Flashcards in Athersclerosis Deck (17):
A progressive disease of the arteries. Accumulation of lipids and fibrous tissue in tunica intima
What can atherosclerosis cause?
CHD and stroke - underlying cause of 50% deaths in west
What is myocardial ischemia?
An imbalance of demand and supply of oxygenated blood to arteries. Mainly occurs when there is an increase in demand of O2...exercise (angina of effort)
What happens when the fibrous cap ruptures?
Thrombogenic lipid core comes into contact with blood - platelet aggregation and thrombus formation which can occlude coronary arteries resulting in sudden death or a MI
What are the modifiable and non-modifiable risk factors for atherosclerosis?
Non-modifiable: male gender, menopause, history of CHD, age
Modifiable; diet, exercise, smoking, obesity, high LDL/HDL, hypertension etc
Describe the mechanism of atherogensis.
Endothelial damage and lipid accumulation result in decreased NO production. LDL are oxidised. Endothelial cells expression adhesion molecules (VCAM) to which inflammatory cells attach.
Inflammatory cells are attracted by chemotactic stimuli and migrate to intiman. Monocytes differentiate to macrophages.
Macrophages proliferate (in response to mitogenic stimuli) and ingest oxidised LDL to form foam cells.
Accumulated foam cells die to leave a lipid core. Fibrous cap forms to prevent contact with blood.
Problem is when cap ruptures.
What does the treatment of atherosclerosis focus on?
Reduction of risk
Describe the different lipoproteins, when they are found in the body and what APO they contain
Chylomicrons - postpyrandial, TG rich
VLDLs; fasting state, APOE
LDLs; high protein;lipid ration, APOB
HDL; highest protein lipid ratio; APO A (1and2)
Statins - eg, how they work and side effects
Inhibit HMG-CoA reductase (involved in cholestrol synthesis)
- upregulated LDL receptors in liver and increased removal of LDL from circulation
- reduction synthesis and secretion of lipoproteins from liver
- lower serum LD by 50%
anti inflammatory actions
enhanced DNA repair and decreased SM senescence
Cause headaches, fatigue, GI intolerance and flu like symptoms.
increase liver enzymes
myopathy (muscle weakness/pain and increase creatine kinase).
Bile acid resins
inhibit enterohepatic shunt...increase bile acid synthesis from cholestrol
increase hepatic LDL receptor expression and uptake...results in lowered serum LDL.
Side effects; GI intolerance
Drug interaction - bind other negatively charged drugs (excretion without absorption)
impede absorption of other drugs and fat soluble vitamins.
Fibric acid derivatives
Activate PPAR-alpha which regulated expression of protein involved in HDL synthesis and HDL mediated cholestrol reverse transport
Therefore increase HDL
Causes GI upset, gallstones and myopathy if used with statins.
Activates GPCR in adipocytes which inhibits lipolysis and to decrease FFA levels. This decreased hepatic VLDL production and decreases serum LDL.
But...itching, flushing, headaches, hepatotoxicity, hyperglycemia and decreased insulin sensitivity
blocks cholestrol absorption by indirectly inhibiting NPC1L1
But some GI intolerance and back/joint pain.
How could you increase HDL?
Inhibit cholesterylester transfer protein
BUT increase mortality
How could you target the lesion associated with inflammation?
Daraladip which inhibits lipoprotein assocaited PLA2...decrease inflammatory markers
How could you stimulate reverse cholesterol transport?
Liver X receptor antagonists - decrease HDL secretion - inhibit atherosclerosis
But elevate inducible degrader of LDLR and therefore increases LDL