How do Statins (HMG-CoA reductase inhibitors) work?
They limit the rate limiting step of cholesterol synthesis. They also upregulate LDL receptors in the liver (SREBP channels). Reduce lipoprotein secretion by the liver.
What is the effect of statins?
Lower LDL up to 60%, Lower TG by 37%, increase HDL
What are the major drug interactions for statins
Drugs that inhibit CYP3A4
Drugs that inhibit P-glycoprotein mediated intestinal reabsorption (cyclosporine and grapefruit juice), drugs that inhibit other pathways involved in statin metabolism.
Why do statins have such a low bioawvailabilty?
Because they are so heavily reabsorbed in the small intestine by p-glycoprotein
Adverse Effects of Statins
mild GI distress and others. pretty well tolerated
Statin use with Gemfibrozil leads to Rhabdomyolysis
WHat do Bile Acids do?
Interrupt enterohepatic recycling of cholesterol by binding negatively charged bile acids in the gut
What are the advantages of Bile Acid sequestrants?
Old and safe, safely used in children and people with liver disease
What effect do bile acid sequestrants have on cholesterol levels
Lowers LDL by 25%...not as effective as Statins
Bile Acid Sequestrants adverse effects
GI upset - bloating, farting, constipation
Prevents absorption of other drugs
Cholesterol Absorption Inhibitors prototype drug
How does Ezetimibe work>
prevents intestinal uptake of cholesterol itself whereas bile acids prevent re-uptake of bile acids
Does Ezetimibe have an effect on the plasma levels of vitamins ADEK?
Ezetimibe drug interactions
Bile acid sequestrants decrease the absorption of ezetimibe up to 80% (do not co-administer)
Cyclosporine increases ezetimible levels
Fibric Acid Derivatives do what?
Reduce VLDL and triglycerides and raise HDL
Macromolecular complexes in the blood that transport lipids
Atorvastatin Metabolized how and where?
CYP3A4, beta oxidation, hydroxylation.
Why do you have to reduce the dose of statins in those with liver disease
Because some statins, like provaststin are excreted renally
Atorvastatin, simvastatin, and lovastatin should not be given with what drugs
Drugs that inhbit CYP3A4 like macrolide antibiotics (mycins), azole antifungals, selected SSRIs, calcium channel blockers, HIV protease inhibitors (-avirs), Immunosuppresants like cyclosporine.
Gemfibrozil given with a statin
Bile Acid Sequestrants prevent absorption of what other drugs
Beta Blockers, Digoxin, Thyroxine, Coumadin
Bile acid sequestrants side effects
Constipations, farting, fecal impaction
Bile Acid sequestrants contraindicated in who?
Old constipated ppl, those with complex drug regimens, those with hypertriglyceridemia
inhibts cholesterol absorption by small intestine, no effect on fat soluble vitamins ADEK, reduces cholesterol delivery to the liver which in turn causes LDL receptors to be upregulated
What should you not give Ezetimibe with
Bile acid sequestrants, they reduce ezetimibe absorption by 80%
Cyclosporine increases ezetimibe levels 3-4 fold
Fibrates: increase the risk of gallstones
Two fibric acid derivative
Mecahnism of action for fibric acid derivatives
Lipoprotein effects of fibrates
reduce VLDL, inc HDL, tri reduced by 50%, HDL increased up to 15%
Adverse effects of Fibric acid derivatives
GE reflux, diarrhea, increased liver enzymes
Fenofibrate can do what to creatinine levels
PPAR alpha does what
Suppresses transcription of APOCIII which inhibits LPL. This leads to increased LPL activity which clears triglycerides from VLDL
Increased APO AI synthesis leads to more HDL
Increases phospholipid transfer protein leads to the transfer of PL from VLDL to HDL
Increased fatty acid oxidation leads to less triglyceride synthesis
Increaed biliary cholesterol excretion