PHARM; Lecture 16, 17 and 18 - Haemostasis and thrombosis, Atherosclerosis & lipo metabolism, NSAIDS Flashcards
What are the constituents of blood?
What is the balance between clotting and bleeding?
What is haemostasis?
Essential physiological process -> blood coagulation prevents excessive blood flow
What is thrombosis?
Pathophysiological process -> blood coagulates within blood vessel and obstructs blood flow. Can be dangerous if it dislodges from the vessel
What is the difference between red vs white thrombi?
Red = venous thrombi with high fibrin components. Whiite = arterial with high platelet components
What is atherosclerosis?
Pathophysiological process -> thrombus forms within atherosclerotic plaque; plaque rupture (thrombus released into lumen)
Why does a thrombus form?
Virchow’s triad -> 1) rate of blood flow 2) consistency of blood 3) blood vessel wall integrity (!!!!)
What is the cell based theory of coagulation and which drugs act on which stage?
NB: all 3 drugs work on all 3 components (but easy to remember)
What is the initiation phase of the cell based theory of coagulation?
x
Which drugs can act on the initiation stage of the cell based theory of coagulation?
What is the amplification phase of the cell based theory of coagulation?
How are platelets activated?
Which drugs can act on the platelet aggregation phase of the cell based theory of coagulation?
What is the propagation phase of the cell based theory of coagulation?
Which drugs can act on the propagation phase of the cell based theory of coagulation?
What is DVT/PE and how is it managed?
What are acute coronary syndromes?
If clot present then treat with fibrinolytics
How do you treat different thrombosis diseases?
What are lipoprotein particles?
Cholesterol, TG and PL. HDL (A1) v LDL (B) the apoproteins are the main differences; which allow them to circulate in the blood
How do we get exogenous lipids for metabolism?
Dietary TG and cholesterol are broken down an packaged into chylomicrons which are then broken down further into chylomicron remnants, which can end up in the adipose tissue and the blood vessels
How do we get endogenous lipids for metabolism?
Liver is the main organ that deals with cholesterol -> most are metabolised and most do very little but a small proportion ends up in walls of blood vessels
What is reverse cholesterol transport?
Mediated largely by HDL -> cholesterol can’t be broken down in body, so eliminated intact via HDL from peripheral tissues to liver
How does atherosclerosis occur?
Foam cells (macrophages/smooth muscle cells - filled with cholesterol/HDL/LDL) - remnant cholesterol is pro-inflammatory.
How does the endothelial layer become dysfunctional?
- Characterised by series of early changes that precede lesion formation.
- Greater permeability of endothelium,
- upregulation of leucocytes and endothelial adhesion molecules
- migration of leucocytes into artery wall
What is fatty streak formation in atherosclerosis?
- Earliest recognisable lesion of atherosclerosis;
- caused by aggregation of lipid rich foam cells within tunica intima and inner most part of artery wall.
- Later lesions will include smooth muscle cells -> formed usuallly in direction of blood flow
How does the complicated atherosclerotic plaque form?
Results from death and rupture of foam cells in fatty streak, migration of smooth muscle cells into intima and lay down collagen fibres forming protective fibrous cap around lipid core
What are the types of atherosclerotic lesions?
- Complicated lesions often contain Ca;
- CAD can be detected doing CT scan of heart to detect Ca -> more Ca = more symptomatic
What is the vulnerable atherosclerotic plaque?
- Vulnerable plaques are characterised by a thin fibrous caps, a core rich in lipid and macrophages, and less evidence of smooth muscle proliferation.
- In contrast, the stable plaque has a relatively thick fibrous cap protecting the lipid core from the contact with blood.
- Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi.
- The size of the plaque does not appear to predict whether a plaque is prone to rupture, stable plaques more often show luminal narrowing detectable by angiography than do vulnerable plaques.
- Rupture usually occurs at sites of thinning (particularly at the shoulder area of the plaque) and is associated with regions where there are relatively few smooth muscle cells but abundant macrophages and T cells.
- Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen.
What is LDL?
- LDL cholesterol has been shown to be strongly associated with the development of atherosclerosis and the risk of CHD events in patients with established CHD (history of angina pectoris, MI etc.) and in those without CHD.
- This applies to women as well as men, but in women the general level of CHD risk is lower.
- A 10% increase in LDL cholesterol is associated with an approximate 20% increase in risk for CHD.
- The association between LDL cholesterol and the risk of CHD events is considerably modified by other risk factors, such as low HDL cholesterol, smoking, hypertension and diabetes.
- This modification is apparent especially when total cholesterol and LDL cholesterol are only moderately elevated.
