Hypolipidemics

1. Hypolipidemics This study material is recommended specifically for practical courses from Pharmacology II for students of general medicine and stomatology. These brief notes could be used to prepare for the lesson and as a base for own notes during courses. Addititonal explanations and information are given in single lessons.

2. Plasma lipoproteins

3. Compositionoflipoproteins Chylomicron Triacylglyceroles Cholesterol Phospholipides Proteins

4. Lipoprotein metabolism Lipids from meal Endogenous lipids Extrahepatic tissue Intestine Endocytosis via receptors Liver * Fats Fatty acids Chylomicrons Cholesterol re-entry Chylomicrons remnants Lipoprotein lipase Muscle Lipoprotein lipase free FA Lipids and apoproteins change Adipose tissue free FA free FA free FA

5. Dyslipidemia changeof cholesterol levels and/or TAG and/or HDL cholesterol serumsamplingafter 10 hoursafter last meal Tot-Ch / HDL-Ch ratio= atherogenic index idealapo-B / apo-A1 optimum < 5 (< 4 in personswith CVS risk) ↑ ↑ cardiovascular risk

6. LIPID PLASMA LEVELS (mmol. l-1) normallowintermediate very high risk TC < 5. 2 5. 2 - 6. 5 6. 5 - 7. 8 > 7. 8 TG< 2. 3 2, 0 - 2. 5 2. 5 - 4. 6 > 4. 6 LDL < 4. 1 4. 0 - 5. 0 5. 0 – 5. 5 > 5. 5 HDLf > 1. 2 < 1. 0 < 0. 8 HDL m > 1. 4 < 1. 2 < 1. 0 HDL 0. 25 < 0. 2 0. 2 – 0. 25 << 0. 2 > - LDL

7. Dyslipidemia primary secondary(caused by otherdisease)

8. Hyperlipoproteinemiaclassification

9. HYPOLIPIDEMICS • Purposeofadministration: • myocardialinfacrtionprevention • preventionofothercomplications (ictus, peripheralvesselsischaemicdisease) • Maineffect: • prophylaxisofatheroscleroticplaquesformation = vesseldiameterreduction Hyperlipidemia risk factors: • CH and lipid‘shighbloodlevels (from diet, synt. de novo) • increased BP • tobacco smoking • obesity, diabetes mellitus • sedentarylifestyle

10. Regimeprecautions quit smoking, regularphysicalactivity, diet adjustment weightreduction, decreaseoffats in diet (mainly animal) and increaseoffibreintake

11. Dyslipidemiapharmacotherapy Plasma cholesterol decrease decreaseintestinal (re)absorptionofbileacids/cholesterole RESINS, EZETIMIB inhibits cholesterol and VLDL synthesis STATINS, NICOTINIC ACID increase cholesterol clearence PROBUCOL Plasma TAG decrease inflence on VLDL synthesis NIKOTINIC ACID influence on plasma lipoprotein conversion FIBRATES

12. 1. Drugsplasma CH decreasingintesrinalbile acid/CH reabsorption RESINS EZETIMIB inhibitsynthesisof CH and VLDL STATINS NIKOTINIC ACID increaseof CH clearence PROBUCOL

13. RESINS colestyramine, colestipol, colesevelam syntheticresins, binds to bileacidsin intestine 1g binds 100 mg ofbileac. → decreaseofbile acid re-entry to liver → increaseofbileacidssynthesisfrom CH (activationof 7-α-hydroxylasis) → increaseof liver LDL uptake(up-regulationof LDL-receptor) → cholesterol tissuemobilization and uptakefrom plasma to liver combinationwith …

14. RESINS PK:are not absorbed (1 mil.D), not biotransformed → AE:common and complicatingtherapy(mainly adherence to therapy) constipation, flatulence, vit. Kmalabsorption;dry, peeling skin  TAG, ALP, transaminases interactionswith co-administereddrugs - ↓ bioavailability 1 hourbeforeor 4 hoursafterresins colesevelamlowest incidence of AE cab bealsoused in bileductobstructionto reducetheamountofbileacids

15. EZETIMIB intestinalabsorption inhibitorofallsterols (fyto- and cholesterol) blockof transport protein*→ decrease cholesterol availability maineffect: decreaseof LDL synergisticeffectwithstatins(when co-administered– LDL reduction up to 25%) PK:p.o. fast absorption, conjugated to activeglucuronide enterohepatalrecirculation- long T1/2 (22 hrs), 80 % eliminated in bile AE:cephalgia, GIT dyscomfort should not becombinedwithresins *Niemann Pick C1 Like 1 (NPC1L1)

16. STATINS simvastatin, lovastatin, fluvastatin, pravastatin atorvastatin,rosuvastatin(long acting) MofA:  cholesterol in hepatocytes → ↑ LDL-receptorssynthesisin liver (LDL receptor up-regulation) → ↑ cholesterol liver uptake → ↑ LDL clearence

