antihyperlipidemias 57/58 Flashcards
Ezetimibe (Zetia)
Cholesterol Absorption Inhibitor
oral 1x day
inhibits a specific protein-mediated transport system on or within the brush border membrane of the intestinal wall cell
less delivery of cholesterol to liver via exogenous pathway, liver may compensate by taking up more LDL via up regulating LDL receptors
slight increase HDL
use: lower LDL type hyperlipoproteinemias, used with diet, statins
Converted to an active glucuronide metabolite in the small intestinal wall cells and in the liver where recycled back into the intestinal lumen via biliary system. This enterohepatic recirculation presents more active metabolite
excreted in feces
Cholestyramine (Questran)
Bile Acid Binding Resin
Colestipol (Colestid)
Bile Acid Binding Resin
Colesevelam (WelChol)
Bile Acid Binding Resin
*less SEs
Lovastatin (Mevacor)
HMG-CoA Reductase Inhibitor
prodrug which requires activation
Pravastatin (Pravachol)
HMG-CoA Reductase Inhibitor
active as ingested
Simvastatin (Zocor)
HMG-CoA Reductase Inhibitor
prodrug which requires activation
Atorvastatin (Lipitor)
HMG-CoA Reductase Inhibitor
active as ingested
now “combined” with the calcium channel blocker amlodipine (Caduet) to treat both high cholesterol and high blood pressure
Rosuvastatin (Crestor)
HMG-CoA Reductase Inhibitor
active as ingested
Gemfibrozil (Lopid)
Fibric Acid Analogue (Fibrate)
Enterohepatic recycling
Fenofibrate (Tricor, Triglide)
Fibric Acid Analogue (Fibrate)
prodrug
also ↑ hepatic LDL receptors via PPAR-α, thus ↓ plasma LDL levels more than gemfibrozil
Niacin (Niacor, Niaspan)
LOWERS LDL, RAISES HDL
inhibits intracellular (hormone-sensitive) lipase activity in adipocytes-->inhibits intracellular lipolysis in fat cells-->reduces the major source of fatty acids for hepatic triglyceride biosynthesis-->reduces plasma VLDL by indirectly inhibiting VLDL synthesis in the liver -leads to lower IDL & LDL
enhances the activity of the extracellular lipoprotein lipase–>increases VLDL catabolism
↓ levels of lipoprotein(a) (an unusual, small, highly atherogenic form of LDL)
↓clearance of HDL- apolipoprotein A-1–>considerably ↑ plasma HDL (most effective drug for this)
*tx for all primary forms of hyperlipidemias and isolated HDL deficiency
cheap! oral admin, short duration, some sustained release
-Metabolized to nicotinamide, the vitamin, which has no lipid lowering activity
Omega-3-Acid Ethyl Esters (Lovaza)
Highly purified concentrated preparation of ethyl esters of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids
other formulations (not listed in handout): Icosapent Ethyl (Vascepa) Omega-3-Carboxylic Acids (Epanova)
Mipomersen (Kynamro)
Lomitapide (Juxtapid)
newer, adjuncts to diet and other drugs in patients with HOMOZYGOUS familial hypercholesterolemia
decrease VLDL and LDL by inhibiting formation of apolipoprotein B-containing lipoproteins in GI and liver
Mipomersen: oligonucleotide type inhibitor, given subQ
Lomitapide: microsomal triglyceride transfer protein (MTP) type inhibitor, taken orally
SEs: serious liver toxicity (restricted availability thru REMS)
Alirocumab (Praluent) and Evolocumab (Repatha)
very new drugs, used for pts with atherosclerosis who require additional lowering of LDL cholesterol
“Statin-intolerant” patients
given subQ
SEs: non-specific GI, metabolic and neurocognitive reactions currently under FDA concern
many concern with increase in cholesterol:
atherosclerosis, a condition which can lead to ischemic coronary heart disease (CHD) with MI (Figure 1), and to CVAs
Some types of hyperlipidemias are also associated with an increased risk of pancreatitis and xanthomas in skin and tendons.
