Antihyperlipidemic Drugs Flashcards
How does LDL become oxidized?
LDL is modified by malondialdehyde addition, acetylation, or Cu2+ oxidation. Enters cell by “scavenger receptor” (SR-B1). Macrophage internalizes it, inflammation occurs and atheroma is formed
Which drugs cause hyperlipoproteinemia?
Oral contraceptive pill Glucocorticoids β blockers Thiazides Isotretinoin (vit A derivative) ) Protease inhibitors (anti HIV drugs)
Which drugs are HMG-CoA reductase inhibitors?
Simvastatin Rosuvastatin Fluvastatin Pravastatin Lovastatin Atorvastatin
MOA of HMG-CoA reductase inhibitors
Reversibly and competitively bind HMG-CoA reductase leading to:
Decreased liver cholesterol synthesis
Increased LDL receptor expression
Decreased plasma LDL
These drugs also reduce the production of apoB in the liver and increase liver uptake of VLDL through poE by LDL receptor –> decreased VLDL
Side effect of statins: myopathy and rhabdomyolysis
Rare. Anion transporter (OATP1B1) variant is related with severe myopathy induced by statin.
Mechanism is unclear.
It may be related with decreased downstream products in cholesterol synthesis process.
One of these is farnesyl pyrophosphate, which is needed for CoQ which is needed for formation of ATP by the mitochondria, thus statin decreases ATP in muscle.
The other products of cholesterol synthesis are associated with prenylation, which is needed for protein translocation.
What is myopathy?
Myalgia
Stiffness and muscle weakness
What is rhabdomyolysis?
When muscles are damaged, myoglobin is released and excreted in the urine –> cola coloured urine (can also cause acute renal failure)
Which muscle enzymes are elevated in the blood in the diagnosis of rhabdomyolysis?
Creatine phosphokinase-MM (CPK-MM), SGOT (AST), SGPT (ALT), and LDH
How do statins cause liver damage?
Aminotransferase may increase (within 3 fold of normal value is intermittent). Avoid use in chronic alcohol drinkers, patients with liver diseases
How do statins interact with gemfibrozil?
Taking gemfibrozil with statins increases the chance of rhabdomyolysis by interfering with statin clearance
How do p450 inhibitors affect statins?
Statins are metabolized by cytochrome p450 CYP34A or 2C9
p450 inhibitors enhance toxicity of statins
When are statins contraindicated?
Pregnant and lactating women
Children less than 8 years old
Which drugs are bile acid binding resin?
Cholestyramine
Colestipol
Colesvelam
MOA of bile acid binding resin
Bind to bile acids in the gut resulting in:
Decreased enterohepatic recirculation of bile salts
Increased synthesis of new bile acids in the liver by 10 fold, leading to an increased demand for cholesterol synthesis
Net result is decreased liver cholesterol
Up-regulate LDL receptor –> decreasing blood LDL by 20%
Side effects of bile acid binding resin
Increased VLDL and triglycerides
Constipation (increase dietary fiber to treat)
Cholesterol gall stones
Interfere with absorption of other drugs (Other medications such as digoxin, thiazide, warfarin, tetracycline, thyroxine, iron, statin, ezetimibe, folic acid, vit C, can be given 2 hours apart from resin)
Contraindications of bile acid binding resin
Hypertriglyceridemia
MOA of ezetimibe
Inhibits cholesterol absorption in intestinal brush border (NPC1L1 - Niemann Pick C1 like 1 cholesterol absorption receptor) –> leading to up regulation of LDL receptor
Lowers LDL by 15-20% and increases HDL by 4-9%
Disrupts enterohepatic circulation
How is ezetimibe excreted?
80% of ezetimibe is excreted in the feces as glucuronide
Which drugs are the PCSK9 inhibitors?
Alirocumab and evolocumab
MOA of PCSK9 inhibitors
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) binds to LDLRs on the surface of hepatocytes to promote LDLR degradation within the liver
PCSK9 inhibitors are human monoclonal antibody, binding to PCSK9, and inhibiting LDLR degradation
Increase LDL receptor number to clear LDL, reduce LDL by 48-71%, Apo B by 42-55%
When are PCSK9 inhibitors indicated?
As adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease
ADR of PCSK9 inhibitors
Allergy, nasopharyngitis, injection site reaction
Mechanism of niacin (B3)
Decrease triglyceride by 35-45% by reducing
VLDL secretion and increasing VLDL clearance by LPL
Increase HDL by 30-40% (the most effective one)
Decreases LDL by 20-30%
Decrease lipoprotein (a) (Lp(a))
Side effects of niacin (B3)
Flushing, pruritus, rashes (it is caused by production of prostaglandin, can be avoided by taking NSAID (aspirin) 30min before niacin).
Hepatotoxicity
Which are the fibric acid drugs?
Gemfibrozil
Fenofibrate
Clofibrate
Bezafibrate
Fibric acids MOA
Bind to the PPARa and increase expression of lipoprotein lipases resulting in:
Decreased VLDL and IDL
Slight decrease in LDL
Increased HDL
What is the role of Apo-A1?
In HDL, it removes cholesterol from the fatty streak in BVs and activates LCAT in order to esterase cholesterol. The cholesterol esters are then transported to IDL and LDL by CETP.
What is CETP?
Exchanges cholesterol esters of HDL for triglycerides of IDL
What does Apo-C3 do?
Inhibits LPL activation
Inhibits apo B-mediated binding of lipoprotein to LDL receptor
Inhibits LCAT
Net result: causes hypertriglyceridemia
What is PPARa?
It is the transcription factor which up regulates gene expression of LPL, ApoA1, ApoA2 and for downregulating ApoC3
When are fibric acids used?
Hypertriglyceridemia
How do fibric acids affect protein bound drugs such as warfarin?
Displaces other drugs from protein binding because it is highly albumin bound
Do fibric acids cause myopathy?
Yes, but not as often as statins
Combination with statins is not advised, especially for Gemfibrozil. Fenofibrate is the safest to use with statins.
How do fibric acids cause gallstones?
They increase LDL uptake in the liver because VLDL conversion to LDL increases, thus increasing cholesterol excretion in the liver
Do not combine with resin binding drugs
When should fribric acids not be used?
Chronic liver diseases
Omega-3 fatty acids
Reduce hepatic triglyceride synthesis and increases triglyceride clearance
Unknown mechanism
Reduces TGs by 27-45%
Lomitapide
Microsomal triglyceride transfer protein (MTP) inhibitor
MTP is required for assembly of apo-B containing lipoproteins in enterocytes and hepatocytes.
By inhibiting MTP, Lomitapide reduces synthesis of chylomicrons and VLDL –> reducing plasma LDL levels
Mipomersen
Mipomersen is an oligonucleotide (siRNA) to destroy apo B-100 mRNA, thus decreases the synthesis of apo B, which provides the structural core for all atherogenic lipids, including LDL cholesterol. LDL synthesis in liver is reduced.
When is lomitapide contraindicated?
Pregnancy
How do you treat high LDL?
Exercise, diet –> if still high, statins –> if still high, ezetimibe
How do you treat high TGs?
Exercise, diet –> if still high, fibre –> if still high, niacin
How do you treat low HDL?
Exercise, diet –> if still low, niacin
Orlistat MOA
Weightloss drug (4-8lbs/year) inhibits pancreatic lipase, decreasing TG breakdown in the intestine
Orlistat side effects
Steatorrhea, diarrhea, decreases the absorption of lipid soluble vitamins
