Antihyperlipidemics DSA

Question 1

HMG-CoA Reductase Inhibitors

Answer 1

= Statins

a) Atorvastatin (Lipitor)
b) Fluvastatin
c) Lovastatin
d) Pitavastatin
e) Pravastatin
f) Rosuvastatin (Crestor)
g) Simvastatin

Question 2

Niacin

Answer 2

Nicotinic acid, vitamin B3

Question 3

Fibric Acid Derivatives

Answer 3

= fibrates

a) Fenofibrate (Tricor)
b) Gemfibrozil

Question 4

Bile Acid Sequestrants

Answer 4

(Resins)

a) Cholestyramine
b) Colesevelam
c) Colestipol

Question 5

Cholesterol Absorption Inhibitors

Answer 5

a) Ezetimibe (Zetia)

Easy! (EZ) Just don’t absorb it.

Question 6

Drug Combinations

Answer 6

Simvastatin and ezetimibe (Vytorin)

Question 7

Homozygous Familial Hypercholesterolemia

Answer 7

a) Lomitapide (Juxtapid)

b) Mipomersen (Kynamro)

Question 8

Heterozygous Familial Hypercholesterolemia

Answer 8

a) Alirocumab (Praluent)

b) Evolocumab (Repatha)

Question 9

Major plasma lipids

Answer 9

= cholesterol and triglycerides.

Essential for cell membrane formation, hormone synthesis, and source of free fatty acids (FFA’s).

Question 10

Lipids

Answer 10

water immiscible, not present in free form but must circulate as lipoproteins.

Question 11

Lipoprotein:

Answer 11

any lipid-protein complex in which lipids are transported in the blood; consist of a spherical hydrophobic core of triglycerides (TG’s) or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins.

i) Principal classes include HDL (high-density lipoprotein), LDL (low-density lipoprotein), VLDL (very low-density lipoprotein), and chylomicrons.
ii) Density of lipoproteins determined by protein and lipid content.
iii) Certain lipoproteins contain very high-molecular weight B proteins.
(1) B-48, formed in the intestine, found in chylomicrons and their remnants.
(2) B-100, synthesized in the liver, found in VLDL, VLDL remnants, LDL, and Lp(a) lipoproteins.

Question 12

Dyslipidemia (hyperlipoproteinemias or hyperlipidemias):

Answer 12

elevated total cholesterol, LDL-C, or triglycerides (hyperlipemia), low HDL-C, or combination of these abnormalities.
i) Major clinical sequelae: pancreatitis (hyperlipemia) and atherosclerosis.

Question 13

Chylomicron

Answer 13

large, triglyceride rich; comprised of dietary fat which has been solubilized by bile salts in intestinal mucosal cells.

i) Normally not present after a fast of 12-14 hours.
ii) Functions to deliver dietary TG’s to skeletal muscle and adipose tissue.
iii) Catabolized by lipoprotein lipase (LPL) to chylomicron remnants.
iv) Remnants taken up by liver where free cholesterol is liberated.

Question 14

VLDL

Answer 14

lipoprotein regulated by diet and hormones; synthesized in liver; production inhibited by chylomicron remnant uptake in liver.

i) Transports TG’s from liver to peripheral tissues.
ii) VLDL TG’s hydrolyzed by LPL which yields free fatty acids (FFAs) for storage in adipose tissue or for oxidation in tissues (cardiac and skeletal muscle).
iii) Serially converted to IDL (intermediate-density lipoprotein) as TG’s are depleted; then LDL by LPL.

Question 15

LDL

Answer 15

: major cholesterol transport lipoprotein; transports cholesterol to extrahepatic tissues.

i) Product of VLDL catabolism and cellular synthesis (formation of mevalonic acid by HMG-CoA reductase).
ii) Liver and extrahepatic uptake via receptor mediated endocytosis.
iii) Production of HMG-CoA reductase enzyme and LDL receptors is transcriptionally regulated by cholesterol content within the cell.

Question 16

HDL:

Answer 16

reverse cholesterol transporter.

i) Derived from liver and gut synthesis.
ii) Much of lipid content comes from surface of chylomicrons and VLDL during lipolysis.
iii) Also, takes excess cholesterol from peripheral tissues for secretion into bile or conversion to bile acids (protects cholesterol homeostasis of cells).

