Hyperlipidemia drugs Flashcards
Drug therapy of hyperlipidemia goals
-dec reabsorption of excreted bile acids
-decrease secretion of VLDL from liver
-dec synthesis of cholesterol
-inc liver LDL receptors
-inc hydrolysis of lipoprotein TGs
-each 10% reduction in cholesterol levels reduces coronary heart disease risk by 10-30%
Drugs mainly for cholesterol levels
-BARs
-inhibitors of cholesterol absorption
-inhibitors of cholesterol synthesis
-PCSK9 inhibitors
-MTTP inhibitors
Drugs mainly for TG levels
-fibrates
-niacin
-omega-3
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Bile Acid-Binding Resin drugs
-cholestyramine (Questran)
-Colestipol (Colestid)
-
Bile Acid-binding resin mech
-inhibit reabsorption of bile acids from intestine by binding bile acids to form insoluble complex excreted in feces
-upregulate LDL receptors in liver
-reabsorption inhibits conversion of cholesterol to bile acids
-sequestration of bile acids in intestine can increase excretion x10 = cant be recycled
-forces liver to use more cholesterol to produce cholic acid
Bile acid-binding resin strucures
-large molecular weight polymers (resins) that exchange chloride ion for bile acids
Bile Acid Binding Resins use
-tx primary hypercholesterolemia (high LDL)
-produces 20% reduction in LDL cholesterol in 2-4 weeks
-may cause 5% inc in HDL
-may inc TG
-take before meals
Bile Acid resins side effects
-constipation
-bloating
-5-20g sand-like resin taken w juice or apple sauce
-high fiber diet and water helps
Bile Acid Binding resin interactions
-may bind w other drugs and interfere absorption
-acetaminophen
-thiazides
-warfarin
-digoxin
-fibrates
-exetimibe
-oral contraceptive
-corticosteroids
-thiazolidinediones
Cholesterol absorption inhibitor drug
-ezetimibe
-small molecule
-first drug in new class that inhibit cholesterol absorption
Ezetimibe mech
-inhibts intestinal absorption of cholesterol from diet and reabsorption of cholesterol excreted in bile
-inhibits NPC1L1
Neimann-Pick C1-Like 1 (NPC1L1)
-expressed on enterocytes in small intestine
-cholesterol transporter from intestine into enterocytes to process into chylomicrons
-cholesterol binding triggers endocytosis
Cholesterol bidning to NPC1L1
-cholesterol binding triggers endocytosis
-cholesterol binds in sterol sensing domain (SSD)
-recruits AP2 that recruits Clathrin which triggers endocytosis
-cholesterol internalized with NPC1L1
-ezetimibe binds to block recruitment of AP2 = no endocytosis
Ezetimibe (Zetia) indication
-reduce LDL levels (17%)
-usually used in combo w statins (may enhance statin action up to 20%)
Ezetimibe adverse effects
-low incidence of liver/skeletal muscle damage
-generally well tolerated
HMG-CoA reductase inhibitors (statins)
-inhibit cholesterol synthesis in liver
-structure w mevalonic acid like group to bind active site of CYP
-lovastatin and simvastatin are prodrugs
prodrug statins
-lovastatin
-simvastatin
non CYP substrate statins
-pravastatin
-pitavastatin
HMG-CoA reductase inhibitor mech
-HMG-CoA reductase inhibitor (rate limiting enzyme in cholesterol biosynthesis
-up regulate LDL receptors enabling more LDL delivered to liver
=reduce plasma cholesterol
-structurally related to HMG-CoA
-resemble mevalonic acid that is produced by HMG-CoA reductase reaction
HMG-CoA reductase inhibitor mech
-SREBP and SCAP in ER
-moves to golgi in absence of sterols
-S1P and S2P cleave complex to bHLH fragment (transcription factor)
-bHLH goes to nucleus = upregulate LDL receptors
=LDL uptake by liver
statin indications
-hypercholesterolemia (elevated LDL)
-initiate after MI +/- lipid levels
statin expected results
-20-60% LDL reduction
-10-33% reduction in TG
-5-10% inc HDL
Properties of statins
-diff CYPs
-some active metabolites
-effect on food absorption
-some w short-half life give in evening to inhibit nocturnal cholesterol synthesis
CYP3A4 statins
-lovastatin
-simvastatin
-atorvastatin
-tend to accumulate in presence of cyp3A4 inhibitors (antibiotics, cyclosporine, ketoconazole, grapefruit)
CYP2C9 statins
-fluvastatin
-rosuvastatin
-inhibitors may inc plasma levels (cimetidine, metronidazole, amiodarone)
Statins metabolized by sulfation
-pravastatin
-most excreted unchanged
Pitavastatin metabolism
-mostly excreted unchanged in bile
-undergoes enterohepatic recirculation
statin averse effects
-skeletal muscle effects (rhabdomyolysis)
-hepatotoxicity
-inc incidence of T2DM
Rhabdomyolysis
-skeletal muscle issue
-myopathy w renal dysfunction secondary to myogloinuria
-dose related
-monitor serum creatinine phosphokinase (CPK)
-inc incidence when co adm w CYP inhibitors, may occur w gemfibrozil
Hepatotoxicity from statin
-monitor serum transaminase activity
-2% incidence usually underlying liver disease or alc use
drugs used as adjuncts to statins
-bempedoic acid
-PCSK9 inhibitors
Bempedoic acid