What is the vulnerable atherosclerotic plaque?
- Characterised by thin fibrous caps, a core rich in lipid and macrophages, and less evidence of smooth muscle proliferation -> stable has thick fibrous cap.
- Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi.
- Rupture usually occurs at sites of thinning and is associated with regions where there are relatively few smooth muscle cells but abundant macrophages and T cells.
- Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen.
What is LDL?
- LDL cholesterol has been shown to be strongly associated with the development of atherosclerosis and the risk of CHD events in patients with established CHD (history of angina pectoris, MI etc.) and in those without CHD.
- 10% increase in LDL cholesterol is associated with 20% increase in risk for CHD.
- Modifiable risk factors: low HDL, smoking, hypertension and diabetes.
What are HDLs?
- HDL cholesterol has a protective effect in patients with CHD and is independent of LDL cholesterol and other risk factors.
- The lower the HDL cholesterol level the higher the risk for CHD.
- Concentrations of HDL cholesterol tend to be low when triglycerides are high.
- HDL cholesterol is lowered by smoking, obesity and physical inactivity.
What are the comparative pharmacological properties of statins?
NB: higher selectivity ratio = greater likelihood of molecule being concentrated in the liver cell. Potency: lower number = more powerful drug is as an inhibitor of enzyme
What is the effect of statins on lipids?
NB: although doubling the dose reduces LDL (only by 6%), the side effect profile increases sharply with the increase of the dose
What are the effects of each of the drug therapies and their tolerability?
Statins - first line treatment for dyslipidaemia; bile acid sequestrants - lower cholesterol effectively but with poor compliance due to bloating, nausea and constipation; nicotinic acid - increases HDL cholesterol with adverse reactions (skin problems, GI distress, hyperglycaemia and hyperuricaemia); fibrates - lower TG; probucol - modest effect lowering LDL
What are the key statin trials with the spectrum of risk?
What are the uses of NSAID’s?
Widely prescribed and widely used, especially in the elderly; available over the counter
Why are chylomicron remnants important?
They are very good at getting into blood vessel wall in the tunica intima and are very important in process of atherosclerosis
What do NSAIDS inhibit?
Blocks both forms of COX -> reversibly inhibited; COX2 selective reversible inhibitors = coxib family (celecoxib)
What are the prostanoid receptors?
10 -> DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP -> names based on agonist potency.
All G-protein coupled and have effects independent of g-proteins.
Physiological and pro-inflammatory
What is the function of PGE2?
- Unwanted actions:
- Increased pain perception,
- thermoregulation,
- acute inflammatory response,
- immune responses,
- tumorigenesis,
- inhibition of apoptosis (NSAIDS taken to reduce these actions).
- Desirable actions:
- Gastroprotection,
- renal salt/water homeostasis,
- bronchodilation,
- vasoregulation (dilation and constriction depending on receptor activated)
How do prostanoids lower the pain threshold?
Not entirely clear but include EP1/4 receptors and endocannabinoids (neuromodulators in thalamus, spine and periphery)
How is PGE2 pyrogenic?
Stimulates hypothalamic neurones initiating a rise of body temp
How does PGE2 stimulate pain?
PGE2 lowers the pain threshold with stimulation of PG receptors, sensitising the nociceptors which can cause pain (acutely/chronically)
How does PGE2 act in gastric cytoprotection?
PGE2 downregulates HCl secretion, stimulates mucus and bicarbonate secretion -> which if NSAID given we’re going to block these protective properties using selective COX2 antagonist (celecoxib)
How does PGE2 regulate salt and water homeostasis and which enzymes are involved?
Regulates reabsorption and secretion of salts and water
How can NSAIDS affect renal blood flow?
PGE2 increases RBF; NSAIDS constrict afferent arteriole, reduce renal artery flow and GFR, causing renal toxicity
What are the indications for NSAIDS with asthmatic patients?
10% of asthma patients experience worsening of symptoms; COX inhibition favours production of leukotrienes (bronchoconstrictors) -> SHOULDN’T be taken by patient
How can NSAIDS affect the vasoregulator effects of prostanoids?
Overall physiological function of EP receptors in brain -> vasoconstriction (EP1), vasodilation (EP2/4), decreased cAMP production (EP3)
What are the cardiovascular effects of COX2 inhibitors?
Pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear
What is aspirin?
Unique amongst NSAIDS; selective for COX-1; binds irreversibly, with anti-inflammatory, analgesic and anti-pyretic actions; reduces platelet aggregation
What are the effects of prostanoids on platelet aggregation?
No nucleus = no resynthesis of COX-1 in platelets
What is paracetamol?
