Drugs used in the treatment of hyperlipidemias By S.Bohlooli, PhD

Introduction Introduction Cholesterol Used to prevent or slow progression of atherosclerosis to reduce the risk of coronary artery disease and prolong life Cholesterol Advantages Serves as a component of cell membranes and intracellular organelle membranes Is involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroids Needed for the synthesis of bile salts which are needed for digestion and absorption of fats.

Introduction Cholesterol Advantages Origin Is deposited in the stratum corneum of the skin to help ↓ evaporation of water and create impermeability to water soluble compounds (helps keep moisture in skin) Origin Is synthesized in the liver. Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase.

Introduction Cholesterol Origin Endogenous synthesis of cholesterol increases at night An increase in dietary cholesterol produces only a small ↑ in blood levels of cholesterol because ingestion inhibits endogenous synthesis Dietary saturated fats ↑ blood cholesterol levels because they are converted to cholesterol in the body.

Introduction Lipoproteins Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood. Apolipoproteins Embedded in the lipoprotein shell Three functions 1. Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein. 2. Activate enzymes that will metabolize the lipoprotein 3. ↑ structural stability of the lipoprotein

Introduction Lipoproteins Apolipoproteins All lipoproteins that deliver lipids to peripheral tissues (nonhepatic tissues) contain apolipoprotein B-100 (Ex: VLDL, LDL) All lipoproteins that transport lipids from peripheral tissues back to the liver contain apolipoprotein A-I (Ex: HDL)

Introduction Lipoproteins Lipoproteins of importance VLDL (very low density lipoprotein) Contain triglycerides (TGs) and some cholesterol Account for nearly all TGs in the blood Contain B-100 Deliver triglycerides from the liver to adipose tissues and muscles.

Introduction Lipoproteins Lipoproteins of importance VLDL (very low density lipoprotein) Remnants of hydrolysis are IDL (intermediate density lipoproteins), which can be transported to liver or converted to LDL

Introduction Lipoproteins Lipoproteins of importance LDL (low density lipoprotein) “Bad cholesterol” Contain cholesterol Account for 60-70% of cholesterol in the blood Contains B-100 Delivers cholesterol to peripheral tissues

Introduction Lipoproteins Lipoproteins of importance LDL (low density lipoprotein) Formed from IDL, the remnants of VLDL Makes the greatest contribution to coronary atherosclerosis Oxidized LDL contributes to atherosclerotic plaque Removed from plasma via endocytosis by liver converting it to bile acids excreted in GI

Introduction Lipoproteins Lipoproteins of importance HDL (high density lipoprotein) “Good cholesterol” Contain cholesterol Account for 20-30% of cholesterol in the blood Some contain Apo A-I and Apo A-II Apo A-I is cardioprotective Transports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removal Antiatherogenic

Characteristics of Plasma Lipoproteins LIPOPROTEIN CLASS DENSITY OF FLOTATION, g/ml SIGNIFICANT APOPROTEINS SITE OF SYNTHESIS MECHANISM(S) OF CATABOLISM Chylomicrons and remnants <<1.006 B-48, E, A-I, A-IV, C-I, C-II, C-III Intestine Triglyceride hydrolysis by LPL   ApoE-mediated remnant uptake by liver VLDL <1.006 B-100, E, C-I, C-II, C-III Liver IDL 1.006-1.019 B-100, E, C-II, C-III Product of VLDL catabolism 50% converted to LDL mediated by HL, 50% apoE-mediated uptake by liver 50% apoE-mediated uptake by liver LDL 1.019-1.063 B-100 ApoB-100-mediated uptake by LDL receptor (~75% in liver) HDL 1.063-1.21 A-I, A-II, E, C-I, C-II, C-III Intestine, liver, plasma Complex: Transfer of cholesteryl ester to VLDL and LDL Uptake of HDL cholesterol by hepatocytes Abbreviations: apo, apolipoprotein; CHOL, cholesterol; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; Lp(a), lipoprotein(a); LDL, low-density lipoproteins; NS, not significant (triglyceride is less than 5% of LDL and HDL); TG, triglyceride; VLDL, very-low-density lipoproteins; HL, hepatic lipase; LPL, lipoprotein lipase.

The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apoC lipoproteins and apolipoprotein E (apoE) from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apoE are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apoE. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum. (Modified and redrawn, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological Disease. Butterworth-Heinemann, 1993.)