17. Cholesterol synthesis HMG-CoA-reduktáza

18. STATINS PK:lova- a simvastatinprodrugs 30 % intestinalabsorption significantfirstpasseffect CYP3A4 and 2C9 biotransformation CYP3A4 inhibition(e.g.ketoconazole, macrolides, fibrates…) →cumulation and sign of toxicity simvastatinonly CYP3A4 metabolism –↑ risk ofinteractions! concentrated in liver bileexcretion; pravastatinalsokidneyelimination

19. STATINS I:hypercholesterolemiawith↑LDL (in monotherapydecreaseupt o 40%) in combinationwithresins – LDL decrease up to 60 % pleiotropic (extralipid) effectsofstatines: CI:gravidity, lactation, children (limited knowledge), hepatopathy

20. STATINs AE: liver impairment: oftransaminases and creatinekinases (shouldbemonitored) skeletalmusclesmyositis(0,5% incidence) canlead tok rhabdomyolysis and renalfailure(most oftenaftercombinationofsimvastatin + gemfibrozil; generalyaftercombinationswithfibrates and CYP3A4 inhibitors) interactions!!

21. Statins‘ drug-druginteractions CYP 450 effectdrugs ↑statin plasma cyclophosphamide, codeincyclosporine, diazepam,keto-inhibition 3A4levelconazole, nifedipine, vera- pamil,lidocain, grapefruit juice  statin plasmabarbiturates, carbamazepine, induction 3A4levelphenytoin, rifampicine, primidone. . . ↑statin plasmaamiodarone, cimetidine, inhibition 2C9levelfluoxetine, isoniazide, ketoconazole, metronidazole. . .  statin plasmabarbiturates, carbamazepine, induction 2C9levelphenytoin, rifampicine. . .

22. NICOTINIC ACID (niacin) derivatives: acipimox, xantinolnicotinate MofA:decrease TAG synthesis (up to 60 %) – not fullydescribed  VLDL from liver → follow –up by LDL, necessary  dosesthan in vitamine supplementation PK:watersoluble, p.o. readilyabsorbed, liver metabolism, renalexcretion I: alltypesofdyslipoproteinemia (decreaseof TAG leveluptot 60% and CH up to15-30%)

23. NICOTINIC ACID (niacin) AE:typicalisrashphenomenon flushing(most evident on face and neck - PGD2 release) pruritus (decreased by ASA administration) hyperurikemia (KI gout), GIT disturbances, hyperglycaemia, glycosuria reg. only in combinationwithlaropiprant(PGD2rec.antagonist - blocksrashphenomenon!!!)

24. PROBUCOL MofA: leads to productionofstructurallydifferent LDL→ fastereliminationfromcirculation in comparison to normal LDL antioxidant – preventsproductionofoxidized LDL and thuspreventsfoamcellsformation  HDL! sdecreaseLDL-cholesterol up to 15 – 20% PK:lowperoralbiolavailability highliposolubility→ elimination in weeksafterdrugdiscontinuation AE: GIT disturbances(diarrhoeaetc.)headache, vertigo

25. 2. Plasma TAG agents influencingsythesisof VLDL NICOTINIC ACID influencingplas,a lipoprotein conversion FIBRATES physiological plasma levels TAG – 2 mmol/l (1,7) conc. TAG – risk ofpancreatitis mediumconc. of TAG in combinationwithHDL plasma levelbeneath 1 mmol/l – high risk ofatherosclerosis mild TAG - diet + ω3 PUFA

26. FIBRATES fenofibrate, ciprofibrate, bezafibrate (gemfibrozil, clofibrate) MofA:PPAR-α* rec. agonists – inhibit liver VLDL production and↑ VLDLkatabolism(↑ LPL activity) circulating VLDL (TG) up to 35 % → total and LDL-cholesterol mild HDL (decrease TAG releasesthe HDL bindingcapacityforchol. esters) I: insteadoffamiliarhypertriglyceridemia(type I – LPL deficiency) PK:goodintestinalabsorption, ↑protein binding., enterohepatalrecirc.renalexcretion *peroxisome proliferator-activated receptors

27. FIBRATES AE:nausea, vomiting, risk ofcholelithiasis (CH in bile), myalgia, tiredness dangerousmyositisup to rhabdomyolysis, dysrhytmias–  risk withstatines! clofibrate- chronic toxicity (cholelithiasis,  overal mortality) CI: hepatopathy,  renalfunctions

28. OTHER AGENTS WITH HYPOLIPIDEMIC ACTIVITY ABSORBABLE esentialphosholipides vitamines C and E magnesium heparinoids UNABSORBABLE: neomycine plant sterols – sitosterol, sitostatol activated charcoal dietaryfibre