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Pharm exam 2 > hyperlipidemic drugs > Flashcards

hyperlipidemic drugs Flashcards

1
Q

A. Fibrates

A

Gemfibrozil and fenofibrate

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2
Q

Therapeutic uses of fibrates

A

 These agents cause a significant reduction in VLDL (triglycerides), a small reduction in LDL, and a small increase in HDL.
 Generally used to treat hypertriglyceridemia and mixed hyperlipidemia

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3
Q

Fibrates used to treat

A 
 Primary chylomicronemia
 Familial hypertriglyceridemia
 Familial combined hyperlipoproteinemia
 Familial dysbetalipoproteinemia
 Secondary hypertriglyceridemia
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4
Q

Fibrates MOA

A

The fibrates bind to and activate the peroxisome-proliferator-activated receptor α (PPARα).
PPARα is a transcription factor that increases the expression of lipoprotein lipase (LPL) gene, decreases the expression of LPL inhibitor apolipoprotein C-III, increases the oxidation of fatty acids in liver and muscle cells, and increases the expression of apo A-I and apo A-II. Activated
PPARα also increases the
expression of genes that encode proteins that increase the fatty acid uptake in muscle cells. Thus,
collectively, fibrates decrease plasma triglycerides. In addition, fibrates increase the expression of apo A-I, and apoA-II, which leads to increased plasma HDL levels

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5
Q

Fibrate adverse effects

A

 Rarely cause rashes, gastrointestinal symptoms, and myopathy
 Risk of myopathy increases with combination with statins

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6
Q

Bile acid-binding resins

A

Cholestyramine, colesevelam, and colestipol

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7
Q

Therapeutic uses Bile acid-binding resins

A

These agents used to be used more extensively, but since the introduction of statins, they are generally used in combination with statins to treat severe hypercholesterolemia that occurs in individuals with familial hypercholesterolemia.
 Because they are not systemically absorbed, they can
be used to reduce LDL in children, lactating women, and pregnant women.

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8
Q

Bile acid-binding resins MOA

A

 Bind to bile acids and bile salts in intestine
 Normally 95 % of the bile acids and salts are reabsorbed and returned to the liver via enterohepatic circulation. However, when these agents bind to the bile acids and bile salts, they cannot be reabsorbed and are excreted in the feces.
 The Liver has to increase the synthesis of bile acid to replace lost bile acids and salts. This, in turn, causes a reduction in liver cholesterol. This leads to an increase in hepatocyte expression of LDL receptors. Thus, plasma LDL levels decrease due to increased receptor-mediated endocytosis by the liver.

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9
Q

Adverse effects Bile acid-binding resins

A

 These agents tend to increase plasma triglycerides. Thus, they should not generally be used in patients with hypertriglyceridemia.
 Can cause bloating and constipation

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10
Q

Inhibitors of HMG-CoA reductase (Statins)

A

Atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin

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11
Q

Therapeutic uses statins

A

 Used to treat all forms of hypercholesterolemia
 Prescribed to individuals that have clinically evident cardiovascular disease
 Prescribed to individuals with elevated LDL levels and have a 10 year risk of cardiovascular disease of > 7.5 %

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12
Q

Statins MOA

A

The statins competitively inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) the rate limiting enzyme in cholesterol biosynthesis.
 Inhibition of HMG-CoA reductase reduces de novo synthesis of cholesterol.
 In an attempt to increase cholesterol levels, hepatocytes and cells in extrahepatic tissue upregulate LDL receptors in order to obtain cholesterol from
Antihyperlipidemic agents from the plasma. This leads to an increase in receptor mediated LDL endocytosis and a lowering of plasma LDL levels.
 Statins also potentially have numerous other cardiovascular protective effects independent of their ability to decrease LDL. These are sometimes referred to as the pleiotropic effects.
 Pleiotropic effects: (List is from: Rang & Dale’s Pharmacology, 23, 285-292, Eighth Edition, © 2016, Elsevier Ltd)
 Improved endothelial function
 Reduced vascular inflammation
 Reduced platelet aggregability
 Increased neovascularization of ischemic tissue
 Increased circulating endothelial progenitor cells
 Stabilization of atherosclerotic plaque
 Antithrombotic actions
 Enhanced fibrinolysis
 Inhibition of germ cell migration during development
 Immune suppression
 Protection against sepsis

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13
Q

Adverse effects statins

A

Generally very well tolerated
 Myopathy and/or myositis
 Patients with an inherited variant in a anion transporter are at higher risk for myopathy
 Rarely rhabdomyolysis occurs
 Liver toxicity in low percentage of patients
 Alanine transaminase (ALT) and aspartate transaminase (AST) often elevated in patients treated with high-potency statins
 Most often reflect adaptive responses of liver and not liver toxicity
 True liver toxicity is diagnosed when serum bilirubin concentrations as well as ALT and AST are elevated.

