Drugs Flashcards
What are statins good at?
Reducing LDL
What are fibrates good at?
Reducing triglycerides
What is niacin good at?
Increasing HDL
Reducing triglycerides
How do statins work?
Inhibition of enzyme (HMG-CoA reductive) has two effects:
(1) decrease liver cholesterol synthesis => inc. LDL receptor expression => dec. LDL and VLDL
(2) decrease liver cholesterol synthesis => dec. liver VLDL production => dec. TG
Which statins are the best at lowering LDL?
Atorva, Rosuva
Simva
Which statin is the lowest intensity?
Fluva
What are some other statin benefits, besides lipid reduction?
Increased endothelial vasodilation
Inc. plaque stability
Dec. inflammation
Dec. lipoprotein oxidation
Dec. platelet aggregation + fibrinogen (less clots!)
Why are statins dosed at night?
Period with highest cholesterol synthesis
Which statins would be best for AM dosing?
Atorva and Rosuva
Have longer half-lives and will last longer to reach night-time cholesterol synthesis
Which statins are prodrugs that get activated in the liver?
Lova
Simva
AE’s for statins
Mild: headache, rash, GI upset
Liver dysfunction
Myalgia
Statins DDIs
CYP3A4 inhibitors - ex: amiodarone
(Affects lova, simva > atorva»_space;> Prava, rosuva, fluva)
Fibrates
Niacin = 1+ g/day
Bile acid resins
Warfarin
Red yeast rice
How do fibrates work?
Activate receptor - PPARalpha
PPAR = peroxisome proliferator-activated receptors
How do fibrates work?
PPAR activators
(1) more ffa oxidation => less TG made in liver (less building blocks for VLDL)
(2) Inc. LPL and less apoC made => more clearance of TG-rich lipoproteins = dec. VLDL and TG
(3) More LDL receptors made => dec. VLDL and LDL
(4) Inc. apoA made => more HDL => more reverse chol. Transport
What are some other effects fibrates have?
Inc. HDL
Dec. triglycerides
Which fibrate is metabolized in the liver and thus contraindicated in hepatic dysfunction?
FENOfibrate (converted to fenofibric acid)
What are some adverse effects of fibrates?
GI (nausea, dyspepsia, abdominal pain)
Myopathy
What are some DDI’s with fibrates?
Statins => myopathy (avoid with GEMIfibrozil)
Bile acid resins => dec. bioavailability
Take fibrate 1 hour before or 4 hours after
Warfarin => inc. INR
When are fibrates contraindicated?
Severe renal or hepatic failure
Pregnancy
Children
What is another name for Niacin?
Vitamin B3
What sites does Niacin work at?
Adipose tissue
liver
Plasma
Macrophages
What effect does niacin have in adipose tissue?
Inhibits adenylyl cyclase => dec. cAMP
=> dec. hormone-sensitive lipase
=> dec. TG lipolysis and FFA release
What effects does Niacin have in the liver?
Dec. FFA transport => dec. TG made in liver => less VLDL => dec. TG and LDL
Dec. liver clearance of ApoA in HDL => more HDL in plasma => more reverse cholesterol transport => dec. LDL
What effect does Niacin have in plasma?
Increased LPL activity => dec. TG, VLDL, chylomicron
What effect does niacin have in macrophages?
Increased scavenger receptor and cholesterol exporter => dec. cholesterol in foam cells
What are two metabolites of niacin (and their effects)?
Nicotinuric acid = vasodilation (flushing)
Nicotinamide = toxic metabolites for liver
What are Niacin adverse effects?
Flushing, headache, itching
GI: nausea, dyspepsia, peptic ulcer
Dry skin
Acanthus nigricans (darkening of skin)
Hepatotoxicity
Hyperglycemia
Myopathy
Hyperuricemia
What are some Niacin DDIs?
Statins: lower risk with niacin @ less than 1 g/day
Bile acid resins: colestipol»_space;> cholestyramine
Separate by 4-6 hours!
Niacin is the only drug that does what?
Lower LpA
For which patients should Niacin be avoided?
Uncontrolled diabetics
Active PUD
liver disease
Gout
What does Ezetimibe do?
Inhibits cholesterol absorption
How does Ezetimibe inhibit cholesterol absorption?
Binds cholesterol transporter and leads to decreased dietary and biliary cholesterol uptake
Decreased cholesterol in chylomicrons and less delivered to liver
Dec. delivery to liver leads to increased production of LDL receptors (which will take up more LDL)…but then that also leads to more cholesterol made in liver from LDL uptake :(
What effects does ezetimibe have?
Decreases LDL
NO EFFECT on TG or HDL
What are some adverse effects of Ezetimibe?
Headache, diarrhea
Arthralgia
fatigue
Cough
Inc. serum transaminases
Hypersensitivity (rare)
What are DDIs associated with Ezetimibe?
Minimal (since not absorbed!)
Bile acid resins will decrease Ezetimibe’ absorption - take 2 hrs before or 4 hours after BAR
Warfarin : may inc. levels
Cyclosporine : may inc. levels
What’s Ezetimibe’ relationship with statins?
Additive to decreased LDL by additional percentage
What are some bile acid resins (BARs)?
Cholestyramine
Colestipol
Colesevelam
How do BARs work?
In anion exchange resins:
Bind bile acids in gut to excrete them in stool => dec. bile acid stores
In the liver:
Inc. bile acid synthesis with dec. hepatic cholesterol => more LDL receptors made => dec. LDL (from uptake)
Dec. cholesterol in liver also increases HMG-CoA reductase activity to increase chol. Synthesis => dec. LDL receptor, Inc. VLDL, Inc. TGs
Which BAR would you recommend for a patient with GI upset?
Colesevelam
What are adverse effects associated with BARs?
GI intolerance: bloating, dyspepsia, gas, nausea, constipation
Gritty slurry from cholestyramine and colestipol
Increased TGs (avoid in severe hypertriglyceridemia)
What are some BAR DDIs?
Interfere with drug absorption so separate 1 hour before or 3-4 hours after!!!
Fluva/Pravastatin
Niacin
Fibrates
Ezetimibe
Warfarink, beta-blockers, thiazides, furosemide
Propranolol, levothyroxine
Vitamins A, D, E, K
What effect does Fish oil have?
Inhibits VLDL and TG synthesis in liver
What are adverse effects of fish oil?
GI upset, burping, altered taste
What are some cons of fish oil?
Does not lower LDL (may actually increase it)
No effect on HDL
How do PCSK9 inhibitors work?
Prevent PCSK9 from binding to LDL receptors (which would promote their degradation within the liver and result in higher LDL levels in the blood)
What are indications for PCSK9 inhibitors?
Familial hypercholesterolemia
Clinical atherosclerotic CVD
Adjunct to diet and maximally tolerated statin therapy in pts who require additional LDL lowering
What are some adverse effects associated with PCSK9 inhibitors?
Hypersensitivity/ injection site reactions
Increased liver function tests (Alirocumab)
Nasopharyngitis, upper respiratory infection, flu
Very low LDL
Antibody formation
What are some Tx combos?
Statin + Ezetimibe
Statin + BAR
Niacin + BAR
Statin + Niacin + BAR
Which combo lowers LDL the least?
Niacin + BAR
Which combo lowers LDL the most?
Statin + niacin + BAR
