Flashcards in 11 05 2014 Lipid drugs Deck (23)
What are the types of drugs used to treat hyperlipidemias?
1. HMG-CoA reductase Inhibitors ( AKA STATINS)
2. Bile-absorbing Resins
5. Cholesterol absorbing
Who are the Statins used?
Mechanism of statins and their benefits due to the mechanism?
inhibit HMG CoA reductase = blocks denovo cholesterol synthesis
= deplete the intracellular supply of cholesterol. Now patient needs to use cholesterol in blood.
1. increase LDL receptor
2. Remove LDL from blood
3. Decrease hepatic VLDL production
- Decrease in LDL = plaque stabilization
- Plaque stabilization = decrease in thrombotic event
- Also decreases the vulnerability of LDL oxidation
= anti-inflammatory effect
- improvement of coronary endothelial function due to increase synthesis of NO
Overall effect of Statin use? And who benefit most from it?
Lowering of LDL and increase HDL
EVERYONE -- any familial hyperlipidemia and CAD patients (improve mortality)
Pharmacokinetics of statins?
- All delivered orally
-absorption enhanced by food
- All have high first pass extraction
- All are bio-transformed into products that retain activity
- excreted via bile and feces but some are eliminated via kidneys
Lovastin and Simvastatine are Pro drugs (30-50% available)
Rosuvastatin and atorvastatin are most potent
Adverse effects of statins?
1. Dose related HEPATOTOXICITY
* check AST and ATL enzymes
2. Myopathy of proximal legs and arms symmetrically (especially with combination w/ niacin and vibrates)
* check creatine levels regularly
-Rhabdomyolysis: myoglobinuria ** renal failure
3. Drug interaction !! * CYP34A -- P450
4. Contraindicated in pregnancy and nursing mothers
What are the names of the bile acid sequestrates (resins) used?
What is the overall result of bile acid sequestrate use?
Decrease LDLs (not as well as statins)
Mechanism of Bile acid resins?
(+) charged resin that binds to (-) charged bile acid/salt in the small intestine
-complex is excreted in feces
PREVENTS bile salts from returning to liver via enterohepatic circulation
Decrease bile = decrease LDL in plasma = bile acid synthesis
What are the therapeutic uses for Resins?
Heterozygous Familial hyperlipidemias ( type IIa: increase in LDL with no increase in VLDL); and Type IIb: increase in LDL and VLDL)
Patients with cholestasis/ bile salt accumulation
Removal of digitalis from GI tract
Must take with food
Pharmacokinetics of resins?
- Not absorbed or metabolized because they are insoluble in water AND they are HUGE!!
- totally excreted in feces
- potency is less than statins
Adverse effects of resins?
1. GI: constipation, flatulence, nausea
- Colesevelam has less GI effects
2. Impaired absorption of fat soluble vitamins A, D, E, and K
3. Drug interactions: Cholestyramine and Colestipol interfere with MANY DRUGS
4. Cause increase in cholesterol synthesis = increase in VLDL = increase in TAG
1. Overall effect
Decrease in LDL AND TAGS
* great for treatment of familial hyperlipidemias
Most effective agent for increase in HDL
Also known to decrease lipoprotein(a)
-cardivascular disease risk factor when elevated
Mechanism of niacin
inhibits lipolysis of adipose tissue
= decrease in FFA
- have to use VLDL = decrease in LDL
Increase in HDL by blocking Apo AI reuptake
Reverse endothelial cell dysfunction and thrombosis due to an increase in plasminogen activator and decrease level of plasma fibrinogen.
Adverse Effects of niacin
1. intense cutaneous flush due to increase in prostacyclin (take aspirin)
2. Nausea and exacerbation of peptic ulcers
3. Gout/ Hyperuricemia
4. impaired glucose tolerance
5. Hepatotoxicity: fatigue, weakness, increase in AST and ALTs
6. Myopathy when prescribed with statins
Overall therapeutic effect of Fibrates? What are the names of Fibrates?
decrease TAGs and increase HDL
Type III, IV< and V familial hyperlipidemia
mechanism of action for fibrates?
Block PPAR alpha : peroxisomer proliferator-activated receptor : regulators of lipid metabolism
-ligand activated transcription factors
Blockage = increase expression of lipoprotein lipase and decrease ApoCII concentration
= increase HDL via increasing api AI and apo AII expression
Pharmacokinetics of Fenofibrate
Prodrug! and is more effective than gemfibroazil
Pharacokinetics of Fibrates in general:
2. distribute widely
3. bound to albumin
4. undergo extensive biotransformation and are excreted in urine
Adverse effects of Fibrates
2. Lithiasis = increase cholesterol excretion = gallstone formation
3. myositis: inflammation of voluntary muscles
4. Drug interactions: compete with coumarin anti coagulates = potentiate their effect
5. DO NOT USE during Pregnancy or breast feeding
6. raise lipoprotein lipase = increase VLDL catabolism = raise circulating LDL --- bad in patients with baseline hyperlipidemia
Overall effect of Ezetimibe
Cholesterol absorption inhibitor
Decrease LDL and TAGs
No adverse effects
Mechanism of Ezetimibe
selective inhibitor of cholesterol uptake at the brush border of epithelial cells in the small intestine