Dyslipidemia pharmacology Hypercholesterolemia injectable preparation

Hypercholesterolemia

1. Dyslipidemia pharmacotherapy Dr Mahesh B Mudhol

2. Plasma lipoproteins Size , composition - 7 types Chylomicrons Chylomicron remnants: VLDL, IDL, LDL, and Lp (a) HDL is non atherogeic Cholesterol synthesis occurs in both peroxisomes and endoplasmic reticulum (ER) (Fig. 1) and shows a diurnal rhythm peaking at 0300–0500 Rusnak & Krisans, 1987, Krisans, 1996, Wanders & Tager, 1998, Aboushadi et al., 1999, Hogenboom et al., 2002, Kovacs et al., Apolipoproteins have four major functions 1) serving a structural role, 2) acting as ligands for lipoprotein receptors, 3) guiding the formation of lipoproteins, and 4) serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins

3. Plaque rupture, which provides a substrate for-------thrombosis Inflammatory fibroproliferative response-----dense fibrous cap overlying a lipid-rich core ---- Plaque Protective mechanisms------‘reverse cholesterol transport’ Subendothelial accumulation of foam cells and T lymphocytes to form fatty streaks Ox LDL uptake by macrophages via ‘scavenger’ receptors. Low-density lipoprotein (LDL) cholesterol transport Injury of dysfunctional endothelium Atherogenesis Endothelial dysfunction

4. HYPOLIPIDAEMIC DRUGS HMG-CoA reductase inhibitors (Statins) Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin, Pitavastatin Bile acid sequestrants (Resins) Cholestyramine, Colestipol Lipoprotein lipase activators (PPARα activators, Fibrates) Clofibrate, Gemfibrozil, Bezafibrate, Fenofibrate Lipolysis and triglyceride synthesis inhibitor Nicotinic acid Sterol absorption inhibitor Ezetimibe CETP INHIBITORS Torcetrapib, Anacetrapib

5. Cholesterol,Chylomicron familial hyperlipoproteinemia type 2A or Fredrickson type 2A hyperlipidemia

6. Statins Statins : HMG CoA reductase inhibitors transported into cells by the organic anion transporter (OAT), and some may be excreted by the action of the multiple drug resistance protein MDR-2 whose action they may also inhibit (Wang et al., 2001). Lovastatin (20-80mg) Simvastatin (10-40mf) Atorvastatin(10-80mg) LDL 30-70% reduction Rosuvastatin(5-40mg) Pravastatin (10-80mg) Pitavastatin(1-4mg) AE:gastrointestinal disturbance, abnormal liver transaminases, and myalgia-myositis The mechanism of rhabdomyolysis and myositis (painful myalgia with a significant creatine kinase release [>2000 IU/L]) induced by statins remains obscure, though contributors include low muscle mass, age (different muscle subfibre type), hypothyroidism, and concomitant medications (Wierzbicki, 2002). statins can induce a transient acute phase response on initiation, especially at high doses which can cause transient hepatitis Wierzbicki et al., 1998, Wierzbicki et al., 2001 discontinue statin therapy due to liver transaminase levels exceeding 3 times the upper reference limit (∼150 IU/L). CI: ALF,pregnancy category X,breast feeding,with Fluconazole,Itraconazole

7. Bile acid sequestrants (BASs) T./Cap. Cholestyramine Colestipol Colesevelam BASs highly positively charged,bind to bile acids in the intestine, preventing them from being reabsorbed into the body. This causes the liver to produce more bile acid, which competes with cholesterol production. with restriction of dietary saturated and trans-fatty acids Safe in paediatric,can be used in Statin intolerant Also in Tx of Pruritus of Partial Biliary Obstruction,T2DM,Chronic diarrhoea CI: Severe hyper triglyceridemia Lower LDL-10–20%, and slightly raise HDL

8. Nicotinic acid /Niacin / Vitamin B3 Recommended Daily Allowance (RDA) for adults ranges between 16 and 18 mg daily anti-inflammatory effects, inhibition of free oxygen radical , increase of serum adiponectin levels In adipose tissue, inhibits the lipolysis of triglycerides by hormone sensitive lipase, thereby reducing transport of free fatty acids to the liver and decreasing hepatic triglyceride synthesis. raises HDL-C levels by decreasing the fractional clearance of apo A-I in HDL AE: Flushing,Niacin also elevates uric acid levels and may reactivate gout. 35-50% reduction in TG 4-7days to be effective Niacin is the most effective agent available for increasing HDL-C (30%–40%) Concurrent use of niacin and a statin can cause myopathy.