Classification of Plasma Lipid Levels Total cholesterol   <200 mg/dl Desirable 200-239 mg/dl Borderline high ≥240 mg/dl High HDL-C <40 mg/dl Low (consider <50 mg/dl as low for women) >60 mg/dl LDL-C <70 mg/dl Optimal for very high risk (minimal goal for CHD equivalent patients) <100 mg/dl Optimal 100-129 mg/dl Near optimal 130-159 mg/dl 160-189 mg/dl ≥190 mg/dl Very high Triglycerides <150 mg/dl Normal 150-199 mg/dl 200-499 mg/dl ≥500 mg/dl

Secondary Causes of Dyslipidemia DISORDER MAJOR LIPID EFFECT Diabetes mellitus Triglycerides > cholesterol; low HDL-C Nephrotic syndrome Triglycerides usually > cholesterol Alcohol use Triglycerides > cholesterol Contraceptive use Estrogen use Glucocorticoid excess Hypothyroidism Cholesterol > triglycerides Obstructive liver disease

Treatment of hyperlipidemia Treatment (tx) Non-Pharmacological Therapy – 1st line tx 1. Diet modification Decrease intake of total fat and especially saturated fat Increase fiber intake Increase Omega-3-fatty acids (found in fish) ↑ fruits and vegetables (antioxidants) ↓ simple sugars (sucrose)

Sites of action of drugs used for treatment of dislypidemia Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.

Treatment of hyperlipidemia Non-Pharmacological Therapy – 1st line tx 2. Exercise (will ↑ HDL levels) 3. Reduce risk factors if possible Drug Therapy Niacin (vitamin B3) Decreases VLDL and LDL and significantly ↑ HDL MOA 1. Inhibits VLDL secretion into the blood thereby preventing production of LDL 2. Increases clearance of VLDL via lipoprotein lipase pathway

Niacin: chmeistry

Antilipemic agents Niacin MOA 3. Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system 4. Reduces circulating fibrinogen (contributes to clot formation) and ↑ tissue plasminogen activator (clot dissolver) 5. HDL catabolic rate is decreased 6. Reduces the plasma level of Lp(a) lipoprotein, which can increase risk of CAD

Antilipemic agents Niacin Indications Drug of choice for ↓ levels of TG (VLDL) in pts at risk for pancreatitis Mixed elevation of LDL and VLDL (alone or in combination with reductase inh.) Elevation of TG (VLDL) and low levels of HDL (Niaspan® - approved for elevating HDL levels) Start with low dose and gradually increase Given 1-3g/day in divided doses or once daily with extended release. Give at night with food.

Antilipemic agents Niacin - Adverse effects Flushing Harmless cutaneous vasodilation Uncomfortable sensation of warmth Occurs after drug is started or ↑ dose Lasts for the first several weeks Can give 325mg aspirin 30 minutes before each dose (prevents prostaglandin synthesis). Can also take ibuprofen QD in place of ASA

Antilipemic agents Niacin - Adverse effects Pruritis, rashes, dry skin acanthosis nigricans (eruption of velvet warty benign growths and hyperpigmentation) Associated with insulin resistance Will have to d/c drug if occurs Nausea and abdominal discomfort Reduce dosage and may need to use inhibitors of gastric acid secretion or antacids (not containing aluminum) Avoid in pts with severe peptic disease

Antilipemic agents Niacin - Adverse effects Hepatotoxicity Severe is rare, and reversible Occurs mostly with older sustained release forms Monitor liver fx regularly Liver injury is less likely with Niaspan® (given once daily) the new extended release formulation Carbohydrate tolerance may be moderately impaired (hyperglycemia) Reversible Can still be given to diabetics receiving insulin

Antilipemic agents Niacin - Adverse effects Hyperuricemia Hypotension Occurs in about 1/5 of pts Occasionally precipitates gout Hypotension Especially seen in pts on antihypertensive meds Can ↑ homocysteine levels which ↑ risk of CAD (give folic acid to ↓ homocysteine levels)

Fibrates: chemistry

Hepatic and peripheral effects of fibrates Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

Antilipemic agents Fibrates (gemfibrozil, fenofibrate, clofibrate, bezafibrate) Little or no effect on LDL ↓ VLDL (TG) moderate ↑ of HDL MOA Ligand for the nuclear transcription regulator, peroxisome proliferator-activated receptor-α (PPAR- α) MOA mostly unknown

Antilipemic agents Fibrates MOA ↑ activity of lipoprotein lipase for lipolysis of triglyceride (↑ clearance) ↓ lipolysis in adipose tissue, ↓ FFA release ↓ secretion of VLDL by liver ↓ uptake of FFA by liver ↑ HDL levels moderately

Antilipemic agents Fibrates Indication: Hypertriglyceridemia Gemfibrozil – 600mg QD-BID (half life 1.5hrs) Fenofibrate – 1-3 67mg tablets QD (half life 20hrs) Taken with food - ↑ absorption Max reduction of VLDL is achieved within 3-4 weeks of treatment Adverse Effects Rashes GI disturbances (nausea, abdominal pain, diarrhea)