-ATP-Citrate Lyase inhibitors (ACL)
-ACL is enzyme upstream of HMG-CoA reductase
-oral qd
-adjunct to statins
-21hr half life
bempedoic acid mech
-reduce serum LDL and TC when added to statin therapy in pt with HeFH or ASCVD
-metabolized by glucuronidation
-excreted by kidneys
-inhibits OAT2 in renal tubules
=may cause hyperuricemia and GOUT
PCSK9
-proprotein convertase subtilisin kexin type 9
-promotes degradation of LDL receptors in liver
PCSK9 inhibitor drugs
-alirocumab (praluent)
-Evolocumab (repatha)
-human IgG abs against PCSK9
-increase LDLR# and reduce serum LDL-C
alirocumab (praluent)
-inj SQ q2 weeks
-75mg or 150mg
Evolocumab (repatha)
-injected SQ q2weeks 140mg or
-once month 420mg
PSCK9 inhibitor use
-adj to diet and max statin therapy in pt w:
-ASCVD
-HeFH or HoFH
PSCK9 inhibitor mech
-inc LDLR#
-reduce LDLC
-binds LDL receptors to prevent PSCK9 binding and internalizing receptors
new PSCK9 inhibitor
-Inclisiran
-siRNA hybridized PSCK9 mRNA and directs degradation in hepatocytes (dec PSCK9 levels)
-lowers LDL cholesterol
-inj SQ at 3 then 6 mo intervals
-use adj to statins in HeFH and ASCVD
-inj site pain
HoFH
-LDLR function reduced
-or B100 binding to LDLR reduced
-or PCSK9 activity inc
Drugs for HoFH pt
-juxtapid (lomitapide)
-mipomersin
-evinacumab-dgnb
juxtapid (lomitapide)
-small molecule microsomal TG transfer protein (MTTP inhibitor)
-oral dq increase dose every 2 weeks to max dose (5,10,20,40,60mg)
-use for HoFH
Juxtapid (lomitapide) mech
-inhibit MTTP
-inhibits assembly of Apo B containing lipoproteins in liver AND intestine (chylomicorns and VLDL)
-interfere with assembly of VLDL in liver (B100)
-chylomicrons in intestine (B48)
-pt needs to be put on linoleic acid or low fat diet bc no chylomicron interfereance
-does NOT effect LDLR activity = good for HoFH
Juxtapid risks
-high risk of liver damage
-restricted prescription program
MTTP mech
-Apo B + TG in liver make VLDL w ApoB in blood vessel
-LPL turns it into LDL w Apo B
-lomtapide blocks this
-does NOT require LDL-R
Mipomersen (Kynamro) mech
-phosphorothioate anti-sense oligonucleotide inhibitor of Apo B100
-hybridizes Apo B100 mRNA in liver and promotes degradation (no effect on intestine and chylomicrons)
-very stable synthetic oligo, inj SQ once/week 200mg
Mipomersen use
-inhibits Apo B100 in liver
-adj tx for HoFH
Mipomersen adverse effects
-high risk of liver damage
-restricted Rx program (heptaice steatosis)
Evinacumab-dgnb (Evkeeza)
-mAB gainst angiopoitein like protein 3
IV infusion once month
-tx HoFH
-does NOT require LDLR
Eviinacumab-dgnb (Evkeeza) mech
-inc LPL and endothelial lipase (EL) activity
-prevents ANGPTL3 mediated inhibition
-lowers LDL
-enhances VLDL remanant clearance (=more LDL taken up into liver as IDL)
-prevents VLDL from maturing to LDL, just IDL that gets taken up by liver
=does NOT require LDLR
Drugs that primarily reduce serum TGs
-fibrates
-niacin
-omega-3
Fibric acid drugs
-fenofibrate
-gemfibrozil
Fibric acid derivatives
-peroxisome proliferator-activated receptor alpha activators (PPARa)
-aromatic ring-O-spacer-carboxylic acid
Fibrate prodrug
-fenofibrate
-bioactivation to fenofibric acid
Fibrate mech
-bind PPAR-a and regulated gene transcription along w retinoic acid receptor RXR
-effects of fibrates are complex
-reduces TG levels in blood
fibrate effect
-activation of PPRAa in liver
-reduce LDL
-reduce TG (dec secretion and inc FA oxidation)
-elevate HDL
Fibrate indications
-hyperTG where VLDL predominate
-second line for mixed hyperlipidemia
Fibrate side effects
-gall stones
-skeletal muscle effects (rhabdomylosis = use w caution w statins)
Fibrate drug interaction
-potentiate effects of warfarin
Niacin
-vitamin B3 at dietary levels
-high doses 1-3g/day lowers lipids
Niacin mech
-reduce TG
-inc LPL activity to inc clearance of VLDL
-dec hepatic VLDL production
-may reduce serum LDL and TG
-usually inc HDL
Niacin mech on adipose tissue
-bind GPR109A
-dec cAMP and PKA
-inhibits hormone sensitive lipase
=block TGs from turning to FFAs and leaving tissue to go to liver
Niacin mech on liver
-suppress PPARy and DGAT2
=reduce TG production and VLDLs
=lowers LDLs bc they come from VLDLs
-inhibits FA synthesis and esterification = de TG export via VLDL
-reduces clearance of APOA-I but not CEs = inc HDL levels and reverse transport
Niacin mech on macrophages
-inc expression of CD36 and ABCA1
=dec CE content via HDL-mediated reverse transport
Niacin indications
-mixed hyperlipidemias
-hyperTG w risk of pancreatitis (dec TG 25-30%)
-effective for raising HDL (15-35%)
-use in combo w resin drugs to treat severe cases of hyperlipidemia also combo statins
Niacin adverse effects
-marked vasodilation (flushing)
-itching
-tingling of upper body
-headache
-w initial dosing
-bc of prostaglandins so give aspirin or ibuprofen
-hepatotoxicity - sustained release preparations
