What is the MOA of Ezetimibe?
Blocks absorption of cholesterol at the brush border of enterocytes - hence causing the system to increase LDL expression.
Adverse Effects of Ezetimibe and why?
Diarrhea because cholesterol has a high osmotic gradient. Can cause hepatitis with elevated LFTs because this chemical is metabolized by the liver.
What is the Rate Limiting Enzyme for Cholesterol Synthesis? Which famous class of drugs inhibit it?
HMG-CoA Reductase. Statins - Atorvastatin, Pravastatin, Lovastatin, etc.
What are the MC adverse effects of Statins?
Cause cause liver injury. Myositis, especially if combined with Fibrates which decrease the metabolism of Statins. Statins with Niacin can also induce Myositis. Very rarely, Metabolic Acidosis.
Name 3 Fibrates and their MOA.
Gemfibrozil, Fenofibrate, Bezafibrate. Fibrates ACTIVATE at the PPAR-alpha enzyme causing LPL upregulation.
What are 2 adverse effects of Fibrates?
Myositis, esp if taken with statins. Can cause gallstones by inhibiting Cholesterol-7-a-hydroxylase.
Niacin has what effect on Prostaglandins and what relationship with uric acid? What other strange metabolic effect does Niacin use cause?
Niacin competes with Uric acid at the PCT, which can lead to Podagra/Gout. Niacin increases Prostaglandin synthesis leading to dilation and flushing.
Can also cause Hyperglycemia.
What will be seen in the synovial fluid of a pt with Podagra or Gout?
Negative birefringent crystals of monosodium urate.
Name 3 Bile Acid Resins and their polarity.
Highly positive so they can bind with negativity of cholesterol. Cholestyramine, Colestipol, Colesevalam.
Disco Started in 1972
K-dependent clotting factors and Warfarin related.
With Bile Acid Resins, you lose which vitamins in conjunction with other fat?
A, D, E, K
Which Lipid Lowering Agents can increase TGs?
Bile Acid Resins. Hepatocytes make up for lack of bile acid by making more.
Adverse Effects of Bile Acid Resins…
Constipation/GI Upset (because pt is eating bile acid resin). Elevates Triglycerides (only drug to do so) with almost no benefit to HDL. Decreased Fat-soluble vitamin absorption (and everything that goes with that sorta sucks)
Name the PCSK9 Inhibitors also known as monoclonal antibodies. MOA?
Alirocumab and Evolocumab. These mabs inhibit the pathway which leads to LDL receptor degradation, thereby allowing receptors longer life and more LDL removed from the blood.
Both Statins and PCSK9 Inhibitors decrease mortality in which type of pts?
CAD pts. PCSK9 Inhibitors like Statins have a profound LDL lowering effect.
What are adverse effects of PCSK9 Inhibitors?
Myalgias, just like Statins but also cause neurocognitive defects such as delirium, dementia, etc.
Fish oil and Omega 3.
Decrease Fatty Acid delivery to liver. Cause elevation of HDL, LDL, but lowers TGs.
What is Niacin’s MOA and what are its main adverse effects?
MOA is inhibition of Lipolysis in Adipose tissue of Hormone Sensitive Lipase. Decreases VLDL in Hepatocytes. Adverse: Hyperglycemia, Hyperuricemia, increased PGs can cause facial flushing.
Name 7 classes of Lipid Lowering Drugs, including Fish Oil aka Omega 3.
Ezetimibe, Bile Resins, Statins, Fibrates, Niacin, PCSK9 Inhibitors, Fish Oil.
If I am specifically targeting TGs in a pt with otherwise normal lipids, which drug class do I turn to first?
Fibrates! And recall that Bile Acid Resins actually increase TGs.
Pt has FHx of myocardial infarction at a young age, physical findings of corneal arcus and tendon xanthomas, and a very high LDL cholesterol level. What medication do you add to her statin?
Type IIA Hyperlipidemia. Add Ezetimibe or PCSKIs.
Afaf, which type of genetic hyperlipidemia do you have in your family? What is the ideal treatment?
type IIA familial hyperlipidemia. (normal HDL, normal TGs)
Statins alone find this disease challenging. Add Ezetimibe or PCSK9 Inhibitors.
Why would you not take Cholestyramine with a Statin?
It would lower the absorption of the Statin.
Pt presents w/abdominal pain, N/V, Triglycerides: >1000 mg/dL
Lipase: 714 U/L elevated Lipase levels suggestive of what?
Acute Pancreatitis. Without other RFs, we think High Triglyceride Pancreatitis. Pt has history of DM and Fibrates are indicated.
Fibrates activate peroxisome proliferator-activated receptor-α (PPARα), a nuclear transcription factor. Activated PPARα increases lipoprotein TG lysis via lipoprotein lipase and increases HDL levels.
Diabetics or anyone with high Triglycerides should be given which drug class?
Fibrates reduce high triglycerides, modestly increase HDL, and may reduce the progression of CAD in patients with type 2 diabetes.
Classic risk factors for cholelithiasis include the 4 F’s. Which dyslipidemia drug is also implicated in cholelithiasis?
Fat, Female, Fertile, and Forty. Gemfibrozil or any Fibrate.
Colicky RUQ pain. Severe.
Classic triad of Rhabdomyolsis? Which enzyme is blocked by Fibrates causing increase of Statins in blood?
Muscle pain, muscle weakness, and Hematuria (not RBCs, but myoglobin that is identified incorrectly on urinalysis). A serious consequence of rhabdomyolysis is the development of acute kidney injury.
Competitive inhibition of CYP3A4 and liver glucuronidation by gemfibrozil, causing an increase in the blood concentration of the statin.
If a Fibrate must be added to a Statin, which is the safest to prescribe?
Cholesterol gallstones, myalgia or myositis when combined with Statins. Triglyceride acute pancreatitis treatment. Excellent for use in Type II DM. Not used in my type IIA hyperlipidemia.
Works by inhibiting gastric and pancreatic lipase, which inhibits the hydrolyzation of fats.
Serum creatine kinase levels can be measured in patients suffering from muscle pain to determine whether tissue breakdown is occurring. What can Rhabdomyosysis progress to?
Renal Failure from muscle breakdown accumulation.