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14
Q

Specific conditions requiring statin use

A
  • Familial combined hyperlipoproteinemia
  • Familial hypercholesterolemia
  • Familial ligand-defective apoB
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15
Q

Potency statin drugs

A

Fluvastatin is the least potent and atorvastatin and rosuvastatin are the most potent

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16
Q

Inhibitors of cholesterol absorption

A

Ezetimibe (Zetia)

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17
Q

Therapeutic use of cholesterol inhibitors

A

Useful in the treatment of hypercholesterolemia

 Familial combined hyperlipoproteinemia, familial hypercholesterolemia, familial ligand-defective apoB

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18
Q

MOA cholesterol inhibitors

A

Blocks intestinal absorption of cholesterol by inhibiting Niemann-Pick C1-like 1 protein
 Blocks uptake of both dietary cholesterol and reabsorption of cholesterol excreted in bile
 Reduces incorporation of cholesterol into chylomicrons
 Reduced chylomicron remnants delivered to liver increases expression of hepatic LDL receptors
 Reduces plasma LDL levels by 15-20 %

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19
Q

Adverse effects cholesterol inhibitors

A

 Great safety profile

 Few if any adverse effects

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20
Q

Niacin therapeutic use

A

Useful in treatment of all types hypertriglyceridemia and hypercholesterolemia

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21
Q

MOA Niacin

A

Niacin can bind to a G protein-coupled receptor (GPCR) on adipocytes.
 The activation of this receptor decreases adipocyte hormone-sensitive lipase activity.
 Activation of hormone-sensitive lipase during fasting states by epinephrine and other hormones increases the hydrolysis of lipids in adipocytes causing an increase in plasma fatty acid levels. Thus, inhibition of this enzyme by niacin reduces plasma fatty acid levels.
 Plasma fatty acids can be converted into triglycerides and VLDL particles in the liver. VLDL particles then are secreted into the plasma and can become converted into LDL. Thus, by decreasing VLDL synthesis and secretion, niacin also decreases LDL in the plasma.
 Niacin can decrease plasma VLDL by up to 45 % and LDL by up to 20 %.
 Niacin also increases plasma HDL levels by increasing levels of apo A-I. This can lead to an increase of plasma HDL by up to 30 %.

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22
Q

Adverse effects Niacin

A

 Cutaneous flushing and itching (most common side effect)
 Flushing caused by niacin-induced secretion of prostacyclins from skin
 Reduced by pretreatment with an NSAID
 Hyperuricemia (induce gout attacks in susceptible individuals)
 Hepatotoxicity (slight risk)
 Slightly increases risk of statin-induced myopathy
 Safest combination is niacin with fluvastatin and highest risk is with lovastatin

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23
Q

A standard blood test reveals that your patient has hypertriglyceridemia. You order a genetic test which indicates that this patient has a homozygous mutation that causes the complete absence of apo E. Thus, you diagnose this patient with familial dysbetalipoproteinemia. Which antihyperlipidemic drugs would not be useful for the treatment of this patient? Which antihyperlipidemic drugs would be useful for treatment?

A

Statins wont work anything that treat hyper tri will.

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24
Q

Useful*

A

Elevations in triglycerides: Think elevated chylomicrons and/or VLDL
Elevation in cholesterol: Think elevated LDL

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25
Q

How are chylomicrons formed?

A

Upon consumption of dietary lipids, the lipids are digested in the stomach and small intestine into unesterified cholesterol, free fatty acids, monoglycerides, and lysolecithin. Shortly after the consumption of food, the gall bladder secretes concentrated bile into the lumen of the small intestine. Bile acids and bile salts constitute a large percentage of the bile. Cholesterol, monoglycerides, and lysolecithin combine with the bile salts to form mixed micelles. These micelles diffuse to the apical membrane of the intestinal enterocytes and the lipid components are absorbed by different mechanisms.
Cholesterol enters the enterocytes through the protein channel called the Niemann-Pick C1-like 1 protein (NPC1L1). Once inside the enterocyte, fatty acids and monoglycerides are re-esterified to form triglycerides. Cholesterol is re-esterified by the enzyme acetyl-CoA: cholesterol acyltransferase (ACAT). The triglycerides and cholesteryl esters then are combined with the apolipoprotein apo B-48, to form the chylomicron lipoprotein. Chylomicrons are then exocytosed into the lymphatic system and eventually enter the circulation. Once in the circulation, apo E and apo C-II are transferred from high density lipoprotein (HDL) to chylomicrons. Chylomicrons are the least dense of all of the lipoproteins and contain high levels of triglycerides, with much lower levels of cholesteryl esters and free cholesterol. The ratio of triglycerides to cholesteryl esters is approximately 10:1.

