Atherosclerosis & Lipid Lowering Drugs Flashcards
What is Hypercholesterolaemia?
Elevated plasma cholesterol, often leading to Atherosclerosis
What is Atherosclerosis?
Focal lesions (plaques) on the inner surface of an artery
What can Atherosclerosis lead to?
Ischaemic heart disease (IHD)
Peripheral vascular disease (PVD)
Cerebrovascular disease
What are the non modifiable risk factors for Atherosclerosis?
Genetics
Infection (dental)
What are the modifiable risk factors for Atherosclerosis?
Hypercholesterolaemia (raised LDL/lowered HDL) Hypertension Smoking Obesity Hyperglycaemia Reduced physical activity
What is dyslipidaemia?
Abnormal levels of lipids in the blood
What drugs are known to induce dyslipidaemia?
Beta-blockers Thiazides Corticosteroids Retinoids Oral contraceptives Anti-HIV
What are lipoproteins?
A group of soluble proteins that transport lipids in the blood
What is the structure of lipoproteins?
Central hydrophobic lipid core
Encased in phospholipid, cholesterol & apolipoproteins
What are the four main types of lipoprotein?
HDL - High density lipoprotein
LDL - Low density lipoprotein
VLDL - Very low density lipoprotein
Chylomicrons
What are Chylomicrons?
Type of lipoprotein that transport TGs/cholesterol from GI tract to the liver
Free FA released
Cholesterol stores/oxidised
What is the function of VLDL?
Transports cholesterol/TGs to tissues –> becomes LDL
What is the function of LDL?
Transports cholesterol to liver/tissues, taken up by endocytosis
What is the function of HDL?
Transports cholesterol from cell breakdown to VLDL/LDL (in liver)
What is the ideal level of cholesterol?
<5.0 mmol/L
High HDL:LDL
What are the diagnostic criteria for Hypercholesterolaemia?
TC >6.5 mmol/L
High LDL:HDL
What are some diagnostic signs of Hypercholesterolaemia?
Xanthoma (cutaneous fatty deposit)
Xanthomata - nails
Xanthelasma - around eyes
What is Atherogenesis?
An inflammatory response to injury leading to the development of atheromatous plaques
What are risk factors for damage to the arterial endothelium?
Turbulent flow
Smoking
Hypertension
What causes Atherosclerosis?
Damage to the endothelium followed by the inflammatory response
What cells make up the inflammatory response in Atherogenesis?
Monocytes/Macrophages
What is the main effect of Monocytes/Macrophages in Atherogenesis?
Release of Ox radicals
What effect does the release of Ox radicals have on LDL?
Converts it to oxLDL
What is oxLDL?
Oxidised LDL
Damages receptor
Cholesterol accumulates underneath endothelium
How do fatty streaks form?
Cholesterol rich foam cells forming underneath endothelium
What is an atherosclerotic plaque?
Cholesterol rich plaque, calcified w/ connective tissue
At what point does narrowing of an artery due to an atherosclerotic plaque lead to symptoms?
70% occlusion
What are the three main stages of Atherosclerotic formation?
Damage to blood vessel - inflammation/infiltration
Formation of fatty streaks - deposition of foam cells
Formation of plaques - calcification of cholesterol deposits
What are the causes of symptoms in Atherosclerosis?
Stenosis (70%) - angina
Rupture of plaque - clot formation/platelet aggregation
What are the main treatments for Atherosclerosis?
Lifestyle measures/hyperlipidaemia treatments
Angioplasty & stenting
Antiplatelets/clot-busting drugs
How is most cholesterol produced?
In the liver (70%)
Key enzyme - HMG-CoA Reductase
How do Statins work?
HMG-CoA Reductase Inhibitors
What are the clinically most common Statins?
Simvastatin
Atorvastatin
Pravastatin
Fluvastatin
What is the effect of Statins?
Reduced plasma cholesterol (therefore)
Upregulation of hepatic LDL receptors - LDL uptake
In what condition are Statins less effective?
Homozygous familial hypercholesterolaemia (cannot make LDL-receptor)
ATORVASTATIN
What is the most important metabolic factor of Statins?
Hepatoselective - 95% 1st pass metabolism
In what conditions are Statins effective?
Types IIa & IIb Hyperlioproteinaemia
(LDL & LDL/VLDL)
Heterozygous Familial Hypercholesterolaemia
Are Statins effective at reducing CV risk?
Yes, even if normal cholesterol
- Improve endothelial function
- Reduce atherosclerosis
- Reduce progression of carotid disease
To what patients should Statins be given?
Hypocholesterolaemia
Raised LDL
Atherosclerosis
Patients w/ >10% risk of CVD
How should Statins be given?
At night - increased cholesterol synthesis at night
EXCEPT ATORVASTATIN
What is the dosing structure of Statins in patients with low risk of CVD?
Low intensity
ie. 20 mg Atorvastatin
What is the dosing structure of Statins in patients with high risk/secondary prevention of CVD?
High intensity
ie. 80 mg Atorvastatin
When should Statins be avoided?
Use in care with liver disease - serious risk of dysfunction
Monitor function
What is the main ADR of Statins?
Myopathy leading to Rhabdomyolysis
1:1000/10,000
Fibrates increase risk
PRAVASTATIN
Which drugs interact with Simvastatin?
Contraindication with Macrolides Interactions -Amlodipine -Verapamil -Diltiazem
What Statin can be given OTC?
Simvastatin 10 mg
Which patients can receive Simvastation OTC?
All males >55 Males 45-55/Females >55 with -Family history IHD -Smokers -Overweight -S. Asian ethnicity
What are Fibrates?
Derivatives of fibric acid used to reduce the levels of TGs
How do Fibrates work?
Activate PPAR-a - alters lipoprotein metabolism
What are the effects of Fibrates?
Promote breakdown in VLDL
Reduce TGs
Decrease glucose
Reduce IHD (not mortality)
What are the adverse effects of Fibrates?
Rhabdomyolysis
What is Ezetimibe?
Cholesterol Absorption Inhibitor
How do fish oils affect lipid levels?
Contain EPA
EPA competes w/ Arachidonic acid for COX
Reduce TGs/Increase LDL
What effect do supplemental Vitamins have on lipid levels?
No benefits seen with supplementation
What is Sitostanol?
A phytosterol that prevents absorption of cholesterol
Reduces LDL 10-15%
