Pharmacology - Lipids Flashcards
Define atherosclerosis
A progressive disease of large and medium sized muscular arteries, characterised by inflammation and dysfunction of the lining of the involved blood vessles, and the the build up of cholesterol, lipids and cellular debris
Resulting in a formation of a plaque (atheroma)
What are the normal levels of cholesterol in people?
Total = Less than 5mmol/L
Non HDL = Less than 4 mmol/L
LDL = Less than 3 mmol/L
HDL = Greater than 1 for men and 1.2 for women (mmol/L)
TC:HDL Ratio = Less than 6
How are lipoproteins and cholesterol transported around the body?
LDL –> Have a low ratio of protein:cholesterol
This is bigger than HDLs
HDL –> Have a high ratio of protein:cholesterol
IDL –> Carry mainly cholesterol
Chylomicrons (CM) –> Transport exogenous (dietary) triglycerides
VLDL –> Transports endogenous cholesterol from the liver to the muscle and adipose tissue
Explain what happens to free cholesterol in the body?
It is esterified (by LCAT) and then transfered to VLDL/LDL (via CETP). The VLDL/LDL then bind to LDL-receptors in the liver
Or the free cholesterol is taken up by HDL and binds to SR-B1 receptors in the liver (true also for esterified cholesterol)
What controls the degredation of LDL receptors?
PCSK9 (proprotein convertase subtilisin/kexin type 9)
What are the 5 main stages in the formation of an Atheromatous plaque?
Endothelial Cell Dysfunction (initiation)
Lipid accumulation and oxidation
Immune cell accumulation
Smooth Muscle Cell Rercruitment
Unstable atheromatous plaque
What is lipoprotein (a)?
A cholesterol rich LDL
A CV risk factor and a proatherogenic marker
Name 4 signs of Familial Hypercholestermia (FH)
Cornal Arcus
Tendons Xanthomata
Xanthoma
Skin Xanthomata
How do statins work?
Inhibition of HMG-CoA Reductase
This prevents the conversion of HMG-CoA to mevalonate
This decreases the amount of LDL in the body by reducing the number of LDL-receptors, and increasing its clearance from the body
What are the 2 types of statins?
Type 1 –> Fungal derived (Pravastatin/Simvastatin)
Type 2 –> Synthetically derived (Atorvastatin/Rousuvastatin/Fluvastatin)
What are the 3 statins that are metabolised by CYP3A4s?
Lovastatin
Simvastatin
Atorvastatin
How does Ezetimibe (Ezetrol) work?
Inhibits the NPC1L1 membrane transport protein
This prevents cholesterol from being absorbed in the gut
However this includes plant stanols, which are part of a cholesterol-lowering diet
How do Fibrates (Fenofibrate) work?
Agonist of PPAR(a) –> A nuclear transcription factor
This dimerises with RXR (retonoid X receptor) –> Which increase the transption of Lipoprotein Lipase (LDL)
So causes an increase in uptake in LDL and formation of HDL
Also decreases VLDL levels
What are bile-binding acid residues? (eg, colestyramine)
They bind bile acids in the gut and reduce reabsorption of cholesterol via the enterohepatic circulation
Only effect is that they decrease LDL (no effect on HDL or triglycerides)
How does Nicotinic Acid (Niacin/Vitamin B3) work?
A precursor of NAD+/NADH/NADP+/NADPH
Activates the Gi/o coupled HCA2 receptor in adipocytes
Increases APO-A1 –> which increases HDL levels
Inhibits lipolysis
How do Fish Oil Derivitives work?
Act as precursors of ‘beneficial’ eicanosoids……eg prostaglandins/thromboxanes and leukotrienes
They reduce triglycerides and LDL cholesterol
What things will be raised in the plasma, indicating atherosclerosis?
C-Reactive Protein (CRP) –> Pro-inflammatory
Homocysteine
Coagulation Factors
Lipoprotein(a) –> Prothrombotic
What is Apolipoprotein (a)?
Lipoprotein (a) with an additional protein that is bound via a disulphide bond
It is prothrombotic and profibrotic
What are Evolocumab and Alirocumab?
Anti-PCSK9 monoclonal antibodies
Used in hypercholesterolaemia