26
Q

Which 2 lipoproteins are tansferred by HDL to cylomicrons in circulation?

A

Apo E asd apo C-II

27
Q

How are chylomicrons cleared from plasma?

A

The chylomicrons travel in the blood plasma to capillaries contained within body tissues such as adipose tissue and muscle tissue. The enzyme lipoprotein lipase (LPL), which is expressed on the surface of the capillary endothelial cells, breaks down the chylomicron triglycerides into glycerol and fatty acids. The triglycerides and glycerol then can be used by the tissues. Once the chylomicron is depleted of much of its triglycerides, it is called a chylomicron remnant. Apo C-II is returned to circulating HDL, but the remnant keeps its apo E. The chylomicron remnant travels to the liver where its apo E binds to remnant receptors, which facilitate the endocytosis of the remnant into the hepatocytes.

28
Q

Function of Apo-C-II regarding cylomicrons?

A

cofactor which allows the binding of the chylomicron to LPL. Thus, a decrease in apo C-II expression can lead to a reduction in the ability of LPL to break down the chylomicron triglycerides, which leads to severe hypertriglyceridemia. added in circ by hdl

29
Q

Role of Apo-E regading chylomircrons

A

expressed on surface chylomicrons and retained by chylo remnants, allows binding of remnants to remnant receptors on liver which facilitate the endocytosis of the remnant into the hepatocytes.

30
Q

Diff of B lipos

A

Apo B-48 added to make chylos in liver and Apo- B-100 added to VLDL in liver

31
Q

VLDL synthesis

A

Triglycerides in the liver, either from de novo synthesis, or acquired from the plasma, are assembled into very-low-density lipoproteins (VLDL). A small amount of free cholesteryl esters and free cholesterol are also incorporated into the VLDL particles. The ratio of triglyceride to cholesteryl ester in VLDL lipoprotein is approximately 5:1. Apo B-100 is incorporated into the VLDL particles within the liver. VLDL particles are secreted by the liver into the plasma where the acquire most of their apo E, and apo C-II from circulating HDL particles.

32
Q

VLDL clearance from plasma and IDL sythesis

A

VLDL can then be catabolized in a similar fashion as chylomicrons by LPL in the capillaries. After most of the triglycerides are depleted from VLDL, the remnants, which are called intermediate density lipoprotein (IDL), are released into the circulation.

33
Q

IDL clersnce from plasma and synthesis LDL

A

IDL particles, which have approximately a 1:1 ratio of triglycerides to cholesteryl esters, have two fates. Approximately 40-60 % of IDL particles travel in the blood plasma to the liver. The apo E lipoprotein on the IDL particles binds to the LDL receptors on the hepatocytes, which facilitates receptor-mediated endocytosis. The remaining IDL particles are converted to low density lipoprotein (LDL) when additional triglycerides are removed by lipoprotein lipase and hepatic lipase. As IDL is converted to LDL, apo E and apo C-II are removed and transferred to HDL.

34
Q

LDL excretion

A

LDL consists primarily of cholesteryl esters and free cholesterol. LDL is then taken up by either the liver or other tissues by LDL-receptor-mediated endocytosis. Apo B-100 on LDL is the ligand for the LDL-receptor. In the liver, cholesterol can be eliminated by being secreted into bile or by being converted into bile acids and bile salts. Some of the cholesterol can also be repackaged into VLDL by the liver. Extrahepatic tissues endocytose LDL and use the cholesterol for multiple purposes such as lipid bilayer synthesis or steroid synthesis.

35
Q

LDL liver receptor apo p

A

Apo B-100

36
Q

IDL receptor apo P on liver

A

Apo-E

37
Q

Apo A-I

A

Contained by HDL. HDL particles dock to hepatocytes via an interaction between the hepatocyte SRBI
scavenger receptors and Apo A-I in HDL. Apo A-I on the HDL particles also facilitate the interaction of
HDL with ABCA1 (facilitate cholesterol efflux
from macrophages and allow it to be incorporated into HDL particles)., as well as stimulating LCAT (cholest aceyl transferase conversts cholest to chol esters once in HDL) activity.

38
Q

ABCA1 and ABCGI

A

facilitate cholesterol efflux

from macrophages and allow it to be incorporated into HDL particles.

