Lipid Lowering Drugs Flashcards
Name the lipoproteins in ascending order of density.
- Chylomicrons
- VLDL
- IDL
- LDL
- HDL
the greater the content of triglycerides, the lower the density of lipoprotein. greater the content of protein, the higher the density of lipoprotein.
What are the major components of each lipoprotein particle?
Chylomicron :
- 85% triglyceride and 7% cholesterol
VLDL :
- 50% triglyceride and 20% cholesterol
IDL :
- 30% triglyceride and 37% cholesterol
LDL :
- 5% triglyceride and 50% cholesterol
HDL :
- 10% triglyceride and 20% cholesterol and 45% proteins
What are the different types of Apolipoproteins?
- ApoB-48 is a structural protein on chylomicron
- ApoB-100 is present on lipoproteins originating from liver and they enable binding to hepatocyte receptors for reuptake
- ApoA-1 activates LCAT to convert free cholesterol to cholesterol ester in HDL
- ApoC-II activates lipoprotein lipase
- ApoE binds to receptors on hepatocytes for CM
Describe Chylomicron metabolism.
- form in small intestine mucosal cells and contain dietary lipids
- secreted as nascent chylomicrons with only ApoB-48
- in cirulation, HDL transfers ApoC-II and ApoE to nascent CM making it mature
- at capillary endothelium of muscle and adipocytes, ApoC-II activates lipoprotein lipase to degrade TG in CM so that adipocytes and muscle can absorb the Free Fatty Acids
- ApoE on CM remnant enables it to be endocytosed by hepatocytes (does not have ApoB-100)
Describe VLDL metabolism.
- triglyceride, cholesterol ester, and cholesterol synthesised by liver are secreted in nascent ApoB-100 VLDL
- during circulation, HDL transfers ApoC-II and ApoE to VLDL making it mature
- ApoC-II activates lipoprotein lipase at endothelium of adipocytes and muscles for them to absorb free fatty acids
- after VLDL loses most of its TG, becomes IDL. some IDL can be taken up by liver through ApoE receptor. other IDL undergo ApoE dependent hepatic lipase which hydrolyses more TG transforming the IDL into LDL and then the ApoC-II and ApoE on LDL is returned to HDL
- some LDL will be endocytosed into liver by ApoB-100 while others bind to extrahepatic tissue like adrenocortex/gonads which need cholesterol for steroid hormone synthesis or for cell membrane maintenance
Describe HDL metabolism.
- HDL is circulating reservoir of apoproteins
- synthesized in liver and released as discoidal nascent HDL which has many ApoA-1
- in circulation, it collects free cholesterol from cell membranes of peripheral tissue including foam cells for reverse cholesterol transport
- as nascent HDL collects more cholesterol, it becomes more spherical and LCAT activated by ApoA-1 converts free cholesterol into cholesterol esters to maintain the concentration gradient of free cholesterol so HDL can pick more free cholesterol
- CETP is a protein that enabled CE transfer from HDL to VLDL in exchange for TG transfer from VLDL to HDL. VLDL becomes cholesterol rich and is now called IDL
- TG rich HDL reuptake by direct SR-B1 receptor on hepatocytes
What are the different hyperlipoproteinemias?
Type 1 : Familial hyperchylomicronemia due to defective lipoprotein lipase/ ApoC-II so excess CM builds up
Type 2a : Familial hypercholesterolemia due to LDL receptor defect on hepatocytes so excess LDL builds up and high risk atheroma formation
Type 2b : Familial combined hyperlipidemia due to overproduction of VLDL and hence LDL by liver so there is increase in both TG and cholesterol
Type 3 : Familial dysbetalipoproteinemia due to abnormal ApoE receptors on hepatocytes so there will be increased IDL and VLDL levels in plasma
Type 4 : Familial hypertriglyceridemia where there is increased VLDL production and decreased clearance because of DM, obesity, alcohol
What are the different classes of drugs used as lipid lowering drugs?
- PCSK9 inhibitor
- Niacin
- Fibrates
- Resins
- HMG-CoA reductase inhibitors (Statins)
- Ezetimibe
- Omega-3 Acid Ethyl Esters
What are some HMG-CoA Reductase inhibitors?
- Atorvastatin
- Pravastatin
- Simvastatin
“vastatin”
What is the MOA of HMG-CoA Reductase inhibitors?
