Drugs for Dyslipidemia

It describes all the drugs classified for dyslipidimia

1. DRUGS USED IN DYSLIPIDEMIA Dr.Arthi Post graduate in Pharmacology

2. HMG co-A Reductase Inhibitors : Statins Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin . Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available. Mechanism of action : Inhibiting cholesterol synthesis Increasing LDL uptake by increasing LDL receptors in liver. And also Improve endothelial function Modulate inflammatory responses Maintain plaque stability Prevent blood clot formation Effects: ↓↓ LDL ↑↑ HDL

3. INHIBITS HMG Co-A reductase -rate limiting enzyme Inhibits Hepatic cholesterol synthesis Increses LDL receptor gene expression

4. LDL reduction: Dose Dependent Effect LOVASTATIN 40mg PRAVASTATIN 40mg SIMVASTATIN 20mg upto 80mg ATORVASTATIN 10mg upto 80mg ROSUVASTSTIN 5mg upto 40mg PITAVASTATIN 2mg LDL is reduced by about 6% with each doubling the dose. Statins not effective in Ho-FH. 10MG 20MG 40MG 80MG ATORVASTATIN 33% 40% 45% 55% LOSUVASTATIN 25% 32% 40% Reduction in LDL cholesterol percentage

5. Why Statins are given at night ?? Hepatic cholesterol synthesis is maximal between midnight and 2 a.m so statins with half life <4 hrs are given at night except Atorvastatin and rosuvastatin.

6. Lovastatin Simvastatin Pravastatin First clinically used t1/2 is short. 1-4 hrs. Twice potent t1/2 is 2-3 hrs. t1/2 is 1-3 hrs. reduces plasma fibrinogen Atorvastatin Rosuvastatin Pitavastatin Newer, more potent t1/2 is long. 18- 24 hrs. anti-oxidant property. New, commonly used t1/2 is 18-24 hrs. Raises HDL by 15-20%. Latest, more potent. t1/2 is 12hrs.

7. Adverse Effects Hepatotoxicity-is rare. measure ALT levels Myopathy - major adverse effect which increases with the dose. Rosuvastatin and pitavastatin is better tolerated than other statins. Drugs inhibiting statin catabolism is associated with increased risk of myopathy and rhabdomyolysis. Drug interactions - occur with fibrates commonly Gemfibrozil (38%)and also with cyclosporine(4%), digoxin(5%), warfarin(4%) , macrolide antibiotics(3%), azole antifungals like itraconazole (1%) and HIV protease inhibitors namely amiodarone . FDA withdrew niacin with statin therapy due to increased myopathy. Contraindicated in pregnancy and before conception. Pravastatin is used in children 8 yrs or older.

8. STEROL ABSORBTION INHIBITOR: Ezetimibe inhibits cholesterol uptake by jejunal enterocytes by inhibiting NPC1L1 . It inhibits the cholesterol absorption. Available as 10mg tablet Dual therapy- ezetimibe with statins causes additive reductions in LDL-C levels. LDL is reduced by 15% to 20% Simastatin plus ezetimibe reduces LDL by 60%.

9. COMBINATION THERAPY

10. BILE ACID SEQUESTRANTS/RESINS Bile acid resins - they bind bile acids and it get exceted through faeces . The liver then produces more bile acids to replace those that have been lost. Hence the body uses cholesterol to make bile acids, this reduces the amount of LDL cholesterol circulating in the blood. Also causes upregulation of LDL receptors. Three drugs are members of this class; all are synthetic polymeric resins: Cholestyramine -granular form 16gm/d Reduces 12-18% of LDL Colestipol -10 to 15 gm Colesevelam -625mg , 6 tab /day. Reduces 18% of LDL

11. Cholestyamine susp colestipol suspension Tab. Colesevelam

12. Bile acid resins causes increase in hepatic TGL level , so TGL is to be mointored. so it is contraindicated in Hypertriglycerdemia. Adverse effects : dyspepsia and bloating Drug interactions : Interferes with absorption of many drugs like fursemide, propranolol,L-tyroxine, digoxin, warfarin ,

13. FIBRATES/LPL activators Fibrates are effective in hypertriglyceridaemia and hypercholesterolaemia. They are Lipoprotein Lipase enzyme activators activate nuclear receptor PPAR- α (Peroxisome proliferator activated receptor α) Activation of PPAR- α causes LPL activation Decreased APO-C3( LPL inhibitor) Increased APO-C1( Reverse chL trans) Fibrates have antithrombotic effects- anticoagulant effect and promotes fibrinolysis.

14. I st GENERATION GEMFIBROZIL TYPE 3 LIPOPROTEINEMIA PREVENTS MI IN KNOWN CAD PATIENTS DECREASES CLOTTING FACTOR 7 AND HENCE PROMOTES FIBRINOLYSIS. HAS ANTI-ATHEROSCLEROTIC EFFECT 600 mg BD SECOND GENERATION BENZFIBRATE TYPE 3,4 AND 5 DYSLIPIDEMIA DECREASES LDL-CHOLESTEROL BIP- BENZFIBRATE INFARCT PREVENTION 200 mg TDS FENOFIBRATE GREATER HDL -C AND LOWERS LDL-C MOST SUITABLE FIBRATE TO COMBINE WITH STATINS 200 mg OD ↓ ↓ ↓↓ ↓

15. Adverse effects - Fibrates GI side effects , myalgia and skin rashes Promotes the action of Warfarin Drug interactions : Gemfibrozil inhibits hepatic uptake of statins ,causing increased levels of statins leading to myopathy. Fenofibrate with statin >> Gemfibrozil with statin Gall stone formation increases- it increases lithogenicity of bile.

