INOTROPIC AGENTS



Pharmacy 753, Winter 2007

Medicinal Chemistry/Pharmacology

Cardiovascular Agents

V: Antihyperlipidemics

Dr. J.F. Stevens

Reading assignment: W&G 11th ed., pp. 657 – 663

Lipids

Triglycerides (TGs): biofuel, esters of fatty acids and glycerol

Cholesterol: essential building block of biological membranes (biosynthetically speaking not a fatty acid metabolite but a C27-triterpenoid).

Both lipids are water-insoluble and require ‘packaging’ for transport in the aqueous media of blood and lymph. Packaging is achieved by coating with a layer of phospholipids and with additional proteins (apolipoproteins). Size and composition of packages determine type of particle: VLDL (mainly TGs; 100-200 nm), LDL (mainly cholesterol, LDL-C; 25 nm), and HDL (cholesterol; 5-10 nm).

Elevated plasma LDL is a risk factor for atherosclerosis, especially when there is a decline in HDL. Can be result of defect gene for LDL-receptor, metabolic disorders, diet and lack of physical activity. Elevated LDL-C > down-regulation of LDL receptors in cell membranes > decreased cellular uptake of LDL-C > increased accumulation of LDL-C in arterial wall > atherosclerosis. The atherosclerotic process is accelerated by oxidized LDL (promoted by lipid peroxidation) because uptake of oxidized LDL by monocytes/macrophages (precursor foam cells) is unlimited (does not require LDL receptors).

Antihyperlipidemics lower plasma cholesterol by decreasing uptake of dietary cholesterol or by decreasing endogenous (hepatic) synthesis of cholesterol > upregulation of LDL receptors and improved cellular uptake of LDL.

Classes of antihyperlipidemics

1. HMG CoA inhibitors (Statins)

2. Fibric Acid Derivatives (Fibrates)

3. Bile Acid Sequestrants (polymeric anion exchange resins)

4. Inhibitors of cholesterol transport in GI tract (ezetimibe)

5. Miscellaneous: Plant Sterols, Niacin

Cholesterol biosynthesis

HMG CoA Reductase binding interactions with the endogenous HMG CoA substrate

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Mevaldehyde formation: [pic]

HMG CoA Reductase binding interactions with atorvastatin

HMGR Inhibitor (Statin) SAR

Free COOH group in statins mimics COOH group of HMG CoA. Anchoring as carboxylate anions to protonated 735Lys. Esters, lactones (prodrugs) and glucuronides (metabolites) at COOH are inactive.

HMGR enzyme is stereoselective and preferentially binds the (3R,5R)-dihydroxy side-chain configuration of atorvastatin. All marketed statins have this required stereochemistry.

Statins contain a lipophilic ring system that binds to the general area that is occupied by the coenzyme A component of the endogenous HMG CoA substrate. This ring system prevents displacement of the inhibitor by the natural substrate (affinity 103-104 x higher than that of HMG CoA).

Mevastatin and related natural statins

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Pravastatin (Pravachol)

> Obtained from mevastatin by microbiological hydroxylation using Streptomyces carbophilus and lactone ring opening

> Sold as sodium salt of the β-hydroxy acid > more hydrophilic, less CNZ penetration

> More rapid onset than previous three statins. Not much CYP metabolism.

> Absorption can be inhibited by cholestyramine resin (carboxylic acid)

Synthetic Statins

Fluvastatin (Lescol)

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Atorvastatin (Lipitor)

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Rosuvastatin (Crestor)

50% of oral dose absorbed, bioavailability 20%

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Metabolism: 76% excreted unchanged, major metabolites are N-desmethyl rosuvastatin and rosuvastatin lactone. 90% of total dose excreted in feces, rest in urine.

Comparison of Statins

| |More hydrophilic |Lipophilic |

|Two Statin groups |Pravastatin, rosuvastatin |Lovastatin, simvastatin, atorvastatin, fluvastatin |

|Absorption |Oral, absorption 30-85%, peak conc 1-4 hours, t½ 1-4 hours, except atorvastatin an rosuvastatin with t½ 20 hours |

|Interactions |CYP3A4 (atorvastatin, lovastatin, simvastatin)-erythromycin, azole antimycotics, grapefruit juice (flavones) |

| |CYP2C9 (fluvastatin)-ibuprofen, losartan |

|Contra indications |Pregnancy and nursing (no data available). Approved for use in children with familial hypercholesterolemia |

