Medicinal Chemistry II313 PHC • Dr. Ebtehal S. Al abdullah • email@example.com • Antihyperlipedimic drugs • duiretics
Antihyperlipidemic Drugs 313 PHC
What is Hyperlipidemia? Hyperlipidemia a broad term, also called hyperlipo- proteinemia, is a common disorder in developed countries and is the major cause of coronary heart disease. It results from abnormalities in lipid metabolism or plasma lipid transport or a disorder in the synthesis and degradation of plasma lipoproteins
Causes of hyperlipidemia • Mostly hyperlipidemia is caused by lifestyle habits or treatable medical conditions. • Obesity, not exercising, and smoking • diabetes, kidney disease, pregnancy, and an under active thyroid gland. • inherit hyperlipidemia
The chemistry and biochemistry of Plasma lipids What are lipids? Lipids are the fats that are present in the body. The major lipids in the bloodstream are cholesterol and it’s esters, triglycerides and phospholipids.
Hyperlipidemia ; Increases concentrations of lipids • Hyperlipoproteinemia ; Increases concentrations of lipoproteins • Hypercholesterolemia; high concentration of cholesterol • Atherosclerosis and coronary artery disease • Hypertriglyceridemia; high concentration of triglyceride • Pancreatitis & Development of atherosclerosis and heart disease
Cholesterol Is C27 steroid that serves as an important componant of all cell membranes and important precursor molecule for the biosynthesis of bile acids, steroid hormones, and several fat-soluble vitamins
What are the normal functions of cholesterol in the body? • It is necessary for new cells to form and for older cells to repair themselves after injury. • Cholesterol is also used by the adrenal glands to form hormones such as • cortisol, by the testicles to form testosterone, and by the ovaries to form estrogen and progesterone.
major dietary sources of Cholesterol cheese, egg yolks, beef, pork, poultry, and shrimp • total fat intake, especially saturated fat and trans fat, plays a larger role in blood cholesterol than intake of cholesterol itself Cholesterol Synthesis 20–25% of total daily cholesterol production occurs in the liver other sites of high synthesis rates: intestines, adrenal glands, and reproductive organs
What are the normal functions of triglycerides and Phospholipidsin the body? • Triglycerides supply energy for the body. Triglycerides either meet immediate energy needs in muscles or • stored as fat for future energy requirements. • Phospholipids are compounds that are used to make cell membranes, generate second messengers, and store fatty acids for the use in generation of prostaglandins
What are lipoproteins? And the transport of Cholesterol & Triglycerides • Since blood and other body fluids are watery, so fats need a special transport system to travel around the body. • They are carried from one place to another mixing with protein particles, called lipoproteins. • There are four (or five) types of lipoproteins, each having very distinct job.
What are lipoproteins? And the transport of Cholesterol & Triglycerides A lipoprotein contains both proteins and lipids, bound to another proteins which is called apolipoproteins, which allow fats to move through the water inside and outside cells. ** provide structural support and stability, binds to receptors Lipoprotein structure (chylomicron)
What are the "bad" and the "good" types of cholesterol? LDL cholesterol, the cholesterol carried in LDL particles, is the "bad" cholesterol because. When elevated, LDL cholesterol can promote coronary artery disease. HDL cholesterol, the cholesterol carried in HDL particles, is the "good" cholesterol. It protects against coronary artery disease.
Plasma Transport • Chylomicrons • transporters fats from the intestine to muscle and other tissues that need fatty acids for energy or fat production. • Cholesterol • is not used by muscles • remains in more cholesterol-rich chylomicron remnants, which are taken up from the bloodstream by the liver
Plasma Transport • VLDL molecules • produced by the liver • contain excess triacylglycerol and cholesterol that is not required by the liver for synthesis of bile acids • in the bloodstream, the blood vessels cleave and absorb more triacylglycerolto leave IDL molecules
Plasma Transport • LDL molecules • have the highest percentage of cholesterol within them • major carriers of cholesterol in the blood • LDL-apolipoprotein B complex - recognized by the LDL receptor in peripheral tissues
Hyperlipidemias are classified according to the Fredrickson classification which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation. It was later adopted by the World Health Organization (WHO). It does not directly account for HDL, and it does not distinguish among the different genes that may be partially responsible for some of these conditions
GROUPS OF HYPERLIPIDEMIA: • Primary or familial hyperlipoproteinaemia • Secondary hyperlipoproteinaemia The current classification of hyperlipidemias is based on the pattern of lipid abnormality in the blood.