16. NIACIN - Vitamin B 3 Niacin - Mechanism : Through G-protein (GPR109A) inhibits cyclic AMP thereby reduces TGL synthesis, increases apo B degradation,increases LPL activity and raises HDL-C by increasing clearance of apo A 1. t1/2 is 1 hour ., so requires 2 or 3 times dosing daily A Dose of 2-6g/d reduces TGL by 35%-50% and max effect in 4-7 days A Dose of 4.5-6 g/d reduces LDL-C by 25% and HDL 30%-40%. Two forms - crystalline and sustained release forms

17. Adverse effects - niacin Cutaneous - flushing and pruritis which is PG D2 mediated treated by taking aspirin every day. Flushing is more with hot drinks and can be reduced with low doses. Dry skin GIT: Dyspepsia, avoided in peptic ulcer. Most common - is Hepatotoxicity with >2g of Niacin It causes increase in insulin resistance , hence avoided in DM. Gout : increases uric acid levels. CVS : Atrial tachycardia and AF is reported.

18. MISCELLANEOUS AGENTS Gugulipid - From Guggul gum inhibits cholesterol synthesis . Dose is 25mg three times daily. Reduces LDL and increases HDL level. Loose stools is the only side effect. Fish oil- Omega 3 fatty acids: It contains PUFA namely EPA and DHA in CAD patients . Pure EPA is available or icosapent ethyl 1gm capsule. EPA- Eicosa penta-enoic acid DHA- Docosa hexa-enoic acid

19. PCSK 9 INHIBITORS: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of cholesterol-lowering medications that provide significant reductions in lipids but at a large cost relative to statins. PCSK9 inhibitors - A lirocumab and E volocumab are monoclonal antibodies to PCSK 9. Inclisiran is a s.c injection-inhibits PCSK-9 mRNA. PCSK9 reduces the number of LDLR in hepatocytes by promoting their metabolism and subsequent degradation PCSK9 inhibitors are especially beneficial in the treatment of familial hypercholesterolemic patients who are intolerant to statins or have an elevated LDL-C level despite being on maximally tolerated statin therapy

20. inj.Evolocumab (Repatha ) single 420 mg s.c every 2 weeks and A lirocumab ( PRALUENT) 150 mg every 2 weeks for use in adult patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical ASCVD requiring additional lowering of LDL cholesterol after being on a controlled diet and maximally-tolerated statin therapy.

21. cost of Evolocumab- Rs.20,000 The common side effects of Repatha include nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising where the injection is given. Bococizumab is another pcsk-9 inhibitor to reduce LDL cholesterol is phase 3 clinical trial. In India, these injections are made available only with doctors prescriptions from Indian pharm network.

22. Apo-B 100 Inhibitor: It is used as an adjunct in hypolipidemic drugs and hoFH. Mipomersen binds to the messenger RNA coding for ApoB-100, a protein that is the main component of LDL and VLDL thus inhibiting apoB translation. Mipomersen is the first antisense oligonucleotide inhibitor of apo B-100 synthesis, an essential component of lipoproteins such as VLDL and LDL. Kynamro ,SC dose is 200 mg once weekly is used to treat homozygous familial hypercholesterolemia and is administered by injection. Maximal LDL reduction occurs in 6 months of treatment. Risk Evaluation and Mitigation Strategy (REMS) - The drug has a black box warning about the risk of liver damage; specifically it can cause elevations in the levels of transaminases and causes fatty liver disease.

23. In whom we have to use ?? In Familial hyper cholesterolemia, who lack LDL receptors in whom statins and PCSK-9 inhibitors are ineffective. It reduces Apo B by 30- 54 % LDL-c by 34-52% Lp(a) by 24%

24. MTP INHIBITOR- Lomitapide Lomitapide inhibits the microsomal triglyceride transfer protein (MTP ) which is necessary for VLDL assembly and secretion in the liver. Juxtapid is supplied as a capsule for oral administration. Juxtapid was initiated at 5 mg daily . This inhibits the synthesis of chylomicrons and VLDL ,this leads to reduced levels of plasma LDL-C up to 50%. It is combined with maximally tolerated statins . SE : Diarrhoea, vomiting and abdominal pain. In a Phase III study , lomitapide led to elevated aminotransferase levels and fat accumulation in the liver.

25. APO -C3 INHIBITOR- Volanesorsen Inhibits apo-c3 by antisense therapy inhibits LPL and Hepatic Lipase Hence TGL and LDL decreases HDL increases. It is in Phase 3 clinical trial

26. CETP inhibitors CETP inhibitors inhibit cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels and reduces LDL levels. Torcetrapib, Dalcetrapib, Evacetrapib and Anacetrapib. These drugs have generally failed in clinical trials , either causing a marked increase in deaths (torcetrapib), or having no meaningful clinical improvement despite HDL increases (dalcetrapib, evacetrapib). Anacetrapib- 100mg oral. In 2017, the REVEAL trial based on more than 30,000 participants showed a modest benefit of the addition of anacetrapib to statin therapy. Despite the successful trial, Merck halted the development of the drug.

27. Combination drug therapy Statin Plus Ezetimibe- in primary Hypercholesterolemia. Statins Plus fenofibrates- in Hypercholesterolemia. , however it causes myopathy. FDA withdrew combination of statins with gemfibrozil. Statins with Niacin -is also withdrew by FDA , due to increased myopathy eventhough it increases HDL. Bile acid resins-Cholesteramine with statins -is effective in type 2a Bile acid resins with Niacin -is effective in type 2a and 2b. Bile acis resins with fibrates -is effective in type 2b ,however causes Gallstones . Statins with PCSK-9 inhibitors- a synergistic combination in primary and type 2a.

28. THANK YOU