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Hypolipidaemic drugs

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Biochemistry, physiology and pathology of lipid metabolism in brief and its applied pharmacotherapeutics in details

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Hypolipidaemic drugs

  1. 1. HYPOLIPIDAEMIC DRUGS Dr Anshuman Parida Department of Pharmacology
  2. 2. Introduction • Hypolipidemic agents, or antihyperlipidemic agents • A diverse group of pharmaceuticals used in T/t of high levels of fats (lipids), such as cholesterol, in the blood (hyperlipidemia). • They are also called lipid-lowering drugs.
  3. 3. Lipid transport and metabolism • Lipids originate from two sources: ▫ Endogenous lipids : synthesized in the liver, ▫ Exogenous lipids: ingested and processed in the intestine. • Dietary cholesterol & triglycerides : packaged into chylomicrons in the intestine into bloodstream via lymphatics. • Liver synthesizes TG and cholesterol packages them as VLDLs before releasing them into the blood
  4. 4. • VLDLs in muscle and adipose blood vessels, their TG are hydrolyzed by LPL to fatty acids. • The fatty acids that are released are taken up by the surrounding muscle and adipose cells. • During this process, the VLDLs become progressively more dense and turn into LDLs • Most LDLs taken up by Liver for disposal, • some circulate and distribute cholesterol to the rest of the body tissues. • HDLs, which are also secreted from the liver and intestine, have the task of preventing lipid accumulation. • They remove surplus cholesterol from tissues and transfer it to LDLs that return it to the liver.
  5. 5. Hyperlipidemia • Elevated concentrations of lipid i.,e, Hyperlipidemia  development of atherosclerosis and CAD. • Dyslipidemia can be primary or secondary. • Primary forms : genetically determined • Secondary forms : Consequence of other conditions such as Diabetes mellitus, Alcoholism, Nephrotic syndrome, Chronic renal failure, Administration of drug…
  6. 6. • Minor (and emerging) factors include: obesity, physical inactivity, athrogenic diet, lipoprotein (a), homocysteine, prothrombotic and proinflammatory factors, impaired fasting glucose.
  7. 7. Management of Dyslipidemia • Drug therapy to lower plasma lipids is only one approach to treatment • Used in addition to dietary management And • Correction of other modifiable cardiovascular risk factors • Several drugs are used to decrease plasma LDL-CHO
  8. 8. CLASSIFICATION 1/2 • HMG - Co A Reductase inhibitors ( Statins ) : Atorvastatin, Simvastatin, Lovastatin, Pravastatin, Fluvastatin, Rosuvastatin • Bile acid binding resins : Cholestyramine, Colestipol, Colesavelam. • Inhibitors of intestinal absorption of cholesterol : Stanol esters , Ezetemibe
  9. 9. CLASSIFICATION 2/2 • Activators of Lipoprotein lipase (LPL) (Fibrates) : Gemifibrozil, Bezafibrate, Fenofibrate, and Ciprofibrate • Inhibitor of VLDL secretion and lipolysis : Niacin (Nicotinic acid) • New drugs (CETP Inhibitors) : Torcetrapib, Anacetrapib
  10. 10. Class: HMG-CoA reductase inhibitors • Mechanism: ↓rate-limiting step in cholesterol synthesis. • Clinical use: ↓ LDL, ↓ triglycerides • Side effects: H : Hepatotoxicity M : Myositis,rhabdoMyolysis G : ↑ FPG C : ↑ Creatinine phosphokinase A : HeadAche, Joint pain R : Rash
  11. 11. Drug Fluvasta tin Pravast atin Rosuva statin Lovast atin Simvas tatin Pitavast atin Atorva satin Dose mg/day 10-80 10-40 5-40 10–40 5–20 1–4 mg 10-80 Absorpti o complete Incomplete, Varies from 45-75% T ½ (hours) 1-3 1-3 18–24 1-4 2-3 12 14 CYP CYP2C9 CYP3A4 DRC Non linear linear LDL-CH lowering efficacy 35% <25% 51-55% 40% 40% 40% 51-55% Special features ↓ Plasma Fibrinoge n Max ↑ HDL First clinicall y used Inactive pro drug C/I - 80 mg Latest & Most Potent Antioxida nt property
