Lipid-lowering drugs

1. 2011 Mgr. Petra Hirsova Lipid-lowering drugs

2. Plasma lipids Cholesterol, triglycerides, phospholipids, free fatty acids Transported as lipoproteins Core – hydrofobic lipids: cholesteryl esters, triglycerides Coat – hydrophiliclipids: cholesterol, phospholipids

3. Hyperlipoproteinemia Assessed by levels of cholesterol, LDL, HDL a LDL/HDL ratio (atherogenic index) Total cholesterol 5-6 mmol/L, LDL < 3 mmol/L, HDL >1,5 mmol/L ↑ ↑ cardiovascular risk (endothelial dysfunction, atherosclerosis, AMI…) Primary X secondary (caused by other disease) Unhealthy lifestyle, ↑ “unhealthy“ lipids in the diet, lack of exercise Dyslipidemia False LDL/HDL ratio but total cholesterol within the limits

4. Drugs decreasing plasma cholesterol Decreased (re)absorption of bile acids/cholesterol RESINS, EZETIMIBE Inhibition of cholesterol and VLDL synthesis STATINS, NICOTINIC ACID Increased cholesterol clearance PROBUCOL Drugs decreasing plasma triglycerides VLDL synthesis NICOTINIC ACID and derivatives Conversion of plasma lipoproteins FIBRATES

5. Plasma lipoproteins Chylomicrons VLDL (very low density lipoproteins)‏ IDL (intermediate density lipoproteins)‏ LDL (low density lipoproteins)‏ HDL (high density lipoproteins)‏

6. Chylomicrons Lipoproteiny s nejmenší hustotou (↓ relativní obsah bílkovin x ↑ obsah lipidů) Tvořeny v tenkém střevě– transport TAG do tkání lymfou se dostávájí přímo do systémové cirkulace – obcházejí játra Účinkem lipoproteinové lipázy uvolňují TAG ve tkáních → chylomikronový zbytek (remnant) Vychytáván játry(bohatý na cholesterol z potravy, degradace lysozomálními enzymy) Apolipoproteiny: A-I, A-II, A-IV, B-48, C-III, E

7. VLDL Synthesized in liver (composed of TAG mainly) Transport of TAGfrom liver to periphery (hydrolysis by lipoprotein lipase) Apoproteins:B-100, C-I, C-II, C-III, E IDL (Intermediate density lipoproteins) Taken by liver or converted to LDL by hepatic lipase Composed of cholesterol mainly Final product of VLDL degradation

8. LDL Formed in circulationfrom VLDL(by HDL) Transfer mainly cholesteryl esters to periphery andliver Important for atherosclerosis development (mainly subtype LDL-3) Taken from blood by specific LDL-receptor (both in liver and extrahepatic tissues)→ endocytosis Apoproteins: B-100, lipoprotein a LDL-receptor deficiency → familiar hypercholesterolamia

9. HDL Premature HDL formed in liver → converted to HDL in circulation Important role in chylomicron metabolism and VLDL In periphery bind free cholesterol →esterification→transfer to liver by low-density particle Protective antiatherogeniceffect Apoproteins:A-x, C-x, D, E, (F) Important enzymes: LCAT – free cholesterol esterification CETP – transfer of cholesteryl esters to VLDL and IDL

10. Drugs decreasing plasma cholesterol • Decreased (re)absorption of bile acids/cholesterol RESINS, EZETIMIBE • Inhibition of cholesterol and VLDL synthesis STATINS, NICOTINIC ACID • Increased cholesterol clearance PROBUCOL

11. colestyramine, colestipol, colesevelam Synthetic resins that bind bile acids in the intestinal lumen → decreased return of bile acids to liver → increased synthesis of BA from cholesterol (activation of cholesterol 7-α-hydroxylase) → increased uptake of LDL in liver (up-regulation of LDL-receptor) → mobilization of cholesterol from tissues andremoval from plasma Combined with statins, fibrates, nicotinic acid Used also in bile duct-obstruction (to ↓ BA concentration and pruritus) Bile acid-binding resins - 1

12. pharmacokinetics: Nonabsorbable(106 D), not metabolized → for children and women (in fertile age) Adverse effects: Frequent andcomplicate the therapy (patient compliance) Constipation, flatulence, malabsorption of vit. K, dry and peeling off skin Drug-drug interactions - ↓ BAV Colesevelam– the smallest number of AE Bile acid-binding resins - 2

13. EZETIMIBE Inhibits gut absorption of all sterols (phyto- and chole-sterol) → decreased load of cholesterol to liver Main action: ↓ LDL Synergic action with statins(when combined – reduction of LDL up to 25%) PK:well absorbed, conjugated right in the intestine to a active glucuronide, long biol. half-life (22 h), enterohepatic circulation, excreted to bile (80%) Adverse effects: Headache, GIT dyscomfort Potenciallycancerogenic – future??? Cannot be combined with BA-binding resins

