2020 2017 Created by Dr. Yazan akkam
Learning Objectives should be able to: • Distinguish between the terms dyslipidemia, hyperlipidemia, and hyperlipoproteinemia. • Describe mechanism of action of: • a. Bile acid sequestrants (BAS) • b. Niacin • c. Ezetimibe • d. Phenoxyisobutyric acid derivatives (fibrates) • e. Hydroxymethylglutaryl- (HMG-) CoA reductase inhibitors (statins) • f. Orphan drugs used in the treatment of homozygous familial hypercholesterolemia (HoFH). • Discuss applicable structure–activity relationships (SAR) (including key aspects of receptor binding) of the above classes of antihyperlipidemic agents. • List physicochemical and pharmacokinetic properties that impact in vitro stability and/or therapeutic utility of antihyperlipidemic agents. • Diagram metabolic pathways for all biotransformed drugs, identifying enzymes, and noting the activity, if any, of major metabolites. • Apply all of the above to predict and explain therapeutic utility.
Introduction • Cholesterol : biosynthesis of corticosteroids, sex steroids, bile acids and cell membranes • along with the lipoproteins(transporter), lead to atherosclerosis, a factor in the development of coronary artery disease/coronary heart disease (CAD/CHD) • an excess of serum triglycerides leads to negative cardiovascular consequences→ pancreatitis. • Heredity sometimes wins out over even the healthiest lifestyle
The conversion of cholesterol to bile acids and bile salts. reabsorbed
Dyslipidemia • abnormal level of serum lipids and/or lipoproteins → atherosclerosis and CHD • Causes • Primary dyslipidemias :genetic predisposition • Secondary dyslipidemias : pathologic conditions or lifestyle choices. • Hyperlipidemia: elevation of serum cholesterol, cholesterol esters, triglycerides, and/or phospholipids. • Increases risk of CHD. • increases risk of pancreatitis • Hyperlipoproteinemia: elevation of the lipoproteins that transport lipids through the bloodstream • ↑low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) • ↓high-density lipoproteins (HDLs)
Therapeutic approaches to the treatment of hyperlipidemia and hyperlipoproteinemia 1. inhibiting intestinal reabsorption of bile acids (BAS). 2. inhibiting triglyceride biosynthesis and VLDL formation (niacin). 3. inhibiting intestinal absorption of dietary cholesterol (ezetimibe). 4. stimulating serum triglyceride cleavage and clearance (fibrates). 5. inhibiting de novo cholesterol biosynthesis (HMG-CoA reductase inhibitors).
Cholesterol and Bile Salts • rate-limiting step in cholesterol biosynthesis : of 3-hydroxy-3-methylglutaryl-CoA to R(-) mevalonic acid. • HMG-CoA reductase • Bile acids promote the intestinal absorption of lipids and fat-soluble vitamins • anionic conjugate base of a bile acid is called a bile salt
Triglycerides • long-chain fatty acid esters of glycerol • Enzymes involved in triglycerides biosynthesis • phosphatidic acid phosphatase (PAP) • monoacylglycerol acyl transferase (MAGAT) • diacylglycerol acyltransferase (DAGAT) • normal concentrations are stored in adipose tissue • When is needed , hydrolyzed by lipases to release free fatty acids (FFAs) • transported in serum solubilized by VLDL
Overview of Triglycerides • accumulate primarily in the cytosol of adipose cells • When required for energy production, triglycerides are hydrolyzed by lipase enzymes to liberate free fatty acids that are then subjected to β- oxidation, the citric acid cycle, and oxidative phosphorylation.
The LDL consists of 50% 90% triglycerides by weight and cholesterol and 10% triglycerides originate from exogenous fat from the diet 60% triglycerides, 25% cholesterol 12% cholesterol, and and 50% protein 18% phospholipids 65% of the plasma cholesterol 17% of the total cholesterol in plasma
dietary intake FC, free unesterified cholesterol FFA, free fatty acids LCAT, lecithin-cholesterol acyltransferase LDLR, low-density lipoprotein receptor. synthetic begins in the liver with the formation of VLDL
no longer protected by plasma antioxidants Atherosclerosis
Bile Acid Sequestrants (BAS) • Cholestyramine, colestipol, and colesevelam are used to treat hypercholesterolemia • nonabsorbable anionic exchange resins
Bile acid synthetic pathway (7α-hydroxylase) cholic acid (CA) Chenodeoxycholic Acid(CDCA) deoxycholic acid lithocholic acid
Mechanism of action • trade chloride anions bound to strongly cationic centers for intestinal bile salts glycocholate and taurocholate. • Bile salts have higher affinity for the resin’s cationic amines than chloride anion • strong ion–ion bonds • excreted in the feces • Loss of hepatic return of bile acids • stimulates 7α-hydroxylase-mediated oxidation of hepatic cholesterol • increase in LDL clearance • De novo cholesterol biosynthesis is stimulated, but cannot overcome cholesterol loss from oxidation.
