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Drugs: From Molecules to Man - Lecture 16 (23/03/2018)
Drugs Affecting Blood Coagulation, Platelet Aggregation and Fibrinolysis
Haemostasis is the prevention of blood loss after damage to a vessel through the formation of an external blood clot.
This occurs in 2 steps: Coagulation and Platelet aggregation.
Vasoconstriction also occurs in Haemostasis to reduce the blood flow.
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing blood flow.
This can be pathological and usually leads to DVT (Deep Vein Thrombosis), an Embolism,
Stroke or a heart attack.
There are many drugs that are used to prevent and reverse inappropriate, or pathological blood clotting.
Blood clotting is, of course, a normal and vital physiological process that helps prevent blood loss after an injury that results in vessel damage.
It can be divided into two main components: coagulation (the coagulation cascade) and platelet aggregation.
Vasoconstriction also plays a role in preventing blood loss.
Together, these processes are responsible for haemostasis. When blood clots form inappropriately and in unwanted places (thrombosis), they can cause serious health problems (eg: deep vein thrombosis, stroke and heart attacks).
A thrombus is a pathogenic blood clot, made up of the same components as a normal haemostatic blood clot, namely a meshwork made from the protein fibrin, aggregated platelets and blood cells that become imbedded in it.
A thrombus normally begins attached to a vessel wall. It can impede blood flow to the tissues, reducing their oxygen supply and if this happens in the heart, it can result in a heart attack.
Thrombosis is often classified according to the type of vessel it occurs in: venous or arterial.
The blood clotting processes that are involved in these two types of thrombosis differ somewhat and this can alter the approach to drug therapy.
Venous Thrombosis - In venous thrombosis the coagulation phase plays a major role.
Arterial Thrombosis - In arterial thrombosis platelet aggregation has a more important role that coagulation, although coagulation is still involved.
These factors may influence the approach towards which drugs are used. Embolus
An embolus is a complication of a thrombus. It is where the thrombus, or a fragment of it,
detaches from the vessel wall and is carried through the circulation to other tissues. It can then lodge there and impede or halt blood flow.
This is a serious situation that can result in tissue death.
The results depend on the place where the embolus lodges, for example, pulmonary embolism causes shortness of breath, circulatory disturbances, chest pain and cyanosis.
Whilst, emboli lodging in the brain result in ischaemic stroke and in the heart, it causes a myocardial infarction and if the circulation to a limb becomes blocked by an embolism, limb infarction may result. This can cause necrosis of tissues in the limb.
Each of these disorders has the potential to lead to death.
Acute Coronary Syndrome (ACS)
ACS is a group of disorders characterised by severe chest pain radiating to the left arm and jaw.
ACS is not relieved by rest, and can last more than a few minutes.
These can be split into three main categories:
NSTEMI (Non-ST elevated myocardial infarction).
STEMI (ST elevated myocardial infarction).
All three of these involve cardiac ischaemia and may involve tissue damage.
All three of these are caused by coronary artery thrombosis.
The key differences between STEMI, NSTEMI and UA are that in STEMI there is a complete blockage of the artery.
Treatment of ACS
There are numerous treatments of ACS including:
Opioids to reduce pain.
Beta blockers and GTNs to reduce the cardiac workload
Aspirin (antiplatelet), Ticagrelor/clopidogrel
(antiplatelet), Heparins (antiplatelet), Atorvastatinto to prevent further thrombosis.
PCI; CABG; Thrombolysis for reperfusion, which is the action of restoring the flow of blood to an organ or tissue.
Therapeutic Uses Primary and Secondary Prevention:
Prevent heart attacks.
Reduce damage after heart attacks or strokes (fibrinolysis only).
In patients with atrial fibrillation.
After heart valve replacement surgery.
Aim of Drug Interventions?
Drug interventions are used to inhibit thrombus formation, without preventing normal haemostasis.
It is clear that normal haemostasis should be disrupted as little as possible, as the consequences of completely inhibiting blood clotting would be a rapid and fatal haemorrhage.
What we need to do then is to prevent, or reverse, thrombus formation, whilst leaving haemostasis largely intact.
Targets for modifying thrombosis process?
There are three main therapeutic strategies aimed at preventing or reversing thrombosis.
As mentioned previously, the choice of drug therapy depends on the site of thrombosis.
It is possible to:
Modify coagulation (most successful in venous thrombosis).
Modify platelet aggregation (important in arterial thrombosis).
Modify clot, thrombus breakdown (after prophylaxis fails).
The drugs acting on the clotting cascade are generally termed anticoagulants (as opposed to anti-platelet drugs), but note that this term may also be applied to any drugs that interfere with blood clotting.
The initiating factor in the clotting cascade is the damage to the vessel.
Coagulation is a complex pathway involving a series of enzymes and co-factors.
The components are present in the blood in an inactive state and some are activated by cleaving parts of their structure, whilst other components in the cascade are proteolytic enzymes.
The cascade ends with the activation of thrombim, which converts soluble fibrinogen to insoluble fibrin.
There are two main pathways that the coagulation cascade can be initiated, both of which require calcium ions.
The intrinsic pathway, which happens when blood contacts a surface such as glass, gets its name because all of the components are present in blood.
The extrinsic pathway requires the contribution of factors from outside the blood. The latter is by far the most important for the formation of thrombi.
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