Pharmacology 5 Flashcards
What is haemostasis?
Arrest of blood loss from a damaged vessel at the site of injury
Initiation of haemostasis?
Vascular wall damage exposing collagen and tissue factor (TF - also known as thromboplastin)
Steps of primary haemostasis? (4)
- local vasoconstriction
- platelet adhesion
- activation and aggregation (by fibrinogen)
- activation of blood clotting (coagulation) and the formation of a stable clot (by fibrin enmeshing platelets)
What is TF also known as? What do platelets aggregate together form? What is the purpose of local vasoconstriction in haemostasis?
- Thromboplastin
- Soft plug to arrest blood loss
- Local constriction restricts blood loss
What do platelets bind to? (2)
What do activated platelets do? (2)
- Von Willebrand Factor and collagen
- Extend pseudopodia to aggregate
- Synthesise and release thromboxane A2 (TXA2)
What is the purpose of TXA2? (2)
- Binds to platelet GPCR TXA2 receptors (TP receptors) which causes mediator release – 5-hydroxytryptamine (5-HT – aka serotonin) and adenosine diphosphate (ADP)
- Act on vascular smooth muscle cell TXA2 receptors causing vasoconstriction (5-HT also does the same thing by binding to smooth muscle GPCR 5-HT receptors)
What mediators are released by TXA2 binding to TP receptors? (2)
- 5-hydroxytryptamine (5-HT, Serotonin)
* Adenosine diphosphate (ADP)
What receptors do ADP bind to? What is the purpose of ADP by TXA2 binding to TP receptors? (3)
ADP binds to platelet GPCR purine receptors (P2Y12) that:
- act locally to activate further platelets
- aggregate platelets into a ‘soft plug’ at site of injury via increased expression of platelet glycoprotein (GP IIb/IIIa) receptors that bind fibrinogen
- expose acidic phospholipids on platelet surface that initiate coagulation of blood and solid clot formation
What does increased expression of GP receptors by ADP allow? What also increases expression of GP receptors?
- Allows plasma fibrinogen to bind to receptors to form physical bridge between the platelets as part of aggregation process
- Thomboxane A2
What is the key event in the coagulation cascade?
Production of the protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot
Explain coagulation cascade (3)
- Inactive factor X converted to Xa by tenase (IXa, VIIIa)
- Inactive factor II converted to IIa by prothrombinase (Xa, Va)
- Fibrinogen converted into fibrin by thrombin to form solid clot
What coverts X to Xa? What is this? What converts II (prothrombin) to IIa (thombin)? What is this?
- Tenase - combination of IXa and VIIIa
* Prothrombinase - combination of Xa and Va
What is the purpose of thrombin? What are points of drug intervention to inhibit coagulation cascade?
- Thrombin converts fibrinogen into fibrin causing formation of solid clot
- Inhibit action of Xa or IIa (thrombin)
What is thrombosis? What are predisposing factors for thrombosis?
- Pathological haemostasis - innaproapriate activation of coagulation cascade
- Virchow’s triad - endothelial injury, turbulent flow, hypercoaguability of blood
What are features of an arterial thrombus? (2)
What are arterial thrombi treated with?
- WHITE thrombus - mainly platelets in fibrin mesh
- Forms embolus if it detaches from site of origin and often lodges in artery in the brain (stroke)
- Antiplatelet drugs
What are features of a venous thrombus? (2)
What are venous thrombi treated with?
- RED thrombus - white head, red tail, fibrin rich due to high % of erythrocytes
- Forms an embolus that usually lodges in the lung (PE)
- Anticoagulants
What is the site of action of Warfarin? Rivaroxiban? Heparin? Dabigatran?
What are these drugs classed as?
- Warfarin - blocks modification of factors X and II essential for their function
- Rivaroxiban - directly inhibits factor Xa
- Heparin - inactivates factor Xa and IIa via antithrombin III
- Dabigatran - directly inhibits factor IIa
Anticoagulant drugs
What are clotting factors II, VII, IX and X? How do they produce active factors?
