Lipid Lowering Drugs Flashcards
what are the main lipid lowering drug group?
statins
what is cholesterol needed for?
- As a component of cell membranes
- For synthesis of steroid hormones
- As a component of bile salts
are steroids fat soluble or water soluble?
fat soluble
what is the base structure of a steroid?
tetracyclic
what are the 3 sources of cholesterol?
Intestinal absorption
Peripheral synthesis
Hepatic synthesis
what does the liver do in terms of the source of cholesterol?
acts as the main regulatory organ that determines LDL-C levels in the blood
what is the structure of a lipoprotein?
a hydrophilic coat and a hydrophobic core
what is the hydrophilic coat of a lipoprotein made up of?
• Phospholipids
• Free cholesterol
• Associated proteins
(apoproteins /apolipoproteins)
what is the hydrophobic core of a lipoprotein made up of?
Trigylcerides and/or cholesterol esters
what are the 6 classes of lipoproteins?
Chylomicrons Chylomicron remnants VLDL IDL LDL HDL
what do chylomicrons do?
transport of ingested lipids to tissues
what do chylomicron remnants do?
ingested cholesterol => liver
what do VLDLs do?
transport of lipids from the liver to tissues
what do IDLs do?
intermediate density (VLDL remnant)
what do LDLs do?
supplies cholesterol to tissues that require it
what do HDLs do?
transports cholesterol from tissues to the liver
what are the two lipid pathways?
endogenous
exogenous
what does the endogenous pathway do?
liver -> tissues
what does the exogenous pathway do?
tissues -> liver
what is the sequence of events of the exogenous pathway?
- lipids in GI tract from diet → chylomicrons
2a. chylomicrons pass through vascular endothelium via lipoprotein lipase, into the peripheral tissues and becomes a free fatty acid
2b. turned into chylomicron remnant via lipoprotein lipase - returns to the liver as cholesterol
bile acids and cholesterol can enter GI tract via the bile duct, and return to the liver via the portal vein
what is the sequence of events of the endogenous pathway?
- cholesterol leaves the liver and is turned into VLDL
- VLDL is turned into LDL via lipoprotein lipase
- LDL can enter the peripheral tissues or act on LDL receptors on the liver
- LDL is returned to cholesterol in the liver
also
- cholesterol from cell leaves the peripheral tissues as HDL
- HDL is turned into VLDL which turns into LDL, or is turned into LDL directly
- LDL returns to the liver as cholesterol
what is the major lipid of a chylomicron?
triglyceride
what is the major lipid of VLDL?
triglyceride
what is the major lipid of IDL?
cholesteryl ester
what is the major lipid of LDL?
cholesteryl ester
what is the major lipid of HDL?
cholesteryl ester
what is cholesterol?
a sterol
fluidity/robustness of cell membranes
precursor for steroid hormones
important in vitamin D synthesis and bile acids
how is cholesterol synthesised in the liver?
HMG-CoA reductase → mevalonic acid → cholesterol
how is cholesterol delivered to cells?
- LDL particles bind to specific receptor sites on the surface of peripheral cells
- LDL-receptor is endocytosed
- LDL particle is delivered to lysosomes
- Cholesterol is released by enzyme activity.
- Receptor is recycled to the surface
what happens when free cholesterol accumulates in the cell?
new LDL receptor synthesis is inhibited and the entry of more LDL is prevented
what does the free cholesterol in cells do?
- Esterified with fatty acids => cholesterol esters, (storage form of cholesterol)
- Synthesis of membranes & other cell components
how does atherosclerosis occur?
LDL → oxidised → taken up by foam cells
changes in endothelium → monocytes/leukocytes → attracted to cells → differentiated to macrophage
macrophage releases cytokines
→ further damage to endothelium
→ smooth muscle migration to make fibrous cap
what are the 6 classes of hyperlipidaemia?
type I, IIa, IIb, III, IV, V
what is type I hyperlipidaemia and what does it consist of?
Familial Hyperchylomicronaemia
increase in chylomicron
what is type IIa hyperlipidaemia and what does it consist of?
Familial Hypercholesterolaemia
increase in LDL
what is type IIb hyperlipidaemia and what does it consist of?
Familial Mixed Hyperlipidaemia
increase in VLDL and LDL
what is type III hyperlipidaemia and what does it consist of?
Familial Dysbetalipoproteinaemia
increase in IDL
what is type IV hyperlipidaemia and what does it consist of?
Familial Hypertriglyceridaemia
increase in VLDL
what is type V hyperlipidaemia and what does it consist of?
Familial Mixed Hypertriglyceridaemia
increase in chylomicron and VLDL
which types of hyperlipidaemia are the most important? (increase cholesterol (LDL))
type IIa/IIb
how do statins work?
inhibiting HMG-CoA reductase
which pathway do statins inhibit?
endogenous cholesterol synthesis
what happens when endogenous synthesis is inhibited?
