Anticoagulent and antithrombin drugs Lecture 6 Flashcards
Describe thrombosis
Arterial thrombosis tends to cocur in small vessels in the heart and brain, occurs in high flow conditions
Venuous thrombosis occurs in veins particaullay in the legs, flow conditions are a lot slower
Pateitns with cancer have an increased risk of venous thromoembolism (VTE)
Describe primary and secondary haemostasis
Primary - formation of the platelet aggregate, within 5 mins of bleeding
Secondary - formation of sstable fibrin clot, within 10 mins of bleeding
Both happen at same time
Platelets are pushed to the vessel wall which is lined with vascular epitehlium. These epitherlum inhibit platelets. Platelets monitor intergrity of the vesselwall. Within an injured blood vessel, collagen is exposed aswell as vWF released. PLatelets slow down and roll across the area. vWF acts as a brinding protein which mediates bridging of platelts to collagen. Allows platelets to roll and adhere, become activated and release their granules which promote recruitment of other platelets. Thrombis seals area of damage due to the platelet lug stabilised by fibrin. PLatelets can recuit clotting molecules onto surface which generate thrombin which converts factor-1 into insoluble fibrin (stabilises thrombus)
How to platelets get activated
VWF in plasma and vessel wall
- Collagen exposed to the blood leads to VWF bridging with receptor gp11b
- The platelets begins rolling on the WVF and slow down via these interactions
VWF
Two conformations
Resting - wound up in ball
Activation - when bound to vessel wall - unwinds and exposes binding sites for platelet gb1b receptor
-Becomes stabilised if platelets adhere, spread and aggregate when in more exposure of subendothelial collagen
Describe platelet adhesion
vVF acts as a bridge between collagen and GP1b/IX/V Integrin alpha2-beta1 and GPVI binds to collagen
Receptors on platelets for collagen
- GP6
- Alpha2 beta1
- Platelets slow down and directly bind to collagen through these receptors
- Results in firm adhesion and platelet activation
- Once levels of Ca2+ increase in platelet structural/biochemical changes occur
- Triggers secretion of granules
Describe the amplification mechanisms for platelet function
ADP, TXA2, 5HT released from platelet
Dense granules feeds back to act in platelets to activate them further by increasing intracellular Ca which increases secretion
- Dense granules contain ADP and serotonin which are released locally at high concentrations
- Generate thromboxaneA2
- All have GPCR on surface to amplify initial signal on this and other platelets recruited
- Thrombin generated through coagulation system helps in this loop
Thromboxane made from phospholipids (PLA2, Ca)➡️ arachadonic acid (COX-1)➡️ cyclic endoperoxidases (Tx-synthase)➡️ thromboxane A2
-Targetting COX-1 with aspirin reduces risk of clotting by inhibiting it in all platelets to stop the ability of platelets to make thromboxane and feedback through amplification
How does ATP affect platelet activation?
Binding of P2X1 receptor results in elevation of intracellular platelet Ca2+
Binding P2Y1/P2Y12/GPCR results in platelet shape change and activation
Drugs can target P2Y12 receptor e.g. Clopdogrel
-This stops platelet aggregation
How does Clopdogrel perform its action?
- Clopidogrel undergoes metabolism in liver by cytochrome P450
- This develops active metabolite which can bind to P2Y12 irreversibly on platelets and stop aggregation
- Some patients have CP450 problems and cannot metabolise it to its active form
- Ticagerlor is a direct drug that requires no metabolism - used to prevent secondary thrombosis
Describe platelet secretion
ADP, Ca, 5HT from dense granules
Fibrinogen, beta-Thromboglobulin, VWF, FV, PDGF, multimerin from alpha granules
ADP signalling- acts in P2Y12 and P2Y1 to activate GI, G12 and Gq down regulates AC to increase ADP and up-regulates PLC which causes aggregation and shape change
Describe platelet aggregation
Integrin alphaIIb-beta3 on platelet surface membranes bridged by fibrin and fibrinogen
- When activated, inside-out signalling activates integrin which causes an conformational change which allows binding to clotting factor 1
- Fibrinogen forms bridges between activated forms of this platelet (Tirofiban - drug that blocks this)
Scramblase catalyses the movements of phosphotidylserine (-ve lipids on membrane) from the cytosolic leaflet to the outer leaflet of the platelet cell surface membrane - Ca and Vitamin K dependant coagulation factors will bind to -vely charged biut resulting in efficeient thrombin generation on surface of platelet.
Lost some drugs that affect amplification mechanisms
Effective in preventing thrombotic complications
Example:
- COX-1 inhibitors e.g. aspirin
- ADP receptor antagonists e.g clopidogrel, ticagrelor
- Gp11b antagonist e.g. tirofiban
List some drugs that interfere with ADP signalling?
Clopidogrel Prasugrel- pro drugs
Ticagrelor- direct antagonist
Cangrelor Interfer with the P2Y12 receptor- antagonists
List some drugs involved with platelet aggregation
Abciximab
Eptifibatide
Tirofiban
Affect integrin alphaIIb-beta3, fibrinogen/fibrin/VWF binding- antagonists
Describe the ideal anticoagulant
Oral
A wide therapeutic index
Predictable pharmacokinetics and dynamics
Rapid onset
an antidote
Minimal non-anticoagulant side effects
Minimal interactions with other drugs and food
What is vitamin K for in anticoagulents?
- Needed to perform essential PT modifications of key clotting factors
- Vit K antagonists can therefore be used as anticoagulants i.e. warfarin (inhibits II, VII, IX, X)
What is heparin and how does it work?
-Anticoagulant that prevents the formation of blood clots - used to treat and prevent blood clots in veins, arteries and lungs
Mechanism:
- Binds antithrombin III
- Inactivates thrombin and FXa