Question 17

Lipoprotein Lipase (LPL):

Answer 17

digests TG’s in chylomicrons and VLDL producing FFA’s and glycerol.

i) Located on inner surface of the capillary endothelial cells of muscle and adipose tissue.
ii) FFA’s used for energy production (muscle) or fat storage (adipocytes).
iii) Glycerol metabolized in the liver.

Question 18

Primary Hypertriglyceridemias

Answer 18

i) Primary chylomicronemia
ii) Familial hypertriglyceridemia
(1) Severe
(2) Moderate
iii) Familial combined hyperlipoproteinemia (FCH)
iv) Familial dysbetalipoproteinemia

Question 19

Primary Hypercholesterolemias

Answer 19

i) Familial hypercholesterolemia (FH)
ii) Familial ligand-defective apolipoprotein B
iii) Familial combined hyperlipoproteinemia (FCH)
iv) Lp(a) hyperlipoproteinemia

Question 20

Other Disorders

Answer 20

i) Deficiency of cholesterol 7α-hydroxylase
ii) Autosomal recessive hypercholesterolemia (ARH)
iii) Mutations in the PCSK9 gene
iv) HDL deficiency
(1) Tangier disease
(2) LCAT (lecithin:cholesterol acyltransferase) deficiency
(3) Familial hypoalphalipoproteinemia

Question 21

Secondary Hyperlipoproteinemia

Answer 21

(due to common conditions or drugs).

i) Hypertriglyceridemia
(1) Diabetes mellitus, alcohol ingestion, estrogens, hypopituitarism, and acromegaly.
ii) Hypercholesterolemia
(1) Hypothyroidism, anorexia nervosa, early nephrosis, hypopituitarism, and corticosteroid excess.

Question 22

Adult Treatment Panel (ATP) IV Guidelines

Answer 22

a) Drug therapy is no longer targeted to a specific cholesterol goal.
b) Maximizing statin intensity reduces atherosclerotic cardiovascular disease (ASCVD) events.
i) ASCVD: history of myocardial infarction (MI), stable or unstable angina, coronary or other revascularization, stroke or transient ischemic attack (TIA), peripheral vascular disease (PVD).
c) Statin intensity = evidence based drug therapy.
i) 4 Statin Benefit Groups:
(1) Clinical ASCVD
(2) Primary elevation of LDL-C ≥ 190 mg/dL
(3) Age 40-75 years with diabetes and LDL-C 70-189 mg/dL
(4) No ASCVD or diabetes who are 40-75 years & LDL-C 70-189 mg/dL with ASCVD risk of ≥ 7.5%
d) Addition of non-statin drugs has not shown ASCVD reductions with acceptable safety margins.
e) May under-dose patients if using multiple drugs to target specific levels vs. intensifying statin.
f) Guideline Limitations: no recommendations for patients with NYHA Class II-IV heart failure or those patients requiring dialysis.

Question 23

Therapeutic Lifestyle Change

Answer 23

a) Unless patients are at very high risk (severe hypercholesterolemia, known CHD, CHD risk equivalents, PVD), dietary therapy should be initiated first as a 3-month trial – may obviate the need for drug therapy, augment LDL lowering agents, or allow for lower drug doses.
b) Cholesterol, saturated, and trans-fats increase LDL.
c) Total fat, alcohol, and excess calories increase TG’s.
d) Dietary Recommendations: potential to reduce serum cholesterol 10-20%.

Component Recommended Intake

Total fat 25-35% of total calories
Saturated fat

Question 24

Statin MOA

Answer 24

b) Most effective agents in reducing LDL levels and best tolerated class of lipid lowering agents.
c) MOA: inhibit HMG-CoA reductase, rate limiting cholesterol synthesis enzyme.
i) Inhibiting de novo cholesterol synthesis depletes the intracellular supply of cholesterol, which causes the cell to increase the number of specific cell-surface LDL receptors that can bind and internalize circulating LDLs.
ii) Increased expression of surface LDL receptors reduces circulating LDL levels.
iii) Therapeutic benefits include plaque stabilization, improvement of coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory effects.
iv) Can reduce LDL levels 20-55%.
v) Potency: rosuvastatin > atorvastatin&raquo_space; simvastatin > pitavastatin = lovastatin = pravastatin > fluvastatin.