Synthesis is prevented, causing an increase in the expression of hepatocye LDL receptors and removal of LDLs from the circulation.
statins inhibit the synthesis of cholesterol - what else do they do?
increase the uptake of LDL
which statin is derived from Aspergillus terreus?
lovastatin
lovastatin, what other examples of statins are there?
Simvastatin, fluvastatin, lovastatin, rosuvastatin,
atorvastatin, pravastatin
what are the side effects of statins?
Myopathy rhabdomyolysis (muscle wasting)
what drug interactions are there with statins?
drugs associated with myopathy
examples of Bile Acid Binding Resins
chlolestyramine, colestipol, cholesevelam
what do bile acid binding resins do?
Sequester bile acids in the intestine
prevent their reabsorption via hepatic portal vein
what happens as a result of sequestering bile acids in the intestine?
1.decreased absorption of exogenous cholesterol
- increased metabolism of endogenous cholesterol into bile acids in the liver
- increased LDL receptors on liver
- increased LDL blood removal
what are the side effects of bile acid binding resins?
Bloating, flatulence, heartburn, constipation
what are the drug interactions of bile acid binding resins?
- interfere with absorption of other drugs
- decrease absorption of fat-soluble vitamins, e.g. vitamin A, E, D, K
what is another name for nicotinic acid?
niacin
what does nicotinic acid /niacin do?
inhibits production of VLDLs
inhibits lipolysis in adipocytes
what does the inhibition of VLDL production by nicotinic acid lead to?
reduction in LDL and total cholesterol concentrations
what does the inhibition of lipolysis in adipocytes by nicotinic acid lead to?
reduction in the delivery of FFAs to the liver and TG synthesis
what is the mechanism of action of nicotinic acid?
IN THE HEPATOCYTE:
- decreased fatty acid mobilisation
- decreased TG synthesis
- decreased VLDL synthesis
- decreased VLDL secretion
VLDL enters the systemic circulation and its turned into LDL…….
IN THE SYSTEMIC CIRCULATION
- increase in HDL
- decrease in LDL
- decrease in lipolysis to LDL
- decreased VLDL
what is the name for the nicotinic acid receptor?
HCA2
how does the nicotinic acid receptor work?
usually.. adrenaline and noradrenaline stimulate Gs receptor on the cell which would stimulate adenylate cyclase.
NICOTINIC ACID stimulates the nicotinic acid receptor (Gi) which INHIBITS adenylate cyclase - this inhibits the rest of the process….
both the Gs and Gi act on adenylate cyclase.
adenylate cyclase catalyses the reaction of ATP to cAMP
cAMP -> PKA -> HSL.
triglycerides -> HSL -> FFA which leaves the cell to the liver.
the inhibition of adenylate cyclase lowers cAMP, PKA, HSL and FFA
what is a side effect of niacin?
niacin flush
what do fibrates mainly do?
Stimulate lipoprotein lipase
what happens when lipoprotein lipase is stimulated?
promotes lipolysis of VLDLs
limits availability of free fatty acids for TG synthesis in the liver
what other things do fibrates do?
Accelerate clearance of LDLs from the circulation by the liver
Increase HDL concentrations
what is the mechanism of action of fibrates?
- bind to PPAR-α
- PPAR-α is a nuclear receptor expressed in hepatocytes, skeletal muscle, macrophages and the heart
- leads to changes in the expression of genes involved in lipoprotein metabolism.
examples of fibrates
gemfibrozil, fenofibrate, bezafibrate, ciprofibrate
what is an example of a Cholesterol Uptake Inhibitor?
ezetimibe
what do cholesterol uptake inhibitors do?
Inhibit cholesterol uptake (and plant stanols) from the duodenum into the enterocyte
how do cholesterol uptake inhibitors work?
block transport protein NPC 1L1
for type I hyperlipidaemia, how should you treat it?
no treatment effective
for type IIa hyperlipidaemia, how should you treat it?
Statin and/or ezetimibe
for type IIb hyperlipidaemia, how should you treat it?
Fibrates, statin, nicotinic acid
for type III hyperlipidaemia, how should you treat it?
Fibrates
for type IV hyperlipidaemia, how should you treat it?
Fibrates
for type V hyperlipidaemia, how should you treat it?
Fibrates, niacin, VLDL and statin
what are PC5K9 inhibitors?
reduce cholesterol more than statins
how do PC5K9 inhibitors work?
bind to monoclonal antibodies
send LDL to lysozome - stop receptors from being recycled
what is an example of a PC5K9 inhibitor?
evolocumab
