Management & Medications

Diet, weight loss and drug therapy are the mainstay of treatment, while exercise training is used as adjunctive therapy

Lipid-lowering medications Nicotinic acid – niacin suppresses VLDL

synthesis Bile acid-binding resins – lowers LDL

(Lipitor, Metaprol, Cholestyramine) Fibric acid derivatives – increase enzyme

activity (Gemfibrozil)

Management & Medications

Lipid-lowering medications: HMG CoA inhibitors – inhibit cholesterol

synthesis (Lovostatin, Provostatin) Other medications to be aware of

Beta blockers – increase TG, decrease HDL

Diuretics – increase Chol, VLDL, LDL & TG

Insulin therapy – decrease TG and increase HDL

Estrogens – increase HDL, VLDL, TG

Mechanisms of action of drugs

bind to bile acids/cholesterol inhibit absorption/reabsorption

increase peroxisomal FA oxidation stimulate lipoprotein lipase inhibit triglyceride lipase inhibit HMG CoA reductase stimulates microsomal 7-alpha

hydroxylase

Drug Classification

systemic/non-sytemic cholesterol lowering agents

bile acid sequestrants sitosterols* probucol* d-thyroxin* HMG Co-A reductase inhibitors

*No longer available commercially in the U.S

Drug Classification

mixed activity (nicotinic acid) triglyceride lowering

clofibrate (Atromid-S) gemfibrosil (Lopid) fenofibrate (Tricor)

Mechanism of Action of Statins, Cholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

X Statins

Statin

lovastatin

pravastatin

simvastatin

atorvastatin

cerivastatin

fluvastatin

Protein binding)%(

>95%~50%

95–8%>98% >99%>98%

Metabolisedby CYP450

Yes

No

Yes

Yes

Yes

Yes

Lipophilic

Yes

No

Yes

Yes

Yes

No

Half-life (h)

~2~2~3~15

~3~3

Pharmacokinetics of Statins

(Adapted from Horsmans 1999, Vaughan et al, 2000)

HMG CoA reductase inhibitors

Precautions: mild elevation of serum aminotransferase

(should be measured at 2 to 4 month intervals)

minor increases in creatine kinase (myopathy, muscle pain and tenderness)

do not give during pregnancy

CLOFIBRATE

Primary activity on triglycerides MOA:

increases lipoprotein lipase lowers VLDL increases peroxisomal FFA oxidation inhibits cholesterol biosynthesis increases biliary secretion of cholesterol

ancillary: decreases platelet

adhesiveness/fibrinogen

Clofibrate (Atromid-S)

Precautions enhances coumarin activity renal/hepatic injury contraindication pregnancy/nursing cholelithiasis most commonly reported ADR are GI related liver malignancies (not very common; but

has led to scant usage)

Fenofibrate (Tricor)

a relatively new fibric acid derivative (micronized form of the drug)

lowers plasma TG inhibits TG synthesis stimulates catabolism of VLDL

indicated primarily for hypertriglyceridemia

same side effects and precaution as in other fibric acid compounds

half-life: 20 hours Dose: 67-201 mg/day with meals

Gemfibrosil (Lopid)

MOA stimulates lipoprotein lipase interact with PPAR a (peroxisome proliferator-

activated receptors) inhibits triglyceride lipolysis in adipose tissue decreases FFA uptake by the liver decreases hepatic VLDL/TG synthesis slight cholesterol lowering effect

precautions similar to clofibrate myositis (voluntary muscle inflammation) GI (indigestion, abdominal pain, diarrhea) cholelithiasis (increased cholesterol biliary secretion)

half life: 1.1 hours

NICOTINIC ACID (Niacin)

N

COOH

NICOTINIC ACID (NIACIN)

A water soluble vitamin of the B family;nicotinamide is not activeOnce converted to the amide, it is incorporated into NAD

In order to be effective, it has to be dosed at the rate of 1.5 to 3.5 gm daily.A sustained release dosage form is available

adverse effects: GI disturbances (erosion and ulceration)

red flush especially in the face and neck area caused by vasodilation of capillaries

Nicotinic acid (Niacin) MOA

dual plasma triglyceride and cholesterol lowering decreases VLDL and LDL

decreases TG lipase in adipose tissue increases lipoprotein lipase in adipose

tissue precaution

transient cutaneous flush histamine release potentiates BP effect of antihypertensives

Advicor®

niacin-extended-release and lovastatin tablets

reduces LDL-C, TC, TG and increases HDL-C

available as 500/20, 750/20 and 100/20 mg tablets

16

HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides

*Daily dose of 40mg of each drug, excluding rosuvastatin.

Therapy TC LDL HDL TG Patient tolerability

Statins* ¯ 19-37% ¯ 25-50% 4-12% ¯ 14-29% Good

Ezetimibe ¯ 13% ¯ 18% 1% ¯ 9% Good

Bile acid sequestrants ¯ 7-10% ¯ 10-18% 3% Neutral or Poor

Nicotinic acid ¯ 10-20% ¯ 10-20% 14-35% ¯ 30-70% Reasonable to Poor

Fibrates ¯ 19% ¯ 4-21% 11-13% ¯ 30% Good

Lipid Management Pharmacotherapy

Investigational drugs

acylCoA: cholesterol acyltransferase inhibitors Orphan nuclear receptors:

LXR – “oxycholesterol receptor” --- enhanced cholesterol efflux

FXR – “bile acid receptor” ---- decreased cholesterol conversion to bile salts

Squalene synthase inhibitors squalestin 1, a fermentation product

derived from Phloma species (Coelomycetes)

a potent inhibitor of squalene synthase

produces a marked decrease in serum cholesterol and apoB levels

may represent an alternative clinical therapy to hypercholesterolemia