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Cardiovascular II > Drugs for Lipid Disorders > Flashcards

Drugs for Lipid Disorders Flashcards

1
Q

HMG-CoA reductase inhibitors

A
  • Atorvastatin
  • Fluvastatin
  • Lovastatin
  • Pitavastatin
  • Pravastatin
  • Rosuvastatin
  • Simvastatin
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2
Q

Fabric acid derivatives

A
  • fibrates
  • fenofibrate
  • gemfibrozil
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3
Q

Bile acid sequestrants

A
  • resins
  • cholestyramine
  • cholesevelam
  • colestipol
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4
Q

Cholestrol absorption inhibitors

A

-ezetimibe

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5
Q

Drug combinations

A
  • simvastatin and ezetimibe
  • niacin and lovastatin extended release
  • niacin and simvastatin extended release
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6
Q

New treatment for homozygous familial hypercholestrolemia

A
  • Lomitapide

- Mipomersen

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7
Q

Lipoprotein

A

-any lipid-protein complex in which lipids are transported in the blood; consist of a spherical hydrophobic core of triglycerides or cholestrol esters surrounded by an amphipathic monolayer of phospholipids, cholestrol, and apolipoprotiens; principal classes include HDL, LDL, VLDL, and chylomicrons

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8
Q

Hyperlipoproteinemia

A

-an excess of lipoproteins in the blood due to a disorder of lipoprotein metabolism (may be acquired or familial condition, or combination)

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9
Q

Hyperlipidemia (hyperlipemia)

A

-elevated concentrations of any or all of the lipids in the plasma (e.g. hypertriglyceridemia, hypercholestrolemia)

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10
Q

Chylomicron

A

-transport exogenous, dietary cholestrol and triglycerides from the small intestine to tissues after meals; synthesized in the intestinal mucosa and carried to the bloodstream, they are degraded to chylomicron remnants in the capillaries of muscle and adipose tissue via cleavage of the majority of their triglycerides by endothelial lipoprotein lipase

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11
Q

VLDL

A
  • transports triglycerides from the liver to adipose and muscle tissues
  • synthesized by liver
  • Made up of endogenous TGs
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12
Q

LDL

A
  • transports cholestrol to extrahepatic tissues; formed in circulation when VLDL are degraded first to IDL and then to LDL; taken up and catabolized by both the liver and extra hepatic tissues by specific receptor-mediated endocytosis
  • made up of cholestrol esters
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13
Q

IDL

A
  • formed in the degradation of VLDL; half are absorbed by the liver and the other half are degraded to form LDL
  • made up of endogenous cholestrol esters and TGs
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14
Q

HDL

A
  • promotes the transport of cholestrol from extra hepatic tissue to the liver for excretion in the bile
  • synthesized by the liver
  • Made up of phospholipids, cholestrol esters
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15
Q

Lipoprotein lipase (LPL)

A
  • located on the inner surface of the capillary endothelial cells of muscle and adipose tissue
  • LPL digests the TGs in the chylomicron producing free fatty acids (used for energy production (muscle) or fat storage (adipocyte)) and glycerol (metabolized in the liver
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16
Q

Dietary management of hyperlipoproteinemia

A

-dietary measures are initiated first unless the patient has evident coronary or peripheral vascular disease, which may require the need for drugs

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17
Q

Principal factors that increase LDL

A

-cholestrol and saturated and trans fats

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18
Q

Increase triglycerides

A

-total fat, alcohol and excess calories

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19
Q

General dietary recommendations to control hyperlipoproteinemia

A
  • Limit total calories from fat to 20-25% daily intake
  • Limit saturated fats to less than 8% of daily intake
  • limit cholestrol to less than 200mg/day
  • reductions in serum cholestrol range from 10-20% on the above regimen
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20
Q

Omega-3 polyunsaturated fatty acids

A

-found in fish oils can induce profound reduction of triglycerides in some patients, however there is no evidence from prospective trials that fish oil supplements prevent cardiovascular disease in the general population

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21
Q

Patients with familial hypercholestrolemia or familial combined hyperlipidemia will

A

-always require drug therapy (children may initiate therapy with a resin or statin after 7-8 years of age based on LDL levels, other risk factors and family history)

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22
Q

HMG-CoA reductase inhibitors (statins) are

A

the most effective agents in reducing LDL levels and best tolerated class of lipid lowering agents