Question 25

Statin PK

Answer 25

structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A), an initial precursor of cholesterol.

i) Lovastatin & simvastatin, inactive prodrugs, must be hydrolyzed in GI tract to active compounds.
ii) Oral absorption of the ingested doses varies from 40-75% with the exception of fluvastatin, which is almost completely absorbed (statin absorption is enhanced by food, exception pravastatin and pitavastatin).
iii) Undergo extensive first-pass metabolism by liver; subsequently, their primary action is on the liver.
iv) Half-lives (t1/2) range from 1-3 hours; exceptions: atorvastatin (14 hrs) and rosuvastatin (19 hrs).
v) Most of absorbed dose is excreted in the bile; 5-20% in the urine.
vi) Lovastatin, simvastatin, and atorvastatin are metabolized primarily by CYP3A4; fluvastatin and rosuvastatin are metabolized primarily by CYP2C9; pitavastatin undergoes limited CYP450 biotransformation; pravastatin is not metabolized by CYP450s.

Question 26

Statin Therapeutic Use:

Answer 26

i) Effective in lowering plasma cholesterol levels in all types of hyperlipidemias.
ii) Addition of non-statin drugs has not shown ASCVD reductions with acceptable safety margins.
iii) Cholesterol synthesis occurs primarily at night and as a result, statins (except the longer-acting atorvastatin and rosuvastatin) should be given in the evening.
iv) Now, statins dosed on intensity.

Question 27

Statin ADRs

Answer 27

i) Liver
(1) Elevations of serum aminotransferase activity (up to 3X normal in patients with underlying liver disease or history of alcohol abuse); levels decrease upon suspension of therapy.
ii) Muscle
(1) Creatine kinase activity levels may increase, particularly in those with high physical activity.
(2) Rhabdomyolysis (leading to myoglobinuria) can occur rarely and lead to renal injury.
(3) Myopathy can occur with monotherapy; increased incidence of myopathy in those taking drugs concomitantly including: cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin.

Question 28

Statin CIs

Answer 28

i) Women who are pregnant, lactating, or likely to become pregnant; use is not recommended in patients with liver disease or skeletal muscle myopathy.
ii) Use in children is restricted to those with homozygous familial hypercholesterolemia and some patients with heterozygous familial hypercholesterolemia.

Question 29

Statin DDIs

Answer 29

i) Statins increase warfarin levels.
ii) Avoid use with other agents that inhibit or compete with CYP450 enzymes (except for pravastatin and pitavastatin), such as the inducers phenytoin, griseofulvin, rifampin.

Question 30

Niacin MOA

Answer 30

a) The most effective agent for increasing HDL levels (30-40%); lowers LDL and VLDL levels by 10-20% and triglycerides 35-45%.
b) Only lipid-lowering agent that reduces lipoprotein(a) [Lp(a)] levels significantly (40%).
c) MOA: inhibits triglyceride lipolysis in adipose tissue (primary producer of circulating free fatty acids).
i) Reducing circulating free fatty acids, liver produces less VLDL and, subsequently, LDL levels fall.
ii) Plasma triglycerides (in VLDL) and cholesterol (in VLDL and LDL) decrease.
iii) Fibrinogen levels are reduced and tissue plasminogen activator levels are increased, which can reverse some of the endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis.

Question 31

Niacin PK

Answer 31

: converted to amide (nicotinamide) & incorporated into nicotinamide adenine dinucleotide (NAD).

i) Well absorbed; distributed to mainly hepatic, renal, and adipose tissue.
ii) Extensive first-pass metabolism; t1/2 ~60 minutes, which accounts for 2X- or 3X-daily dosing.
iii) Excreted in the urine unmodified and as several metabolites.

Question 32

Niacin Therapeutic Use

Answer 32

i) Often used in combination with a bile acid sequestrant (resin) or reductase inhibitor in the treatment of heterozygous familial hypercholesterolemia, other forms of hypercholesterolemia, and some cases of nephrosis.
ii) Utilized in the treatment of mixed lipemia that is incompletely responsive to diet.

