Twenty Thousand Lipids Under the Sea Cholestyramine, Ezetimibe

2.2 – “Twenty Thousand Lipids Un Under der the Sea” Sea”:: Cholestyramine, ezet ezetimibe imibe Physiology • Bile acids are essentially cholesterol made a bit more polar to emulsify fats in GI tract. Hepatocytes metabolize cholesterol to cholic acid & deoxycholic acid • These are transported to the gall bladder & conjugated to form water soluble bile acids (aka bile salts) (liver station worker loading up seagulls). Bile acids are then secreted into the biliary tree, then injected into intestinal lumen. • 95% of bile acids delivered to duodenum will be recycled by the enterohepatic circulation. Retaken up at the terminal ileum. Put back into the enterohepatic circulation → taken up in the liver & reused (bile covered ore usually dropped down to liver station). • Bile acids returned to the liver negatively feedback on liver to ↓endogenous cholesterol synthesis Drugs • Bile acid binding resins o Cholestyramine (chol-lobster), colestipol, colesevelam. o Useful in decreasing LDL, usually used in conjunction with statins o Lead to ↑LDLR synthesis (activating Load-L receptors). o Unlike statins, are not first line agents for hypercholesterolemia. Usually used as an adjunct to statin therapy. Work by binding bile acids & dietary cholesterol respectively in the intestines (sea gall droppings on intestinal ore), preventing absorption from intestine & disrupting bile acid recycling (falling liver → liver forced to use more LDL from blood (empty gold chests; HMG CoA-Reductase active). o Bile acid binding resins are large cationic resins insoluble in water. Bind bile acids and prevent reabsorption; secreted from the colon (lobster knocking off ore blocks from colon airship). ▪ Downregulates negative feedback cycles. • ↑HMG-CoA reductase activity to increase cholesterol synthesis for bile acid synthesis, depleting liver cholesterol stores (empty gold chests) • Increases LDLR and uptakes more LDL from circulation (LDL flags; guys pulling in LDL ship) o Used in patients with primary hypercholesterolemia; have up to 20% decrease in LDL cholesterol at maximal doses o Adverse effects ▪ Can result in hypertriglyceridemia, because hepatic VLDL & triglyceride synthesis rises in conjunction with hepatic cholesterol production (air ship with triglyceride trident wielders). Contraindicated if pts already have ↑triglycerides. ▪ Tendency for cholesterol gall stones d/t ↑cholesterol in bile (seagull sitting on a lot of stones) ▪ GI upset, usually constipation & bloating. May have steatorrhea, especially in pts with existing colonic disease (blocked brown pipe). Contraindicated in diverticulosis. ▪ May have ↓availability of fat-soluble vitamins (KADE) (DECK-A). Have to watch out for excess anticoagulation, especially in patients on warfarin/anticoagulation therapy ▪ Decrease absorption of many drugs, notably statins (fighting pirate). Bile acid resin & statins must be taken 4 h. apart. • Ezetimibe (Z-shaped eel) o Similar to bile resins in that it binds GI molecules, preventing dietary cholesterol absorption. Results in decreased chylomicrons, effectively restricting liver’s access to exogenous cholesterol. Forces increased activity of HMG-CoAReductase & LDLR synthesis. o Reduction of hyperlipidemia related mortality is as yet unclear. However, may reduce hyperlipidemia 25% on top of statins when used in conjunction o No gallstones or increased triglycerides! o Adverse effects ▪ Common: diarrhea (muddy water behind sea snake) ▪ Rare: increased LFTs (guy with LFT flag) • PCSK9 inhibitors o evolocumab (Doc Ock) and other antibodies. o PCSK9 is a liver protease that degrades hepatocyte LDLR. Inhibition increases LDLR (Doc Ock removing snails) → significantly decreased LDL levels.