Drugs for Lipid Disorders - DSA

Question 1

HMG-CoA reductase inhibitors

Answer 1

“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

Question 2

Niacin

Answer 2

nicotinic acid

vit B3

Question 3

Fibric acid derivatives (fibrates)

Answer 3

Fenofibrate

Gemfibrozil

Question 4

Bile acid sequestrants (resins)

Answer 4

Cholestyramine
Colesevelam
Colestipol

Question 5

Cholesterol absorption inhibitors

Answer 5

Ezetimibe (Zetia)

Question 6

Drug combinations

Answer 6

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

Question 7

New tx for homozygous familial hypercholesterolemia

Answer 7

Lomitapide

mipomersen

Question 8

Chylomicrons

Answer 8

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

Question 9

VLDL

Answer 9

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

Question 10

IDL

Answer 10

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

Question 11

LDL

Answer 11

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

Question 12

HDL

Answer 12

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

Question 13

Statin pharmacokinetics

Answer 13

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

Question 14

Statin MOA

Answer 14

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

Question 15

therapeutic benefits of statins

Answer 15

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

Question 16

Adverse effects of statins on liver

Answer 16

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

Question 17

Adverse effects of statins on muscle

Answer 17

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

Question 18

Statin contraindications

Answer 18

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)

Question 19

Niacin

Answer 19

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%)

