PBL 5 - PHARMACOLOGY - drugs used in CHD Flashcards
what is it when ischaemia of cardiac tissue from CAD is temporary?
angina
what does thrombus formation on an atherosclerotic plaque lead to?
permanently occludes the artery —> heart attack
what is coronary artery disease?
the process by which coronary arteries become clogged by atherosclerotic plaques
what is coronary heart disease?
the consequences of coronary artery disease
angina vs. heart attack
- angina = heart temporarily deprived of oxygen — not immediately fatal — heart attack in waiting
- heart attack = heart deprived of oxygen — muscle death —much more serious
why are people with angina or heart attack open to the development of dysrhythmias?
heart muscle becomes ischaemic and so it can’t maintain its resting membrane potential so easily
when do dysrhythmais occur?
when you get inappropriate firing of APs in the heart so you get disturbance of rhythm
how do dysrhythmias lead to pumping inefficiencies? the same pumping inefficiencies can also occur due to what?
they disturb the electrical rhythm of the heart but also the mechanical rhythm
the same pumping inefficiencies can also occur because of muscle death that you see inMI
when does HF come about?
when the heart can’t pump enough blood around to supply the body
what is primary vs secondary prevention of CHD?
- primary = stopping it happening
- secondary = stopping it recurring or worsening (after angina, HA, stroke)
what is the link between exercise and heart disease?
people with an active lifestyle have a lower BP, are less likely to be obsese — had a much lower risk of CHD (independent of their physiology)
describe lipoproteins role and structure
- transport lipids in plasma
- cholesterol and triglycerides in core
- phospholipid monolayer on outside — fatty acid tails facing the hydrophobic core
- apolipoproteins — can be recognised by receptors in tissue
how do we classify lipoproteins?
via DENSITY
- HDL
- LDL
- VLDL
- chylomicrons (have the lowest density of them all)
- there are also intermediates between LDL and VLDL
where is cholesterol synthesised?
hepatocyte = liver cell (major drug target)
cholesterol is used by the liver to make what?
bile acids
what happens to bile acids in the liver?
- secreted into the GI tract and act as a detergent, emulsifies dietary cholesterol and fats, and enables it to be taken up
- bile acids are recycled back to the liver
what happens to the dietary fats emulsified by bile acids?
dietary fats are taken up from the GI tract into chylomicrons
what do chylomicrons do?
transport fats to the tissue
what happens to the chylomicron remnant?
taken up by the liver where it delivers cholesterol
after the chylomicron remnant delivers cholesterol, what 2 kinds of lipoprotein does the liver produce?
- VLDL
- HDL
what happens to the VLDL?
- released into circulation
- delivers more fats to the tissues
- converted to LDL
what does LDL do?
delivers cholesterol to tissues
what does HDL do?
takes up cholesterol from the tissues and delivers it to VLDL
tissue takes up fatty acids after breaking down fats using what?
lipoprotein lipase
what does the liver do when it needs more cholesterol?
recognises and takes up LDL
what are LDL and VLDL and what do they do?
= ”bad cholesterol”
- involved in formation of fatty streaks and promote atherosclerosis
- inhibit fibrinolysis (breakdown of blood clots) by preventing fibrin breakdown
- activate platelets by increasing aggregation — increase likelihood of blood clot
INCREASE RISK OF ATHEROSCLEROSIS
what do LDL and VLDL also increase the risk of?
angina, HA and stroke
what is the mechanism for HA and ischaemic stroke?
- plaque is a weak point in vessel wall so it can rupture
- causes formation of blood clot over plaque
- can block the vessel in place or detach and travel in blood steam and block a smaller vessel elsewhere in the body
what roles does HDL have?
- increase fibrinolysis (helps breakdown blood clots) by increasing fibrin degradation
- may also increase prostacyclin (platelet inactivator and vasodilator) formation by decreasing aggregation
LOWERS RISK OF ATHEROSCLEROSIS
what is hyperlipidaemia?
