PHAR2102 Cholesterol - Dr Susan Hua PDF

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Dr Susan Hua...

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Dyslipidemia Pathophysiology ● The interrelationship between dyslipidemia, atherosclerosis & CHD -

Dyslipidemia: 1+ abnormalities of blood lipids Atherosclerosis: build-up of fats & cholesterol in/on the artery walls CHD/CAD: damage/disease in the heart’s major blood vessels Successful management of dyslipidemia can alter the natural course of atherosclerosis & prevent CHD

● The role of cholesterol & how it is derived 1. Structural component of cell membranes → creates fluidity & permeability 2. Precursor of bile acids in liver → fat digestion & absorption 3. Precursor of steroid hormones → homeostatic ability, e.g. glucocorticoids, mineralocorticoids, estrogen, testeroid 4. Precursor of vitamin D: sun activates the precursor (present in cholesterol) in the skin to activate the process to form an active version of vitamin D Derived: 1. Endogenous system (de novo): through intracellular synthesis. Main site is the liver, pushed out by the liver as lipoproteins 2. Exogenous system: fatty acids and cholesterol from dietary fat are packaged into chylomicrons by the gut → pushed to lymphatic system → hepatocytes (liver cells) and → blood circulation

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Cholesterol synthesis: Regulated by HMG CoA reductase (rate limiting enzyme which determines how much cholesterol you have/produce - it’s the slowest step in the synthesis of cholesterol, making it a good step to target through medication) The enzyme is regulated by gene expression, enzyme degradation, hormonal regulation, inhibition by drugs Example of hormonal regulation: HMG CoA reductase: present when blood glucose is high. When insulin secretion is increased → HMG CoA is increased and cholesterol is formed. Opposite: low glucose levels, decrease in HMG CoA and less cholesterol is formed

● How lipoproteins differ -

Lipophilic core, hydrophilic coat (which interacts with blood) Transported in it’s ester form More protein → higher density (heavier)

1. Chylomicrons - Lowest cholesterol - Highest TG - Largest in size & lowest density - Generated by the intestine - Delivers dietary TG to peripheral tissues 2. VLDL - High TG - 20% Cholesterol - Generated by the liver - Deliver de novo TG to peripheral tissue

3. LDL 4. HDL -

Highest cholesterol Low TG Generated by VLDL (enzyme removes TG, becomes highest in cholesterol) Delivers cholesterol to the peripheral tissues and to liver 25% Cholesterol Lowest TG Generated by the liver and intestine Delivers cholesterol to the liver for elimination Good cholesterol

● How lipoproteins promote or protect against atherosclerosis -

High HDL have reduced risk of cardiovascular events/atherosclerotic risk VLDL are quite large, don’t move well in between blood vessels to dump TG/Cholesterol, increase risk. LDL plays a central role.

How HDL protects against atherosclerosis: - HDL takes cholesterol from peripheral tissue and transports it to liver to be discarded - HDL inhibits oxidation of LDL, which is dangerous because it has pro-atherogenic properties - Anti inflammatory - Anti apoptotic (prevents cell death) - Antithrombotic (reduces formation of blood clots) - Vasodilatory - oxHDL: doesn’t perform as well Clearance of lipoproteins - Cholesterol is carried by LDL predominantly - Cells are cleared by the upregulation of LDL receptors - LDL lipoproteins bind to the LDL receptors → taken up by endocytosis into the cell → cholesterol is either degraded or packaged into other things - We want the liver to take up more LDL and discard it in order to reduce LDL in the blood - Uptake of cholesterol into peripheral & hepatic cells following binding of lipoproteins to cell surface LDL receptors - Synthesis of LDL receptors is stimulated by low intracellular [cholesterol]

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I.e when the body senses that the intracellular cholesterol is low, it automatically synthesises more LDL receptors to the surface of the cell. This stimulates more cholesterol being taken up from the blood circulation and taken up into the cells. → Drugs target this mechanism - makes hepatic cells drop its intracellular cholesterol levels → LDL receptors then take more cholesterol from the blood circulation → reduces the plasma LDL concentration Need to fast b/c otherwise the exogenous system interferes with the results (e.g. have more TG/chylomicrons in blood temporarily).

● The development of atherosclerosis (can high cholesterol lead to a heart attack? why?) 1. Tunica intima: main component, has lumen and blood, lined by a monolayer of endothelial cells and has some smooth muscle cells residing there 2. Tunica media: more smooth muscle cells, “extracellular matrix” 3. Tunica adventitia: mast cells, fibroblasts, nerve endings and other microvessels reside here

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Atherosclerosis affects endothelial cells in the tunica intima layer Athersoclerotic legions become more stable as they age. There is a thicker fibrous cap as they progress, which protects the legion from rupturing and protects the core itself. Before the fibrous cap is stable, there is a large lipid core and a thin fibrous cap → more prone to rupturing

Formation of fatty streak

1. Triggered by cell injury to the endothelial cell monolayer (dyslipidemia, hypertension, diabetes can trigger this inflammatory process, causing the endothelial cells not to function well) → causes an oxidised environment 2. Due to injury, the endothelial cells start increasing oxidative stress → oxidised environment (oxidised LDL is dangerous). 3. Endothelial cells decrease nitric oxide, which is important for vasodilation. Thus, the blood vessels don’t constrict/dilate as normal. 4. Also causes an increase cell adhesion molecules (which grab onto the immune cells) 5. Due to inflammation, immune cells (monocytes) are recruited to the site (“body damaging itself”). Monocytes accumulate at the site of inflammation (tunica intima) 6. Monocytes begin uptaking lipids 7. Monocytes convert to macrophages after uptaking lipids 8. Monocytes convert to foam cells → group together, form a fatty streak

Formation of fibrous cap & expanding 1. Smooth muscle cells migrate from the tunica media to intima to protect the area 2. Forms a fibrous cap over the top of the intima layer (still have lipids, fatty streaks forming, macrophages forming, etc → lipid core is continuously getting bigger) 3. The extracellular matrix is expanding to maintain function

Thrombosis 1. The plaque ruptures 2. The blood coagulation system forms platelets 3. A blood clot forms If the clot extends a full diameter of the lumen, a heart attack is possible. If it forms partial, it can cause angina/ischemic heart disease - depends on how much blood is blocked from coming through

● The potential physiological mechanisms of CHD risk reduction by cholesterol lowering 1. Change the composition of atherosclerotic plaques: thin fibrous cap, large lipid core → thick fibrous cap, small lipid core → less prone to rupturing 2. Prevents the progression of culprit lesions: stop it from getting bigger by lowering the cholesterol 3. Restore endothelial function → this is what sets everything off 4. Combat the inflammation associated with atherogenesis ● Identify the lipid-modifying drug classes ● The mechanism of action, indications, precautions, ADRs, practice points of the lipid modifying drug classes ● The comparison between the lipid modifying drug classes ● The main counselling points for lipid modifying drugs Lifestyle interventions 1. Diet 1. Olive, rice bran, canola oil 2. If someone has dyslipidemia, opt for low fat dairy options 3. Lean meat 4. Limit cholesterol rich foods such as egg yolks and offal 5. Address the patient's understanding of healthy eating! 2. Smoking cessation 1. Counselling to encourage quitting 2. Referral to Quitline 3. Nicotine replacement therapy 3. Physical activity: at least 30 mins, moderate 4. Weight reduction 1....