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PM2C: Therapeutics and Patient Care: Summer > Hyperlipidemia and Atherosclerosis > Flashcards

Hyperlipidemia and Atherosclerosis Flashcards

1
Q

Describe what hyperlipidemia is and what it does?

A
  1. Increased fat molecules in the blood
  2. Elevated levels of lipid (TAG and cholesterol) in blood
  3. Forms the initial phase for the progression of atherosclerosis
  4. Asymptomatic and doesn’t usually get noticed until late
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2
Q

How does primary hyperlipidemia occur?

A

Genetic deficiency

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3
Q

How does secondary hyperlipidemia occur?

A

Mainly life style factors and other metabolic diseases

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4
Q

What does TAG stand for?

A

Triacylglyceride

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5
Q

What are Lipoproteins?

A
  1. Formed of lipid and proteins
  2. Transport vehicles for TAG and cholesterol
  3. Classified into 5 broad classes
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6
Q

What are the five broad categories?

A
  1. Chylomicrons
  2. VLDL
  3. IDL
  4. LDL
  5. HDL
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7
Q

What are the purposes of Chylomicrons?

A
  1. Apoprotein C II activates LPL in capillaries and therefore releases fatty acids and glycerol
  2. It transports exogenous TAG and cholesterol from intestines to tissue (muscles) and adipose tissues
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8
Q

What are the purposes of VLDL (very low), IDL (intermediate) and LDL?

A
  1. Transport endogenous TAG and cholesterol from liver to tissues
  2. Liver produces excess TAG from excess CHO
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9
Q

What are the purposes of HDL?

A

Transport endogenous cholesterol from tissue to liver

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10
Q

Describe the structure of a Lipoprotein?

A
  1. Non polar core: triacylglycerols and cholesteryl esters (has no charge)
  2. Amphiphillic surfaces: Apoproteins, phospholipid and cholesterol
  3. Lipoprotein from “intestine is secreted in lymph” and “liver is secreted in plasma”
  4. Apoproteins may come from HDL
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11
Q

Describe the mechanism of action of Lipoprotein? (LONG IMPORTANT MECHANISM)

A
  1. Chyme (mixture of gastric juice and partially digested food) enters small intestine (duodenum)
  2. Release of bile from liver- prevents formation of lipid aggregates by binding to fat droplets and forming micelles
    (bile hydrophilic end at the surface and hydrophobic inside)
  3. Release of digestive enzymes lipase and HCO3 from pancreas neutralises pH into the duodenum
  4. Fat droplets can form aggregates and this prevents the digestion by lipases
  5. Lipase breaks down micelles into fatty acids and monoglycerides
  6. Passes through the intestinal mucosa and enter epithelial cells
  7. These molecules enter endoplasmic reticulum and resynthesised as TAG (Triacylglyceride)
  8. Cholesterol is transported through specific channels
  9. Chylomicrons are formed from TAG with cholesterol, phospholipid and proteins
  10. Proteins on their surface makes them water soluble and facilitate exocytosis
  11. They leave mucosal cells through exocytosis
  12. Transportation through lymphatic vessel into the thoracic duct and entering into the subclavian vein
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12
Q

Explain how LDL’s are formed from VLDL and where LDLs go after?

A
  1. Apoprotein C II activates VLPL to release fatty acid and glycerol from TAG
  2. It becomes smaller to form IDL
  3. Hepatic lipase removes fatty acids from IDL to for “LDL”
  4. LDL rich in cholesterol travels to liver
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13
Q

Describe the lipoprotein HDL function in great detail? (MANY POINTS TO REMEMBER)

A
  1. Synthesised and released as lipid free Apo-A1 (HDL) from intestine & liver
  2. Apo-A1 covers around 70% of protein content in HDL
  3. Circulation: contacts foam cells/macrophages/other peripheral cells
  4. Hydrolase converts Cholesteryl esters into free C
  5. ABCA1 transports free C to the cell membrane from the lipid pool
  6. Apo-A1 binds to ABCA1 receptor and acquires cholesterol and become a nascent HDL
  7. LCAT (lecithin cholesterol acyltransferase) esterifies the free C on the surface of HDL
  8. Cholesteryl esters moves to the core of HDL (HDL3)
  9. Then interacts with ABCG1 & SR-B1 and acquires more cholesterol to become mature HDL (HDL2)
  10. HDL also collects C from the cell membranes and caveoli
  11. HDL delivers cholesterol to the liver through 2 pathways; direct (via SR-B1) and indirect (via LDL)
  12. Through SR-B1 directly delivers cholesterol in to the liver cells
  13. Lipid-free HDL returns to circulation and repeat the process
  14. Indirect pathway via cholesterol ester transfer protein (CETP) which facilitates direct exchange of Cholesteryl ester with TAG between HDL and VLDL/LDL
  15. LDL delivers cholesterol to the liver through LDL receptors or LRP
  16. Cholesterol is excreted as bile via intestine or formed as TAG
  17. HDL can also be degraded in the liver
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14
Q

What are the causes of hyperlipidemia?

A
  1. Diet: intake of food with high cholesterol levels, medication and metabolic diseases
  2. Genetic factors: mutations in overproduction of apoprotein cells can cause an over production of cholesterol
  3. Increased sensitivity to cholesterol
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15
Q

What causes primary hypercholesterolaemia?

A

Genetic cause: Deficiency or defect in LDL receptors

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16
Q

What causes secondary hypercholeterolaemia and what medications are used to manage it?

A
  1. Metabolic diseases such as type 2 diabetes and lifestyle (high caloric diet and inactivity)
  2. Diets: rich in TAG and saturated fats increase cholesterol synthesis (suppress LDL activity)
  3. Medication: beta blockers, estrogen and protease inhibitors (HIV)
17
Q

How do you diagnose hyperlipidemia?

