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Systemic Pharmacology > Lipid Lowering Drugs > Flashcards

Lipid Lowering Drugs Flashcards

1
Q

Name the lipoproteins in ascending order of density.

A
  1. Chylomicrons
  2. VLDL
  3. IDL
  4. LDL
  5. HDL

the greater the content of triglycerides, the lower the density of lipoprotein. greater the content of protein, the higher the density of lipoprotein.

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2
Q

What are the major components of each lipoprotein particle?

A

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

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3
Q

What are the different types of Apolipoproteins?

A
  1. ApoB-48 is a structural protein on chylomicron
  2. ApoB-100 is present on lipoproteins originating from liver and they enable binding to hepatocyte receptors for reuptake
  3. ApoA-1 activates LCAT to convert free cholesterol to cholesterol ester in HDL
  4. ApoC-II activates lipoprotein lipase
  5. ApoE binds to receptors on hepatocytes for CM
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4
Q

Describe Chylomicron metabolism.

A
  • 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)
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5
Q

Describe VLDL metabolism.

A
  • 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
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6
Q

Describe HDL metabolism.

A
  • 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
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7
Q

What are the different hyperlipoproteinemias?

A

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

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8
Q

What are the different classes of drugs used as lipid lowering drugs?

A
  1. PCSK9 inhibitor
  2. Niacin
  3. Fibrates
  4. Resins
  5. HMG-CoA reductase inhibitors (Statins)
  6. Ezetimibe
  7. Omega-3 Acid Ethyl Esters
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9
Q

What are some HMG-CoA Reductase inhibitors?

A
  • Atorvastatin
  • Pravastatin
  • Simvastatin

“vastatin”

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10
Q

What is the MOA of HMG-CoA Reductase inhibitors?

A
  • 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
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11
Q

What are HMG-CoA Reductase inhibitors used for?

A
  • 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

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12
Q

What are the side effects of HMG-CoA Reductase inhibitors?

A
  • 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
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13
Q

What are some PCSK9 Inhibitors?

A
  • Alirocumab
  • Evolocumab

“cumab”

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14
Q

What is the MOA of PSCK9 Inhibitors?

A
  • 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
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15
Q

What are PCSK9 Inhibitors used for?

A
  • 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
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16
Q

What are some side effects of PCSK9 inhibitors?

A
  • 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
17
Q

What are some fibrates used as lipid lowering drugs?

A
  • Gemfibrozil
  • Fenofibrate

“fibr”

18
Q

What is the MOA of fibrates?

A

-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

19
Q

What are fibrates used for?

A
  • 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
20
Q

What are the side effects of fibrates?

A
  • 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
21
Q

What are some omega 3 acid ethyl esters used as lipid lowering drugs?

A

Omacor: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters

22
Q

What is the MOA of omega 3 ethyl esters?

A
  • reduce hepatic TG production and increased TG clearance from VLDL
  • increased FFA breakdown by beta oxidation
  • increased lipoprotein lipase activity
23
Q

What are omega 3 ethyl esters used for?

A
  • can be monotherapy for type 4 hypertriglyceridemia
  • used in combination with statins for type 2b mixed hyperlipidemia
  • not used for type 1 hyperchylomicronemia
24
Q

What are the side effects of omega 3 ethyl esters?

A
  • 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
25
Q

What is the MOA of niacin?

A
  1. niacin/nicotinic acid which is also known as vitamin B3, inhibits lipolysis of TG by hormone sensitive lipase at adipocytes such that lesser FFA is transported to liver so there is also decreased hepatic TG synthesis and the amount of VLDL secreted decreases and hence lesser plasma LDL as well
  2. niacin also increases HDL levels so more free cholesterol uptake
  3. decreases circulating fibrinogen and increases circulating tissue plasminogen activator so niacin reverses thrombosis associated with hypercholesterolemia and atherosclerosis
26
Q

What is niacin used for?

A
  • used for treatment of type IIb and type 4 hyperlipoproteinemia
    *not useful for type IIa because niacin’s main effect is to reduce TG and the increase in HDL does not reduce cholesterol much
27
Q

What are the side effects of niacin?

A
  • intense cutaneous flush and pruritus
  • hyperuricemia and gout
28
Q

What are some bile acid binding resins used?

A
  • Cholestyramine
29
Q

What is the MOA of bile acid binding resins?

A
  1. bind to the negatively charged bile acids/salts in GIT and decrease their reabsorption so there is decreased bile salts/bile acid pool in liver
  2. hepatocytes use more cholesterol stores to produce bile acids for secretion with bile and this depletes hepatic cholesterol so hepatocytes increase LDL receptors to increase LDL uptake and decrease plasma LDL levels
  3. may increase VLDL but little effect on HDL
30
Q

What are bile acid binding resins used for?

A
  • treat patients with primary hypercholesterolemia type 2a
  • if add niacin can also treat type 2b hyperlipoproteinemia
31
Q

What are side effects of bile acid binding resins?

A
  • because resin binds to bile acid in GIT, there is more cholesterol derivatives in the gut which is food stores for colonic bacteria which ferment the bile acid and cause flatulence. there is also nausea and constipation.
  • impaired fat and fat dependent vitamin A,D,E,K absorption because of the reduced bile acid pool subsequently

-also decreases absorption of many drugs like warfarin, digoxin, thryoxine, statins, beta blockers and folic acid so give separately 2 hours before or 6 hours after

32
Q

What is the MOA of ezetimibe?

A
  • ezetimibe is an intestinal sterol absorption inhibitor
  • they selectively inhibit cholesterol transport protein NPC1L1 which transports sterols so these remain in GIT lumen and there is decreased plasma cholesterol levels so helps for type 2a hypercholesterolemia
  • together with simvastatin they have synergistic effect
    *even in the absence of dietary cholesterol, ezetimibe is still effective because it inhibits biliary cholesterol as well in the form of bile acids so lesser bile acids reabsorbed and the hepatocytes will need to increase LDL receptors and use their intrahepatic cholesterol stores to make bile acids
33
Q

What are the side effects of ezetimibe?

A
  • reversible impaired hepatic function

Systemic Pharmacology (8 decks)

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