Question 33

Niacin ADRs

Answer 33

: most common side effect is an intense cutaneous flush accompanied by an uncomfortable feeling of warmth (after each dose when the drug is initiated or when the dose is increased); aspirin taken before niacin or once-daily ibuprofen can mitigate the flushing, which is prostaglandin-mediated.

i) Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans (hyperplasia of the spinous layer of the skin with dark pigmentation found in areas of body folds such as the axillae or groin) have been reported.
ii) May cause hepatotoxicity (extended release niacin is less likely to cause hepatotoxicity).

Question 34

Niacin CIs

Answer 34

patients with hepatic disease or active peptic ulcer; use with caution in patients with diabetes mellitus due to niacin-induced insulin resistance, which can cause hyperglycemia.
(1) Patients with insulin resistance often show signs of acanthosis nigricans due to elevated insulin levels.

Question 35

Fibrates MOA

Answer 35

act as agonist ligands for the nuclear transcription factor receptor peroxisome proliferator-activated receptor alpha (PPARα).

i) When activated, PPARα binds to peroxisome proliferator-response elements in the DNA, regulating the expression of genes encoding proteins involved in lipoprotein structure and function (specifically, the expression levels of lipoprotein lipase are increased, which induces lipolysis of triglycerides and ultimately decreases plasma concentrations).
ii) VLDL levels decrease, LDL levels modestly decrease in most patients (LDL levels can increase as triglycerides are reduced), and HDL levels increase moderately.

Question 36

Fibrates PK

Answer 36

fibrates are derivatives of fibric acid.

i) Well absorbed (> 90%) when taken with a meal but less efficiently when taken on an empty stomach; highly bound to serum albumin.
ii) Gemfibrozil t1/2 1.5 hours, excreted mostly unmodified, some liver modification to hydroxymethyl, carboxyl, or quinol derivatives.
iii) Fenofibrate t1/2 is 20 hours, excreted predominantly as glucuronide conjugates.

Question 37

Fibrates Therapeutic Use

Answer 37

i) Useful in the management of hypertriglyceridemias where VLDL predominate.
ii) Dysbetalipoproteinemia.
iii) Hypertriglyceridemia that results from treatment with viral protease inhibitors (e.g., saquinavir, indinavir, or nelfinavir for HIV therapy).

Question 38

Fibrates ADRs

Answer 38

mild GI disturbances are most common and usually subside as therapy progresses.

i) Lithiasis (the formation or presence of abnormal calculi or other concretions): due to the increased biliary cholesterol excretion, patients are predisposed to the formation of gallstones (cholelithiasis).
ii) Muscle, myositis (inflammation of a voluntary muscle) can occur; evaluate for muscle weakness and tenderness.
(1) Myopathy and rhabdomyolysis have been reported; risk increases in patients taking both fibrates and reductase inhibitors. If combination to be used, fenofibrate is the fibrate of choice to be used with reductase inhibitor.

Question 39

Fibrates CIs

Answer 39

: avoid in patients with hepatic or renal dysfunction; safety has not been established in pregnant or lactating women.
i) Fibrates increase the risk of cholesterol gallstones (due to an increase in the cholesterol content of bile) and should be used with caution in patients with biliary tract disease or in those at high risk (e.g., women, obese patients, and Native Americans).

Question 40

Fibrates DDIs

Answer 40

fibrates potentiate the actions of coumarin (warfarin) and indanedione anticoagulants.

Question 41

Bile Acid Sequestrants (Resins) MOA

Answer 41

sequestrants are positively charged compounds that bind to negatively charged bile acids (metabolites of cholesterol), increasing their excretion up to tenfold.

i) The increased excretion of bile acids enhances the conversion of cholesterol to bile acids in the liver via 7α-hydroxylation, which is normally controlled by negative feedback by bile acids.
ii) The decline in hepatic cholesterol stimulates an increase in hepatic LDL receptor, which enhances LDL clearance and lowers levels; however, this effect is partially offset by enhanced cholesterol

synthesis caused by upregulation of HMG-CoA reductase (therefore, combined use of a statin substantially increases the effectiveness of resins).

Question 42

Resins PK

Answer 42

sequestrants are large polymeric cationic exchange resins that are insoluble in water (molecular weights are greater than 106); neither absorbed nor metabolically altered by the intestine; totally excreted in the feces.

