Lipid Lowering Drugs

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How do statins work?

Back 1

Inhibit HMG-CoA reductase enzyme which converts HMG-CoA to mevalonic acid (rate limiting step)

>95% protein bound for all but pravastatin

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HMG-CoA

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3-hydroxy-3methyl-glutaryl-coenzyme A

HMG-CoA reductase is present in the membrane of the ER

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When to prescribe statins

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Pts' 45-70 who have been unable to lower their cholesterol through lifestyle changes with at least one risk factor for heart disease: DM, HTN, smokers, dyslipidemia)

lower LDL (60%) and triglycerides (40%)

Raise HDL by 10%

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Adverse side effects of statins?

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Common: headache, insomnia, flushing, drowsiness, dizziness and muscle aches/tenderness/weakness.

Rare side: memory loss, confusion, elevated blood glu.

*myaligia is the first sign of rhabdomyolysis.

**don't give to pregnant/breast feeding women due to birth defects

Front 5

Which statins are metabolized by CYP3A4

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atorvastatin, simvastatin, and lovastatin via the CYP3A4 isoenzyme, and fluvastatin (Lescol) via CYP2C9 (no drug interactions with CYP3A4)

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Which are the two most potent statins?

Which is the least potent?

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Atrovastatin and Rosuvstatin

Fluvastatin is least potent

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Drugs that use CYP3A4 pathway and with increase statin levels causing toxicity

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Ditiazem, Fluconazole, Clarithromycin

*if given with Warfarin, it may induce Warfarin toxicity

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Drugs that induce CYP3A4 and will decrease plasma concentration of statin

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Phenytoin, Carbamazepine, Rifampin

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Fluvastatin and Warfarin

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Potent inhibitor of CYP2C9 which also metabolizes Warfarin-S and dramatically lowers the effectiveness of Warfarin. So don't give it.

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Lovastatin

Back 10

Naturally occurring in oyster mushrooms and red yeast rice.

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Which statins are pro-drugs

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Lovastatin and Simvastatin

They cross the BBB

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Pitavastatin

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water-soluble Substrate of CYP2C9

may decrease insulin resistance in humans

Can also increase uric acid levels (gout)

No need to dose adjust for pt's on Warfarin, but check the INR and PT

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Pravastatin

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VLDL inhibition and inhibiting cholesterol synthesis

It is excreted unchanged from by the kidney, making it safe to use with hepatic metabolized drugs.

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Rosuvastatin

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Metabolized by CYP2C9

Will prolong INR if given with coumarin anticoag

If given with Eluxadoline (ab pain/v/d drug) then if can increase risk of rhabdo.

Wait an 2 hours after taking before taking an antacid.

*use half the standard dose with Asian ppl

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Simvastatin

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Pro-Drug

Grapefruit interferes with CYP3A4 and will increase serum statin

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CYP3A4 Inhibitors

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Reduces maximum dose:

Moderate: verapamil, diltiazem, amiodorone and amodipine

Potent: Azithromycin, Clarithromycin/Erythromycin, azole-anti-fungals. Protesase inhibitors, Danazol

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CYP3A4 Inducers

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Increase the maximum dose

Carbamazepine, Phenyton, Rifarmpin and St. John's Wort

*if these are co-prescribed then lipid profiles should be monitored.

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Combination drugs:

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Sitagliptin: dipeptidyl peptidase-4 Inhibitor for type 2 DM given for hypercholesteremia

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How to Bile Acid Sequestrants work

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GI lipid lowering agents that are polymer resins which bind to bile acids in the small intestine and result in a complex that does not get absorbed.

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Absorption and Excretion of Bile Acid

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Bind to and excrete Warfarin and Digoxin, and diminish the absorption of fat soluble vitamins.

Important to time with gall bladder emptying.

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Decrease in cholesterol (BAS)

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Decreased bile acid reabsorption will cause hepatocyte compensation and an increase in bile acid synthesis, decreasing hepatic cholesterol and improving LDL clearance up to 28%.

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Adverse side effects of BAS

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constipation, bloating, ab pain, gas, n/v/d

can lead to compliance issues

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BAS drugs

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Cholestramine, Colesevelam, Colestipol

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Ezetimibe

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Cholesterol Absorption Inhibitor

reduces cholesterol by inhibiting transport at the brush border of the small intestine, decreasing intestinal delivery to the liver, and causing hepatocytes to increase absorption

*no effect on CYP3A4 enymes

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Ezetimibe Adverse Reactions

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headache, steatorrhea, and myopathy, myaligia, angioedema

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Ezetimibe Effects

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Reduces LDL 20%, Triglycerides by 8%

Increases HDL by 3%

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Ezetimibe and Simvastatin

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decrease absorption and liver production and is 15% more effective that the statin alone.

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Fibrates

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Fenofibrate and Gemfibrozil

Works by binding and activating PPAR-alpha type which induces the transcription of a number of genes that facilitate lipid metabolism, breaking lipoproteins into 3 fatty acids and 1 glycerol.

*are metabolized by CYP3A4

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PPAR-alpha type

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Peroxisome proliferator-activated alpha receptors are a class of intrecellular receptors that modulate carb and fat metabolism and adipose differentiation

Located in hepatocytes, skeletal muscle, heart muscle, and adipose and the kidneys.

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Effect of Fibrates

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The increase in lipolysis increases triglyceride-rich uptake of lipoproteins and increase the clearance of triglycerides.

Reduces triglycerides (50%) and VLDL, LDL by 15% and increases HDL by 20%

Indicated for: high triglycerides and high lipids

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Adverse Effects Fibrates

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N/V/D/Gastric Pain

Heart Burns, fatigue, myalgia and rhabdo is possible if given with a statin (HMG-CoA Inhibitor)

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Niacin

(Vitamin B3 or Nicotinic Acid)

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water soluble vitamin

Works through activation of G-Protein coupled receptors (niacin 1&2) in adipose tissue, spleen, and immune cells that inhibit fat breakdown and free fatty acids available for the liver to produce triglycerides and VLDL which leads to a reduction of LDL

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Niacin Effects

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a decrease in triglycerides (45%) and LDL (20%) increase in HDL (30%) by prolonging the half-life of apolipoprotein A-1 which directly increases HDL and reverse cholesterol transport for bile excretion.

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Adverse Side Effects of Niacin:

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Flushing (prevent w/ 325 mg ASA 30 min prior) or take a time-release formula

headache, pain, rhinitis, pruritus, rash, ab pain, n/v/d, dyspepsia, hyperuricemia, impaired insulin sensitivity, jaundice, a-fib, hypotension

*Pregnancy Class C - don't use

**may increase risk of myopathy with statins

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Omega-3 Fatty Acids

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Eicosaplentaenoic and Docosanexaenoic acids

Used for hypertriglyceridemia and may reduce triglycerides up to 50%

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Phytosterols

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Taken twice daily for a full does of 1.3g with a low fat diet and cholesterol may reduce risk of heart disease

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Which statins increase HDLs

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Rosuvastatin and simvastatin

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Which statins would you want to give a renally compromised patient?

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Atorvastatin and Fluvastatin