9. Fibrates activates lipoprotein lypase through nuclear peroxisome proliferator activated receptor alpha. TGs are reduced 1st generation Gemfibrozil Bezafibrate 2nd Generation Fenofibrate 200mg OD č meals Elevated triglycerides are an important risk factor for pancreatitis. with type III hyperlipoproteinemia (dysbetalipoproteinemia) are better responders T.Gemfibrogyl600-mg dose taken twice daily, 30 min before the morning and evening meals. AE: increased risk of gallstone formation CI: children & pregnancy

10. Ezetimibe Ezetimibe inhibits luminal cholesterol uptake by jejunal enterocytes, by inhibiting the transport protein Niemann-Pick C1-Like 1 (NPC1L1) 15-25% reduction in LDL,a nonstatin AE: Flatulance , Diarrhoea CI:

11. Omega-3 fatty acids Omega-3 fatty acids, commonly Eicosapentaenoic acid ( EHA )and DHA docosahexaenoic acid ethyl esters, reduce VLDL triglycerides and are used as an adjunct to diet for treatment of adult patients with severe hypertriglyceridemia. 1-2grans OTC arthralgia, nausea, fishy burps, dyspepsia

12. Glitazars PPAR Alpha & PPAR Gama agonist Orally should be taken before the first meal of the day. AE:stomach inflammation, nausea, vomiting, weakness ,

13. I nhibitors of cholesteryl ester transfer protein (CETP): significantly raises plasma concentrations of HDL but clinical trials showed no benefits Torcetrapib -putative off-target effects not related to CETP inhibition that were specific to torcetrapib. Anacetrapib , Evacetrapib Dalcetrapib -Human arterial imaging was favourable https://doi.org/10.2147/dddt.s34976 PMID: 23055695 PMCID: PMC346067 HDL lifecycle and CETP function.Notes: Pre-β HDL (lipid-poor apo A-I HDL particles) is converted to spherical HDL3 by lecithin-cholesterol acyltransferase (LCAT). HDL3 is converted to HDL2 by fusion of small HDL particles activated by phospholipid transfer protein (PLTP). The modulator role of CETP transfers cholesteryl esters (CE) between HDL particles to create both larger HDL2 and smaller pre-β HDL particles (green arrows), which may be an antiatherogenic process. CETP also mediates heterotropic transfer of triglyceride between LDL/VLDL and HDL (orange arrows), as discussed in the text.Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein.

14. PCSK9 inhibitors Proprotein convertase subtilisin/kexin type 9 is a protease that binds to the LDL receptor on the surface of hepatocytes and enhances lysosomal degradation of the LDL receptor, resulting in higher plasma LDL concentrations. siRNA that targets PCSK9 mRNA Inj.Evolocumab is administered as a 140-mg injection every 2 weeks or 420 mg once monthly. S/C Inj Inclisiran

15. Lomitapide Inhibitor of Microsomal Triglyceride Transfer Lomitapide,reduces VLDL Metabolism: metabolized by CYP3A4 Indicated for lowering LDL as adjuvant CI : with inhibitors of CYP3A4 5mg/d before meal

16. Inhibitor of apolipoprotein B-100 synthesis - Mipomersen first antisense oligonucleotide inhibitor of apo B-100 synthesis acts on mRNA and inhibits apo B in a sequence manner S/C Inj 1ml of 200mg/ml once weekly Maximal LDL reduction can be achieved after 1-2 months

17. Drug interactions Statin interactions occur with fibrates, especially Gemfibrozil (38%), and with Cyclosporine (4%), D igoxin (5%), Warfarin (4%), macrolide antibiotics (3%), and azole antifungals (1%). Ledipasvir (LDV) NS5A inhibitor inhibits BCRP and Rosuvastatin levels will increase Gemfibrozil and higher doses of statins . Gemfibrozil inhibits hepatic uptake of statins by OATP1B1 and competes for the same glucuronosyl transferases that metabolize most statins. Itraconazole is a strong CYP3A4 inhibitor and increases the AUC of Lovastatin acid and Simvastatin acid by 15-20 times and 19 times their original values, respectively. According to a 2012 FDA warning, Simvastatin should not be used in combination with cyclosporine , HIV protease inhibitors, erythromycin , or gemfibrozil

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