Drugs for Lipid Disorders - Kruse Flashcards
Dietary measures are the first mechanism of treatment for hyperlipoproteinemia UNLESS… (3)
- Coronary or peripheral vascular disease
- Familial hypercholesterolemia
- Familial combined hyperlipidemia
Things that increased LDL
Things that increase TGs
- Cholesterol, fats
- Fats, alcohol, excess calories
MOA of Statins
- Direct inhibitors of HMG-CoA reductase, inhibiting de-novo cholesterol synthesis
- Depleted intracellular cholesterol –> increased membrane LDL receptors –> REDUCED CIRCULATING LDL
Absorption, location of action, and excretion of statins
- Absorbed and FIRST-PASS in liver
- Acts in liver
- Excreted mostly in bile
Statins w/ long half lives (most potent)
Atorvastatin, Rosuvastatin
Statin absorption is enhanced how?
With FOOD (take w/ meal)
Statin not metabolized by CYP450 system
Pravastatin
Statin highly absorbed even w/o food
Fluvastatin
Statins are used for what?
Lowering plasma cholesterol in ALL hyperlipidemias
- Atherosclerotic vascular disease
- Acute coronary syndromes
Definite contraindications of statins
- Pregnancy, lactating, likely to be pregnant
- Liver disease
- Skeletal muscle myopathy
Statins and children
ONLY in homozygous familial hypercholesterolemia
- maybe heterozygous too
Drug interactions w/ statins
CYP 3A4 or 2C9 inhibitors, competitors, or inducers
Most effective agent for INCREASING HDL
Niacin (vitamin B3)
MOA of niacin
- Inhibits lipolysis of TGs (ApoA1) in adipose tissue
- Less free FAs –> liver makes less VLDL –> LDL LEVEL DECREASES
Additional benefit of niacin
- Reduced fibrinogen + increased tPA –> decreased thrombosis via hypercholesterolemia and atherosclerosis
Excretion of niacin
URINE
Uses of niacin
- Heterozygous familial hypercholesterolemia (+ RESIN or STATIN)
- Mixed lipemia - not fully responsive to diet
Adverse effect of niacin
Intense cutaneous flush and feeling of warmth
How to combat niacin adverse effect
Take w/ aspirin or ibuprofen (PG decrease)
Contraindications of niacin (2)
Hepatic disease, active peptic ulcer
CAUTION when using niacin
Diabetes mellitus (niacin-induced insulin resistance)
Fibric acid derivatives - drug names (2)
- Gemfibrozil
- Fenofibrate
Administration of fibric acid derivatives
WITH FOOD
Gemfibrozil vs. Fenofibrate
Fenofibrate = MUCH longer half-life
MOA: fibric acid derivatives
- Agonists for PPAR-alpha nuclear txn factor
- INCREASED expression of LIPOPROTEIN LIPASE –> lipoplysis of TGs –> DECREASED plasma TG’s and VLDL secretion
3 uses of fibric acid derivatives
- VLDL hypertriglyceridemias
- Dysbetalipoproteinemia
- Hypertriglyceridemia via HIV viral protease inhibitors (-navir)
Adverse effects of fibric acid derivatives (4)
- Mild GI disturbances
- Gall stones (increased GB cholesterol excretion)
- Myositis (evaluate for muscle weakness/tenderness)
- Rhabdo (when taking statins + fibrates)
Drug interaction of fibrates
Potentiated action of anticoagulants (coumarin, indanedione)
CAUTIONS when using fibrates
- Biliary tract disease
- Those at risk of above (women, obese, native american)
Resins - drug names (3)
- Colestipol
- Cholestyramine
- Colesevelam
Other name for resins
Bile acid sequestrants
MOA of Resins
- (+) polymers that bind (-) bile acids in gut
- Increased excretion of bile acids (FECES)
- Enhanced conversion of cholesterol –> bile acids (via 7-alpha hydroxylation)
- Decreased hepatic cholesterol –> increased hepatic LDL receptor –> DECREASED circulating LDL level
Co-administration w/ Resins
