Anti Hyperlipidemia

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ATP III Framingham risk scoring for CHD -

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1.) Smoker
2.) HTN: 140/90 and above, or treated for HTN
3.) Low HDL: 40 or below. HDL > 60 Cancels out another risk factor
4.) Family history or coronary event in males < 55 y/o, females < 65 y/o
5.) Age in males > 45 y/o, females > 55 y/o

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Bile Acid sequesterants examples -

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Cholestyramine
Colestipol
Colesevelam

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What is function of cholesterol 7 alpha hydroxylase?

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Cholesterol 7 alpha-hydroxylase is the rate-limiting enzyme in the synthesis of bile acid from cholesterol via the classic pathway, catalyzing the formation of 7-alpha-hydroxycholesterol.

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Cholestyramine -

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original drug
poor palatability (dose too large for pill; mix gritty powder with fluid and drink)

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Colestipol -

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similar to cholestyramine

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MOA of Bile Acid sequesterants -

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large nonsoluble polymers that bind bile acids in the intestines to decrease absorption in the ileum. The body makes up for this decreased absorption by using hepatic cholesterol to generate new bile acids. To find the cholesterol to do this, the liver increases hepatic LDL receptors, which decreases circulating LDL.

Upregulates the prodn of cholesterol 7 alpha hydroxylase

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Actions of BAS -

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Decrease LDL modestly (15-30%)
Increase HDL barely (3-5%)

Increase TG (adverse effect, for especially with ppl in high TG)

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S/e of BAS -

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GI distress/constipation
Decreased GI absorption of other drugs (don’t give at the same time (warfarin, thyroid hormone, diuretics can't be absorbed)
affects lipophilic drugs (ie statin)

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Use of BAS -

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monotherapy - not recommended
COmbo with statins - atorvastatin (additive effect, rather than increasing the dose of statins)

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Cholesterol absorption inhibitors -

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Plant stanol esters and sterol esters - Ezetimibe

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MOA of plant stenol esters and sterols -

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Preferentially form micelles instead of cholesterol and cholesterol is excreted

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MOA of Ezetimibe -

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selectively inhibit cholesterol absorption by acting at brush border of small intestine

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Actions of plant sterols/stanols and Ezetimibe -

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↓LDL, modestly (~18%)
↓TG, somewhat (~6%)
↑HDL, barely (~1%)

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S/e of Ezetimibe -

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No significant adverse effects or drug interactions

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Use of Ezetimibe -

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Can be used as monotherapy - not effective

Used in combinatino with statins for additive effect

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Nicotinic acids MOA -

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↓FFA mobilization
↓TG synthesis
↓VLDL secretion in liver
↓LDL synthesis aka apo B
↓HDL uptake, so more HDL available

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Actions of Nicotinic acid -

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↓LDL, modestly (5-25%)
↓TG, significantly (20-50%)
↑HDL, significantly (15-35%)

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S/e of Nicotinic acid -

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Afib or other cardiac arrhythmias

Cause release of prostaglandins from endothelium (vasodilators) flushing/itching, hypotension,

Often need to pretreat with prostaglandin inhibitor (aspirin) or give extended release form
Hyperglycemia (↓glucose tolerance)
Upper GI distress (peptic ulcers)
Hepatotoxicity (LFTs)
Hyperuricemia (interferes with renal excretion of uric acid)
Myopathy (don’t use with fibric acids, or additive myopathy)

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Niacin or BAS?

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Niacin better clinically effective than BAS

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CI of Niacin in -

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Liver disease, Gout, Peptic ulcers, Diabetes

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What form of Niacin is used now a day?

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Only extended/sustained release forms used now (immediate release causes liver damage due to high doses)

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Fibric acid derivatives examples -

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Gemfibrozil
Fenofibrate

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MOA of Fibric acids -

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ligands for PPAR-α protein, a receptor that regulates transcription of genes involved with lipid metabolism => increases formation of HDL. Ultimately gives increased activity of lipoprotein lipase & enhanced clearance of TG loaded lipoproteins. Often used in combination with other drugs, since doesn’t do much for LDL.

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Gemfibrozil -

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worse toxicity/reactions - requires 2 doses per day
No reason to choose this drug

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Fenofibrate -

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more potent and less toxic than genofibrate - only one dose/day

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Actions of fibric acids -

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↓LDL, modestly (5-20%) with normal baseline TG;
Increases LDL with high baseline TG

Transiently ↑LDL particles: however, these are more buoyant /larger & do not form atherosclerotic plaques
↓TG, significantly (20-50%)
↑HDL, significantly (10-20%)

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S/e of Fibric acids -

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Dyspepsia (assoc with PUD), myopathy

Gemfibrozil - gall stones, drug interaction with warfarin, worse myopathy resulting in rhabdomylysis

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CI of Fibric acids in -

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Severe renal or hepatic disease, dose adjustment in renal failure

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Mechanism of action of HMG CoA reductase inhibitors -

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competitively inhibits HMG CoA reductase to reduce the conversion of HMG CoA to mevalonate in the cholesterol synthesis pathway, to reduce cholesterol synthesis & increase hepatic clearance of LDL by increasing hepatic LDL receptors.

