotep Cray, M.D.

Bile Acid Sequestrants

CVS Pharmacology Lecture 2

Mechanism of action: â&#x20AC;˘ Bile acid sequestrants bind to bile acids in the intestine, thus inhibits uptake of intestinal bile salts into the blood and increases the fecal loss of bile salt-bound LDL

Marc Imhotep Cray, M.D.

Bile Acid Sequestrants (2)

CVS Pharmacology Lecture 2

1) Cholestyramine Usual dose: 4 g by mouth 1-2 times a day with meal to a maximum of 24 g per day 2) Colesevelam Usual dose: 3 tablets by mouth twice daily with meals or 6 tablets once daily with a meal 3) Colestipol Usual dose: ď&#x201A;§ Granules: 5-30 g by mouth daily given once or 2-4 times a day with meal ď&#x201A;§ Tablets: 2-16 g by mouth daily Marc Imhotep Cray, M.D.

Bile Acid Sequestrants (3)

CVS Pharmacology Lecture 2

Effectiveness: • Reduces LDL cholesterol by 15-30% • Increases HDL cholesterol by 3-5% • Increases TG Drug interaction: • Decreased absorption of fat soluble vitamins: A, D, E, K, C and folic acid • Decreased absorption of other drugs: tetracycline, thiazide diuretics, aspirin, phenobarbital, pravastatin, digoxin

Marc Imhotep Cray, M.D.

Bile Acid Sequestrants (4)

CVS Pharmacology Lecture 2

Side effects:  Stomach upset, constipation accompanied by heart burn, nausea, and bloating Avoid use in:  A disease called dysbetalipoproteinemia  Triglycerides >400 mg/dL Use caution if:  Triglycerides >200 mg/dL  Colesevalam is much better tolerated than cholestyramine or colestipol  Statins and other drugs should be taken 1-2 hours before and 3-4 hours after bile acid sequestrants

Marc Imhotep Cray, M.D.

Nicotinic Acid

CVS Pharmacology Lecture 2

Mechanism of action:  Nicotinic acid decreases the clearance of ApoA1 to increase HDL  it inhibits the synthesis of VLDL

Effectiveness:  Decreases LDL cholesterol by 5-25 %  Increases HDL cholesterol by 15-35%  Decreases TG by 20-50%  Nicotinic acid is the most potent drug that increases HDL cholesterol

Marc Imhotep Cray, M.D.

Nicotinic Acid (2)

CVS Pharmacology Lecture 2

Side effects:  Flushing (taking aspirin or ibuprofen can reduce symptoms)  Increases blood glucose due to impaired insulin sensitivity  Gout  Liver toxicity associates with sustained release form (Niaspan)  Upper stomach distress and muscle weakness Avoid use in:  Chronic liver disease  Severe gout Use with caution in:  Type 2 diabetes (high dose)  Gout  Peptic ulcer disease Marc Imhotep Cray, M.D.

Fibric Acids

CVS Pharmacology Lecture 2

Mechanism of action: ď&#x201A;§ Fibric acid up-regulates fatty acid transport protein and fatty acid oxidation; thus it reduces the formation of VLDL, increases formation of HDL, and enhances the breakdown of TG Agents: Gemfibrozil Fenofibrate Fibrates activate transcription factors called peroxisome proliferatorâ&#x20AC;&#x201C;activated receptors (PPARs). These are nuclear hormone receptors that respond to lipid based ligands, including hormones, vitamins, and fatty acids VLDL particles are converted into fibrate agonism, resulting in: Increased HDL Reduced LDL Marc Imhotep Cray, M.D.

Fibric Acids(2)

CVS Pharmacology Lecture 2

Effectiveness:  Reduces LDL cholesterol by 20-50% with normal TG  Increases LDL cholesterol with high TG  Reduces TG by 20-50%  Increases HDL cholesterol by 10-20%  Fibric acids are very effective in lowering TG and preventing pancreatitis  Type IV Hypolipoproteinemia (Familial hypertriglyceridemia)

 Fibric acids reduce VLDL, but fibric acids might increase LDL and total cholesterol

Marc Imhotep Cray, M.D.

Fibric Acids(3)

CVS Pharmacology Lecture 2

Side effects:  Dyspepsia, gallstones, muscle ache, rash  Unexplained non-coronary heart disease deaths seen in a World Health Organization (WHO) study  Weakness, tiredness, elevations in muscle enzyme Avoid use in:  Severe renal disease  Severe hepatic disease Drug interaction:  Fibric acids bind to albumin and can increase the effect of anticoagulants Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Ezetimibe (Zetia) Mechanism of action:  Inhibits absorption of cholesterol in the small intestine; thus it decreases the delivery of cholesterol to the liver and increases the clearance of cholesterol from the blood Side effects: chest pain, dizziness, diarrhea, abdominal pain Drug interaction:  Bile acid sequestrants decrease ezetimibe concentrations • Ezetimibe should be spaced 2 hours before or 4 hours after bile acid sequestrants administration  Fibric acids increase ezetimibe concentrations Marc Imhotep Cray, M.D.

THE END

Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Further study (SDL): Online resource center: Medical Pharmacology Cloud Folder

Recommended Reading: Management of Hyperlipidemic States Clinical: eMedicine Article Hypertriglyceridemia Lectures/discussions to follow: 3. Angina 4. Heart Failure 5. Arrhythmias 6. Hypertension 7. Peripheral Vascular Disease Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 2

Links to Cholesterol Metabolism and Lipoprotein themedicalbiochemistrypage.org  Intestinal Uptake of Lipids  Composition of Lipoprotein Complexes  Lipid Profile Values  Classification of Apoproteins  Chylomicrons  Very Low Density Lipoproteins, LDLs

 Intermediate Density Lipoproteins, IDLs  Low Density Lipoproteins, LDLs  High Density Lipoproteins, HDLs

Cholesterol Biosynthesis http://themedicalbiochemistrypage.org/cholesterol.html

 LDL Receptors  Clinical Significance of Lipoprotein Metabolism

Marc Imhotep Cray, M.D.