Question 20

Niacin pharmacokinetics

Answer 20

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

Question 21

MOA of niacin

Answer 21

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

Question 22

Therapeutic uses of niacin

Answer 22

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

Question 23

Adverse effects of niacin

Answer 23

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

Question 24

Contraindications of niacin

Answer 24

hepatic disease or active peptic ulcer

DM due to niacin-induced insulin resistance which can cause hyperglycemia

Question 25

Fibrates pharmacokinetics

Answer 25

``` 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 ```

Question 26

Fibrates MOA

Answer 26

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

Question 27

Therapeutic uses of fibrates

Answer 27

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

Question 28

Adverse effects of fibrates

Answer 28

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

Question 29

Fibrate contraindications

Answer 29

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)

Question 30

Resins

Answer 30

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

Question 31

Resin MOA

Answer 31

sequestrants are positively charged bind to negatively charged bile acids (metabolites of cholesterol), increasing their excretion up to tenfold which enhance the conversion of cholesterol to bile acids in the liver via 7α-hydroxylation, (normally controlled by negative feedback by bile acids) decline in hepatic cholesterol stimulates an increase in hepatic LDL receptor enhancing LDL clearance and lowers levels; however, this effect is partially offset by enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase (combined use of a statin substantially increases the effectiveness of resins)

Question 32

Therapeutic uses of resins

Answer 32

tx primary hypercholesterolemia - reduces LDL by 20% Mono therapy or with niacin to treat Type IIa and IIb hyperlipidemia relieve pruritus in those with bile salt accumulation from biliary obstruction used for digitalis toxicity due to interaction with digitalis glycosides

Question 33

Adverse effects of resins

Answer 33

GI: constipation, N, flatulence High doses of cholestyramine and colestipol impair absorption of fat soluble vits (ADEK)

Question 34

Contraindications of resins

Answer 34

impair absorption of tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, thiazide diuretics - give at least 1 hr before or 2 hrs after sequestrant to ensure absorption Avoid or caution with diverticulitis, preexisting bowel disease, or cholestasis

Question 35

Ezetimibe pharmacokinetics

Answer 35

i) Highly water insoluble; after ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters enterohepatic circulation as an active compound ii) Majority is excreted in the feces (10% in the urine) iii) 22 hour half-life

Question 36

MOA of Ezetimibe

Answer 36

selectively inhibits intestinal absorption of cholesterol and phytosterols (plant sterols); thought to inhibit the transport protein NPC1L1 ii) Effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile iii) Inhibited intestinal cholesterol absorption reduces the incorporation of cholesterol into chylomicrons, which reduces the delivery of cholesterol to the liver by chylomicron remnants iv) On average, ezetimibe lowers LDL by 18% and triglycerides by 6% while raising HDL levels slightly (1.3%)

Question 37

Therapeutic uses of Ezetimibe

Answer 37

Used to treat various causes of elevated cholesterol levels [e.g., primary hypercholesterolemia (as monotherapy or in combination with HMG-CoA reductase inhibitors); homozygous familial hypercholesterolemia (in combination with atorvastatin or simvastatin); mixed hyperlipidemia (in combination with fenofibrate)]

Question 38

Adverse effects of ezetimibe

Answer 38

no drug interactions | avoid combining with bile acid sequestrants due to inhibition of ezetimibe absorption

Question 39

Situations when combination drug therapy useful

Answer 39

i) When VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin ii) When LDL and VLDL levels are both elevated initially iii) When LDL or VLDL levels are not normalized with a single agent iv) When an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias

Question 40

the ENHANCE study

Answer 40

(a) A 2-year study in patients with familial hypercholesterolemia comparing the effects of ezetimibe and simvastatin together with those of simvastatin alone (b) Results showed a 58% reduction in LDL cholesterol with the combination compared to a reduction of 41% with simvastatin alone (c) However, results showed no additional effect of ezetimibe on carotid intima-media thickness, a surrogate marker for coronary atherosclerosis (d) Direct measurements of clinical endpoints such as myocardial infarction, stroke, or cardiovascular death require trials with many participants followed for years and, as a result, surrogate endpoints are often used instead for FDA approval of medication (in the ENHANCE trial, the surrogate endpoint was lower LDL cholesterol levels)

Question 41

SEAS study

Answer 41

found no reduction in major cardiovascular events with simvastatin plus ezetimibe compared to placebo, and actually found an increase in various types of cancer in patients taking the simvastatin-ezetimibe combination

Question 42

Lomitapide

Answer 42

tx of homozygous familial hypercholesterolemia MOA: directly binds to and inhibits microsomal triglyceride transfer protein (MTP) which is located in the lumen of the endoplasmic reticulum. MTP inhibition prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations. substrate and inhibitor of CYP3A4 Adverse effects: GI symptoms, increased aminotransferase levels, hepatic fat accumulation

Question 43

Mipomersen

Answer 43

Tx of homozygous familial hypercholesterolemia MOA: antisense oligonucleotide that targets apoliporotein B-100 (apoB-100) mRNA and disrupts its function (1) ApoB-100 is the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids (2) Elevated levels of apoB, LDL-C and VLDL are associated with increased risk of atherosclerosis and cardiovascular diseases Adverse effects include injection site reactions (administration via subcutaneous injection once per week), flu-like symptoms, headache, and elevation of liver enzymes ≥three times the upper limit of normal (discontinue if elevations persist or are accompanied by clinical symptoms, such as hepatic steatosis

Question 44

Omega 3

Answer 44

``` modify membrane function inhibit thrombus formation decrease inflammation lower plasma TG alter electrical activity of myocardium ```

Question 45

Type I

Answer 45

``` familial hyperchylomicronemia elevated TG deficiency of lipoprotein lipase or normal apoliporotein CII no increase CAD Tx: low fat diet ```

Question 46

Type IIA

Answer 46

familial hypercholesterolemia elevated LDL, normal VLDL due to block of LDL degradation - increased cholesterol but normal TG Defects in synthesis or processing of LDL receptors Ischemic heart disease accelerated Tx: diet Heterozygotes - cholestyramine and niacin or a statin

Question 47

Type IIB

Answer 47

familial combined (mixed) hyperlipidemia increased VLDL and LDL, elevated TG and cholesterol overproduction of VLDL by liver tx: diet, drug therapy like IIA

Question 48

Type III

Answer 48

familial dysbetalipoproteinemia high IDL, increased TG and cholesterol levels overproduction or underutilization of IDL due to mutant poE Xanthomas and accelerated vascular disease develop in patients by middle age Tx: diet, niacin and fenofibrate, or a statin

Question 49

Type IV

Answer 49

Familial hypertriglyceridemia VLDL increased, LDL normal or decreased --> normal or elevated cholesterol and elevated TG Overproduction and/or decreased removal of VLDL TG in serum accelerated ischemic heart disease assoc with obesity, DM, hyperuricemic Tx: diet, niacin and/or fenofibrate

Question 50

Type V

Answer 50

Familial mixed hypertriglyceridemia serum VLDL and chylomicrons elevated, LDL normal or decreased, elevated cholesterol and greatly elevated TG increased production or decreased clearance of VLDL and chylomicrons - genetic defect Tx: diet, niacin and/or fenofibrate, or statin