- HMG CoA reductase is the enzyme responsible for the rate limiting step in producing cholesterol so there is decreased hepatocyte synthesis of cholesterol
- but hepatocytes need cholesterol for cell membrane synthesis and to form bile acids that get secreted in bile so that they can emulsify fat in the small intestine. hence hepatocytes increase the number of LDL receptors to reuptake more cholesterol from LDL particles in the blood and this also decreases atheroma risk
What are HMG-CoA Reductase inhibitors used for?
- used to reduce cholesterol in the body by decreasing the amount of circulating LDL in body so can be used for type 2a and type 2b (will also need additional drug to decrease TG in VLDL) hyperlipidemia
- because cholesterol in the blood increases atheroma risk, HMG-CoA reductase inhibitors reduce the risk of coronary events and mortality in patients with ischemic heart disease
*more effective if taken at night because HMG-CoA reductase enzyme most active at night
What are the side effects of HMG-CoA Reductase inhibitors?
- upregulation in liver enzymes so there will be abnormalities in liver function test
- muscle weakness due to rhabdomyolysis and myopathy so look out for dark coloured urine as well
- CHOLESTEROL VITAL FOR NEURODEVELOPMENT IN BRAIN SO HMG-CoA REDUCTASE INHIBITORS ARE CONTRAINDICATED IN PREGNANCY, NURSING MOTHERS, CHILDREN, TEENAGERS
What are some PCSK9 Inhibitors?
- Alirocumab
- Evolocumab
“cumab”
What is the MOA of PSCK9 Inhibitors?
- PCSK9 is a protease that binds LDL receptor on surface hepatocytes to mark for degradation by lysosomes
- PCSK9 inhibitor antibodies bind to PCSK9 and prevent it from marking LDL receptor for degradation so that more cell surface LDL receptors remain to bind to LDL and internalize it from blood so plasma LDL levels decrease
What are PCSK9 Inhibitors used for?
- used for patients with high cholesterol like type 2a and type 2b hyperlipoproteinemia, especially those intolerant to statins
- also for patients with atherosclerotic coronary vessel disease and needing LDL lowering despite diet control and maximum statin therapy
- PCSK9 inhibitors when combined with statins can lower LDL levels 50%-60% above that achieved by statin therapy alone
*these antibodies are given as injections
What are some side effects of PCSK9 inhibitors?
- contraindicated in patients who develop hypersensitivity reactions like hypersensitivity vasculitis or serious allergies requiring hospitalization (PCSK9 inhibitors are antibodies)
- inflammation at injection site in the form of erythema, itchiness, swelling, pain and tenderness
- may cause sinusitis and nasopharyngitis
What are some fibrates used as lipid lowering drugs?
- Gemfibrozil
- Fenofibrate
“fibr”
What is the MOA of fibrates?
-bind to PPAR-a protein for increased activity of lipoprotein lipase so that more triglycerides will be broken down from VLDL and CM and there is decreased plasma triglyceride
- decreased plasma triglyceride means lesser TG for liver to make VLDL so there are lesser secretions of VLDL
- increased HDL levels
What are fibrates used for?
- treats conditions with high VLDL like type 2b, type 3 and type 4 hyperlipoproteinemia
- not useful for type 2a because it does not target cholesterol levels
What are the side effects of fibrates?
- GIT abnormalities like Nausea
- hypersensitive skin rashes
- gall stones
- inflammation of myocytes
- fibrates displace warfarin from plasma protein binding so they potentiate action of anti coagulant and dose adjustment of warfarin needed
- Gemfibrozil also interferes with clearance of statins so can lead to some toxic levels
What are some omega 3 acid ethyl esters used as lipid lowering drugs?
Omacor: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters
What is the MOA of omega 3 ethyl esters?
- reduce hepatic TG production and increased TG clearance from VLDL
- increased FFA breakdown by beta oxidation
- increased lipoprotein lipase activity
What are omega 3 ethyl esters used for?
- can be monotherapy for type 4 hypertriglyceridemia
- used in combination with statins for type 2b mixed hyperlipidemia
- not used for type 1 hyperchylomicronemia
What are the side effects of omega 3 ethyl esters?
- derived from fish oil so cannot give patients with fish allergy
- GIT symptoms like abdominal distension, pain, constipation, diarrhoea, dyspepsia, flatulence are MOST COMMON SE
- in some patients, DHA can cause increased LDL so need to monitor
- reduces thromboxane A2 production so this causes increased bleeding time and need to be cautious with patients on warfarin or aspirin
