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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
Q

CYP3A4 statins

A

-lovastatin
-simvastatin
-atorvastatin
-tend to accumulate in presence of cyp3A4 inhibitors (antibiotics, cyclosporine, ketoconazole, grapefruit)

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26
Q

CYP2C9 statins

A

-fluvastatin
-rosuvastatin
-inhibitors may inc plasma levels (cimetidine, metronidazole, amiodarone)

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27
Q

Statins metabolized by sulfation

A

-pravastatin
-most excreted unchanged

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28
Q

Pitavastatin metabolism

A

-mostly excreted unchanged in bile
-undergoes enterohepatic recirculation

29
Q

statin averse effects

A

-skeletal muscle effects (rhabdomyolysis)
-hepatotoxicity
-inc incidence of T2DM

30
Q

Rhabdomyolysis

A

-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
Q

Hepatotoxicity from statin

A

-monitor serum transaminase activity
-2% incidence usually underlying liver disease or alc use

32
Q

drugs used as adjuncts to statins

A

-bempedoic acid
-PCSK9 inhibitors

33
Q

Bempedoic acid

A

-ATP-Citrate Lyase inhibitors (ACL)
-ACL is enzyme upstream of HMG-CoA reductase
-oral qd
-adjunct to statins
-21hr half life

34
Q

bempedoic acid mech

A

-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
Q

PCSK9

A

-proprotein convertase subtilisin kexin type 9
-promotes degradation of LDL receptors in liver

36
Q

PCSK9 inhibitor drugs

A

-alirocumab (praluent)
-Evolocumab (repatha)
-human IgG abs against PCSK9
-increase LDLR# and reduce serum LDL-C

37
Q

alirocumab (praluent)

A

-inj SQ q2 weeks
-75mg or 150mg

38
Q

Evolocumab (repatha)

A

-injected SQ q2weeks 140mg or
-once month 420mg

39
Q

PSCK9 inhibitor use

A

-adj to diet and max statin therapy in pt w:
-ASCVD
-HeFH or HoFH

40
Q

PSCK9 inhibitor mech

A

-inc LDLR#
-reduce LDLC
-binds LDL receptors to prevent PSCK9 binding and internalizing receptors

41
Q

new PSCK9 inhibitor

A

-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
Q

HoFH

A

-LDLR function reduced
-or B100 binding to LDLR reduced
-or PCSK9 activity inc

43
Q

Drugs for HoFH pt

A

-juxtapid (lomitapide)
-mipomersin
-evinacumab-dgnb

44
Q

juxtapid (lomitapide)

A

-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
Q

Juxtapid (lomitapide) mech

A

-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
Q

Juxtapid risks

A

-high risk of liver damage
-restricted prescription program

47
Q

MTTP mech

A

-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
Q

Mipomersen (Kynamro) mech

A

-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
Q

Mipomersen use

A

-inhibits Apo B100 in liver
-adj tx for HoFH

50
Q

Mipomersen adverse effects

A

-high risk of liver damage
-restricted Rx program (heptaice steatosis)

51
Q

Evinacumab-dgnb (Evkeeza)

A

-mAB gainst angiopoitein like protein 3
IV infusion once month
-tx HoFH
-does NOT require LDLR

52
Q

Eviinacumab-dgnb (Evkeeza) mech

A

-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
Q

Drugs that primarily reduce serum TGs

A

-fibrates
-niacin
-omega-3

54
Q

Fibric acid drugs

A

-fenofibrate
-gemfibrozil

55
Q

Fibric acid derivatives

A

-peroxisome proliferator-activated receptor alpha activators (PPARa)
-aromatic ring-O-spacer-carboxylic acid

56
Q

Fibrate prodrug

A

-fenofibrate
-bioactivation to fenofibric acid

57
Q

Fibrate mech

A

-bind PPAR-a and regulated gene transcription along w retinoic acid receptor RXR
-effects of fibrates are complex
-reduces TG levels in blood

58
Q

fibrate effect

A

-activation of PPRAa in liver
-reduce LDL
-reduce TG (dec secretion and inc FA oxidation)
-elevate HDL

59
Q

Fibrate indications

A

-hyperTG where VLDL predominate
-second line for mixed hyperlipidemia

60
Q

Fibrate side effects

A

-gall stones
-skeletal muscle effects (rhabdomylosis = use w caution w statins)

61
Q

Fibrate drug interaction

A

-potentiate effects of warfarin

62
Q

Niacin

A

-vitamin B3 at dietary levels
-high doses 1-3g/day lowers lipids

63
Q

Niacin mech

A

-reduce TG
-inc LPL activity to inc clearance of VLDL
-dec hepatic VLDL production
-may reduce serum LDL and TG
-usually inc HDL

64
Q

Niacin mech on adipose tissue

A

-bind GPR109A
-dec cAMP and PKA
-inhibits hormone sensitive lipase
=block TGs from turning to FFAs and leaving tissue to go to liver

65
Q

Niacin mech on liver

A

-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
Q

Niacin mech on macrophages

A

-inc expression of CD36 and ABCA1
=dec CE content via HDL-mediated reverse transport

67
Q

Niacin indications

A

-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
Q

Niacin adverse effects

A

-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 (48 decks)

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