39
Q

How is cholesterol delivered to liver

A

HDL is formed in the liver and intestine and secreted into plasma as nascent particles containing apo A-1
and phospholipids. HDL mediates antiatherogenic effects by retrieving excess insoluble cholesterol from
tissues and depositing it in the liver where it can be excreted in the bile. Cholesterol can be transferred
to HDL particles by membrane transporters located on non-hepatic cells such as arterial wall
macrophages. ABCA1 and another membrane transporter, called ABCG1, facilitate cholesterol efflux
from macrophages and allow it to be incorporated into HDL particles. Cholesterol lecithin: cholesterol
acyltransferase (LCAT) then converts cholesterol into cholesteryl ester in HDL particles.

40
Q

Major risks CVD

A 
Age/male gender
Smoking
Hypertension
Elevated cholesterol (LDL)
Low HDL
Diabetes
Family history of premature coronary heart disease, peripheral vascular disease, or stroke
41
Q

Minor risks CVD

A 
Sedentary lifestyle
Obesity
Dietary saturated fats
Triglycerides
VLDL and IDL remnants
42
Q

Apo-AI

A

Associated with HDL and chylomicrons, Structural protein for HDL
Activates LCAT
Ligand for SR-B1 receptor

43
Q

Apo A-II

A

HDL and cylomicrons

Structural protein for HDL

44
Q

Apo B-48

A

Chylomicrons and chylomicron remnents

Structural proteins

45
Q

Apo B-100

A

VLDL, IDL, LDL, Lp(a
Structural protein for VLDL, LDL, IDL
Ligand for binding to LDL receptor

46
Q

Apo C-II

A

Chylomicrons, VLDL, HDL. Cofactor for lipoprotein lipase (LPL)

47
Q

Apo E

A

Chylomicron , VLDL, IDL, HDL

Ligand for binding to LDL receptor and remnant receptors

48
Q

Niemann-Pick C1-like 1 protein (NPC1L1)

A

Cholesterol enters the enterocytes through the protein channel. Once inside the enterocyte, fatty acids and monoglycerides are re-esterified to form triglycerides. Cholesterol is re-esterified by the enzyme acetyl-CoA: cholesterol acyltransferase (ACAT). The triglycerides and cholesteryl esters then are combined with the apolipoprotein apo B-48, to form the chylomicron lipoprotein.

49
Q

Lipo protein lipase

A

which is expressed on the surface of the capillary endothelial cells, breaks down the chylomicron triglycerides into glycerol and fatty acids. The triglycerides and glycerol then can be used by the tissues. Importantly, apo C-II in the chylomicron is a cofactor which allows the binding of the chylomicron to LPL. Thus, a decrease in apo C-II expression can lead to a reduction in the ability of LPL to break down the chylomicron triglycerides, which leads to severe hypertriglyceridemia.

50
Q

Primary monogenic types

A

hypercholesterolemia
hypertriglyceridemia
mixed hyperlipidemia

51
Q

Polygenic types environmenta;l

A

hypercholesterolemia

mixed hyperlipidemia

52
Q

Hyperlipidemia caused by alcoholism, diabetes mellitus, uremia, or use of β-adrenoceptor antagonists, isotretinoin, oral contraceptives, or thiazide diuretics

A

occur commonly, total cholest is normal, triglycerides elevated

53
Q

Hyperlipidemia caused by hypothyroidism, nephrotic syndrome, or obstructive liver disease

A

More rare, total cholest is elevated triglycerides normal

54
Q

Primary cyclomicronemia

A

Decrease in LPL activity, leading to increase in total chylomicrons and VLDL. classified as a hypertriglyceridemia

55
Q

Familial hypertriglyceridemia

A

Impaired removal of VLDL and/or chylomicrons (polygenic). increase in VLDL (moderate)
VLDL & chylomicrons (severe)
classified as a hypertriglceridemia

56
Q

Hypertriglyceridemias

A

Primary chylomicronemia and damilial hypertriglyceridemia

57
Q

Familial combined hyperlipoproteinemia (also a hypercholesterolemia)

A

increase in VLDL production
high conversion of VLDL to LDL
(most likely polygenic), leads to inc in VDL and LDL
classified as both hypertri and hyperchol

58
Q

Familial dysbetalipoproteinemia

A

dec clearance of VLDL IDL, and chylomicron remnants because of a dysfunction or absence of apo E, leads to inc in chylo and IDL, classified as hyper tri

59
Q

Familial hyper-cholesterolemia

A

LDLR impairments (hetero or homozygous LDLR gene mutations), high fat diet, inactivity, leading to inc LDL

60
Q

Familial ligand-defective apoB

A

Mutation in apo-B100 resulting in impaired endocytosis of LDL, inc LDL classified as hyperchol

Pharm exam 2 (8 decks)

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