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