Lipid lowering Flashcards
What is the exogenous pathway for lipoprotein transport in blood?
Cholesterol and TAGs from GIT enter intestinal lymph, transported to blood as chylomicrons, are hydrolysed at the cell periphery.
What is the endogenous pathway for lipoprotein transport in blood?
Cholesterol and TAGs from liver are transported as VLDL to muscle/adipose to be hydrolysed and lipoproteins become LDL
List the different types of lipid-lowering agents.
Statins, fibrates, inhibitors of cholesterol absorption (resins, ezetimibe), nicotinic acid, fish oil.
What is the mechanism of action of statins?
Competitively inhibit HMG CoA reductase to block cholesterol synthesis in the liver
Reduce cholesterol in the liver, increases expression of LDL receptors, increasing uptake by hepatocytes and clearance.
Improve endothelial function, stabilise plaques.
What is the effect of statins on lipoproteins?
Lower LDL substantially, lower TGs and raise HDL.
What are the indications for statins?
Hypercholesterolaemia, high risk CHD, secondary prevention of MI and stroke
What are the side effects of statins?
GI disturbances, insomnia, rash, myopathic effects - muscle breakdown, pain, enzyme changes
What are the clinical considerations for statins?
Avoid in pregnancy, memory loss in diabetes.
What is the mode of action of fibrates?
Peroxisome proliferator-activated receptor alpha (PPAR) agonists
Stimulate lipoprotein lipase
Decrease hepatic VLDL production, increase hepatic LDL uptake
What is the peroxisome proliferator-activated receptor alpha (PPAR)?
Nuclear receptor that influences metabolism in the liver, adipose, muscle and heart.
What is lipoprotein lipase?
Converts triglycerides into free fatty acids and glycerol to increase lipid availability for muscle.
What are the indications for lipoproteins?
Reduce LDL, substantially reduce TGs and increase HDL.
What are the indications for fibrates?
Hypertriglyceridaemia, mixed hyerlipidaemia
What are the side effects of fibrates?
GI disturbances
Give example of cholesterol absorption inhibitors.
Bile acid binding resins
Ezetimibe
What is the mechanism of action of resins?
Bind with bile acids, reducing absorption of exogenous cholesterol.
Increase metabolism of endogenous cholesterol, reduce intracellular cholesterol in hepatocytes.
There is a compensatory increase in LDL receptors.
What are the indications for resins?
Hypercholesterolaemia, mixed hyperlipidaemia.
What are the side effects of resins?
GI discomfort
What is the mechanism of action of Ezetimibe?
Inhibits cholesterol absorption across the intestinal wall - blocks transport protein NPC1L1 in brush border
Does not stop absorption of fat-soluble vitamins
How is ezetimibe used?
Adjunct to statin
What is the benefit of ezetimibe of resins?
Better tolerance, higher potency.
What is the mechanism of action of nicotinic acid?
Inhibit VLDV secretion from liver, decreases Lp(a) (Lp(a) promotes thrombosis)
Lowers LDL, TG and raises HDL
What are the benefits of omega-3 polyunsaturated fatty acids (PUFA)?
Substitution of PGI2 and TXA2 with PGI3 and TXA3, which are more favourable.
Which drugs are used for hypercholesterolemia?
Statins, resins, nicotinic acid, ezetimibe and fibrates.