RESIN + STATIN = decreased compensatory HMG-CoA reductase upregulation (cholesterol synthesis) due to decreased levels
Uses of Resins (3)
- Primary hypercholesterolemia (reduces LDL)
- Digitalis toxicity
- Relief of pruritis due to bile salt accumulation (biliary obstruction)
Adverse effects of resins
- Constipation, nausea, flattulance
- Impaired absorption of fat-soluble vitamins (ADEK)
- Impaired absorption of many drugs
How to administer other drugs w/ resins
1 hour before OR 2 hours after (avoid absorption decrease via resin)
Contraindications to Resins (3)
- Diverticulitis
- Bowel disease
- Cholestasis (obstructed bile flow)
Cholesterol absorption inhibitor - drug name
Ezetimibe
MOA of Ezetimibe
- Inhibits intestinal absorption of cholesterol (via NPC1L1) in brush border
- Inhibits reabsorption of cholesterol excreted in bile
- Reduced incorporation of cholesterol in chylomicrons
- Reduced delivery of cholesterol to liver
Uses of Ezetimibe (w/ what else?) (3)
- Primary hypercholesterolemia (alone or w/ statin)
- Homozygous familial hypercholesterolemia (w/ statin)
- Mixed hyperlipidemia (w/ fenofibrate)
What NOT to give w/ Ezetimibe
Bile acid sequestrant (resin) - would inhibit Ezetimibe absorption
Where does ezetimibe act?
W/in enterohepatic circulation
Which drug class is best at lowering LDL?
Which drug class is best at raising HDL?
WHich drug class is best at lowering TGs?
- Statins
- Niacin
- Fibrates
4 acceptable drug combinations
- Niacin + resin
- Niacin + statin
- Statin + fibrate
- Statin + ezetimibe
Lomitapide MOA
Direct inbibitor of MTP w/in ER –> prevents assembly of apo-B containing lipoproteins –> reduced chylomicrons and VLDL –> reduced LDL-C concentration
Benefits of omega-3 PUFAs
- Inhibit thrombus formation
- Decrease inflammation
- Lower plasma TGs
- Altered myocardium electrical activity
Type 1 Familial Hyperchylomicronemia:
- What is it?
- Cause?
- Associated w/ heart disease?
- Treatment?
- Massive hyper-chylomicrons during fasting –> high TGs
- Deficiency of lipoprotein lipase
- NO
- Tx = low fat diet, NO DRUGS
Type 2A Familial Hypercholesterolemia:
- What is it?
- Cause?
- Associated w/ ?
- Treatment?
- High LDL, normal VLDL, normal TGs - via blocked LDL degradation
- LDL receptor synthesis defect
- ISCHEMIC HEART DISEASE = VERY accelerated
- Diet + statin, or diet + resin + niacin
Type 2B Familial Mixed Hyperlipidemia:
- What is it?
- Cause?
- Associated w/ ?
- Treatment?
- High LDL, VLDL, and TGs
- Overproduction of VLDL by liver
- Common heart disease
- See type 2 A treatment
Type 3 Familial Dysbetalipoproteinemia:
- What is it?
- Cause?
- Associated w/ ?
- Treatment?
- Increased IDL, increased TGs, increased cholesterol
- Mutant ApoE –> Overproduction or underuse of IDL
- Xanthomas and accelerated vascular disease
- Tx = diet + statin, or diet + niacin + fibrate
Type 4 Familial Hypertriglyceridemia:
- What is it?
- Cause?
- Associated w/ ?
- Treatment?
- Increased VLDL and TGs, normal LDL and cholesterol
- Overproduction or decreased removal of VLDL TGs
- W/ accelerated ischemic heart disease (frequently obese, diabetic, and hyperuricemic)
- Tx = Diet + niacin +/or fibrate
Type 5 Familial Mixed Hypertriglyceridemia:
- What is it?
- Cause?
- Associated w/ ?
- Treatment?
- High VLDL, chylomicrons, cholesterol, TGs…normal LDL
- Increased production or decreased clearance of VLDL/chylomicrons (genetic defect)
- W/ Obesity or diabetes
- Tx = Diet + niacin and/or fenofibrate, or statin
