Anti-Hyperlipidemics Flashcards
1
Q
Statins
A
HMG-CoA reductase inhibitors
2
Q
atorvastin
A
statin
3
Q
fluvastatin
A
statin
4
Q
lovastatin
A
statin
5
Q
pitavastatin
A
statin
6
Q
pravastatin
A
statin
7
Q
rosuvastatin
A
statin
8
Q
simvastatin
A
statin
9
Q
niacin
A
nicotinic acid
vitamin B3
10
Q
fenofibrate
A
fibrate
11
Q
gemfibrozil
A
fibric acid derivative
12
Q
cholestyramine
A
bile acid sequester
13
Q
colesevelam
A
bile acid sequester
14
Q
colestipol
A
bile acid sequester
15
Q
ezetimibe
A
cholesterol absorption inhibitor
16
Q
simvastatin and ezetimibe
A
statin + cholesterol absorption inhibitor
17
Q
lomitapide
A
new treatment for homozygoud familial hypercholesterolemia
18
Q
mipomersen
A
New treatment for homozygous familial hypercholesterolemia
19
Q
what are lipids essential for
A
Cell membrane formation
Hormone synthesis
Source of free fatty acids (FFA’s)
20
Q
what is hyperlipidemia
A
elevated total cholesterol, low-density lipoprotein (LDL), or triglycerides, low high-density lipoprotein (HDL), or combination
21
Q
chylomicron
A
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) Catabolized by lipoprotein lipase (LPL) to chylomicron remnants
iii) Remnants taken up by liver where free cholesterol is liberated
iv) Also functions to deliver dietary TG’s to skeletal muscle and adipose tissue
22
Q
VLDL
A
lipoprotein regulated by diet and hormones, production inhibited by chylomicron remnant uptake in liver
i) Synthesized in liver
ii) Transports TG’s from liver to adipose and muscle tissues
iii) Serially converted to IDL (intermediate-density lipoprotein) then LDL by LPL
23
Q
LDL
A
major cholesterol transport lipoprotein
i) Product of VLDL catabolism and cellular synthesis
ii) Transports cholesterol to extrahepatic tissues
iii) Liver and extrahepatic uptake via receptor mediated endocytosis
24
Q
HDL
A
reverse cholesterol transporter
i) Derived from liver and gut synthesis
ii) Takes excess cholesterol from peripheral tissues for secretion into bile or conversion to bile acids
25
Lipoprotein Lipase (LPL)
digests TG’s in the chylomicron 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
26
what are CHD equivalents
symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes
27
what are major risk factors for CHD
age (men ≥ 45 years, women ≥ 55 years),
family history of premature CHD (CHD in male first degree relative < 55 years;
CHD in female first degree relative < 65 years),
cigarette smoking,
hypertension (BP ≥ 140/90 mmHg or on anti-HTN medication), low HDL cholesterol (< 40 mg/dL)
28
CHD or CHD risk equivalents
LDL goal
LDL level to initiate drug therapy
130 initiate treatmetn
29
2+ risk factors (10 year risk <20%)
LDL goal
LDL level at which to consider drug therapy ?
130
| 10 year risk 160
30
0-1 risk factors
LDL goal
LDL level at which to consider drug therapy
LDL goal 190 for drug therapy
31
what are the 4 statin benefit groups?
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 clinical ASCVD or diabetes who are 40-75 years and LDL-C 70-189 mg/dL with ASCVD risk of ≥ 7.5%
32
what is ASCVD
history of MI
stable or unstable angina, coronary or other revascularization,
stroke or TIA,
peripheral vascular disease
33
what is a high intensity statin
daily dose lowers LDL by approx >50%
34
how long should dietary therapy be done before lipid lower agents?
what does cholesterol, saturated and trans fat increase?
total fat, alcohol, and excess calories increase what?
3 months
unless patients are very high risk
i) Severe hypercholesterolemia
ii) Known CHD
iii) CHD risk equivalents
iv) PVD
c) Cholesterol, saturated, and trans-fats increase LDL
d) Total fat, alcohol, and excess calories increase TG’s
35
should you ever try a diet trial first with familial hypercholesterolemia?
no these always require drug therapy
36
statins
MOA
what do they lower?
therapeutic benefits
b) Most effective agents in reducing LDL levels and best tolerated class of lipid lowering agents
c) Chemistry and pharmacokinetics
i) Statins are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A), an initial precursor of cholesterol
iv) All statins undergo extensive first-pass metabolism by the liver; subsequently, their primary action is on the liver
plasma half life --> 1-3 hrs
statins inhibit MHG-CoA reductase, the rate limiting enzyme in cholesterol synthesis
(1) 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 AND decrease VLDL synthesis
(2) Increased expression of surface LDL receptors reduces circulating LDL levels
ii) Therapeutic benefits include plaque stabilization, improvement of coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory effects
iv) Potency: rosuvastatin > atorvastatin >> simvastatin > pitavastatin = lovastatin = pravastatin > fluvastatin
37
which statins are prodrugs
lovastatin and simvastatin
38
which statin is almost completely absorbed
fluvastatin
39
therapeutic uses of statins
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) Statin dosing now based on “intensity”
high intensity =
atorvastatin 40-80 mg
Rosuvastatin 20 mg
40
adverse effects of statins on liver, muscle, warfarin
i) Liver
(1) Elevations of serum aminotransferase activity (up to three times normal in patients with underlying liver disease or a history of alcohol abuse); levels decrease upon suspension of drug therapy
ii) Muscle
(1) Creatine kinase activity levels may increase, particularly in patients who have a high level of physical activity
(2) Rhabdomyolysis (leading to myoglobinuria) can occur rarely and lead to renal injury
(3) Myopathy can occur with monotherapy; an increased incidence of myopathy occurs in patients concomitantly taking drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin
iii) Statins increase warfarin levels
41
contraindications of statins
iv) Statins are contraindicated in women who are pregnant*** lactating, or likely to become pregnant; use is not recommended in patients with liver disease or skeletal muscle myopathy
v) Use in children is restricted to those with homozygous familial hypercholesterolemia and some patients with heterozygous familial hypercholesterolemia
vi) Avoid use with other agents that inhibit or compete with CYP450 enzymes (except for pravastatin and pitavastatin), such as the inducers phenytoin, griseofulvin
42
Niacin (nicotinic acid, vitamin B3)
MOA
what does it lower and how?
