MedChem 5-Lipids
Types of Lipids
Cholesterol Triglyceride Fatty Acid Phospholipid
OATP!B! inhibitors Gemfibrozil and cyclosporin interact with statins, some can be given at reduced doses
rosuvastatin and fluvastatin DONT GIVE FLUVASTATIN AND GEMFIBROZIL
CYP3A4 Metabolism DDI: macrolide, anti fungal, HIV
simvastatin lovastatin atorvastatin
Drugs affecting endogenous cholesterol biosynthesis
statins (HMG CoA reductase inhibitors)
Colestipol
the basic secondary and tertiary amines (2o and 3o amines)
What is the statin pharmacophore?
3,5-Dihydroxy acid
Fat Soluble Vitamins
ADEK
A"er being counseled about lifestyle and dietary changes, the patient was started on atorvastatin. During his treatment with atorvastatin, it is important to routinely monitor serum concentrations of which of the following? (A) Blood urea nitrogen (B) Alanine and aspartate aminotransferase (C) Platelets (D) Red blood cells (E) Uric acid
Alanine and aspartate aminotransferase The 2 primary adverse e!ects of the HMG-CoA reductase inhibitors are hepatotoxicity and myopathy. Patients taking these drugs should have liver function tests performed before starting therapy, and at regular intervals as needed during therapy. Serum concentrations of alanine and aspartate aminotransferase are used as markers of hepatocellular toxicity. The answer is B.
PJ is a 4.5-year-old boy. At his checkup, the pediatrician notices cutaneous xanthomas and orders a lipid panel. Repeated measures confirm that the patient's serum cholesterol levels are high (936 mg/dL). Further testing confirms a diagnosis of homozygous familial hypercholesterolemia. Which of the following interventions will be least e!ective in this patient? (A) Atorvastatin (B) Ezetimibe (C) Lomitapide (D) Mipomersen (E) Niacin
Atorvastatin Homozygous familial hypercholesterolemia is caused by mutations leading to dysfunctional LDL receptors incapable of taking up LDL from the bloodstream. Options B-E would have a cholesterol-lowering e!ect. Lomitapide and mipomersen are specifically indicated for patients with familial hypercholesterolemia. Reductase inhibitors such as atorvastatin rely on functional LDL receptors to achieve a LDL-lowering e!ect and thus will not work in patients with homozygous familial hypercholesterolemia. The answer is A.
Which statin drugs have a long duration of action?
Atorvastatin Rosuvastatin Can take at anytime
Drugs affecting endogenous lipoprotein and cholesterol metabolism
Bile acid sequestrants Peroxisome proliferator-activated receptors (PPARα) activators Lipolysis inhibitors Omega-3 fatty acids
A 35-year-old woman appears to have familial combined hyperlipidemia. Her serum concentrations of total cholesterol, LDL cholesterol, and triglyceride are elevated. Her serum concentration of HDL cholesterol is somewhat reduced. Which of the following is a major toxicity associated with gemfibrozil therapy? (A) Bloating and constipation (B) Cholelithiasis (C) Hyperuricemia (D) Liver damage (E) Severe cardiac arrhythmia
Cholelithiasis A major toxicity of the fibrates is increased risk of gallstone formation, which may be due to enhanced biliary excretion of cholesterol. The answer is B.
A 35-year-old woman appears to have familial combined hyperlipidemia. Her serum concentrations of total cholesterol, LDL cholesterol, and triglyceride are elevated. Her serum concentration of HDL cholesterol is somewhat reduced. Which of the following drugs is most likely to increase this patient's triglyceride and VLDL cholesterol concentrations when used as monotherapy? (A) Atorvastatin (B) Cholestyramine (C) Ezetimibe (D) Gemfibrozil (E) Niacin
Cholestyramine In some patients with familial combined hyperlipidemia and elevated VLDL, the resins increase VLDL and triglyceride concentrations even though they also lower LDL cholesterol. The answer is B.