- Glycoprotein precursors of the active factors IIa (thrombin), VIIa, IXa and Xa that act as SERINE PROTEASES
- Precursors are post-translationally modified (gamma-carboxylation of glutamate residues) to produce active factors
Why is vitamin K essential for coagulation cascade?
The carboxylase enzyme that mediates y-carboxylation requires vitamin K from diet (K1) and intestinal flora (K2) in its REDUCED form as an ESSENTIAL COFACTOR
What is vitamin K in its oxidised form? Reduced form? Which form is req for y-carboxylation? What enzyme is required for conversion from oxidised form to reduced form?
- Epoxide
- Hydroquinone
- Reduced form
- Vitamin K reductase
How does Warfarin block modification of factors X and II?
- Warfarin nhibits vitamin K reductase, which means hydroquinone cannot be formed
- Hydroquinone required for y-carboxylation of precursors to form active factors
What are anticoagulants used to treat/prevent? Examples? What is the risk of using anticoagulants?
- VENOUS (not arterial) thrombosis and embolism
- deep vein thrombosis (DVT)
- prevention of post-operative thrombosis
- patients with artificial heart valves
- atrial fibrillation
- All carry a significant risk of haemorrhage
What is the effect of Warfarin? Can it be used both in vivo and in vitro? How is it administered?
- renders factors II, VII, IX and X inactive
- Blocks coagulation in vivo but not in vitro
- Administered orally + is v well absorbed
What is Warfarin’s onset of action? What can be added for a more rapid anticoagulant effect? What is Warfarin’s half-life? How long must Warfarin administration be suspended before an operation?
- 2-3 days as inactive factos replace the y-carboxylated factors that are slowly cleared from the plasma
- Heparin may be added for rapid anticoagulant effect
- Has a long half-life (about 40 hr)
- Around 4-5 days as takes about 5 half-lives to be cleared from body
Why is it difficult to strike balance between anticoagulant effect and haemorrhage with Warfarin? How is the effect of Warfarin monitored? How is overdosage of Warfarin treated? (2)
- Warfarin has low therapeutic index
- Must be monitored on reg basis as international normalised ratio (INR)
- Overdosage treated with administration of Vit K1 (phytomenadione) OR IV administration of plasma clotting factors
What do factors that potentiate warfarin action do? Examples? (5)
Increase risk of haemorrhage
- Liver disease (decreased clotting factors)
- High metabolic rate (increased clearance of clotting factors)
- Drugs that inhibit hepatic metabolism of warfarin by CYP2C9
- Drugs that inhibit platelet function (e.g. aspirin, other NSAIDs)
- Drugs that inhibit reduction, or decrease availability, of vitamin K
What do factors that lessen warfarin action do? Examples? (4)
Increase risk of thrombosis
- Pregnancy (increased clotting factor synthesis)
- Hypothyroidism (decreased degradation of clotting factors)
- vitamin K consumption
- drugs that increase hepatic metabolism of warfarin
What is antithrombin III? What does Heparin do?
- Important inhibitor of coagulation - neutralises all serine protease factors in coagulation cascade by binding to their active site in 1 to 1 ratio
- Heparin binds to antithrombin III, increasing its affinity for serine protease clotting factors Xa and IIa to increase their rate of inactivation
How does heparin inhibit IIa? Xa? What do LMWHs do?
- Must bind to both AT III and IIa to inhibit IIa
- Need bind only to AT III to inhibit Xa
- Will accelerate inactivation of Xa but will not affect rate of inactivation of IIa (thrombin)
What is heparin? What is it extracted from?
- Naturally occurring sulphated glycosaminoglycan of variable molecular size
- Extracted from animal offal
What are generally preferred over heparin? Examples? When can they not be used?
- LMWHs
- e.g. enoxaparin and dalteparin
- In renal failure as they can only be excreted from body via kidneys (whereas Heparin can be metabolised by liver)
What agents act similarly to LMWHs? How is heparin administered? (2)
How are LMWHs administered?