14. STATINS:simvastatin, lovastatin, atorvastatin,fluvastatin, pravastatin, rosuvastatin competitive inhibitors of HMG-CoA reductase lack ofcholesterol in hepatocytes→ ↑ syntesis of LDL-receptors in liver→ ↑uptake of cholesterol in liver Kinetics and metabolism: Sign. first-pass effect in liver – mainly CYP3A4 and 2C9 (newer drugs) inhibition of CYP3A4 (by e.g. ketoconazole, makrolids, fibrates…) →Accumulation and signs of toxicity Simvastatin metabolized only by CYP3A4 –↑risk of interactions! Pravastatinexcreted also by kidney After absorption and metabolism – concentrated in liver by active transport

15. Indication- hyperlipoproteinemia with ↑LDL(Combination with BA-binding resins – ↓LDL by up to 60%) Contraindication: pregnancy, lactation, children (limited experience) Pleiotropic effects → improvement of endothelial dysfunction Anti-platelet action Block proliferation of endothelial smooth muscle Adverse effects!!! ↑aminotransferasesand creatinekinase (need to be monitored!) Myositis of skeletal muscles (up to0.5% of patients) Dependent on dose and accumulation of the drug Can lead to rhabdomyolysis and renal failure Most often after combination of cerivastatin + gemfibrozil (inhib. CYP3A4) Combination of statinswithfibrates is possible and frequent – but it is necessary to balance risks/benefits!!! STATINS - 2

16. NICOTINIC ACID (niacin) and derivatives – acipimox, xantinolnicotinate MA: ↓TAG synthesis (by up to 60 %) – not fully understood Inhibition of VLDL secretion from liver → ↓ VLDL and consequently LDL, ↓ HDL clearance PK: water soluble, metabolized in liver, excreted by kidney AE: typically:rash phenomenon Skin flare (flashing) and pruritus – can disappear later (feeling hot – can be lessened by ASA) 1/5 of patients - hyperurikemia !!! Registered only in combination with laropiprant (PGD2 rcp antagonist) that blocks the rash phenomenon!!! Indication: All dyslipoproteinemias (↓TAG and cholesterol) Not recommended in pregnacy

17. Probucol Structurally altered LDLis formed → removed fasterfrom circulation than noramal LDL Antioxidant –blocks formation of oxidized LDL, and thereby formation of foam cells ↓ levels of cardioprotective HDL! ↓ LDL-cholesterol by 15 – 20% PK: highly lipophilic → elimination takes weeks after the end of therapy AE: GIT disorders (diarrhea etc.), headache, dizziness Not registered in Czech (2009)

18. Drugs lowering plasma triglycerides • VLDL synthesis • NICOTINIC ACID and derivatives • Conversion of plasma lipoproteins • FIBRATES • Normal range of plasma triglycerides – 2 mmol/l • High levels of plasma triglycerides – risk of pancreatitis • Medium-elevated triglyceride levels together with HDL below 1 mmol/l –> risk of atherosclerosis development

19. FIBRARATES:fenofibrate, ciprofibrate, bezafibrate(gemfibrozil, clofibrate) Mode of action: PPARαrcp agonists (Peroxisome Proliferator-Activator Receptor Alpha) ↓VLDL production in liver and ↑VLDL catabolism↑ HDL cholesterol ↑ expression and activity of lipoprotein lipase and↑ β-oxidation of FA ↑ FA synthesis in liver (limits sythesis of TAG and VLDL) ↑ synthesis of apo A-I a A-II (cofactor of LCAT and component of HDL) ↓ synthesis of apo C-III rcp (inhibits lipoprotein lipase and uptake of TAG) Indication: All dyslipoproteinemias (esp. those with high LDL chol.) Except for familiar hypertriglyceridemai(lipoproteinlipase deficiency) Frequent combination with statins

20. FIBRATES PHARMACOKINETICS: Well absorbed from GIT ↑ bound to plasma proteins Enterohepatic circulation Excreted by kidney mainly Adverse effects: Minimal for clinically used drugs Nausea, vomiting, rashes Risk of gallstones??? Very rare - myopathy to rhabdomyolysis(most common with gemfibrozil, which is not in use anymore), arrhythmia Clofibrate – chronic toxicity(cholelithiasis, increased mortality)

21. Examples of dyslipoproteinemia pharmacotherapy: Combination of a non-pharmacological approach andpharmacotherapy Monotherapy replaced with a combination of synergically acting drugs Primary hypertriglyceridemia: Higher intake of omega-3 acids Fibrates, nicotinic acid Primary hypercholesterolemia: BA-binding resins, statins, nicotinic acid Low levels of HDL: nicotinic acid directly increases HDL Secondary hyperlipoproteinemia: Causal treatment + symptomatic therapy according to plasma lipid levels

22. New drugs in the treatment of hypercholesterolemia CETP inhibitors (= cholesteryl estertranfer protein) CETP transports cholesteryl esters from HDL to LDL and VLDL Inhibition leads to ↑ HDL and ↓LDL and VLDL Not registered Torcetrapib (Pfizer) In 2006 withdrawn from phase 3 of clinical trials (in combination with atorvastatin ↑ mortalituy by 60 % compared to atorvastatin) Anacetrapib (Merck) In trials (study DEFINE, ends in 2012), no increase in mortality