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23
Q

Statin chemistry

A

-structural analogs of HMG-CoA, an initial precursor of cholestrol

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24
Q

Lovastatin and simvastatin are

A

inactive prodrugs that must be hydrolyzed in the GI tract to active compounds

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25
Q

Statin pharmakokinetics

A
  • oral absorption of the ingested disease varies from 40-75% with the exception of fluvastatin, which is almost completely absorbed
  • extensive first pass metabolism by the liver; subsequently, their primary action is on the liver
  • Plasma half life 1-3 hours except for atorvastatin (14 hours) and rosuvastatin (19 hours)
  • most of absorbed dose is excreted in the bile; 5-20% in the urine
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26
Q

Statins metabolized primarily by CYP3A4

A
  • Lovastatin
  • Simvastatin
  • atorvastatin
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27
Q

Statins metabolized primarily by CYP2C9

A
  • fluvastatin

- rosuvastatin

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28
Q

Pitavastatin metabolism

A

-undergoes limited CYP450 biotransformation

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29
Q

Pravastatin metabolism

A

-not metabolized by CYP450

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30
Q

Statin MOA

A
  • statins inhibit HMG-CoA reductase, the rate limiting enzyme in cholestrol synthesis
  • inhibiting de novo cholestrol synthesis depletes in the intracellular supply of cholestrol, which causes the cell to increase the number of specific cell surface LDL receptors that can bind and internalize circulating LDLs
  • Increased expression of surface LDL receptors reduces circulating LDL levels
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31
Q

Therapeutic benefits of statins include

A

-plaque stabalization, improvement of coronary endothelial function, inhibition of platelet thrombus formation

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32
Q

Statin potency

A

-atorvastatin=rosuvastatin>simvastatin>pitavastatin=lovastatin=pravastatin>fluvastatin

33
Q

Statin therapeutic uses

A
  • effective in lowering plasma cholestrol levels in all types of hyperlipidemia
  • statins are useful alone or with resins, niacin, or ezetimibe in reducing LDL levels
34
Q

Statin side effects

A
  • creatine kinase activity levels may increase, particularly in patients who have a high level of physical activity
  • rhabdomyolysis (leading to myoglobinuria) can occur rarely and lead to renal injury
  • myopathy can occur with mono therapy; an increased incidence of myopathy occurs in patients concominatantly taking drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin
  • increase wrafarin levels
35
Q

Statins are contraindicated in

A
  • women who are pregnant, lactating, or likely to become pregnant
  • not recommended in patients with liver disease or skeletal muscle myopathy
36
Q

Statins use in children is

A

-restricted to those with homozygous familial hypercholestrolemia and some patients with heterozygous familal hypercholestrolemia

37
Q

Avoid statin use with

A

other agents that inhibit or compete with CYP450 enzymes (except for pravastatin and pitavastatin), such as the inducers phenytoin, griseofulvin

38
Q

Niacin chemistry

A

-converted to the amide (nicotinamide) and is incorporated into nicotinamide adenine dinucleotide (NAD)

39
Q

Niacin MOA

A
  • inhibits the lipolysis of triglycerides in adipose tissue (primary producer of circulating free fatty acids)
  • by reducing circulating free fatty acids, the liver produces less VLDL and subsequently, LDL levels decreased
  • plasma trigylcerides (in VLDL) and cholestrol (in VLDL and LDL) decrease
  • fibrinogen levels reduced and tissue plasminogen activator levels are increased, which can reverse some of the endothelial cell dysfunction contributing to thrombosis associated with hypercholestrolemia and atherosclerosis
40
Q

Niacin therapeutic uses

A
  • often used in combination with a bile acid sequestrate (resin) or reductase inhibitor in the treatment of heterozygous familial hypercholestrolemia, other forms of hypercholestrolemia, and some cases of nephrosis
  • Utilized in the treatment of mixed lipemia that is incompletely responsive to diet
41
Q

Niacin adverse effects

A
  • an intense cutaneous flush accompanied by an uncomfortable feeling of warmth (after each dose when the drug is started or when the dose is increased); aspirin taken before niacin or once-daily ibuprofen can mitigate the flushing, which is prostaglandin mediated
  • pruritis, rashes, dry skin or mucous membranes, and acanthuses 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
  • may cause hepatotoxicity (extended release less likely to cause this)
42
Q

