antihyperlipidemias 57/58 Flashcards Preview

Pharm > antihyperlipidemias 57/58 > Flashcards

Flashcards in antihyperlipidemias 57/58 Deck (55):

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)


also ↑ hepatic LDL receptors via PPAR-α, thus ↓ plasma LDL levels more than gemfibrozil


Niacin (Niacor, Niaspan)


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:



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



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-->


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

(↑ TG, ↑ cholesterol)

↑↑ risk CHD


Type IV: Isolated Familial hypertriglyceridemias

(↑↑ 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



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:

1. increased beta-oxidation of eFFA (like fibrates)
2. decreased delivery of eFFA to the liver
3. decreased synthesis of eFFA
4. 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)

specifically intended to raise circulating HDL