Antilipemic agents Fibrates - Adverse Effects Gallstones (upper abdominal discomfort, intolerance of fried food, bloating) Gemfibrozil ↑ biliary cholesterol saturation Use with caution in pts with biliary tract ds, women, obese pts, and Native Americans Myopathy (muscle injury) Tenderness, weakness, or unusual muscle pain Will increase risk of statin-induced myopathy when used together (rhabdomyolysis has occurred rarely)

Antilipemic agents Fibrates - Adverse Effects Hepatoxicity Arrythmias Hypokalemia Displaces warfarin from plasma albumin since drug is highly protein bound. Need to ↓ warfarin dose

Bile Acid-Binding Resins :chemistry

Antilipemic agents Bile Acid-Binding Resins (colestipol and cholestyramine) Will ↓ LDL, may ↑ VLDL (would require niacin combo if ↑ TG prior to tx) MOA Bile acids, the metabolites of cholesterol, are normally reabsorbed in the jejunum and ileum. When resins are given, they bind to bile acids in the intestinal lumen, prevent their reabsorption and increase their excretion.

Antilipemic agents Bile Acid-Binding Resins MOA Indication ↑ excretion creates a demand for ↑ synthesis of bile acid. Liver cells must have an ↑ cholesterol supply (provided by LDL) to synthesize bile acid. Liver cells will ↑ their LDL receptors, ↑ing uptake of LDL from plasma. Indication Used alone to ↓ LDL (by 15-20%) Normally used as adjuncts to the statins to ↓ LDL (by 50%)

Antilipemic agents Bile Acid-Binding Resins Indication Adverse Effects Can be used to relieve pruitis in pts who have cholestasis Can be used for severe digitalis toxicity Dispensed in powder form (must be mixed with fluid). Cholestyramine 4-12g BID. Colestipol 5-30g/day in divided doses and also in 1g tablets (2-16g/day) taken w/ fluid Adverse Effects Max reductions of LDL occur in one month Must be taken with meals

Antilipemic agents Bile Acid-Binding Resins Adverse Effects Constipation Bloating, indigestion, nausea Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K) Drug Interactions Resins bind digoxin, warfarin, thiazide diuretics, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, ascorbic acid (these agents should be given 1 hour before the resin or 4 hours after)

chemistry

Antilipemic agents HMG COA Reductase Inhibitors (“statins”) (lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, cerivastatin) Most Effective for ↓ LDL Will ↑ HDL and ↓ VLDL Fewest adverse effects and tolerated best

Inhibition of HMG-CoA reductase Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas).

Antilipemic agents (“statins”) MOA Inhibits hepatic HMG CoA reductase Inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptors Hepatocytes are able to remove more LDLs from the blood Decrease production of apolipoprotein B-100, thereby ↓ production of VLDL ↓ plaque cholesterol content

Antilipemic agents (“statins”) MOA ↓ inflammation at the plaque site Improve abnormal endothelial function Enhance the ability of blood vessels to dilate ↓ risk of thrombosis (inhibits platelet aggregation and blocks thrombin synthesis) Statins have high first pass extraction by liver (only a small fraction of each dose reaches the general circulation) Prodrugs – lovastatin and simvastatin

Antilipemic agents (“statins”) – Indications Used alone to ↓ LDL Used with bile acid – binding resins to ↓ LDL Used with niacin to ↓ LDL, ↓ VLDL, and ↑ HDL Enhanced if taken with food (except for pravastatin – taken without food) Give in the evening Half life is 1-3 hours (except atorvastatin – 14 hours)

Antilipemic agents (“statins”) – Indications Atorvastatin is most efficacious agent for use in severe hypercholesterolemia High potency (>40-50% LDL lowering) – atorvastatin, simvastatin, cerivastatin Low potency (20-40% LDL lowering) – lovastatin, fluvastatin, pravastatin ↓ LDL within 2 weeks; max reduction in 4-6 weeks

Antilipemic agents (“statins”) – Indications New Drug: Altocor® Extended release lovastatin Slightly more effective than regular lovastatin Take without food

Antilipemic agents (“statins”) – Adverse Effects Since LDL cholesterol levels will return to pretreatment values if drugs are withdrawn, treatment must continue lifelong Statins are pregnancy category X rash, GI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain)

Antilipemic agents (“statins”) – Adverse Effects Hepatotoxicity Myopathy (0.5% of pts) Risk highest with lovastatin and especially in combination with Fibrates Cyp3A4 drug interactions with all statins excepts for pravastatin and fluvastatin

Ezetimibe:chemistry

Antilipemic agents Ezetimibe ezetimibe reduced cholesterol absorption by 54% Cholesterol lowering agent Will challenge the statins Approved for monotherapy or in combo with statins reduction of 60% with simvastatin for LDL-C

Inhibitors of Cholesteryl Ester Transfer Protein a plasma glycoprotein synthesized by the liver mediates the transfer of cholesteryl esters In animal models inhibition of CETP result in: higher HDL levels decreased LDL levels resistance to developing atherosclerosis JTT-705 and torcetrapib