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Similar to Inhibitors of PCSC9 - indications, class effects, interactions, side effects by Shahid Raja and Poulomi Jana
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Inhibitors of PCSC9 - indications, class effects, interactions, side effects by Shahid Raja and Poulomi Jana
- 2. ABSTRACT • Cardiovascular diseases: leading cause of morbidity and mortality in the world. • Elevated Low-Density Lipoprotein-Cholesterol (LDL-C) levels is the major riskfactor. • Lower levels of LDL-C can effectively reduce the risk of cardiovascular diseases. • PCSK-9 plays animportant role in regulating the degradation of hepatic LDL receptorsthatremoveLDL-Cfromthecirculation. • PCSK-9 inhibitors area new class of agents for the treatment to reduce LDL- Clevels. • Two PCSK-9 inhibitors, alirocumab andevolocumab,have beenapproved to treathypercholesterolemia. • Through the inhibition of PCSK-9 and increased recycling of LDL receptors, serumLDL-Clevelscanbesignificantlyreduced.
- 3. CHOLESTEROL SYNTHESIS • Liveristhemajororganwherecholesterolissynthesized. • AcetylCoAismetabolizedintoHMGCoA • HMG CoA undergoes a reaction catalyzed by HMG CoA reductase enzyme to make Mevalonate and this is the rate limiting stepincholesterolsynthensis. • Mevalonate undergoes a series of reaction to convert into cholesterol. • Cholesterol will have a negativefeedback effecton HMG CoA reductaseaswellasthegeneencodingfortheLDLreceptor. • So there will be less LDL receptors expressed on the cell membraneofhepatocyte.
- 4. CHOLESTEROL SYNTHESIS • The cholesterol is converted into cholesterol ester by ACAT enzyme (Acylcholesterolacyltransferase). • Now thecholesterol ester will be loaded on to ApoB100 to make VLDL molecule • VLDL is released into the circulation and VLDL undergoes metabolism tomakefirstIDLandthenLDLmolecules. • 60% of circulatingLDL will gobackto the liverand40% is taken upby extrahepatictissues. • So for LDL to get into the cells it has to bind to LDL receptor that is expressedonthecellmembraneofhepatocytes. • LDL receptor has got an extracellular domain and also a cytoplasmic domain. • LDL interacts with the LDL receptor and it is internalized into the cytoplasmmakingaLDL-LDLreceptorendosome.
- 5. CHOLESTEROL SYNTHESIS • Theendosomefuseswiththelysosome. • Inthelysosome,LDLisbrokendownandthecholesterolgetsintothecell. • In theendosome, thereisadrop in thepH andbecauseof thedrop in thepH there will be change in the confirmation of the interaction of LDL receptor with the LDL. So because of the change in that conformation, LDL receptor will be circulated back to the surface of the hepatocyte membrane or any othercell. • So,itmeans thereisarecycling ofLDL receptor.LDLreceptor comesback to themembraneagain. Note,that LDLreceptor isa short livedmolecule witha halflifeofonly20minutes.Soevery5minutesitundergoesrecycling. • Thereceptor is recycledback. It means there is availabilityof LDL receptor onthesurface.
- 6. PCSK-9 • PCSK-9 (Proprotein convertasesubtilisin/kexin type 9 serine protease)controls theamount of cholesterol that is presentinsidethe cell.It means, ifthere is more cholesterol insidethe cell,PCSK-9aresynthesizedandtheybindtotheextracellulardomainof theLDLreceptor. • Because of the binding of PCSK-9 with the LDL-LDL receptor complex the entire thing becomesapartoftheendosome. • PCSK-9 boundLDL receptordoes not undergoconfirmation changeand the entirecomplex istakenupbythelysosome. • Instead ofLDL receptors recirculating back tothe surface because ofthe bound PCSK-9, it isdegradedbythelysosome,intoaminoacids.
- 7. PCSK-9 • LDL receptordoes not comeback to thesurface of hepatocytestotakeupmoreLDLmolecules. • So, PCSK-9 molecules enhances the degradation of LDL receptor, thereby decreases the availability of LDL receptor on the surface of plasma membrane. Because of this, the circulating LDL is nolongergettingintothecell. • Shortly after its discovery in 2001, the gene encoding PCSK9 was implicated in familial hypercholesterolemia(FH).
- 8. PCSK-9 INHIBITORS • There are 2 PCSK-9 inhibitors that has been approved by the FDA, Evolocumab (Repatha) and Alirocumab (Praluent). • These aremonoclonalantibodies, which arereferred as PCSK-9inhibitors. • These monoclonal antibodies bind with the PCSK-9 molecules. Hence PCSK-9 cannot bind to the LDL receptor. • ThusLDLreceptorscan berecycled,therebyenhancing LDLmoleculereuptakebythehepatocytes. • ThusreducingtheamountofcirculatingLDL.
- 9. PCSK-9 INHIBITORS (INDICATION) • Thedrugsareapprovedforthefollowingindications: • PatientswithheterozygousFH • IndividualswithASCVD(Atheroscleroticcardiovasculardisease) • Patientswhoareunabletoachieveasufficientlylowcholesterolleveloncurrentlyprescribedmedications • Patientswhoareunabletotolerateothercholesterolloweringmedications. • Onereview ofstudies foundthatPCSK-9inhibitors slash LDLlevelsby anaverageof47%.This canprevent heartattacks orstrokes:Thedrugswereshowntoreducetheriskofheartattackby27%. • Bothmedications,EvolocumabandArilocumabhavetheoptiontobeinjectedsubcutaneously. • Evolocumab(Repatha),140mgeverytwoweeksor420mgmonthly. • Alirocumab(Praluent),75-150mgeverytwoweeks. • PCSK9inhibitorscanbeusedwithstatinstoboosttheirbenefit.ThecombinationcanlowerLDLlevelsbymorethanhalf.
- 10. PCSK-9 INHIBITORS (SIDE EFFECTS) • Commonadverseeffects(seenin≥5percentoftreatedpatients)included: • upperrespiratorytractinfections • nasopharyngitis • influenza(symptomssuchassorethroat,runnynoseandfever) • injectionsitereactions(redness,itchingorpainatthesiteofinjection) • nausea,diarrheaandfatiguemayoccuraswell • Forevolocumab,backpainwasadditionallydescribed. • Andlastly,thismedicationmaycauseariseinbloodsugarlevel. • Thesedrugsmayalsocauseanallergicreactionincertainpeople.
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