Bile Acid Sequestrants Bind negatively charged bile acids in the intestine and ↑ their fecal excretion May increase VLDL or TG
Cholestyramine (Questran®), Colestipol (Colestid®), Colesevelam (Welchol®) Positively charged amines (cationic) Called as anion-exchange resins
Cholestyramine
Contains approximately 4 mEq of fixed quaternary ammonium groups (4o amine) per gram of dry resin DDI with other anionic drugs and fat soluble vitamins DDI with anionic drugs like warfarin, digoxin, thiazides, phenobarbital (solution: give 1h before or 4-6h after drug)
rosuvastatin Ring B Most Hydrophilic Amphoteric
Crestor
PPARα Activators//Fibrates
DECREASE TG INCREASE HDL THESE ARE THE MAJOR EFFECTS Risk of gallstone formation (cholelithiasis) Nausea is most common
Fenofibric Acid
DR formulation Lesser LFT elevations Lesser hepatic SEs
Six months a"er beginning atorvastatin, the patient's total and LDL cholesterol concentrations remained above normal, and he continued to have anginal attacks despite good adherence to his antianginal medications. His physician decided to add ezetimibe. Which of the following is the most accurate description of ezetimibe's mechanism of an action? (A) Decreased lipid synthesis in adipose tissue (B) Decreased secretion of VLDL by the liver (C) Decreased gastrointestinal absorption of cholesterol (D) Increased endocytosis of HDL by the liver (E) Increased lipid hydrolysis by lipoprotein lipase
Decreased gastrointestinal absorption of cholesterol The major recognized e!ect of ezetimibe is inhibition of absorption of cholesterol in the intestine. The answer is C.
Secondary disturbances
Diet, endocrine conditions, disease
fluvastatin Ring B lipophilic Elimination mostly bile
Lescol
Which statin drugs have ring B ( 5-6 member heterocyclic ring attached with floro-phenyl )?
Fluvastatin Atorvastatin Rosuvastatin Pitavastatin R = Aryl groups/hydrocarbon chains/amides/SO2NH2 ↑ Activity Generally more lipophilic, longer DOA and more potent
Primary disturbances
Genetic condtions
Fenofibrate
Half life (20h) = ~ 7 times more than gemfibrozil
Colesevelam
Has 4 amino functional groups primary, alkylated, secondary and secondary
A 43-year-old man has heterozygous familial hypercholesterolemia. His serum concentrations of total cholesterol and LDL are markedly elevated. His serum concentration of HDL cholesterol, VLDL cholesterol, and triglycerides are normal or slightly elevated. The patient's mother and older brother died of myocardial infarctions before the age of 50. This patient recently experienced mild chest pain when walking upstairs and has been diagnosed as having angina of e!ort. The patient is somewhat overweight. He drinks alcohol most evenings and smokes about 1 pack of cigarettes per week. Consumption of alcohol is associated with which of the following changes in serum lipid concentrations? (A) Decreased chylomicrons (B) Decreased HDL cholesterol (C) Decreased VLDL cholesterol (D) Increased LDL cholesterol (E) Increased triglyceride
Increased triglyceride Chronic ethanol ingestion can increase serum concentrations of VLDL and triglycerides. This is one of the factors that places patients with alcoholism at risk of pancreatitis. Chronic ethanol ingestion also has the possibly beneficial e!ect of raising, not decreasing, serum HDL concentrations. The answer is E.
A 35-year-old woman appears to have familial combined hyperlipidemia. Her serum concentrations of total cholesterol, LDL cholesterol, and triglyceride are elevated. Her serum concentration of HDL cholesterol is somewhat reduced. The patient is started on gemfibrozil. Which of the following is a major mechanism of gemfibrozil's action? (A) Increased excretion of bile acid salts (B) Increased expression of high-a!inity LDL receptors (C) Increased secretion of VLDL by the liver (D) Increased triglyceride hydrolysis by lipoprotein lipase (E) Reduced uptake of dietary cholesterol
Increased triglyceride hydrolysis by lipoprotein lipase A major mechanism recognized for gemfibrozil is increased activity of the lipoprotein lipase associated with capillary endothelial cells. Gemfibrozil and other fibrates decrease VLDL secretion, presumably by stimulating hepatic fatty acid oxidation. The answer is D.
What is the mechanism of action for Alli or orlistat
Inhibits pancreatic lipase, stops triglycerides from breaking down
atorvastatin Ring B Most lipophilic Elimination mostly bile
Lipitor
pitavastatin Ring B lipophilic
Livalo
Which statin drugs have ring A (Two cyclohexene rings )? Hydroxyl group at R1 ↑ hydrophilicity and may provide some cellular specificity Methyl substitution at R2 ↑ activity
Lovastatin Simvastatin Pravastatin Simvastatin (R2 = methyl) more potent than lovastatin (R2 = Hydrogen) Generally less lipophilic (unless prodrugs), with shorter duration of action
Which statin drugs have a short half life?