4 main risk factors for atherosclerosis: T2 DM smoking HTN hyperlipidemia
lipoproteins
central core of lipids (triglycerides and cholesterol esters) encased in a coat of phospholipids, free cholesterol and apoproteins (also called apolipoproteins)
chylomicrons do not contribute to atherosclerosis bc ??
they are too big
When plasma LDL rises ??
the rate of such oxidation and nonspecific uptake increases leading to atherosclerotic lesions
HDL
tiny, almost completely made up of cholesterol
exogenous pathway
cholesterol and triglycerides derived from the GIT (EXOgenous) are transported as chylomicrons to muscle and adipose tissue
LPL (EC) breaks down TAGs in chylomicrons–>FFAs–>taken up by fat cells–>TAGs
or–>skel musc for energy
taken up by liver–>bile made–>excreted in GIT for digestion aid
OR liver can make own VLDL (endogenous pathway begins)
**HMG-CoA reductase in liver is rate-limiting
VLDL from liver–>
(LPL)–>IDL–>LDL
can be taken up by liver via LDL receptor
or extra hepatic tissue take up LDL to make new cell membranes, hormones, etc via LDL receptors
if LDL builds up to high
spills into arterial wall leading to oxidation and accumulation of macrophages–>atherosclerotic lesion (VLDLs can also contribute)
HDL role
is to take up cholesterol (rather than deliver)
can pick up from arterial wall
–>convert to cholerterol ester–>transfer to IDLs->transport back to liver via HDL receptors and dump cholesterol contents and pick up more
transport of cholesterol by HDLs is opposite of transport by LDLs (reverse transport)
Type 1: Isolated Familial hyperchylomicronemias
↑↑ chylomicron (↑↑ TG)
NO CHD risk
Type IIa: Isolated Familial hypercholesterolemias

↑↑ LDL
(↑↑ cholesterol)
↑↑↑ risk CHD

Type IIb: Mixed Familial hyperlipoproteinemias
↑↑ VLDL, ↑↑ LDL * (↑↑ TG ,↑↑ cholesterol)
↑↑↑ CHD risk
Type III: Familial dysbetalipoproteinemias
↑IDL,↑LDL
(↑ TG, ↑ cholesterol)
↑↑ risk CHD
Type IV: Isolated Familial hypertriglyceridemias
↑↑ VLDL
(↑↑ TG, ↑ or normal cholesterol)
↑ risk CHD
Type V: Mixed Familial hypertriglyceridemias
↑↑ chylomicron, ↑↑ VLDL (↑↑ TG, ↑ or normal cholesterol)
↑ CHD risk
Type VI: Isolated HDL deficiency
newer form
Ezetimibe (Zetia) SEs
diarrhea and abdominal pain
slightly greater risk of ↑ liver enzymes in serum when combined with statin
Fibrates INCREASE and bile acid binding resins DECREASE availability of Ezetimibe
bile acid binding resins (bile acid sequestrates)
copolymers that have an ion-exchange capacity
exchange chloride for bile acids
-more cholesterol must be converted to bile acid and secreted by the liver into the intestine
-liver must synthesize more cholesterol and/or get more in from the circulation through an increase in hepatic LDL receptor numbers (which take up circulating LDL)
decreases plasma LDL
initially, VLDL synthesis and release into plasma (due likely to increased hepatic synthesis of cholesterol) may be increased, may be prolonged in patients with preexisting high VLDLs.
HDL may slightly increased
tx for high LDL type hyperlipoproteinemias with diet and other drugs
may aggravate some other types by raising plasma concentrations of VLDL
oral, not digested or absorbed, not metab but dir. excreted in feces
bile acid binding resins (bile acid sequestrates) SEs
Because resins are not absorbed they do not cause systemic toxicity.
G.I. adverse reactions are common. Bloating, mild nausea, constipation, fecal impartation,
epigastric distress. Least with Colesevelam.
Not very palatable. Colesevelam not as bad.
bile acid binding resins: Drug and Nutrient Interactions
Resins can sequester and thus inhibit absorption of many other drugs – e.g. thiazide diuretics, antibiotics, barbiturates and even ezetimbe and certain statins.
-Recommend separate times of administration if combinations required. Colesevelam less a problem.
•interference with fat soluble vitamin and iron absorption occurs.
At very high doses, cause weight loss by malabsorption of various other nutrients.
HMG-CoA reductase inhibitors (statins)
site of action: liver
catalyzes the conversion of HMG-CoA to mevolonate
reduce overall systemic availability of circulating endogenous cholesterol
indirectly induce the liver and other peripheral tissues to increase the number of LDL receptors, reduction in level of LDL in plasma
VLDLs, IDLs also reduced
Most powerful LDL-cholesterol (and non-HDL-cholesterol) lowering agents!
indicated alone or as adjunct to diet and other drugs for the reduction of elevated LDL cholesterol
May also increase HDL levels slightly
anti-inflammatory action, reduce fibrinogen levels, decrease oxidation of LDLs
HMG-CoA reductase inhibitors (statins) (pharmacokinetics)
oral, “first-pass” uptake by liver (can be inhibited)
excreted in the feces by secretion in the bile
HMG-CoA reductase inhibitor (statin) SEs
constipation, diarrhea, abdominal pain, headache, dizziness, rash, blurred vision, nausea (mild)
- Liver Dysfunction*- increase in serum transaminase (aminotransferase)
- do LFTs 1x/yr
Myopathy (skel musc) - ↑ plasma creatine kinase levels (as much as 10x!)
