DRUGS USED IN HYPERLIPIDEMIAS

-causes of heart disease: high LDL& VLD&TAGs, hypertension, diabetes and other metabolic diseases, smoking ( nicotine causes vasocontriction( BP increases), sub.smoliste cause only damage to endothelium), alcohol consumption ( increasing TAGs), kidney and liver diseases, estrogen (exogenous hormones therapies), lack of excercising ( min. time for atherosclerotic person: min 20 min, max 1 hour), stress, age, sex ( men have higher risk-hormonal connection)

-atherosclerosis plugs contain: TAGs, LDL, macrophages, collagen

-chylomicrons (the highest after meal {ca.2 hours}, are present in blood up to ten hours: measurment in the morning after whole night starvation), increase TOTAL CHOLERSTEROL FRACTION NOT HDL, VLDL OR TAGS! Norm for total cholersterol ca. lower than 200 mg/dl , TAGs norm: less than 150 mg/dl, LDL less than 130 mg/dl, HDL less than 40, 30 ( dep. of sex)

1) HMG-CoA REDUCTASE INHIBITOR ( STATINS)

FIRST CHOICE FOR CORONARY HEART DISEASE WITH ATHEROSCLEROSIS AND INCREASED LDL FRACTION

*HMG-CoA--------> mevalonic acid--------> cholersterol

*up-regulation of LDL receptors

*all mechanisms are still not aknowledged

*additionala ctions= pleiotrophic effects: not connected to decreased LDL so protective action of endothelium ( increases release of NO-> used in acute coronary syndrome), antiinflammatory action ( inhibit prostaglandins, local effect on vessels), decreased PLT aggregation, stabilization of atherosclerotic plaques, cardioprotective effect, decreased risk of developing free radicals ( decreased oxidation of lipoproteins) [ free radicals can lead to breakdown of atheroslcerotic plaques],

* THE EFFECT IS NOT ALWAYS VISIBLE: CHOLERSTEROL LEVELS CAN STILL BE UNSATISFACTORY, but the most important is antiinflammatory effect----> DECREASED MORTALITY

* oral route of administration, increased with taking with meal, first pass effect

*half life ca.4 hrs ( excluding atorvastatin {14 hrs, rosuvastatin 19hrs})

* effective when used in high dose once daily ( before bedtime excluding atorvastatin and ROSUVASTATIN)

*CYP 3A4, CYP 2C9

*many ineractions ( with warfarin for example) because of beeing metabolized by CYP (?)

* in UK- OTC

* developing tolerance to the drug ( drugs don't work effective after MI for example)

*side effects: hepatotoxicity ( before statins taken, liver enzymes should be examined-attention in alcoholics), myopathy and rabdomiolasis ( permanent damage to the muscles: creatine kinase should be examined in patients taking statins), has teratogenic effect ( contradicated in pregnancy and breast feeding) , in children can be used in heterozygous hypercholesterolemia, should be avoided in children below 12 yrs

*ATORVASTATIN (long action): inhibits HMG-CoA enzyme; reduces cholersterol synthesis and up-regulate LDL receptors on hepatocytes; modest reduction of TAGs; used in atherosclerosis ( primary and secondary prevention), acute coronary syndrome; used orally , duration 12-24 h ( may cause myopathy, hepatic dysfunction, teratogen; PHARMACOKINETICS: interactions: CYP-dependent metabolism, interacts with CYP inhibitors, THE STRONGEST!

*SIMVASTATIN: as above but short acting

*ROSUVASTATIN: as above ( long action)

*PITAVASTATIN: as above but short action

*FLUVASTATIN, PRAVASTATIN ( used in children older than 8yrs), LOVASTATIN: similar but less eficiacious and short action

2) RESINS ( BILE ACIDS BINDERS)

*cationic particles, not absorbable ( binding of bile acids)

*colesevelam: tablet form and in gel

*colestipol & cholestyramine: tavlets and granule form ( for dissolving in water)

-40 grams per day!!! very high dose

*used 1-4 times daily together with meals

*side effects: constipation ( should be used along with fiber), problems with vit. K absorption, many interaction with another drugs

*NO HEPATIC TOXICITY, can be prescribed in hepatic diseases

*COLESTIPOL: prevents reabsorption of bile acids from the GI tract, increases cholesterol catabolism, up- regulates LDL receptors ( decreases LDL); used in elevated LDL, digitalis toxicity, pruritus; used orally, taken with meals, not absorbed, can cause constipation, bloating; interferes with absorption of some drugs and vitamins

*CHOLESTYRAMINE, COLESEVELAM: similar

3) STEROL ABSORPTION INHIBITOR = EZETIMIBE

*inhibits absorption from GI

*EZETIMIBE: blocks sterol transporter NPC1L1 in intestine brush border, reduces intestinal uptake of cholesterol, decreases LDL and physosterols ; used in elevated LDL, phytosterolemia; used orally, duration 24 h; may cause heptic dysfunction ( but less incidence), myositis

4)NIACIN

second use drug, used in polytheraphy with statins

*niacin=nicotinic acid

*effective for lowering TAGs, LDL, increasing HDL, decreaing lipoprotein A

* side effects: flushing, GI symptoms (nausea, vimiting, diarrhea), akhanthosis nigricans, pruritus, hyperuricemia (--> gout; allopurinol can be used), arrythmias ( niacin should be used together with anticardiosensitive (?) drugs)

*aspirin and ibuprofen can be used to relieve flushings and pruritus

* NIACIN: decreases catabolism of Apo Al, reduces VLDL secretion from liver, decreases LDL, increases HDL, decreases lipoprotein A and TAGs; used in low HDL and elevated LDL, VLDL; used orally in large doses; may cause gastric irritation, flushing, low incidence of hepatic toxicity, may reduce glucose tolerance

-can be in XR form

-can be in SR form : should be avoided

5) FIBRATES

*decreasing TAGs, minimal effect on decreasing LDL and increasing HDL

*combination with statins is a mistake!

*once/twice daily

*side effects: rush, nausea, vomiting, hepatotoxicity, myopathy, increased alkaline phosphatase level

*GEMFIBROZIL, FENOFIBRATE: peroxisome proliferator-activated recpetor alpfa ( PPAR- alpha) agonists- responsible for TAG lowering effect of omega-3 fatty acids; decreases VLDL secretion, incleases LPL activity, increases HDL; used in hipertriglyceridemia, low HDL; used orally, duration 3-24 h; may cause myopathy, hepatic dysfunction

Prescriptrion:

1) statin

Rp. Simvastatin 40 mg

tab.

Lag.orig.No1

D.S. take one tablet

orally once daily

before bed time

(max dose 80 mg/day)

2) cholestyramine

Rp. Cholestyramine 4g/ sachette

gran.

Lag.orig.No1

D.S. dissolve one sachette in glass

of water three times daily together

and drink with meals.

3) ezetimibe

Rp. Ezetimibe 10 mg

tab.

Lag.orig.No1

D.S. take one tablet

orally once daily

4) phenofibrate

Rp. Fenofibrate 200 mg

caps.

Lag.orig.No1

D.S. take one capsule

orally once daily

5)

Rp. Nicotinic acid 500 mg

tab.

Lag.orig. No1

D.S. Take ne tablet orally

twice daily with meals