Drugs for Lipid Disorders Flashcards
List of HMG-CoA reductase inhibitors (statins)
- Atorvastatin (Lipitor)
- Fluvastatin
- Lovastatin
- Pitavastatin
- Pravastatin
- Rosuvastatin (Crestor)
- Simvastatin (Zocor)
List of Niacin (nicotinic acid, vitamin B3) drugs
Niacin
List of Fibric Acid Derivatives (fibrates)
- Fenofibrate
- Gemfibrozil
List of bile acid sequestrants (resins)
- Cholestyramine
- Colesevelam
- Colestipol
List of cholesterol absorption inhibitors
Ezetimibe (Zetia)
List of New Treatments
- Lomitapide
- Mipomersen
- Evolocumab, alirocumab
Most effective agents in reducing LDL levels and best tolerated class of lipid lowering agents
HMG-CoA reductase inhibitors (statins)
What is the mechanism of action for statins?
statins are structural analogs of HMG-CoA (initial precursor of
cholesterol) and inhibit MHG-CoA reductase, the rate limiting enzyme in cholesterol synthesis; inhibiting de novo cholesterol synthesis depletes the intracellular supply of cholesterol, which causes the cell to increase the number of specific cell-surface LDL receptors that can bind and internalize circulating LDLs; increased expression of surface LDL receptors reduces circulating LDL levels
List the potency of drugs for statins
atorvastatin = rosuvastatin > simvastatin > pitavastatin = lovastatin = pravastatin > fluvastatin
What are the therapeutic benefits to statins?
- plaque stabilization
- improvement of coronary endothelial function
- inhibition of platelet thrombus formation
- anti-inflammatory effects
- Statins are also effective in lowering plasma cholesterol levels in all types of hyperlipidemias
Are statins usually take alone or in combination with something else?
Used alone or with resins, niacin, or ezetimibe
What time would you take a statin?
Primarily taken at night (cholesterol synthesis occurs predominantly at night) except the longer-acting atorvastatin, pitavastatin, rosuvastatin)
What is the function of Niacin?
Decreases TGs, LDL, Lp(a); increases HDL
What is the mechanism of action for Niacin?
inhibits the lipolysis of triglycerides in adipose tissue (the primary producer of circulating free fatty acids); by reducing circulating free fatty acids, the liver produces less VLDL and LDL levels decrease; catabolic rate for HDL is decreased; fibrinogen levels are reduced and tissue plasminogen activator levels are increased
What is the most common side effect of niacin?
- An intense cutaneous flush
accompanied by an uncomfortable feeling of warmth that occurs after each dose when drug is started or when the dose is increased (aspirin taken before niacin or once-daily ibuprofen can mitigate the flushing, which is prostaglandin-mediated); - pruritus, rashes, dry skin or mucous membranes, and ACANTHOSIS NIGRICANS
What are some contraindications for Niacin?
- Avoid in patients with hepatic disease or active peptic ulcer
- Use with caution in patients with diabetes mellitus due to niacin- induced insulin resistance, which can cause hyperglycemia (patients with insulin resistance often show signs of acanthosis nigricans due to elevated insulin levels)
- Can elevate uric acid levels
What is the mechanism of action for Fibrates?
- Agonists for peroxisome proliferator-activated receptor alpha (PPARα, a nuclear receptor); when activated, PPARα binds to DNA, regulating the expression of genes encoding proteins involved in LIPOPROTEIN structure and function (lipoprotein lipase,
apo A-I, apo A-II expression is increased and apo C-III is decreased); - Major effect is increased oxidation of fatty acids in liver and striated muscle; INCREASED LIPOLYSIS OF TG VIA LIPOPROTEIN
LIPASE WHILE INTRACELLULAR LIPOLYSIS IN ADIPOSE TISSUE IS DECREASED; VLDL levels decrease, LDL levels modestly decrease in most patients (LDL levels can increase as triglycerides are reduced), HDL levels increase moderately
Why are Fibrates useful?
Fibrates are useful in the management of hypertriglyceridemias where VLDL predominates, dysbetalipoproteinemia, and hypertriglyceridemia that results from treatment with viral protease inhibitors (e.g., saquinavir, indinavir, or nelfinavir for HIV therapy)
What is the most common adverse effect to Fibrates?
mild GI disturbances are most common adverse effects and
usually subside
What are some adverse effects of Fibrates?
- GI: increased the risk of cholelithiasis (due to an increase in the cholesterol content of bile) and should be used with caution in patients with biliary tract disease or in those at high risk (e.g., women, obese patients, Native Americans)
- Liver: increased SERUM TRANSAMINASES (up to 3X normal)
- Muscle: myositis can occur (evaluate for muscle weakness and tenderness); MYOPATHY and rhabdomyolysis have been reported (increased risk when fibrates and statins combined)
- Fibrates may potentiate the actions of anticoagulants
What are some contraindications to Fibrates?