|First-pass metabolism |More hepatoselective (‘one-way active transport, |Can ‘escape’ liver by passive diffusion liver into the |

| |OATP2’ of carboxyl cmpds) |general circulation (desired and undesired side effects) |

|Side effects |Less myalgia, rhabdomyolysis |More pronounced myalgia and rhabdomyolysis (has been |

| |Hepatotoxic |questioned by some authors) |

| | |Hepatotoxic |

|Other effects |Less apoptosis of VSM cells |More apoptosis of VSM cells |

| | |(good for early-stage atherosclerosis, bad for plaque |

| | |stability > thrombus rupture) |

| |Less CNS penetration |Better CNS penetration > can reduce incidence of |

| | |Alzheimer’s dementia by decreasing amyloid (protective |

| | |effect claimed) |

| |Reduction of LDL oxidation |

Other antihyperlipidemic agents

FIBRATES: Clofibrate (Atromid) and gemfibrozil (Lopid)

> lower concentrations of VLDL (triglycerides) and LDL (cholesterol)

> may cause damage to liver and skeletal muscle (myopathy, rhabdomyolysis, renal failure)

> MOA not completely understood. Bind to peroxisome proliferators-activated receptor (PPARα) and so influence genes regulating lipid metabolism.

|Metabolism |Ester hydrolysis (both ester and acid are active); |Glucuronidation |

| |glucuronidation | |

|Effect on lipoprotein |Greater effect on VLDL than on LDL |

|Interactions (dose adjustment) |Anticoagulants (displacement from plasma proteins) |Statins (competition for the same glucuronyl transferases)|

|Contra-indications |Children, pregnant women |

Ezetimibe

> MOA: Inhibits dietary uptake of cholesterol by inhibiting a specific transporter in the jejunum, which takes up cholesterol. Compensatory increase in cholesterol synthesis in the liver (combination with statin, e.g., ezetimibe + simvastatin = Vytorin can lower LDL-C by up to 60% at 24 weeks).

> No effect on TGs

> Ezetimibe is water insoluble. Glucuronidated in intestinal epithelium and absorbed as glucuronide.

> Interaction with bile acid sequestrants: inhibition of absorption (glucuronide has free carboxyl group!)

Other antihyperlipidemic agents (continued)

Bile Acid Sequestrants

MOA: highly positive charged polymers (basic anion exchangers) that bind bile acids in GI tract > depletion of hepatic bile acids > hepatic bile acid synthesis increases (7-α-hydroxylase activity increases, see below) > hepatic cholesterol content declines > upregulation of LDL receptors > plasma LDL-C declines.

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Cholestyramine (Questran) and Colestipol (Colestid)

> binds sulfonate group of taurocholic acid.

> high-molecular weight, insoluble, no absorption

> interaction with anionic drugs (e.g., statins, furosemide: not to be taken simultaneously with resin)

> increases hepatic TG synthesis (C.I.: hypertriglyceridemia)

> S.E. bloating, dyspepsia (not to be taken in dry form but as a slurry in water or juice)

Other antihyperlipidemic agents (continued)

β-Sitosterol

> Plant sterol (‘plant stanol’), structure identical with that of cholesterol but ethyl group at C-27.

> MOA not well understood, but probably inhibits absorption of dietary cholesterol from GI tract (sitosterol itself is poorly absorbed)

> Effect on plasma cholesterol weak. Added to some margarines (‘neutriceutical’ Becel, Benecol)

Nicotinic acid (Niacin)

> One of oldest drugs to treat hyperlipidemia. Reduces VLDL and LDL synthesis. Best agent available for increasing HDL-C. MOA: inhibits lipolysis of TGs in adipose tissue by hormone-sensitive lipase > reduction of FFA transport to liver > reduction of hepatic TG synthesis. Niacin may also inhibit diacyl glycerol acyltransferase 2, a rate-limiting enzyme of TG synthesis. Identification of the nicotinic acid receptor may permit the development of new compounds that may affect FA metabolism, dyslipidemia, and atherosclerosis.

> Water soluble vitamin B3; precursor of NAD and NADP.

> Use is limited due to vasodilation (S.E. Flushing occurs in practically all patients. Vasodilation is prostaglandin-mediated and can be prevented by low doses of aspirin).

> Medically serious S.E.: hepatotoxicity, hyperglycemia, birth defects in animals (C.I.: pregnancy).

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