Question 43

Resins Therapeutic Use

Answer 43

i) Used to treat patients with primary hypercholesterolemia (reduces LDL by approximately 20%).
ii) Monotherapy (or combined with niacin) for treatment of Type IIa and Type IIb hyperlipidemias.
iii) Used to relieve pruritus in patients who have bile salt accumulation (e.g., from biliary obstruction).
iv) May be used for digitalis toxicity due to interaction with digitalis glycosides.

Question 44

Resins ADRs

Answer 44

GI effects (e.g., constipation, nausea, and flatulence) are the most common (colesevelam has the fewest GI effects of this class).

Question 45

Resins CIs

Answer 45

avoid or use with caution in patients with diverticulitis, preexisting bowel disease, or cholestasis.

Question 46

Resins DDIs

Answer 46

cholestyramine and colestipol impair the absorption of numerous drugs, including tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, and thiazide diuretics. As a result, any additional medication (except niacin) should be given at least 1 hour before or at least 2 hours after the sequestrant to ensure adequate absorption.

Question 47

Cholesterol Absorption Inhibitor MOA

Answer 47

a) Ezetimibe is the first and only approved member of this drug class.
b) MOA: selectively inhibits intestinal absorption of cholesterol and phytosterols (plant sterols); thought to inhibit the transport protein NPC1L1.
i) Effective even in the absence of dietary cholesterol because it also inhibits reabsorption of cholesterol excreted in the bile.
ii) Inhibited intestinal cholesterol absorption reduces the incorporation of cholesterol into chylomicrons, which reduces the delivery of cholesterol to the liver by chylomicron remnants.
iii) On average, lowers LDL by 18% and triglycerides by 6% while raising HDL levels slightly (1.3%).

Question 48

Cholesterol Absorption Inhibitor PK

Answer 48

highly water insoluble; after ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters enterohepatic circulation as an active compound.
i) Majority is excreted in the feces (10% in the urine); t1/2 22 hours.

Question 49

Cholesterol Absorption Inhibitor Therapeutic Use

Answer 49

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 50

Cholesterol Absorption Inhibitor DDIs

Answer 50

no significant drug interactions reported; avoid concomitant administration of ezetimibe and bile acid sequestrants due to inhibition of ezetimibe absorption.

Question 51

Lomitapide MOA

Answer 51

FDA approved December 2012 for homozygous familial hypercholesterolemia.

i) Once daily oral dosing.
ii) 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.

Question 52

Lomitapide ADRs and DDIs

Answer 52

iii) ADRs: GI symptoms, increased liver aminotransferase levels, and hepatic fat accumulation.

iv) DDIs: substrate and inhibitor of CYP3A4, causing interactions with a number of drugs.
v) Estimated cost > $250,000/year.

Question 53

Mipomersen MOA

Answer 53

FDA approved January 2013 for homozygous familial hypercholesterolemia.

i) Administered as a subcutaneous injection once per week.
ii) MOA: antisense oligonucleotide, targets apolipoprotein B-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. Elevated levels of apoB, LDL-C and VLDL are associated with increased risk of atherosclerosis and cardiovascular diseases.

Question 54

Mipomersen: Therapeutic Use and ADRs

Answer 54

indicated, in addition to lipid-lowering medications and diet, to reduce LDL-C, VLDL, apoB, non-HDL-C, and total cholesterol.

iv) ADRs: injection-site reactions, flu-like symptoms, headache, and elevation of liver enzymes ≥ 3X the upper limit of normal (discontinue if elevations persist or are accompanied by clinical symptoms, such as hepatic steatosis).
v) Estimated cost ~ $176,000/year.

Question 55

a) Alirocumab; MOA, Use, ADs

Answer 55

FDA approved July 2015 for heterozygous familial hypercholesterolemia.

i) Given every two weeks as a subcutaneous injection.
ii) MOA: human monoclonal antibody; targets PCSK9 (proprotein convertase subtilisin kexin type 9).
(1) PCSK9 binds hepatic LDL receptors, promotes receptor degradation, prevents LDL-C clearance from blood, which leads to increased LDL-C serum concentrations.
(2) Alirocumab prevents PCSK9 binding to LDL receptors and increases hepatic uptake of LDL-C.
iii) Therapeutic Use: indicated as an adjunct to diet and maximally tolerated statin therapy.
iv) ADRs: injection-site reactions and myalgia; some patients experienced amnesia, memory impairment, and confusion.
v) Estimated cost ~ $14,000/year.