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Therapeutics II > Hyperlipidemia drugs > Flashcards

Hyperlipidemia drugs Flashcards

1
Q

Drug therapy of hyperlipidemia goals

A

-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%

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2
Q

Drugs mainly for cholesterol levels

A

-BARs
-inhibitors of cholesterol absorption
-inhibitors of cholesterol synthesis
-PCSK9 inhibitors
-MTTP inhibitors

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3
Q

Drugs mainly for TG levels

A

-fibrates
-niacin
-omega-3

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4
Q

graph slide 24

A

slide 24`

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5
Q

Bile Acid-Binding Resin drugs

A

-cholestyramine (Questran)
-Colestipol (Colestid)
-

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6
Q

Bile Acid-binding resin mech

A

-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

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7
Q

Bile acid-binding resin strucures

A

-large molecular weight polymers (resins) that exchange chloride ion for bile acids

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8
Q

Bile Acid Binding Resins use

A

-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

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9
Q

Bile Acid resins side effects

A

-constipation
-bloating
-5-20g sand-like resin taken w juice or apple sauce
-high fiber diet and water helps

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10
Q

Bile Acid Binding resin interactions

A

-may bind w other drugs and interfere absorption
-acetaminophen
-thiazides
-warfarin
-digoxin
-fibrates
-exetimibe
-oral contraceptive
-corticosteroids
-thiazolidinediones

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11
Q

Cholesterol absorption inhibitor drug

A

-ezetimibe
-small molecule
-first drug in new class that inhibit cholesterol absorption

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12
Q

Ezetimibe mech

A

-inhibts intestinal absorption of cholesterol from diet and reabsorption of cholesterol excreted in bile
-inhibits NPC1L1

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13
Q

Neimann-Pick C1-Like 1 (NPC1L1)

A

-expressed on enterocytes in small intestine
-cholesterol transporter from intestine into enterocytes to process into chylomicrons
-cholesterol binding triggers endocytosis

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14
Q

Cholesterol bidning to NPC1L1

A

-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

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15
Q

Ezetimibe (Zetia) indication

A

-reduce LDL levels (17%)
-usually used in combo w statins (may enhance statin action up to 20%)

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16
Q

Ezetimibe adverse effects

A

-low incidence of liver/skeletal muscle damage
-generally well tolerated

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17
Q

HMG-CoA reductase inhibitors (statins)

A

-inhibit cholesterol synthesis in liver
-structure w mevalonic acid like group to bind active site of CYP
-lovastatin and simvastatin are prodrugs

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18
Q

prodrug statins

A

-lovastatin
-simvastatin

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19
Q

non CYP substrate statins

A

-pravastatin
-pitavastatin

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20
Q

HMG-CoA reductase inhibitor mech

A

-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

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21
Q

HMG-CoA reductase inhibitor mech

A

-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

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22
Q

statin indications

A

-hypercholesterolemia (elevated LDL)
-initiate after MI +/- lipid levels

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23
Q

statin expected results

A

-20-60% LDL reduction
-10-33% reduction in TG
-5-10% inc HDL

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24
Q

Properties of statins

A

-diff CYPs
-some active metabolites
-effect on food absorption
-some w short-half life give in evening to inhibit nocturnal cholesterol synthesis

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25
CYP3A4 statins
-lovastatin -simvastatin -atorvastatin -tend to accumulate in presence of cyp3A4 inhibitors (antibiotics, cyclosporine, ketoconazole, grapefruit)
26
CYP2C9 statins
-fluvastatin -rosuvastatin -inhibitors may inc plasma levels (cimetidine, metronidazole, amiodarone)
27
Statins metabolized by sulfation
-pravastatin -most excreted unchanged
28
Pitavastatin metabolism
-mostly excreted unchanged in bile -undergoes enterohepatic recirculation
29
statin averse effects
-skeletal muscle effects (rhabdomyolysis) -hepatotoxicity -inc incidence of T2DM
30
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
31
Hepatotoxicity from statin
-monitor serum transaminase activity -2% incidence usually underlying liver disease or alc use
32
drugs used as adjuncts to statins
-bempedoic acid -PCSK9 inhibitors
33
Bempedoic acid
-ATP-Citrate Lyase inhibitors (ACL) -ACL is enzyme upstream of HMG-CoA reductase -oral qd -adjunct to statins -21hr half life
34
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
35
PCSK9
-proprotein convertase subtilisin kexin type 9 -promotes degradation of LDL receptors in liver
36
PCSK9 inhibitor drugs
-alirocumab (praluent) -Evolocumab (repatha) -human IgG abs against PCSK9 -increase LDLR# and reduce serum LDL-C
37
alirocumab (praluent)
-inj SQ q2 weeks -75mg or 150mg
38
Evolocumab (repatha)
-injected SQ q2weeks 140mg or -once month 420mg
39
PSCK9 inhibitor use
-adj to diet and max statin therapy in pt w: -ASCVD -HeFH or HoFH
40
PSCK9 inhibitor mech
-inc LDLR# -reduce LDLC -binds LDL receptors to prevent PSCK9 binding and internalizing receptors
41
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
42
HoFH
-LDLR function reduced -or B100 binding to LDLR reduced -or PCSK9 activity inc
43
Drugs for HoFH pt
-juxtapid (lomitapide) -mipomersin -evinacumab-dgnb
44
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
45
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
46
Juxtapid risks
-high risk of liver damage -restricted prescription program
47
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
48
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
49
Mipomersen use
-inhibits Apo B100 in liver -adj tx for HoFH
50
Mipomersen adverse effects
-high risk of liver damage -restricted Rx program (heptaice steatosis)
51
Evinacumab-dgnb (Evkeeza)
-mAB gainst angiopoitein like protein 3 IV infusion once month -tx HoFH -does NOT require LDLR
52
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
53
Drugs that primarily reduce serum TGs
-fibrates -niacin -omega-3
54
Fibric acid drugs
-fenofibrate -gemfibrozil
55
Fibric acid derivatives
-peroxisome proliferator-activated receptor alpha activators (PPARa) -aromatic ring-O-spacer-carboxylic acid
56
Fibrate prodrug
-fenofibrate -bioactivation to fenofibric acid
57
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
58
fibrate effect
-activation of PPRAa in liver -reduce LDL -reduce TG (dec secretion and inc FA oxidation) -elevate HDL
59
Fibrate indications
-hyperTG where VLDL predominate -second line for mixed hyperlipidemia
60
Fibrate side effects
-gall stones -skeletal muscle effects (rhabdomylosis = use w caution w statins)
61
Fibrate drug interaction
-potentiate effects of warfarin
62
Niacin
-vitamin B3 at dietary levels -high doses 1-3g/day lowers lipids
63
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 -dec FFA release from adipose tissue -
64
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
65
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
66
Niacin mech on macrophages
-inc expression of CD36 and ABCA1 =dec CE content via HDL-mediated reverse transport
67
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
68
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

Therapeutics II (55 decks)

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