- Fondaparinux and idabriotaparinux
- IV for immediate onset or SC (delayd 1 hr onset)
- LMWHs given SC
How is optimum dosage of heparin (NOT LMWHs) determined? What is the elimation of heparin? HMWHs?
- In vitro clotting test
- Heparin - zero order
- HMWHs - first order
What are adverse effects of heparin and LMHWs? (4)
- haemorrhage – discontinue drug, if necessary administer protamine sulfate IV (inactivates heparin)
- osteoporosis (long term treatment)
- hypoaldosteronism
- hypersensitivity reactions
What are orally active agents that act as direct inhibitors of thrombin? Xa? What are the advantages of these agents? (2) Major disadvantage??
- Thrombin inhibitors - dabigatran etexilate
- Xa - rivaroxaban
- Convenience of administration
- Predictable degree of coagulation
- Major disadvantage - NO agent available to reduce haemorrhage in overdose D:
What are rivaroxiban and dabigatran etexilate used for?
To prevent venous thrombosis in patients undergoing hip and knee replacements
What are actions of anti-platelet drugs? (4)
- Clopidogrel - blocks ADP irreversibly
- Tirofiban - blocks GP IIb/IIIa receptor on platelets
- Aspirin - blocks cyclo-oxygenase-1 (COX-1) irreversibly (prevents conversion of arachidonic acid to cyclic endoperoxides and thus synthesis of more TXA2)
- Ifetroban blocks thromboxane synthase (prevents conversion of cyclic endoperoxides to TXA2)
Note: arachidonic acid produced by platelet-synthesised TXA2
What are anti-platelet drugs used for? What is aspirin? What does it do? (2)
- Used for ARTERIAL thrombosis
- Main antiplatelet agent
- Irreversibly blocks cycoxygenase (COX) in platelets preventing TXA2 synthesis
- Also blocks COX in endothelial cells inhibiting production of antithrombotic prostaglandin I2 (PGI2)
Why does TXA2 synthesis not recover for 7-10 days once treatment with aspirin is stopped?
- Endothelial cells can synthesise new COX enzyme whereas platelets cannot
- TXA2 synthesis does not recover until affected platelets are replaced (7-10 days)
How is aspirin administered? What patients is it used in? Adverse effects? (2)
- Orally
- Thromboprophylaxis in patients at high cardiovascular risk
- GI bleeding and ulceration
What does clopidogrel do? What patients used for? Administered how? What happens when used in combo with apsirin?
- Links to P2Y12 receptor by a disulphide bond producing irreversible inhibition
- Patients intolerant to aspirin
- Orally
- When combined with aspirin has a synergistic action
How is tirofiban administered? Used in what patients? With what other drugs?
- IV
- Prevent MI in high risk patients with unstable angina
- Used with heparin and aspirin
What cascade opposes coagulation cascade? Explain cascade (2)
Fibrinolytic cascade
- Plasminogen activated to form plasmin by endogenous tissue plasminogen activator (tPA)
- Plasmin breaks down fibrin into fibrin fragments resulting in clot lysis
What are fibinolytics used for? (2) Administered? What can give an additive beneficial effect?
- To reopen occluded arteries in acute MI or stroke
- Less frequently in PE or venous thrombosis
- IV
- If combined with aspirin
What are examples of fibrinolytic drugs? (3) What do they do?
- Streptokinase, alteplase and duteplase
* Activate plasminogen
What is streptokinase? What is it used for? Administered? What are the problems with streptokinase?
- Don’t be fooled by its name - it is not an enzyme, it’s a protein extracted from strep cultures
- Used to reduce mortality in acute MI
- IV or intracoronary
Problems
- Action blocked after 4 days by generation of antibodies
- May cause allergic reactions (so can’t be given to patients with recent strep infections)
What are alteplase and duteplase? Administered? Advantage over streptokinase? Adverse effects??
- Recombinant tissue plasminogen activators (rt-PA)
- IV since short half-life
- Does not cause allergic reactions like streptokinase
- Adverse effect - haemorrhage (controlled by oral tranexamic acid that inhibits plasminogen activation)