Lovastatin Simvastatin Pravastatin Fluvastatin
Omega-3 fatty acids
Lovaza
lovastatin Ring A lipophilic Prodrug
Mevacor
Statin toxicity
Mild ↑ serum aminotransferases (check ALT, AST) Severe muscle pain and even rhabdomyolysis (most common with lipophilic atorvastatin, lovastatin and simvastatin) Teratogenic
Apoprotein surface is
Mostly phospholipid, free cholesterol, and protein [Amphipathic]
Lipolysis inhibitors
Niacin MOA-Inhibits lipase in the adipose tissue Usefulness in the treatment of hypercholesterolemia, hypertriglyceridemia, and low levels of HDL Can worsen glycemic control in diabetics Facial flushing
If the patient has a history of gout, which of the following drugs is most likely to exacerbate this condition? (A) Colestipol (B) Ezetimibe (C) Gemfibrozil (D) Niacin (E) Simvastatin
Niacin Niacin can exacerbate both hyperuricemia and glucose intolerance. The answer is D.
A 46-year-old woman with a history of hyperlipidemia was treated with a drug. The chart below shows the results of the patient's fasting lipid panel before treatment and 6 mo a"er initiating drug therapy. Normal values are also shown. Which of the following drugs is most likely to be the one that this patient received? (A) Colestipol (B) Ezetimibe (C) Gemfibrozil (D) Lovastatin (E) Niacin
Niacin This patient presents with striking hypertriglyceridemia, elevated VLDL cholesterol, and depressed HDL cholesterol. Six months a"er drug treatment was initiated, her triglyceride and VLDL cholesterol have dropped dramatically and her HDL cholesterol level has doubled. The drug that is most likely to have achieved all of these desirable changes, particularly the large increase in HDL cholesterol, is niacin. Although gemfibrozil lowers triglyceride and VLDL concentrations, it does not cause such large increases in HDL cholesterol and decreases in LDL cholesterol. The answer is E.
Alirocumab and Evolocumab are approved for familial hypercholesterolemia. These drugs increases recycling of LDL-R helping in removal of LDL from circulation. What class are they?
PCSK9 Inhibitors Approved for familial hypercholesterolemia
Which statin drug has an intermediate duration of action?
Pitavastatin Can take at anytime
pravastatin Ring A 2nd most Hydrophilic
Pravachol
A 35-year-old woman appears to have familial combined hyperlipidemia. Her serum concentrations of total cholesterol, LDL cholesterol, and triglyceride are elevated. Her serum concentration of HDL cholesterol is somewhat reduced. If this patient is pregnant, which of the following drugs should be avoided because of a risk of harming the fetus? (A) Cholestyramine (B) Ezetimibe (C) Fenofibrate (D) Niacin (E) Pravastatin
Pravastatin The HMG-CoA reductase inhibitors are contraindicated in pregnancy because of the risk of teratogenic e!ects. The answer is E.
Lowering Potency
Rosuvastatin Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin
Gemfibrozil
Significant interactions with statins
2 Fatty Acid Roles
Stored as triglycerides Component of membrane phospholipids
Main reasons for dyslipidemia
Total cholesterol increase in LDL increase in TG decrease in HDL
Chylomicron has highest TGs
True
HDL has highest protein All apo's except B
True
LDL has highest cholesterol only B100
True
simvastatin Ring A lipophilic Prodrug
Zocor
Drugs affecting cholesterol absorption
ezetimbe (Cholesterol transport inhibitors)
Which drug is a NPC1L1 receptor blocker
ezetimibe Intereferes with cholesterol absorption in intesine Increase LDL receptors on liver
CYP2C9 Metabolism
fluvastatin rosuvastatin atorvastatin
An increase in these lipids in the plasma leads to hyperlipidemia. Soluble Lipoproteins help transport these lipids, so it also causes......
hyperlipoproteinemia
Which drug inhibits MTTP (which is needed for VLDL assembly)
lomitapide Can cause accumulation of triglycerides in the liver and elevations in transaminases (fatty liver).
Which drug inhibits mRNA responsible for production of ApoB100. Less ApoB100 leads to decreased LDL and VLDL
mipomersan To treat patients with a rare type of high cholesterol called homozygous familial hypercholesterolemia (HoFH) Weekly injections
Apoprotein core is
mostly triglyceride and cholesterol ester [Hydrophobic]
Glucorinadation Metabolism
pitavastatin