Lipid Lowering Flashcards
Blocks conversions of cholestend to bile acids
Bile and resins
Lowers plasma LDL by indirectly increasing rate of LDL clearance from plasma
Bile acid resin
What enzyme does bile acid block and with what effect
Inhibits 7 alpha hydroxylase
Blocks conversion of cholesterol to bile acids
What is the other mechanism of action of bile acids in the GI tract
Bind major bile acids and increase their fecal excretion
What is the effect of bile acids MOA in the GI
Net decrease of bile acids returned to the liver
Removing the negative inhibition of 7 alpha hydroxylase to make more bile acids from cholesterol
What is the effect of hepatic cholesterol reduction due to bile acid production
Increase in LDL receptor expression
Increase in uptake of plasma LDL
HMG-COA reductase induction
Increased cholesterol biosynthesis
What is the crosslinking agent of bile acid resins
Positively charge groups with amines acting as a binding site for bill acids
What are ADR of bile acids
Constipation is common
Increased frequency of loose stool
Hypoprothrombonemia (impaired clotting)
Bleeding events since bile acids bind Vit K
What are bile acids drug interaction
Bind acidic compounds and can decrease oral absorption
What medication is of major concern with bile acids therapy and vit K
Warfarin. Vitamin K is important concern can induce supratherapeutic INR
How is drug interaction avoided for patients on bile acid resins
Take 1 hour before or 4 hours after bile acids.
What is the mechanism of action of statins and why
Block HMG- COA reductase because it is the rate limiting step in cholesterol biosynthesis
Blocking of HMG-COA reductase by statins lead to what effect
Decreased cholesterol, increasing expression of HMG-COA reductase and LDL receptors
What are other mechanism of action of statins
Inhibit cholesterol synthesis
Enhance LDL uptake
Recheck VLDL precursors
What is the primary mechanism of lowering LDL levels with statins
Enhanced LDL receptor expression
What are the natural or semi-synthetic statins
Lovastatin (mushroom)
Simvastatin
Pravastatin (bacteria)
Which two natural or semi-synthetic are inactive produng form and why
Lovastatin and Simvastatin due to Lactone ring
Metabolized by CYP3A4
Simvastatin and lovastatin
Not metabolized by 3A4
Pravastatin
What are the synthetic statins
Fluvastatin - Lescol
Atorvastatin - Lipitor
Pitavastatin - Livalo
Rosuvastatin- Crestor
2C9 (70%) and 3A4 (20%)
Fluvastatin
Mostly 3A4
Atorvastastin
2C9 and lactonization
Pitavastatin
Partly 2C9 (10%)
Rosuvastatin
What are the toxicity of statins
GI
Rhabdomylosis
Avoid in pregnancy and lactation due to muscle effect
Mild increase in creatnine phosphokinase
Increased myopathy
What drug class increase myopathy when given with statins
3A4 inhibitors
3A4 inhibitors
Cyclosporine
Azole of antifungal
macrolides: erythromycin and clarithromycin
HIV protease inhibitors
Nefazodone
Grapefruit juice
Verapamil
How does statin induce myoporthy
Blocking mevalonate production, decreases ubiquinones (coenzyme Q) required for electron transfer through mitochondrial membrane
What is PCSK9
Protein that bind to LDL receptors promoting its degradation and increases plasma levels of circulating LDL
What are medication is used to lower lipid in this pathway
PCSK9 inhibitor
What medication are classified under PCSK9 intribitors
Evolocumab, Repatha
Alirocumab, Praluent
What type of drugs are PCSK9
Monoclonal antibodies that binds to circulating PCSK9
What is the effect of PCSK9 binding
Increase in LDL receptors and LDL-Cholesterol clearance in plasma
How is PCSK9-Inhibitors administered
2-4 weeks injections
What patient group is placed on PCSK-9 inhibitors
LDL:500-600 mg/dL
Patient with hypertipidemia or hypercholestrolemia
Which medication is a cholesterol transport inhibitor
Ezetimibe (Zetia)
What is the drug class of ezetimibe
Azetidinones
What is the effect of ezetimibe
Inhibits cholesterol absorption
Decreasing cholesterol and increasing its brosynthests
Causing overall lowering of LDL
True or false: ezetimibe interfers with absorption of other compounds
False
Where is ezetimbe metabolized
Intestinal wall and liver
What is the major active metabolite of ezetimibe
Phenolic glucuronide
How is the glucuronide metabolite metabolized
Excreted in bile and undergoes enterohepatic recirculation
When is ezetimbe used
When patient has failed all therapy
Can be used as mono therapy or in combo with statins
Toxicity of ezetimbe
Abdominal pain
Diarrhea
Cramping
Fatigue
Back pain
When used with statin incidence of myopathy is the same with statin monotherapy
Fibrates Effects
Decrease plasma triglycerides
Significantly decrease in VLDL levels
Increase HDL levels
Mechanism of action fibrates
Binds to PPAR a
Causes effects on lipoprotein metabolism
Activation of PPARs and altered gene expression
Fibrates binding toPPARa causes
Fatty and oxidation, lowering VLDL
Fibrate stimulation of lipoprotein lipase causes
Removal of TG from plasma VLDL
What to all fibrates do
Increase turnover and removal of cholesterol from liver
True or false: Fenofibrate and chlorofibrate are prodrugs
True
Metabolism of Fibrates
undergo hydrolysis to produce acid form
Active metabolite can be further oxidized or conjugated until products are inactive
Active fibrates
Gemfibrozil
Ciprofibrate
Bezafibrate
How are active fibrates deactivated
Oxidation and conjugation
Fibrate toxicity
Chlorofibrate has many side effects
§ Higher morbidity and mortality § Malignancy, gallbladder disease, pancreatitis
§ Like HMGRIs, they can cause myopathy,
myositis, rhabdomyolysis
§ Increased risk of gallstones due to increased excretion of cholesterol in bile
§ Increases hypoprothrombinemic effect when taken with anticoagulants (low prothrombin)