  12. 12. Interactions CYP3A4 CYP2C9 INHIBITORS INDUCERS INHIBITORS Macrolide Phenytoin Ketoconazole Cyclosprin Gresiofulvin Metronidazole Tacrolimus Thiazolidinediones Cimetidine Ketoconazole Rifampicin Sulphinpyrazone Protease inhibitor Barbiturates Paroxetine Venlafexine Verapamil Amiodarone
  13. 13. Contraindications • Pregnancy & lactation • Children < 7-8 years • Active liver diseases
  14. 14. Class: Fibrates • Mechanism: binds with PPAR α ↑ lipoprotein lipase → ↓ VLDL ↓TG • Clinical use: Elevated TG and remnants. • Side effects: GI upset (dyspepsia), Cholelithiasis, Myositis Hepatitis Rare • Drug interaction: Warfarin ,OHA
  15. 15. Drug Gemfibrozil Fenofibrate Benzafibrate Clofibrate Dose 600 mg BD 145mg QID 200 mg TDS T ½ (hours) 1.5 20 18-24 Absorption Intestine, Enterohepatic circulation Completely intestine Distribution Tightly bound to plasma protein Excretion Kidney, liver urine, faeces Kidney Special feature Trial for Cancer, Alzheimer Discontinue d
  16. 16. Interactions • Increased risk of myopathy when combined with statins.(fenofibrate) • Displace drugs from plasma proteins( e.g. oral anticoagulants and oral hypoglycemic drugs). Contraindications: • 1- Patients with impaired renal functions. • 2- Pregnant or nursing women. • 3-Preexisting gall bladder disease
  17. 17. Class : Nicotinic Acid • Mechanism: ↓ fatty acid release from adipose tissue, ↓ hepatic synthesis of LDL • Clinical use: ↑ HDL, ↓ LDL, ↓TG • Side effects: Skin flushing, paresthesias, pruritus, GI upset, ↑LFTs, hyperglycemia, hyperuricemia • Prevention of side effects: Aspirin
  18. 18. • Wide spectrum antilipidemic drugs • Most effective in reducing TG level. • Dose: Start with 100 mg TDS, gradually increase to 2–4 g per day in divided doses. • To be taken just after food to minimize flushing and itching.
  19. 19. Class: Cholesterol absorption inhibitors • Ezetinib • Mechanism: inhibits the luminal cholesterol uptake by inhibiting the transport protein on NPC1L1 • Clinical use: ↓ LDL • Side effects: Diarrhea, abdominal pain Angioedema.
  20. 20. • Reduces both dietary and billiary cholesterol. • Dose : 10 mg OD • T 1/2 ~ 22 hours • Long half-life: ▫ Permits once-daily dosing ▫ May improve compliance
  21. 21. Class: Bile acid resins • Mechanism: Bind intestinal bile acids → ↓bile acid stores & ↑ catabolism of LDL from plasma. • Clinical use: ↓ LDL • Side effects: Constipation, ↑ Gallstone formation, GI upset, LFT abnormalities, Myalgias. ↓ Absorption of drugs ADEK vitamins from the small intestine.
  22. 22. • Dose : 4 to 8 g OD/BD, max dose 24 g/d. • Drug interactions : due to the risk of decreased absorption of these drugs. Digitalis, Estrogens and progestins,Oral diabetes drugs, Penicillin G,Phenobarbital,Spironolactone,Tetracycline Thiazide-type diuretic pills,Thyroid medication Warfarin,Leflunomide • Contraindication ▫ 1- Complete biliary obstruction( because bile is not secreted into the intestine). ▫ 2- Chronic constipation. ▫ 3-Severe hypertriglyceridemia(TG >400 mg/dL)
  23. 23. Class : CETP INHIBITORS • Torcetrapib and Anacetrapib  banned. • Dalcetrapib (Clinical trails) • Anacetrapib – Increases HDL-C by 129% • Obicetrapib (TA-8995), Phase II results reported in 2015 • Cholesteryl ester transfer protein (CETP) Facilitates transfer of cholesteryl esters (CE) from HDL-C to LDL-C, VLDL-C during “reverse cholesterol transport”
  24. 24. Antihyperlipedemic combinations Indications: • Increased VLDL during treatment of hypercholesterolemia with resins. • Combined increase in LDL & VLDL. • High LDL or VLDL not normalized with a single drug. • Severe hypertriglycerdemia or hypercholesterolemia. • To take lower doses of each drug
  25. 25. SUMMARY
  26. 26. Thank you……

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