Niacin contraindications

A
  • 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
  • Patients with insulin resistance often show signs of acanthosis nigricans due to elvated insulin levels
43
Q

Fibric Acid derivatives Pharmakokinetics

A
  • well absorbed when taken with meal but less efficiently when taken on an empty stomach; highly bound to serum albumin
  • half-life is 1.5 hours while fenofibrate half life is 20 hours
  • excreted predominantly as glucuronide conjugates
44
Q

Fibric acid derivatives MOA

A
  • act as agonist ligands for the nuclear transcription factor receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha)
  • when activated, PPARa binds to peroxisome proliferator-response elements in the DNA, regulating the expression of genes encoding proteins involved in lipoprotein structure and regulating the expression of genes encoding proteins involved in lipoprotein structure and function (specifically, the expression levels of lipoprotein lipase are inquired, which induces lipolysis of triglycerides and ultimately decreases plasma concentrations)
  • VLDL levels decrease, LDL levels modestly decrease in most patients (LDL levels can increase as triglycerides are reduced), and HDL levels increase moderately
45
Q

Fibric acid therapeutic uses

A
  • useful in the management of hypertriglyceridemias where VLDL predominate
  • dysbetalipoproteinemia
  • hypertriglyceridemia that results from treatment with viral protease inhibitors
46
Q

Fibric acid adverse effects

A
  • mild GI disturbances are most common adverse effects and usually subside as therapy progresses
  • Lithiasis due to the increased biliary cholestrol excretion, patients are predisposed to the formation of gallstones (cholelithiasis)
  • myositis (inflammation of a voluntary muscle) can occur
  • Myopathy and rhabdomyolysis have been reported; risk increases in patients taking bout fibrates and reductase inhibitors
47
Q

Fibric acid drug interactions

A

-fibrates potentiate the actions of coumarin and indanedione anticoagulants

48
Q

Fibric acids should be avoided in

A

-patients with hepatic or renal dysfunction; safety has not been established in pregnant and lactating women

49
Q

Fibrates increase the risk of

A

cholestrol gallstones (due to an increase in the cholestrol 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, Native Americans)

50
Q

Bile Acid Sequestrants (Resins) pharmacokinetics

A

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

51
Q

Resin MOA

A
  • positively charged compounds that bind to negatively charged bile acids, increasing their excretion up to 10-fold
  • increased excretion of bile acids enhance the conversion of cholesterol to bile acids in the liver via 7a-hydroxylation, which is normally controlled by negative feedback by bile acids
  • 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 up regulation of HMG-CoA reductase
52
Q

Resin Uses

A
  • treat patients with primary hypercholesterolemia
  • monotherapy or in combination with niacin for treatment of Type IIa and Type IIb hyperlipidemia
  • used to relieve pruritis in patients who have bile salt accumulation
  • may be used for digitalis toxicity due to interaction with digitalis glycosides
53
Q

Resin Adverse effects

A
  • GI effects are the most common
  • at high doses, cholestyramine and cholesterol impair the absorption of fat-soluble vitamins
  • Cholestyramine and colestipol impair the absorption of numerous drugs
54
Q

Resin Contraindicated in

A

patients with diverticulitis, preexisting bowel disease, or cholestasis

55
Q

Ezetimibe pharmacokinetics

A
  • cholesterol absorption inhibitors
  • highly water insoluble; after ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters enterohepatic circulation as an active compound
  • majority excreted in feces
56
Q

Ezetimibe MOA

A
  • selectively inhibits intestinal absorption of cholesterol and phytosterols (plant sterols); thought to inhibit the transport protein NPC1L1
  • effective even in absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in bile
  • inhibited intestinal cholesterol absorption reduces the incorporation of cholesterol into chylomicrons, which reduces the delivery of cholesterol to the liver by chylomicron remnants
57
Q

Ezetimibe Uses

A

-used to treat various causes of elevated cholesterol levels

58
Q

Ezetimibe Adverse effects and contraindications

A

-no significant drug interactions are reported; avoid concomitant administration of ezetimibe and bile acid sequestrates due to inhibition of ezetimibe absorption

59
Q

Combination drug therapy is useful in the following situations

A
  • when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin
  • When LDL and VLDL levels are both elevated initially
  • when LDL or VLDL levels are not normalized with a single agent
  • when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemia
60
Q