Mechanism of action • Colesevelam : • structure is novel • It does not possess the chloride ions, however, and, strictly speaking, is not an anion-exchange resin . • has good selectivity for both the trihydroxy and dihydroxy bile acids→ reduced side effects • Does not have a high incidence of causing constipation→ ability to “pick up” water as a result of its affinity for hydroxyl system (i.e., hydrogen bonding with either the bile acid or water)→ yields softer, gel-like materials that are easier to excrete
The net effect: -decrease in total serum cholesterol and LDL -Triglyceride and VLDL levels may rise (definite in hypertriglyceridemia)
Administration of BAS • dry resins (powder or granules) that are commonly administered as thick slurries by mixing with a noncarbonated beverage • distasteful, which impacts adherence. • Can sprinkle drug on foods (pulpy fruits, or cereals) • Colestipol and colesevelam: tablets with plenty of water • Cholestyramine and colesevelam are administered with meals • Colestipol administration is not restricted with regard to meals.
SAR • BAS contain permanently or potentially cationic amines that strongly bind intestinal glycocholic and taurocholic acids. • Cholestyramine and colesevelam are quaternary amines and exhibit pH independent action. • Colestipol’s secondary and tertiary amines must protonate in the intestine→ pH dependent action lowers anion exchange capacity • Colesevelam→ greater bile salt selectivity→ fewer drug–drug interactions
Physicochemical and Pharmacokinetic Properties • water-insoluble resins. They are not absorbed across gastrointestinal membranes. • metabolically inert and, along with their irreversibly bound bile salts, are excreted in feces. • The normal transit time of BAS within the gastrointestinal tract is 4 to 6 hours.
Clinical Applications • administered once or twice daily • Cotreatment with niacin or statins requires careful attention to administration timing • The statin in BAS–statin cotherapy blocks the cholesterol biosynthesis surge by the fecal loss of bile acids. • BAS tablets are large and should not be used in patients with swallowing disorders • Therapeutic benefit is realized within 1 week (decreased LDL) to 1 month (decreased cholesterol).
DRUG–DRUG INTERACTIONS • Drugs anionic at intestinal pH (e.g., warfarin, thyroid hormone, phenytoin) and some nonanionic drugs that are coadministered with a BAS can be sequestered by the resin and will not be absorbed. • Give potentially interacting drugs 1 hour before or 4 to 6 hours after the BAS. • Colesevelam’s coadministration of some anionic drugs, including antihyperlipidemic statins • BAS can absorb dietary vitamin K, leading to possible hemorrhage • BAS may prevent absorption of folic acid and the fat- soluble vitamins A , D , E , and K.
Keto Enol
ADVERSE EFFECTS • Bloating, abdominal discomfort • Potentially severe constipation or bowel obstruction • Aggravation of pre-existing hemorrhoids • Gallstones (cholelithiasis) • Pancreatitis • Hyperprothrombinemia and bleeding
CHEMICAL NOTE • Cholestyramine can be compounded into ointments for the topical treatment of diaper rash (very effective) • the resin will sequester the highly irritating bile acids that are excreted in stool and held against the diapered skin
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors • hepatic enzyme is involved in cholesterol homeostasis • binding of this enzyme to LDL receptors leads to their degradation and an overall increase in plasma LDL levels • Alirocumab (Pradulent) and evolocumab (Repatha) are human monoclonal IgG antibodies that bind to PCSK9 and inhibits its action. • must be administered subcutaneously
Mechanism of PCSK9
SAR (Fab)
Niacin (B3) - (Nicotinic Acid) Nicotinic Acid vitamin essential structural component - nicotinamide adenine dinucleotide (NAD+) - nicotinamide adenine dinucleotide phosphate (NADH+)
Niacin(B3) (Nicotinic Acid) • MOA : inhibition of lipolysis in adipose tissue 1. stimulates the GPR109A (Niacin 1) receptor found in adipocytes, spleen, and macrophage • Ion-ion bond with a cationic receptor Arg is important to activity • Lipolysis of stored triglycerides is inhibited, resulting in decreased production of triglycerides, FFA, VLDL, and LDL 2. lowers serum triglycerides by inhibiting diacylgycerol acyltransferase 2(DAGAT2) • Acylation of diglycerides to triglycerides is blocked. 3. Niacin inhibits receptor-mediated uptake of HDL, resulting in increased serum HDL 4. Nicotinic acid does not have any effects on cholesterol catabolism or biosynthesis.