Fibrates should be avoided in patients with hepatic or renal dysfunction; safety has not
been established in pregnant or lactating women
What is the mechanism of action for Bile Acid Sequestrants (Resins)?
- positively charged compounds bind to negatively charged bile acids (metabolites of cholesterol) and increase bile acid excretion up to tenfold
- increased excretion of bile acids enhance the conversion of cholesterol to bile acids in the liver via 7α-
hydroxylation (normally controlled by negative feedback via bile acids); - the decline in hepatic
cholesterol stimulates an increase in hepatic LDL receptor, which enhances LDL clearance and lowers levels; - however, this effect is partially offset by enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase (therefore, combined use of a statin substantially increases the effectiveness of resins)
What kind of patients receive Bile Acid Sequestrants?
- Used to treat patients with primary hypercholesterolemia (reduces LDL by approximately 20%);
- prescribed as monotherapy or in combination with niacin for
treatment of Type IIa and Type IIb hyperlipidemias; - used to relieve pruritus in patients who have bile salt accumulation (e.g., from biliary obstruction)
What are most common adverse effects to Bile Acid Sequestrants?
GI effects (e.g., constipation, nausea, and flatulence) are the most common
What are some adverse effects to Bile Acid Sequestrants?
- GI effects (e.g., constipation, nausea, and flatulence)
are the most common; - high doses impair the absorption of fat-soluble vitamins (A, D, E, and
K); - impaired absorption of numerous drugs, including tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, and thiazide diuretics (as a result, any additional medication (except niacin) should be given at least 1 hr before or at least 2 hrs after)
What are some contraindications to Bile Acid Sequestrants?
Avoid or use with caution in patients with diverticulitis, preexisting bowel disease, or cholestasis
What is the mechanism of action for cholesterol absorption inhibitors?
- Selectively inhibits intestinal absorption of cholesterol and
phytosterols (plant sterols); - Thought to inhibit the transport protein NPC1L1;
- Effective even in the absence of dietary cholesterol due to inhibition of reabsorption of cholesterol excreted in bile;
- On average, ezetimibe lowers LDL by 18% and triglycerides by 6% while raising HDL levels slightly (1.3%)
What are some therapeutic uses for cholesterol absorption inhibitors?
- used to treat various causes of elevated cholesterol levels [e.g., primary hypercholesterolemia (as monotherapy or in combination with HMG-CoA reductase inhibitors);
- homozygous familial hypercholesterolemia (in combination with atorvastatin or simvastatin);
- mixed hyperlipidemia (in combination with fenofibrate)]
What are some adverse effects of cholesterol absorption inhibitors?
- no significant drug interactions are reported;
- avoid administration of ezetimibe and bile acid sequestrants due to impaired ezetimibe absorption
Which drug class has the greatest therapeutic effect on lowering LDL?
Statins ***
Which drug class has the greatest therapeutic effect on increasing HDL?
Niacin **
Which drug class has the greatest therapeutic effect on decreasing TG’s?
Fibrates **
What are some new treatments for homozygous familial hypercholesterolemia?
- Lomitapide
- Mipomersen
- PCSK9 inhibitors
How is Homozygous familial hypercholesterolemia caused?
Homozygous familial hypercholesterolemia is caused by mutations leading to dysfunctional LDL receptors incapable of taking up LDL from the bloodstream
What is the mechanism of action for Lomitapide?
- directly binds to and inhibits microsomal triglyceride transfer protein (MTP) which is
located in the lumen of the endoplasmic reticulum. - MTP inhibition prevents the assembly of
apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced
production of chylomicrons and VLDL and subsequently reduces plasma LDL-C
concentrations.
What are some adverse effects to Lomitapide?
most common adverse effects are gastrointestinal symptoms, increased liver aminotransferase
levels, and hepatic fat accumulation
What is the mechanism of action for Mipomersen?
- antisense oligonucleotide that targets apoliporotein B-100 (apoB-100) mRNA and
disrupts its function; - ApoB-100 is the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids;
- elevated levels of apoB, LDL-C and VLDL are associated with increased risk of atherosclerosis and cardiovascular diseases
What are some adverse effects to Mipomersen?
Adverse effects include injection site reactions (administration via subcutaneous injection
once per week), flu-like symptoms, headache, and elevation of liver enzymes
What is the mechanism of action for PCSK9 Inhibitors?
- Antibodies bind to PCSK9 (proprotein convertase subtilisin/kexin type 9) and inhibit LDL receptor metabolism;
- results in LDL reductions of up to 70%
What patients use PCSK9 Inhibitors?
- restricted to patients who have familial hypercholesterolemia or
clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. - They are given with diet and maximal tolerated statin and/or ezetimibe.