Is a good analgesic for mild-to-moderate pain Has anti-pyretic action Does NOT have any anti-inflammatory effect Therefore it is not a NSAID
What does an OD of paracetamol cause and how can you cure it?
Add compound with SH groups; usually IV acetyl cysteine (cases of attempted suicide) and oral methionine. Early enough admin = liver failure may be preventable
What does an OD of paracetamol cause and how can you cure it?
Add compound with SH groups; usually IV acetyl cysteine (cases of attempted suicide) and oral methionine. Early enough admin = liver failure may be preventable
What is the legislation on over the counter sales of analgesics?
No more than 2 packs per transaction and illegal to sell more than 100 paracetamol in one transaction
Why is aspirin unique amongst NSAIDS?
It binds covalently to COX
Inhibition of which enzyme will reduce platelet aggregation with fewest side effects - COX1, COX2, Prostacyclin synthase, prostaglandin E synthase, thromboxane A2 synthase?
Thromboxane A2 synthase
Assertion: Inhibition of PGI2 synthesis by low dose aspirin decreases the risk of stroke Because : Decreased PGI2 reduces platelet aggregation
False, False -> Synthesis of PGI2 (prostacyclin) is inhibited by low dose aspirin, but it is not this action which decreases the risk of stroke, because PGI2 actually reduces platelet aggregation. It’s the inhibition of thromboxane synthesis
What is atherosclerosis?
An inflammatory fibro-proliferative disorder
What are the stages of atherosclerosis?
LDL enters endothelium -> release of GF and cytokines which attract inflammatory cells (monocytes), then formation of foam cells in endothelium and proliferation of fibroblasts and smooth muscle cells, expanding the plaque
Why is the fibrous cap important in the formation of atherosclerotic plaque?
Separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors
What characterises an stable plaque?
Necrotic lipid core surrounded by a thick vascular smooth muscle rich fibrous plaque
What is an unstable atherosclerotic plaque?
Plaque ruptures and exposes the thrombogenic lipid core to the circulating platelets and coagulation factors -> leads to THROMBOSIS. Also, cells release inflammatory mediators causing other cells to become attracted to the plaque, proliferate and cause plaque erosion. Plaque erosion can also cause hardening of the vessels, which thins and weakens the arteries, leading to aneurysms and haemorrhage
What is an unstable atherosclerotic plaque?
Plaque ruptures and exposes the thrombogenic lipid core to the circulating platelets and coagulation factors -> leads to THROMBOSIS. Also, cells release inflammatory mediators causing other cells to become attracted to the plaque, proliferate and cause plaque erosion. Plaque erosion can also cause hardening of the vessels, which thins and weakens the arteries, leading to aneurysms and haemorrhage
What is the mechanism of action of statins?
- Act on mevalonate pathway to inhibit HMG-CoA reductase ->
- main 2 products of the pathway are geranyl/farnesyl pyrophosphate which are needed for normal cell function;
- by blocking cholesterol synthesis, the liver increases the number of LDL receptors, which bind to circulating LDL and lower it
What are the side effects of statins?
Statins have pleiotropic effects; with anti-inflammatory effects not related to lowering cholesterol -> cholesterol level should be used as a guide for statin treatment
What are fibrates?
Activate PPAR-alpha receptors; lower plasma fatty acids and lower TG -> often given to patients with diabetes and high TG
What is ezetimibide?
Inhibits cholesterol absorption; absorbed and activatd as glucuronide, reduces LDL levels; used in addition to statin treatment
What is cholesteryl ester transferase protein and why is it an important target?
CETP is responsible for metabolic process where HDL is broken down and converted into LDL -> a CETP blocker drug was developed and found that it had a positive effect in increasing HDL and decreasing LDL but many people died because of off-target effects (activation of aldosterone synthesis, ^BP), so is no longer used. Only Torcetrapib with this effect, other -rapibs don’t.
What is PCSK9 and why is it important in treatment of cholesterol?
- PCSK9 is an inhibitor of LDL receptor; monoclonal antibodies have been produced to inactivate PCSK9 which protects LDL receptor so it can continue to work.
- When given with atorvastatin, can cause big decline in cholesterol
What is the role of PGE 2 -EP3 signaling in acute inflammation?
Very complex role in inflammation
What is the effects of NSAIDS on risks of GI bleeds and CVS events?
What are the risks vs benefits of NSAIDS use?
How would you decrease the GI side effects of NSAIDS apart from COX-2 selective NSAIDS?
What are the anti-platelet actions of aspirin due to?
What are the major side effects of Aspirin use at therapeutic doses?