A
  1. Checking the blood cholesterol levels of a patient (fasted): has to be equal to 5 or below
  2. Cholesterol levels should be between 0.8 to 1.8mmol/L
  3. LDL levels should be less than 3 or equal to
  4. Triglycerides should be less than 1.7 or equal to
18
Q

What are the non pharmacological options to treat hyperlipidemia?

A
  1. Healthy diet: increased intake of fruit and veg, less animal saturated fats
  2. Increase in Omega 3 fat from fish
  3. Regular exercise to lose weight
  4. Limit alcohol intake and avoid smoking
19
Q

Describe the main medications used to treat hyperlipidemia?

A
  1. Statins: Inhibit cholesterol by synthesis and only used in patients at risk of cardiovascular disease
    - taken for life as it can reverse cholesterol if stopped
  2. Aspirin: Anti-platelet drug that inhibits platelet activation
    - Prescribed at low dose
    - Periodic liver function test
  3. Ezetimibe: blocks absorption of cholesterol from food and bile
    - Reduced side effects compared to statins
    - Can be taken on its own or in conjunction with statins to reduce cholesterol levels
20
Q

Describe the use of bile sequestrants in hyperlipidemia?

A
  1. Binds to bile acid in small intestine and increases release from liver and reduction in cholesterol
  2. Can interfere with absorption of lipids from food
21
Q

Describe the use of fibrates in hyperlipidemia and give some examples?

A
  1. PPARα agonists (nuclear receptors) that induce hepatic uptake and oxidation of cholesterol and TAG
  2. Examples: Bezafibrate, ciprofibrate, fenofibrate, gemfibrozil
  3. Can be given when patients cannot take statins
22
Q

Describe the use of nicotinic acid, niacin or vitamin B3 in hyperlipidemia?

A
  1. Inhibits lipolysis in adipocytes and thus reduce lipid synthesis in the liver
  2. Usually high concentrations are required
  3. Side effects: vasodilation, skin rash, hepatotoxicity and hyperglycaemia
23
Q

Define what Arteriosclerosis is?

A

The hardening of the arteries that usually come about from age due to non plaque factors

24
Q

What does hyperlipidemia lead to?

A

Development of atherosclerosis

25
Q

What are the different stages of progression of atherosclerosis?

A
  1. Endothelial cell injuries
  2. Migration of LDLs
  3. Adhesion, migration & transformation of monocytes
  4. Engulfing ox-LDLs
  5. Migration and proliferation of SMCs
  6. Expansion and occlusion
26
Q

Describe the structure of an artery wall?

A
  1. Tunica intima (inner coat): endothelium, connective tissue and internal elastic membrane
  2. Tunica media (middle): smooth muscle cells
  3. Tunica externa (outer coat): collagen and elastic fibres
27
Q

Describe stage one of endothelial cell injuries in progression of atherosclerosis?

A
  1. The endothelial gets damaged due to excess LDL’s, smoking, immune mechanisms and mechanical stress due to hypertension
  2. Causes irritation and damage or dysfunction to endothelial cells
28
Q

Describe stage two of migration of LDLS in progression of atherosclerosis?

A
  1. Endothelial dysfunction allows migration of LDLs into intima
  2. LDLs get oxidised by ROS produced from EC, SMCs and macrophages at later stages
29
Q

Describe stage three of adhesion, migration and transformation of monocytes in progression of atherosclerosis?

A
  1. Damaged endothelium expresses P-selectin and signalling molecules
  2. Attracts monocytes to damaged region
  3. Monocytes adhere to P-selectin on EC and migrate into intima (inner coat)- transform into macrophages
30
Q

Describe stage four of engulfing oxidised LDLs in progression of atherosclerosis?

A
  1. Macrophages engulf all oxidised LDLs and become foam cells
  2. Enhances HDL reverse cholesterol transport, continuous accumulation leads to further development of fat streak
  3. Macrophages and foam cells release growth factors
31
Q

Describe stage five of migration and proliferation of smooth muscle cell?

A
  1. Growth factors enhance migration and proliferation of smooth muscle cell (SMC)
  2. Forms fibrous cap with collagen and elastin etc
  3. The SMC calcifies the fibrous cap leading to hardness
  4. Dead cells release the lipid core
32
Q

Describe stage six of expansion and occlusion of smooth muscle cell?

A
  1. Initially plaque grows towards the Tunica externa
  2. Grows towards the lumen
  3. At final stage, plaque can rupture, activate platelets and lead to thrombosis
33
Q

What are the major risk factors for atherosclerosis?

A
  1. Unchangeable factors: Family history, genetic factors, ageing and gender (male)
  2. Modifiable factors: hyperlipidaemia, metabolic diseases, smoking and hypertension
34
Q

What are the minor risk factors for atherosclerosis?

A
  1. Physical inactivity
  2. Poor diet
  3. Heavy stress
  4. Alcohol and medications
35
Q

How do you diagnose atherosclerosis?

A
  1. Blood tests
  2. Electrocardiogram (ECG- measuring QRS, ST waves)
  3. Echocardiogram (image of the heart, looking at valves etc)
  4. Angiogram: looking at an image of the blood vessels in the heart
  5. CT scan: image of the heart
36
Q

How do you treat atherosclerosis?

A
  1. Same method as hyperlipidaemia
  2. Anti-hypertensive treatment: ACE inhibitors, calcium channel blockers and diuretics
  3. Anti-platelet treatment is to prevent thrombosis
  4. Surgical procedures: coronary angioplasty (Stent in heart) and coronary artery bypass graft

PM2C: Therapeutics and Patient Care: Summer (25 decks)

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