half life?
effect on fibrinogen and tPA
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%)
1/2 life of 60 minutes - 2x-3x daily dosing
i) MOA: inhibits the lipolysis of triglycerides in adipose tissue (the primary producer of circulating free fatty acids)
ii) By reducing circulating free fatty acids, the liver produces less VLDL and, subsequently, LDL levels decrease
iii) Plasma triglycerides (in VLDL) and cholesterol (in VLDL and LDL) decrease
iv) 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
43
therapeutic use of niacin
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
44
adverse effects of niacin
skin? how can this be prevented?
liver?
i) Most common side effect is 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
ii) 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
iii) May cause hepatotoxicity (extended release niacin is less likely to cause hepatotoxicity)
45
contraindication for niacin
iv) Contraindicated in patients with hepatic disease or active peptic ulcer
v) 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
46
fibric acid derivatives
MOA
ii) Well absorbed (>90%) when taken with a meal but less efficiently when taken on an empty stomach;
highly bound to serum albumin
fenofibrate 1/2 life= 20 hrs
Gemfibrozill 1/2 life = 1.5 hrs
MOA:
act as agonist ligands for the nuclear transcription factor receptor peroxisome proliferator-activated receptor alpha (PPARα)
ii) 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)
iii) VLDL levels decrease, LDL levels modestly decrease in most patients (LDL levels can increase as triglycerides are reduced), and HDL levels increase moderately
47
therapeutic uses of fibric acid derivatives (Fibrates)
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)
48
adverse effects of fibrates?
i) Gastrointestinal effects: mild GI disturbances are most common adverse effects and usually subside as therapy progresses
ii) 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)
iii) Muscle
(1) Myositis (inflammation of a voluntary muscle) can occur; evaluate for muscle weakness and tenderness
(2) 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.
iv) Drug interactions: fibrates potentiate the actions of coumarin and indanedione anticoagulants
49
contraindications of fibrates
should be avoided in patients with hepatic or renal dysfunction; safety has not been established in pregnant or lactating women
vi) 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)
50
bile acid sequestrants (resins)
colestipol
cholestyramine
colesevelam
MOA
what other drug should be combined with bile acid sequestrant in order to make it more effect
ii) Neither absorbed or metabolically altered by the intestine; totally excreted in the feces
i) MOA: sequestrants are positively charged compounds that bind to negatively charged bile acids (metabolites of cholesterol), increasing their excretion up to tenfold
ii) The increased excretion of bile acids enhance the conversion of cholesterol to bile acids in the liver via 7α-hydroxylation, which is normally controlled by negative feedback by bile acids
iii) 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)
51
therapeutic uses of bile acid sequestrants
i) Used to treat patients with primary hypercholesterolemia (reduces LDL by approximately 20%)
ii) Monotherapy (or in combination 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
52
adverse effects of bile acid sequestrants
which has the least GI effects?
drug /drug interactions?
i) Gastrointestinal effects (e.g., constipation, nausea, and flatulence) are the most common (colesevelam has the fewest GI effects of this class)
ii) At high doses, cholestyramine and colestipol impair the absorption of fat-soluble vitamins (A, D, E, and K)
iii) 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.***
53
contraindications for bile acid sequestrants
iv) Avoid or use with caution in patients with diverticulitis, preexisting bowel disease, or cholestasis
54
Cholesterol absorption inhibitors - ezetimibe
1/2 life
MOA
22 hour half life
highly water insoluble
; after ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters enterohepatic circulation as an active compound
i) MOA: 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%)
55
therapeutic uses of ezetimibe (cholesterol absorption inhibitor)
i) 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)]
56
what should you NOT take with ezetimibe
i) No significant drug interactions are reported; avoid concomitant administration of ezetimibe and bile acid sequestrants due to inhibition of ezetimibe absorption
57
Lomitapide
i) 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.
ii) FDA approved in December 2012 for treatment of homozygous familial hypercholesterolemia
iii) Once daily oral dosing
iv) Substrate and inhibitor of CYP3A4, causing interactions with a number of drugs
v) Most common adverse effects are gastrointestinal symptoms, increased liver aminotransferase levels, and hepatic fat accumulation
vi) Estimated cost > $250,000/year
`
58
mipomersen
i) 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
ii) FDA approved in January 2013 for treatment of homozygous familial hypercholesterolemia
iii) Indicated in addition to lipid-lowering medications and diet to reduce LDL-C, VLDL, apoB, non-HDL-C, and total cholesterol
iv) 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)
v) Estimated cost ~ $176,000/year