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Actions of Statins -

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Most potent cholesterol lowering drug; other beneficial effects besides cholesterol lowering
↓LDL, significantly (18-36%): ↓LDL is the most correlated with ↓coronary artery event
Rosuvastatin > Atorvastatin > Simvastatin > Pravastatin/Lovastatin > Fluvastatin
↓TG, significantly (7-30%)
Rosuvastatin ~ Atorvastatin > Simvastatin > Pravastatin/Lovastatin > Fluvastatin
↑HDL, significantly (5-15%)
Rosuvastatin > Simvastatin > Pravastatin/Lovastatin > Fluvastatin
Atorvastatin is paradoxical (↑dose  less HDL increase)
Other: NO regulation, atherosclerosis (LDL oxidation), clotting factors, BP effects, etc

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S/e of statins -

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Myopathy: general term for disease of muscles – muscle weakness or aching

Types: myalgia (muscle), myositis (muscle, w/↑CK), rhabdomyolysis (muscle, w/↑CK & renal damage)

Cerivastatin taken off market because of huge reports of rhabdomyolysis

Rosuvastatin can’t be dosed higher because of greater risk of myopathy & rhabdomyolysis

↑LFTs if lipophilic

Must monitor CK levels and LFTs, especially if baseline symptoms get worse

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CI of statins -

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High risk groups for myopathies

Do not take with Fibrates (Choose Fenofibrate over Gemfibrozil) & Nicotinic acid, PI (HAART) and p450 inhibitors

Considerations: old age, small frame, multisystem disease, multiple meds, perioperative periods

Liver disease

Pregnancy: cholesterol is important in cell formation for fetus
Several drug interactions

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Benefits of statins -

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↓coronary events
↓CHF mortality
↓coronary procedures
↓stroke
↓overall mortality

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Rule of 6s associated with statins -

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Rule of 6’s: each doubling of dose produces only 6% reduction of LDL

Better to use combinations with other drugs than to increase dose of statins

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Study outcomes of Simvastatin + Fibric acids = vytorin

Dual inhibition approach - attacking cholesterol prodn and absorption

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): greater decrease in LDL & c-Reactive protein, than statin alone

However, no improvement in carotid inter-media thickness (combo not associated with better outcomes)

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Which statins are lipophilic?

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Atorvastatin
Lovastatin
Simvastatin

increased risk of myopathies

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Which statins are hydrophilic?

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Pravastatin
Fluvastatin
Rosuvastatin

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Metabolism of statins -

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Kidney metabolism: Pravastatin, via sulfonation (no hepatotoxicity)

Liver metabolism:
CYP3A4 (Lovastatin, Simvastatin, Atorvastatin) &

CYP3C9 (Fluvastatin, Rosuvastatin)

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Alternative therapies of treating cholesterol -

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Soluble fiber in diet ↓LDL, (1-10%)

Soy protein ↓LDL, (5-7%)

Fish oils* ↓TG, (25-30%)
↑HDL, (6%)

Stanol esters ↓LDL, (10-15%)

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Lovaza -

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Omega 3 acid ethyl ester

Decreases lipogenesis in liver, increase plasma lipoprotein lipase activity

Only by prescription

Contains 3 times omega-3 content as OTC fish oil caps

Less fish belch than with OTC fish oil capsules

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Probucol -

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Probucol is an anti-hyperlipidemic drug[1] initially developed in the treatment of coronary artery disease.

Decreases HDL - s/e

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At what time of day should statins be taken?

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in evening to maximize the lipid lowering effect (except atorvastatin - taken anytime)

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Rhabdomyolysis -

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muscle symptoms with marked CK elevation (10x the upper limit of normal [ULN]) and creatinine elevation (usually with brown urine and urinary myoglobin)


Breakdown of muscle proteins (myoglobin, creatine kinase) that leads to renal toxicity. Symptoms include muscle pain and weakness and dark urine due to muscle catabolism


Led to cerivastatin (Baycol) withdrawal from the market since this statin had ~20-fold greater risk compared to other statins

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Myositis -

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muscle symptoms with increased CK levels

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Myalgia -

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muscle aches or weakness without CK elevation