Drugs for Lipid Disorders - DSA Flashcards Preview

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Flashcards in Drugs for Lipid Disorders - DSA Deck (50)
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1

HMG-CoA reductase inhibitors

"statins" - analogs of initial precursor of cholesterol

Atorvastatin (lipitor)
Fluvastatin
Lovastatin*
Pitavastatin
Pravastatin
Rosuvastatin (crestor)
Simvastatin* (zocor)

*prodrugs hydrolyzed in GI tract to active compounds

2

Niacin

nicotinic acid
vit B3

3

Fibric acid derivatives (fibrates)

Fenofibrate
Gemfibrozil

4

Bile acid sequestrants (resins)

Cholestyramine
Colesevelam
Colestipol

5

Cholesterol absorption inhibitors

Ezetimibe (Zetia)

6

Drug combinations

simvastatin and ezetimibe (Vytorin)
Niacin and lovastatin extended release (Advicor)
Niacin and simvastatin extended release (Simcor)

7

New tx for homozygous familial hypercholesterolemia

Lomitapide
mipomersen

8

Chylomicrons

contains dietary TGs and cholesterol
TG:Chol is 10:1
Synthesized in intestine
Mech of catabolism: TG hydrolysis by LPL, remnant uptake by liver

9

VLDL

contains endogenous TGs
TG:Chol is 5:1
Synthesized in liver
Mech of catabolism: TG hydrolysis by LPL

10

IDL

contains endogenous cholesterol esters and TGs
TG:Chol is 1:1
Product of VLDL catabolism
Mech of catabolism: 50% to LDL mediated by hepatic lipase, 50% uptake by liver

11

LDL

contains cholesteryl esters
Product of VLDL catabolism
Mech of catabolism: uptake by LDL receptor (75% in liver)

12

HDL

contains Phospholipids, cholesteryl esters
Synthesized in liver
Mech of catabolism: uptake of cholesterol by hepatocytes

13

Statin pharmacokinetics

extensive first pass metabolism by liver
t 1/2 1-3 h, exceptions: atorvastatin 14 hr, rosuvastatin 19 hr
most absorbed dose excreted as bile, 5-20% in urine
Lovastatin, simvistatin, atorvastatin metabolized CYP3A4
Fluvastatin, rosuvastatin CYP2C9
Pitavastatin limited CYP450 biotransformation
Pravastatin not metabolized by CYP450s

14

Statin MOA

inhibit HMG-CoA reductase - rate limiting enzyme in cholesterol synthesis

Inhibits de novo cholesterol synthesis, depletes intracellular supply of cholesterol - causes cell to increase number of specific cell-surface LDL receptors that bind and internalize circulating LDLs

Increased expression of surface LDL receptors reduces circulating LDL levels

15

therapeutic benefits of statins

plaque stabilization
improvement of coronary endothelial function
inhibition of platelet thrombus formation
anti-inflammatory effects
Reduce LDL levels 20-55%

16

Adverse effects of statins on liver

elevations of serum aminotransferase activity (up to 3x) in patients with liver disease or hx of etOH abuse

Levels decrease upon suspension of drug therapy

17

Adverse effects of statins on muscle

creatine kinase activity levels may increase, particularly in patients who have a high level of physical activity

rhabdomyolysis (leading to myoglobinuria) occur rarely and lead to renal injury

Myopathy can occur with monotherapy, increased risk when taken with drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin

18

Statin contraindications

increases warfarin levels

pregnant, lactating, likely to become pregnant

liver disease or skeletal muscle myopathy

use in children limited to homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia

avoid with agents inhibiting or competing with CYP450 enzymes such as inducers phenytoin, griseofulvin (except for pravastatin and pitavastatin)

19

Niacin

Most effective agent for increasing HDL levels (30-40%)
Lowers LDL and VLDL by 10-20% and TG 35-45%
ONLY agent that reduces lipoprotein(a) levels significantly (40%)

20

Niacin pharmacokinetics

well absorbed, distributed to hepatic, renal, adipose tissue
extensive first pass
t1/2 60 min - BID or TID dosing
Excreted in urine unmodified and its metabolites

21

MOA of niacin

inhibits lipolysis of TG in adipose tissue, reducing circulating FAs which leads to less VLDL produced by liver and decreased LDL levels

Plasma TG (in VLDL) and cholesterol (in VLDL and LDL) decrease

Fibrinogen levels reduced and tissue plasminogen activator levels are increased - can reverse some endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis

22

Therapeutic uses of niacin

combined with a bile acid sequestrant (resin) or reductase inhibitor in tx of heterozygous familiar hypercholesterolemia, other forms of hypercholesterolemia, and some cases of nephrosis

utilized in tx of mixed lipemia that incompletely responsive to diet

23

Adverse effects of niacin

intense cutaneous flush (PG mediated) with uncomfortable feeling of warmth - flushing mitigated by taking aspirin before niacin or ibuprofen QD

Pruritus, rashes, dry skin or mucous membranes, acanthuses nigricans

hepatotoxicity with extended release

24

Contraindications of niacin

hepatic disease or active peptic ulcer
DM due to niacin-induced insulin resistance which can cause hyperglycemia

25

Fibrates pharmacokinetics

derivatives of fibric acid
well absorbed (>90%) when taken with meal
highly bound to serum albumin
t1/2 - gemfibrozil 1.5h, fenofibrate 20h
excreted as glucuronide conjugates

26

Fibrates MOA

agonist ligands for peroxisome proliferator-activated receptor alpha (PPARalpha)
PPARa binds to response elements in DNA, regulating expression of genes in lipoprotein structure and function
Expression levels of lipoprotein lipase increased, induces lipolysis of TG and decreases plasma concentrations
VLDL decreases, LDL modestly decreases, HDL increase moderately

27

Therapeutic uses of fibrates

hypertriglyceridemias where VLDL predominate
Dysbetalipoproteinemia
Hypertriglyceridemia from tx with viral protease inhibitors (saquinavir, indinavir, or nelfinavir for HIV therapy

28

Adverse effects of fibrates

mild GI disturbances, usually subside as tx continues
Lithiasis due to increased biliary cholesterol excretion - formation of gallstones

myositis - inflammation of voluntary muscle - evaluate for muscle weakness and tenderness
Myopathy and rhabdomyolysis - risk increased taking fibrates and reductase inhibitors

29

Fibrate contraindications

drug interactions: potentiate actions of coumarin and indanedione anticoagulants

hepatic or renal dysfunction
pregnant or lactating
increased risk of gallstones, caution in biliary tract disease or those at high risk (women, obese, native americans)

30

Resins

insoluble in water

Neither absorbed or metabolically altered by the intestine; totally excreted in the feces