Vytorin

A
  • ezetimibe and simvastatin

- concerns about effectiveness and safety

61
Q

Lomitapide MOA

A
  • directly binds to and inhibits microsomal triglyceride transfer protein (MTP) which is located in the lumen of the ER.
  • MTP inhibition prevents the assemble of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in educed production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations
62
Q

Lomitapide Uses

A

-treatment of homozygous familial hypercholesterolemia

63
Q

Lomitapide Adverse effects

A
  • substrate and inhibitor of CYP3A4, causing interactions with a number of drugs
  • most common adverse effects are GI symptoms, increased liver aminotransferase levels, and hepatic fat accumulation
64
Q

Mipomersen MOA

A

-antisense oligonucleotide that targets apolipoprotein B-100 mRNA and disrupts its function

65
Q

ApoB-100

A

the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids

66
Q

Associated with increased risk of atherosclerosis and CV disease

A

-elevated levels of apoB, LDL-C, and VLDL

67
Q

Mipomersen uses

A
  • homozygous familial hypercholesterolemia
  • indicating in addition to lipid-lowering medications and diet to reduce LDL-C, VLDL, apoB, non-HDL-C, and total cholesterol
68
Q

Mipomersen Adverse effects

A

-injection site reactions, flu-like symptoms, headache, and elevation of liver enzymes greater than 3x the upper limit of normal

69
Q

Omega-3 polyunsaturated fatty acids (PUFAs)

A

-essential human nutrients and can be obtained in the diet through eating fatty fish such as salmon

70
Q

Increased intake of omega-3 PUFAs

A

-has been shown to modify membrane function, inhibit thrombus formation, decrease inflammation, lower plasma triglycerides, and alter the electrical activity of the myocardium

71
Q

Omega-3 PUFAs can lower

A

higher plasma TGs and do not interact with statins to increase the risk of rhabdomyolysis

72
Q

Omega-3 PUFAs have been shown to decrease the risk of

A

cardiac death in patients recovering from a recent myocardial infarction

73
Q

Type 1 Familial hyperchylomicronemia

A
  • massive fasting hyperchylomicronemia, even following normal dietary fat intake, resulting in greatly elevated serum TG levels
  • deficiency of lipoprotein lipase or deficiency of normal apache (rare)
  • not associated with increase in coronary heart disease
  • Low fat diet, no drug therapy is effective
74
Q

Type IIA familial hypercholesterolemia

A
  • elevated LDL with normal VLDL levels due to a block in LDL degradation
  • results in increased serum cholesterol but normal TG levels
  • caused by defects in the synthesis or processing of LDL receptors
  • ischemic heart disease is greatly accelerated.
  • diet
  • heterozygotes: cholestyramine and niacin, or a statin
75
Q

Type II B Familial Combined (Mixed) Hyperlipidemia

A
  • similar to IIA except that VLDL is also increased, resulting in elevated serum TG as well as cholesterol levels
  • caused by overproduction of VLDL by the liver
  • treatment is diet. drug therapy similar to that of type IIA
76
Q

Type III Familial dysbetalipoproteinemia

A
  • serum concentrations of IDL are increased, resulting in increased TG and cholesterol levels
  • cause is either overproduction or underutilization of IDL due to mutant ape
  • xanthomas and accelerated vascular disease develop in patients by middle age
  • diet. drug therapy includes niacin and fenofibrate, or a statin
77
Q

Type IV Familial Hypertriglyceridemia

A
  • VLDL levels increased, whereas LDL levels are normal or decreased, resulting in normal to elevated cholesterol, and greatly elevated circulating TG levels
  • cause is overproduction and/or decreased removal of VLDL TG in serum
  • this is a relatively common disease. It has few clinical manifestation other than accelerated ischemic heart disease. Patients with this disorder are frequently obese, diabetic, and hyperuricemic.
  • diet. if necessary, drug therapy includes niacin and/or fenofibrate
78
Q

Type V Familial Mixed Hypertriglyceridemia

A
  • serum VLDL and chylomicrons elevated, LDL is normal or decreased, this results in elevated cholesterol and greatly elevated TG levels
  • cause is either increased production or decreased clearance of VLDL and chylomicrons.
  • Usually, if it a genetic defect
  • occurs most commonly in adults who are obese and/or diabetic
  • diet. if necessary, drug therapy includes niacin, and/or fenofibrate, or a statin

Cardiovascular II (13 decks)

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