SAR • nonhygroscopic, white, crystalline powder • 3-pyridinecarboxylic acid • Niacin must be anionic to be an effective antihyperlipidemic. • The carboxylic acid is essential. Nonionizable amides (e.g., nicotinamide) are inactive. • Essentially, any change made on the niacin structure results in inactivation.
Physicochemical and Pharmacokinetic Properties • The carboxylic acid (pKa 4.76) , pyridine nitrogen (pKa 2.0) → amphoteric. • log P of −0.20 at pH 6.0 • It exists predominantly as the active anion at pH 7.4. • Absorption of niacin from the gut is rapid. • The short 1-hour half-life necessitates frequent dosing of the immediate release formulation (Extended release formulations→ 8 to 10 hours) • Niacin dosage forms are not interchangeable.
Metabolism • excreted in the urine unchanged or conjugated with glycine (nicotinuric acid)
Clinical Applications • Although niacin is the drug of choice for type II hyperlipoproteinemias, its use is limited because of the vasodilating side effects • As antihyperlipidemic, niacin is dosed up to 6 g/day. Niacin administered as vitamin B3 is dosed at 13 to 20 mg/day • tactics to minimize vasodilation-related adverse effects include: • Bedtime administration. • Titrating the dose upward over 1 to 4 months. • Letting normal tolerance take effect (3 to 6 weeks).
Cholesterol Absorption Inhibitor
Ezetimibe -Intestinal cholesterol absorption, occurring primarily in the duodenum and proximal jejunum, can also contribute to serum cholesterol levels -Dietary intake provides about a quarter of the cholesterol entering the intestinal lumen, while the remaining three-quarters are derived from biliary cholesterol excretion from the liver
MOA 1. selectively blocks a cholesterol-active transporting protein at the intestinal brush border: • Niemann-Pick C1-like 1 (NPC1L1) + Scavenger receptor class B member 1 (SR- BI) + Aminopeptidase N (CD13) + lecithin-cholesterol acyltransferase (LCAT) → sensitive to Ezetimibe blocking 2. Inhibition of dietary cholesterol absorption increases serum LDL clearance and decreases total serum cholesterol. 3. cholesterol biosynthesis surge occurs, but the net result is a decrease in serum LDL. Note: does not interfere with the absorption of triglycerides, lipid-soluble vitamins, or other nutrients.
MOA Niemann–Pick C1-like 1 protein ((NPC1L1)) :the human sterol transport protein that was expressed at the enterocyte/ gut lumen (apical) as well as the hepatobiliary (canalicular) interface
Discovery 2-Azetidinone simplest β-lactam • 2-azetidinones as inhibitors of 34 cholesterol absorption→1994 21 • Approval Date: 2002 • key elements for the inhibition of cholesterol absorption: a. 2-azetidinone b. N-1-aryl group c. 4S-alkoxyaryl substituent d. C-3 arylalkyl substituent Earl, J., & Kirkpatrick, P. (2003). Ezetimibe. Nature Reviews Drug Discovery, 2(2), 97–98. doi:10.1038/nrd1015
SAR keep ezetimibe localized in the small intestine stereospecific benzylic hydroxylation -active metabolite→ longer duration of action block intestinal CYP- 1,4-diaryl-β-lactam ring is mediated aromatic essential for the binding of hydroxylation, ezetimibe to NPC1L1 prolonging duration of action 50-fold increase in in vivo potency over SCH 48461
Physicochemical and Pharmacokinetic Properties • acidic compound: phenolic hydroxyl (pKa 9.72) is predominantly unionized at intestinal pH. • crystalline powder that is practically insoluble in water but is freely soluble in ethanol and other organic solvents. • log P value is 3.50 • Oral absorption is rapid and food independent. • Approximately 60% of an administered dose is absorbed. • Ezetimibe and its active metabolite are highly protein bound and have half-lives approaching 22 hours.
Metabolism Renal 11%, fecal 78%
Fibrates
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