can lead to rhabdomyolysis–>renal failure
by reducing coenzyme Q10 levels?? -not well supported
-exacerbated by exercise
(rare but serious)
FYI: new onset DM (outweighed by dec. in cholesterol)
contraindications to using statins (HMG-CoA reductase inhibitors)
Active liver disease (obvious)
Pregnancy and lactation (not so obvious but yet important)
Niacin SEs
Flushing and itching or burning feeling in the skin is most common (due to dilation of skin vessels)
(prostaglandin release (from immune cells in skin) and therefore may be diminished by taking about 300 mg of aspirin approximately 30 min before niacin)
-may disappear in a few days, may be less severe if drug is taken with meals
Niacin longer lasting SEs
hypotension in those already on antihypertensive drugs (dilation of skin BVs)
moderately increased liver enzymes (like statins, do LFTs)
Mild hyperglycemia and glucose intolerance especially in diabetics
G.I. disturbances and peptic ulcer (gastric acidity, etc) except when combined with a bile acid binding resin
Non-specific renal effects: including elevated plasma uric acid
Fibrates
LOWER VLDL (more than LDL) -therefore decrease triglycerides
increased clearance of VLDL via increased LPL activity
-involves increased activity of peroxisome proliferator-activated receptor alpha (PPAR-α)
A second PPAR-α-related mechanism may be increased enzymes for oxidation of free fatty acids in liver and thus less free fatty acids available for VLDL production and secretion
may increase HDL moderately, not as well as niacin but better than others
(PPAR-α dependent increase in formation of
HDL apolipoprotein A-1 and -2)
fibrate uses
primary hyperlipidemias with high VLDL
hypertriglyceridemia secondary to some
defect in apolipoprotein E (an unusual form of dysbetalipoproteinemia)
fibrate pharmacokinetics
Good oral absorption
(fenofibrate is a prodrug)
Inactivation by both hepatic metabolism and renal excretion
(Enterohepatic recycling for gemfibrozil)
fibrate SEs
gallstone formation (rare but serious)
G.I. upset & nausea (most common)
Risk of myopathy when combined with statins (increase circulating levels of statin) (especially gemfibrozil)
HMG-CoA reductase inhibitors (statins) are best at ??
lowering LDLs
fibrates best at ??
lowering triglycerides (via lowering VLDLs)
niacin best at ??
raising HDLs
instead of using fibrate to take down triglycerides, use ??
Omega-3-Acid Ethyl Esters (Lovaza)
Omega-3-Acid Ethyl Esters (Lovaza) mechanism
Inhibit hepatic synthesis of triglycerides from endogenous free fatty acids (eFFA) via:
- increased beta-oxidation of eFFA (like fibrates)
- decreased delivery of eFFA to the liver
- decreased synthesis of eFFA
- decreased activity of triglyceride-synthesizing enzymes (e.g. diacylglycerol acyltransferase)
- may increase LPL activity
- May ↑ HDL but only slightly
Omega-3-Acid Ethyl Esters (Lovaza) uses
adjunct to diet to reduce very high plasma (triglyceride levels
decreases VLDL like fibrates, LDL not decreased)
In combination with statins to treat patients with both high LDL and VLDL
(safer then fibrates to take down triglycerides (less risk myopathy))
Anti-inflammatory action (like statins)
take 4 1-gram capsules per day
Omega-3-Acid Ethyl Esters (Lovaza) adverse effects
symptoms of the flu and/or infections
mild GI distress, taste perversion and “fishy” belching
may inhibit platelet aggregation too much; cause bleeding
interaction with anticoagulants, monitor pts
Alirocumab (Praluent) and Evolocumab (Repatha) mechanism
Monoclonal antibodies that inactivate PCSK9 (proprotein convertase subtilisin/kexin type 9)–>less degradation of LDL-receptors and more recirculation of LDL-receptors to the surface of liver cells–>lowers blood LDL cholesterol
FYI Orlistat (Alli, Xenical)
inhibit absorption of dietary fat from GIT
used for weight loss
may lower LDL

FYI Cholesterol Ester Transfer Protein (CETP) Inhibitors
Torcetrapib (off the market)
Dalcetrapib
Anacetrapib
specifically intended to raise circulating HDL
