Block 2 - Dyslipidemia Pharm Flashcards
What are some non-pharms of treating HLD?
- Maintain healthy diet and weight
- Better compliance
- Avoid tobacco
- Exercise (150-160 min/week)
What are pharm options of HLD?
- HMG CoA reductase inhibitors
- Cholesterol synthesis inhibitors
- Cholesterol absorption inhibitors
- Fibric Acid derivatives
- Bile-acid binding resins
- Niacin (nicotinic acid)
- Newer drug agents – PCSK9 inhibitors, Lomitapide, and others
What are the mechanism addressed using lipid lowering therapy?
- Improved endothelium-dependent vasodilation
- Stabilization of atherosclerotic lesions
- Reduction of inflammatory stimuli
- Prevention or slow progression of atherosclerotic lesions
What are the hyperclosterolemia drugs?
- Cholesterol synthesis inhibitors (Statins and Bempedoic Acid)
- . Cholesterol absorption inhibitors and sequestrants
- Niacin or Fibrates
- PCK9 inhibitors
What are the hypertriglyceridemia drugs?
- Fibrin acids
- Niacin
- Eicosapentaenoic acid (EPA) & Fish oils
What is the MOA of statins?
Competitively inhibits the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (in nM range) – which is the rate limiting step for cholesterol biosynthesis
How do statins work?
Decreases cholesterol synthesis producing a compensatory increase in the number of cell surface hepatic LDL receptors → Increase plasma LDL clearance
Describe the mechanisms of Statin activity?
What is the purpose of lactone on statins?
Active center and binds to HMG binding site
Lovastatin is hydrolyzed to resemble intermediate while Atorvastatin already resembles intermediate
What falls under high intensity statin therapies?
Daily dose lowers LDL–C on average approximately ≥50%
- Atorvastatin (40-80 mg)
- Rosuvastatin (20 mg)
What is considered moderate intensity statins?
Daily dose lowers LDL–C on average approximately 30% to <50%
- Atorvastatin 10 (20) mg
- Rosuvastatin (5) 10 mg
- Simvastatin 20–40 mg‡
- Pravastatin 40 (80) mg
- Lovastatin 40 mg
- Fluvastatin 40 mg BID
What is considered low intensity therapy?
Daily dose lowers LDL–C on average approximately <30%
- Pravastatin 10-20 mg
- Lovastatin 20 mg
What study noticed that Satins reduced hsCRP → fall in LDL?
CHEST study
What study saw pravastatin reduced CRP by 17%?
PRINCE study
What is the therapeutic benefits of HMG CoA reductase inhibitors?
- Reduce major coronary events
- Reduce mortality
- Reduce coronary procedures
- Reduce stroke
- Reduces total mortality
What are some counseling points associated with satins?
Pravastatin and pitastatin are metabolized with CYP3A4 (excreted in bile unwanted)
Fluvastatin and Rosuvastatin by CYP2C9
CYP3A4 is a source of DDIs
Not safe for pregnancy or breast feeding
What are the side effects associated with statin?
- Muscle pain (myalgia),
- Myopathy and Rhabdomyolysis (Increases to 2% with niacin and 3% with fibrates)
- Hepatotoxicity and liver damage (rare)
What are cormordities for statin ADRs?
- Impaired hepatic (absolute) or renal (caution) function
- CYP3A4 drugs (Fibrates, Niacin)
- Unexplained increase in ALT levels
- > 75 YO
- History of stroke
How common fatal rhabdomyolysis with statin?
Class effect
Increased by combo with vibrates (gemfibrozil) or niacin
What is the MOA of bempedoic acid?
- An oral pro-drug, activated in the liver, that inhibits the ATP-citrate lyase (ACLY)
- Deceases cholesterol synthesis by inhibition of the ATP citrate lyase
- The decrease in cholesterol upregulates the LDL-R, leading to a increase in LDL-C clearance
What is the importance of ATP citrate lyase?
enzyme found upstream of HMG CaA reductase used for cholesterol biosynthesis
Brand of Bempedoic Acid?
Nexletol
Common ADRs of Nexletol?
- Muscle spasm
- Pain in back or limbs
- Gout
- Diarrhea (GI problems)
- Tendon rupture
Common Dis of Bempedoic Acid?
Drug increases simvastatin and pravastatin blood levels
What is the MOA of Ezetimibe?
Zetia is a potent and specific inhibitor of dietary and biliary cholesterol absorption that works in the brush border of the small intestine to inhibit the absorption of cholesterol by inhibiting the intestinal Cholesterol Transporter (Niemann-Pick C1-Like 1 protein (NPC1L1))
How is ezetimibe metabolized?
A glucuronide (EZEG) – which has 400x greater potency
Fibrate MOA?
Alters gene transcription via activity at the peroxisomal proliferation activated receptor (PPAR-α)
One of the drugs of choice for hypertriglyceridemia
What is a PPAR-a?
Nuclear receptor that modulates genes associated with fatty acid regulation
What are the primary effects of vibrates on liver and adipose tissue?
- Increase LPL expression → decreased chylomicron and VLDL and plasma TG
- Increase LDL size (less arthogenic)
- Increase Acyl-coA synthase → fatty acid oxidation
- Increase apoA-I and apoA-II synthesis → Increase HDL-C and reverse cholesterol transport
- Decrease Hepatic apoC-III synthesis → Decrease plasma triglycerides
- Increase anti-inflammatory effects on arterial wall
What are the lab actions of fibrin acids?
- Lowers TGs 30–60%
- Lowers total cholesterol ~20-40%
- Lowers LDL-C ~5–20% (with normal TGs)
- May raise LDL-C (with high TGs)
- Raises HDL-C ~5–20%
ADRs of fibrates?
- Increase risk of gall stones (cholecystitis)
- Fibrates+Statin increase myopathy
What is nicotine acid? Is it first line?
Niacin or Niacor is a Water soluble B-complex vitamin
Niacin MOA?
- Inhibits lipolysis of triglycerides, reducing FFA mobilization from the periphery
- inhibits hormone-sensitive lipase in adipose tissue, reducing the breakdown of triglycerides to free fatty acids and the transport of free fatty acids to the liver
What happens in the liver when Niacin is administered?
- Decreased TG synthesis → Decreased hepatic VLDL production
- Niacin inhibits hepatocyte diacylglycerol acyltransferase-2 (DGAT-2), a key enzyme for triglyceride synthesis
- Increased Hepatic and plasma VLDL → lowers LDL (which eventually comes from VLDL)
- Decreases HDL-apoAI clearance leading to increase HDL-C levels