Primary familial hyperlipoproteinaemia • Subclassified into six phenotypes • I , IIa , IIb, III, IV, and V based on lipoproteins and lipids were elevated. • current literature, however, favour the more descriptive classifications and subclassification • see table 30.2 in foy’s book
Primary Type I • Type I hyperlipidemia is quite uncommon • It is also called familial hyperchylomicronemia and Buerger-Gruetz syndrome. • is due to deficiency of lipoprotein lipase (LPL) or • altered apo lipoprotein C2, resulting in elevated chylomicrons, the particles that transfer fatty acids from the digestive tract to the liver. Its occurrence is 0.1% of the • population.
Primary Type II • the most common form, is further classified into type IIa and type IIb, depending mainly on whether there is elevation in the triglyceride level in addition to LDL cholesterol.
Primary Type II Type IIa Familial hypercholesterolemia This may be sporadic (due to dietary factors), polygenic, or truly familial as a result of a mutation either in the LDL receptor gene on chromosome 19 (0.2% of the population) or the ApoB gene (0.2%).
Primary Type II Type IIb Familial combined hyperlipoproteinemia (FCH) The high VLDL levels (due to overproduction of substrates, including triglycerides). And also high LDL (caused by the decreased clearance of LDL).
Primary Type III is due to high chylomicrons and IDL (intermediate density lipoprotein). It is also known as broad beta disease or dysbetalipoproteinemia,. It is due to cholesterol-rich VLDL.
Primary Type IV also known as hypertriglyceridemia or pure hypertriglyceridemia, is due to high triglycerides.
Primary Type V is very similar to type I, but have high VLDL in addition to chylomicrons. This disease has glucose intolerance and hyperuricemia.
Classification of Antihyperlipidemic Drugs Several different classes of drugs are used to treat hyperlipidemia. These classes differ not only in their mechanism of action but also in the type of lipid reduction and the magnitudeof the reduction.
Drugs for hypercholesterolemia • Bile acid-binding resin • 3-hydroxy-3- methyglutaryl Co A (HMG-CoA) reductase inhibitor • Ezetimibe • Drugs for reducing elevated TG and to raise HDL-C levels • Fibric acid derivatives • niacin
Bile Acid Sequestrants • cholestyramine (Questran) • colestipol hydrochloride (Colestid) • colesevelam (tablet form) • Also called bile acid–binding resins and ion-exchange resins
cholestyramine (Questran) • is a non-absorbed bile acid sequestrant that is used a therapy of hyperlipidemia and for the pruritus of chronic liver disease and biliary obstruction. • is a large, highly positively charged anion exchange resin that binds to negatively charged anions such as bile acids • The binding of bile acids to cholestyramine creates an insoluble compound that cannot be reabsorbed and is thus excreted in the feces.
Mechanism of Action • Bind bile salts in the gut • Bile Acid Binding Resins are not absorbed across the gut into the blood - bile and cholesterol are irreversibly bound in the gut and disposed of in the feces
Moderately effective with excellent safety record • Large MW polymers containing Cl- • Resin binds to bile acids and the acid-resin complex is excreted • prevents enterohepatic cycling of bile acids • obligates the liver to synthesize replacement bile acids from cholesterol • The levels of LDL-C in the serum are reduced as more cholesterol is delivered to the liver • Little effect on levels of HDL-C and TG • Excellent choice for people that cannot tolerate other types of drugs
The net effect - causes the liver to scavenge more cholesterol from the body to make additional bile salts • Liver up-regulates the LDL receptors clearing more LDL from the blood
Adverse effects • Beceause they are not orally absorbed, they produce minimal systemic side effects • Constipation • Heartburn, nausea, belching, bloating • These adverse effects tend to disappear over time
Therapeutic Uses • Type II hyperlipoproteinemia • Relief of pruritus associated with partial biliary obstruction (cholestyramine)
Target: HMG-CoA Reductase (HMGR) • The enzyme that catalyzes the conversion of HMG-CoA to mevanolate. • This reaction is the rate-determining step in the synthetic pathway of cholesterole. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
In 1976…….. • metabolites isolated from a fungus (Penicillium citrinum) were found to reduce serum cholesterol levels in rats. • This work was done by Akira Endo, Masao Kuroda and Yoshio Tsujita at the Fermentation Research Laboratories, Tokyo, Japan. Preliminary experiments showed that these fungal metabolites had no effect on mevanolate or other steps in the biosynthetic pathway. This led to the speculation that their action was somewhere between the mevanolate and the HMG-CoA
Statins • This metabolite was later called compactin (6-demethylmevinolin or mevastatin). A related fungal metabolite called lovastatin (mevinolin) was also found to be another good inhibitor of HMG-CoA reductase. Lovastatin was isolated fromAspergillus terreus. Today, there are two classes of statins: Natural Statins: Lovastatin(mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor). Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin (Lescol). Statins are competitive inhibitors of HMG-CoA reductase. They are bulky and “stuck” in the active site. This prevents the enzyme from binding with its substrate, HMG-CoA.