= too much lipid in blood
- number of different forms
- classified according to which lipoprotein is disturbed or which type of lipid you have too much of
- different disturbances in LDL, VLDL, cholesterol etc
- treated differently
describe familial hypercholesterol
- very high risk of having atherosclerosis
- defect in LDL receptor (the receptor that recognises LDL and allows it to be taken up by the liver)
- or ApopB protein mutation
- autosomal dominant — heterozygous not as bad as homozygous
- 1:500 in UK heterozygotes — CVD by age 30-40
- 1:1000000 homozygous — severe CVD in childhood
what is familial hypercholesterolaemia treated using?
statins but other drugs may be added too
describe the formation of a plaque due to hyperlipidaemia
- excess LDL in circulation enters the intima of a blood vessel
- monocytes migrate to the intima and transform into macrophages
- macrophages take up oxidised LDL and transform into foam cells
- foam cells attach to the endothelium and form the fatty streak
- foam cells release cytokines and other growth factors that recruit smooth muscle cells
- migrating smooth muscle cells thicken the streak into a stable plaque
what are the aims of statins and other lipid lowering drug?
reduce LDL/VLDL and increase HDL
name a statin
atorvastatin
how do statins work?
- completely inhibit HMG-CoA reductase = rate limiting enzyme in production of cholesterol in the liver
- have a similar structure to the substrate for this enzyme, HMG-CoA
- reduces liver production of cholesterol
- more LDL receptors
- increased removal of LDL from plasma
- also increased HDL and lowered triglycerides
what does lowered cholesterol (due to statins) lead to?
- more LDL receptors — liver takes more LDL out of circulation so it produces more receptive on its surface to recognise the apolipoproteins on LDL and remove it from circulation
how is cholesterol formed from Acetyl-coenzyme A?
acetyl-coenzyme A —> HMG-CoA —(HMGCoA reductase)—> mevalonate —> cholesterol
what are some problems with statins?
- myosotis = muscle inflammation
- rhabdomyolysis = muscle breakdown (causes dark coloured urine — myoglobin released = toxic for kidneys = kidney failure)
- altered liver function tests
- complications very rare but lots of people are taking them
what is QRISK3? cut off for statin treatment?
calculates risk that you will have a HA or stroke in the next 10 years
- uses age, ethnicity, weight, other illnesses to assess risk
- cut off for statin treatment for primary prevention is 10%
- also used for secondary prevention
what is ezetimibe?
- inhibits intestinal cholesterol absorption
- inhibits specific cholesterol transporter in the gut
- results in reduced LDL and reduced total cholesterol
who might use ezetimibe?
- can be used in patients who do not tolerate statins
- co-administered with statins in resistant cases or familial hyperlipidaemia — gives dual inhibition of cholesterol absorption and synthesis
what are anion exchange resins?
- drugs that sequester bile acids in the gut (bind to bile acids in gut and stop them from being reabsorbed)
- very large volumes required to unpleasant to take
what are fibrates?
- agonists at a receptor called PRARa
- may be used with elevated VLDL
- commonly produce muscle problems
what about vitamin B3?
- mechanism not well understood
- very high doses required
what about fish oils?
- cold water fish rich in poly unsaturated fatty acids
- omega 3 fatty acids
- consuming such fish is associated with lower risk of CVD
- reduces plasma triglycerides, increases cholesterol
- appears to reduce platelet aggregation and reduce fibrinogen (mechanism not understood)
- NICE concludes there is little evidence to support use
what is a micronutrient that can have beneficial effects on plasma lipid levels if used in gramme quantities?
vitamin B3
how does ezetimibe reduce risk of HA or stroke?
blocks GI cholesterol transporters — lowers LDL levels and this reduces risk
what is rhabdomyolysis? what can it cause and why? what drugs can cause it?
when skeletal muscle breaks down rapidly — the breakdown products are toxic to the kidney and can cause kidney failure
some statins produce rhabdomyolysis as an unwanted effect
name 3 lipid lowering drugs
- statins eg atorvastatin
- ezetimibe
- fibrates
