PBL 5 - PHARMACOLOGY - acute coronary syndromes Flashcards
stable angina is just caused by what?
atherosclerosis
what is the fundamental difference between stable angina and ACS?
in ACS, blood vessels are nit just partially blocked by an atherosclerotic plaque, there is also an involvement of a blood clot (thrombus)
+ not relieved by rest
what are the 3 main categories of ACS?
- unstable angina
- NSTEMI
- STEMI
what is the most acute form of ACS?
STEMI
how do you diagnose which ACS a patient is suffering from?
- ECG — ST elevation = STEMI
- NSTEMI or unstable angina — blood tests — in NSTEMI there is tissue damage to cardiac muscle — releases cardiac specific proteins into the blood
- no blood markers = unstable angina
what can be used to relieve pain in ACS?
opioids
what can be used to reduce cardiac workload/improve blood supply?
- beta blockers - same as in stable angina —> decrease HR and reduce force of contraction, and improve blood supply by lengthening diastole
- GTN (also reduces pain) — causes peripheral blood vessel dilation to reduce cardiac workload, and dilates collateral vessels
how do beta blockers reduce risk of dysthymias?
by reducing sympathetic stimulation
name 2 anti-platelet drugs
- aspirin
- ticagrelor/clopidogrel
name 4 drugs to prevent further thrombosis
- aspirin
- ticagrelor/clopidogrel
- heparins
- atorvastatin
platelets are fragments of cells derived from what?
bone marrow cells called megakaryocytes
what do platelets lack?
a nucleus — they are fragments of cytoplasm
what does damage to endothelium expose?
collagen and glycoproteins
what is the 1st step in platelet aggregation and activation?
adherance to collagen and other glycoproteins through their receptors
the activation of collagen and glycoprotein receptors does what?
activates platelets — enables platelets to change shape (dramatically - more star shaped)
what do activated platelets release into the blood to activate other platelets?
TXA2 and ADP
name 3 stimuli for platelet aggregation/activation
- thrombin
- ADP
- TxA2
what is TxA2 synthesised from?
arachidonic acid by cyclooxygenase (COX)
explain platelet aggregation/activation
- platelets synthesise TxA2 when activated and release it — enhances expression of glycoprotein 2B and 3A receptors on the platelet membrane
- these receptors can bind fibrinogen (precursor of fibrin)
- receptors on the membranes of adjacent platelets can actually bind the same fibrinogen molecule — allows platelets to link together — become aggravated
- clump of platelets form — continue to release ADP and TXA2 — activate other platelets — cross link to those additional platelets
what is released to stop this chain reaction from turning the blood jelly-like?
prostacyclin is released from the intact endothelium
what does prostacyclin do?
has the opposite effect of TXA2 — it inhibits platelet activation
how does TXA2 increase platelet aggregation?
by decreasing amount of cAMP in the platelet
how does prostacyclin decrease platelet aggregation?
by increases cAMP in platelet
why does the TXA2 receptor not directly decrease cAMP levels in the platelet?
it is coupled to Gq
what is COX1?
- “housekeeping gene”
- expressed in most cells
- involved in synthesis of TXA2 and prostacyclin
what is COX2?
- expressed mainly in inflamed tissues
- it is the target of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (and aspirin where it is used as an analgesic and anti-inflammatory)
what is COX3?
has a frameshift mutation and so doesn’t produce an active enzyme
NSAIDs produce their anti-inflammatory effects by acting on COX2 and what?
COX2 but also COX1 — this is what produces most of the side effects (eg. worsening GI tract ulcers)
what are coxibs?
- a group of COX2 selective NSAIDs that are analgesic and anti-inflammatory and avoid the GI tract problems of non-selective drugs
- however now not on the market as they can increase rate of serious CVD problems
describe aspirin
= inhibitor of cyclooxygenases
- irreversibly blocks platelet COX enzyme, reducing TxA2 synthesis
- low doses of aspirin used to avoid reducing enzyme in endothelium (source of prostacyclin)
- aspirin alters balance between platelet TXA2 and endothelial prostacyclin (PGI2)
what happens if we irreversible inhibit COX in platelets and why?
not able to make any more enzyme as they have no nucleus
what are some unwanted effects of aspirin?
- extended bleeding time
- indigestion
- allergy (rare)
- may provoke asthma attacks
- Reye’s syndrome (under 16s) — liver and brain damage, aspirin use during viral illness
what is a signalling molecule produced by vascular endothelium that inhibits platelet activation?
prostacyclin
what 2 drugs act via modulating expression of glycoproteins IIb/IIIa receptors?
clopidogrel and ticagrelor
what does clopidogrel do?
it is a prodrug that inhibits glycoprotein IIb/IIIa receptor expression on platelets by blocking the ADP receptor irreversibly
what does ticagrelor do?
allosterically inhibits the ADP receptor
clopidogrel is a prodrug that needs to be metabolised by what to become active?
CYP2C19
why do around 30% of the population not respond well to clopidogrel?
around 30% of the population have a low functioning allele for CYP2C19
what are some unwanted effects of clopidogrel and ticagrelor?
- extended bleeding time
- GI tract problems (nausea, indigestion etc)
- headaches, dizziness
- gout (ticagrelor)
- breathlessness (ticagrelor)
what are 2 unwanted effects of ticagrelor but not clopidogrel?
gout and breathlessness
what does dipyridamole do?
- phosphodiesterase (PDE3) inhibitor
- prevents the breakdown of cAMP in platelets
- raises cAMP levels — prevent aggregation of platelets
what are some unwanted effects of dipyridamole?
- GI tract problems (nausea, indigestion etc)
- headaches, dizziness
- muscle pain
- flushing/feeling hot (vasodilator)
- can precipitate/worsen angina
what is currently only drug approved in the UK for prevention of atherothrombotic events in patients with ACS or who have had a MI?
ticagrelor
describe coronary steal after dipyridamole
- healthy vessels dilated but no dilation of the collateral vessel
- blood vessel with atherosclerotic plaque has a higher resistance than healthy vessels so therefore the dilation of healthy vessels dilates blood away from partially occluded vessel
- reduces blood flow to ischaemic tissue even further = coroanry steal
what is plasmin?
proteolytic enzyme that breaks down fibrin to fibrin degradation products
what is the inactive precursor of plasmin in circulation?
plasminogen
plasminogen has to be cleaved by what to be activated?
tissue plasminogen activator
what 3 drugs used in thrombolysis act by supplementing the tissue plasminogen activator?
reteplase, alteplase, streptokinase
reteplase vs alteplase vs streptokinase
- reteplase is slightly mutated to have better stability in circulation
- alteplase is a recombinant version
- reteplase and alteplase are very similar to tissue plasminogen activator
- streptokinase is a bacterial enzyme — used less than other 2
- all work if give quickly —useful for dissolving clots
- 4 1/2 hour window to initiate thrombolysis before the clot sits, matures and changes its structure so it is resistant to the thrombolytics
is PCI or thrombolysis used more in the initial stages of HA treatment?
PCI
what is a risk of thrombolyis?
haemorrhage
- alteplase
- plasmin
- aspirin
- COX1
- thromboxane A2
dipyridamole is an anti platelet drug that primarily acts as what?
an inhibitor of phosphodiesterase
what does the block of platelet ADP receptors by clopidogrel inhibit?
glycoprotein receptor mediated aggregation
