Derek warren pharmacology (anti-platelets, coagulation, fibirnolytics etc) Flashcards
(53 cards)
What is haemostasis?
The cessation of bleeding from a damaged blood vessel (arrest of blood loss)
What happens when LDL cholesterol accumulates in the artery (process of atherosclerosis)?
- The LDL cholesterol accumulates in the endothelial layer of the artery wall
- LDL becomes oxidised, this triggers endothelial cells to express markers for immune cells
- immune cells pass into the basement membranes e.g. macrophages and foam cells
- These cells trigger smooth muscle cells to migrate to the area and proliferate to form a fibrous cap
- This fibrous cap blocks the entry of cells and debris from the blood
- Overtime, this thick cap will thin due to death of smooth muscle- the plaque will become unstable and can rupture
- This exposes the contents of the atherosclerotic plaque to the blood e.g. lipids and debris
- this leads to a cascade of events- clotting, blockages of arteries = heart attacks or strokes
What happens when we develop a wound?
Wound is formed
Leads to vasoconstriction of blood vessels to prevent excess blood loss
Platelet activation and increased adhesion of platelets to the vessel wall
Formation of a haemostat plug (coagulation)
Fibrinolytics will the breakdown the coagulation when ready
What is the main difference in an atherosclerotic coagulation cascade?
There is NO bleeding
= Thrombus: the pathological formation of a clot in the vasculature in the absence of bleeding.
What is Thrombosis?
the pathological formation of a clot in the vasculature in the absence of bleeding.
Requires prevention drugs
What blood factors activate platelets in the extra-cellular matrix?
- Von willebrand factor
- Collagen
What factors prevent platelet activation/aggregation?
Nitric oxide (NO)
Prostacyclin
How do we inhibit platelets forming blood clots?
Target factors that promote activation and aggregation:
Thromboxane A2
ADP
Collagen
Von Willebrand factor
Or stalemate factors that prevent a + a:
Prostacyclin
Nitric oxide
What are examples of anti-platelet drugs?
Drugs that decrease aggregation or inhibit thrombus formation:
Aspirin
Clopidogren
Ticragrelor
Glycoprotein iib/iiiab inhibitors e.g. tirotiban, eptifbatide, abciximab
How are platelets adhered to eachtoher?
Binded by fibrinogen that binds to glycoprotein iib/iiia receptors on both platelets
How does aspirin work as an anti-platelet?
- Aspirin irreversibly inhibits Cyclooxygenase 1 and 2 (COX-1 & COX-2)
Irreversible inhibition of COX-1 in platelets:
This prevents the production of Thromboxane A2 from Arachidonc acid
- Reduces platelet aggregation as thromboxane normally promotes aggregation
ALSO
Irreversible inhibition of COX-2 in endothelial cells:
- This reduces the formation of prostacyclin
- Prostacyclin usually prevents aggregation (so by inhibiting = increased platelet aggregation)
SO TOGETHER THEY HAVE A NET EFFECS OF ZERO!
BUT this works as:
Endothelial cells can synthesise new cox-2 as they have a nucleus (platelets don’t so can’t synthesise new cox-1) = more cox-2 = more prostacyclin overtime = more preventing aggregation
How do the thienopyridines (clopidogrel, prasugrel) work?
They inhibit ADP-induced aggregation by inhibiting the P2Y12 receptor (purinergic receptor) which normally binds ADP and triggers platelet activation- by blocking this receptor- prevents ADP binding = decreased platelet activation and aggregation
How does Ticagrelor work?
Is a nucleotide analogue- mimics adenosine
- It blocks the P2Y12 ADP receptors by acting as an allosteric inhibitor (doesn’t directly compete for binding with adp = reversible)
How do glycoprotein iib/iia receptor antagonists work?
Prevent the binding of fibrinogen to allow aggregation by occupying the gp iib/iiia receptors that fibrinogen uses to form bridges between adjacent platelets.
What is the coagulation cascade?
The formation of a fibrin clot
Process:
leads to conversion of of soluble fibrinogen to insoluble fibrin
2 pathways:
INTRINSIC: Exposure to abnormal surface e.g. glass
All components are present in blood
EXTRINSIC: Switched on in presence of tissue damage- release tissue factor
Some components from outside of blood
Both paths converge at factor 10- cleaved to 10a
= cleavage of prothrombin to thrombin. Thrombin cleaves fibrinogen to small insoluble fibrin fragments
- is activated by factor x111- further strengthens fibrin links
= Fibrinogen –> Fibrin –> Polymer formed- CROSS-LINKED fibrin clot
LOOK AT DIAGRAM
What are the different treatment options depending on whether the patient has a red thrombi or white thrombi (platelet-rich)?
White= antiplatelets
Red = anticoagulants
What are some of the anti-coagulants available?
- injectable e.g heparin
- oral e.g. warfarin
What do heparin activate?
Activates antithrombin III
- This inactivates thrombin and factor x a (10a)
What are the types of heparins?
Unfractionated
low molecular weight
UFH- inhibits thrombin and Xa
LMWH- Mainly habits factor Xa- more predictable
What are the advantages of using low-molecular weight heparins over unfractioned heparins?
- LMWH bind to endothelial and plasma proteins = increases bioavailability = more available to function
- Dose is more predictable as it only affects factor Xa
- Decreased dose frequency
- Decreased side effects as only targets 1 factor
- Can be used at home = more convenient
How does warfarin work?
Competitively inhibits vitamin K reductase and therefore inhibits the formation of factors II, VII, IX & X (as vitamin K is essential for synthesis of coagulation factors). Also anticoagulation protein C and it cofactor protein S
Does warfarin have effects on clots existing before treatment is initiated?
NO- as it acts indirectly- it reduces clotting factors so will only prevent new clots
Is warfarin ok to be used in pregnancy or breastfeeding?
Warfarin is not used in pregnancy or breastfeeding as it is lipophilic and can cross the placenta and also can enter breastmilk - can be harmful to baby
What are fibrinolytic drugs used for?
Used to resolve and remove clots by degrading fibrin via plasmin enzymes.
