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Cardiovascular > Pharmacology 5 > Flashcards

Pharmacology 5 Flashcards

1
Q

What is haemostasis?

A

Arrest of blood loss from a damaged vessel at the site of injury

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2
Q

Initiation of haemostasis?

A

Vascular wall damage exposing collagen and tissue factor (TF - also known as thromboplastin)

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3
Q

Steps of primary haemostasis? (4)

A
  • 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)
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4
Q

What is TF also known as? What do platelets aggregate together form? What is the purpose of local vasoconstriction in haemostasis?

A
  • Thromboplastin
  • Soft plug to arrest blood loss
  • Local constriction restricts blood loss
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5
Q

What do platelets bind to? (2)

What do activated platelets do? (2)

A
  • Von Willebrand Factor and collagen
  • Extend pseudopodia to aggregate
  • Synthesise and release thromboxane A2 (TXA2)
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6
Q

What is the purpose of TXA2? (2)

A
  • 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)
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7
Q

What mediators are released by TXA2 binding to TP receptors? (2)

A
  • 5-hydroxytryptamine (5-HT, Serotonin)

* Adenosine diphosphate (ADP)

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8
Q

What receptors do ADP bind to? What is the purpose of ADP by TXA2 binding to TP receptors? (3)

A

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
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9
Q

What does increased expression of GP receptors by ADP allow? What also increases expression of GP receptors?

A
  • Allows plasma fibrinogen to bind to receptors to form physical bridge between the platelets as part of aggregation process
  • Thomboxane A2
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10
Q

What is the key event in the coagulation cascade?

A

Production of the protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot

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11
Q

Explain coagulation cascade (3)

A
  • 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
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12
Q

What coverts X to Xa? What is this? What converts II (prothrombin) to IIa (thombin)? What is this?

A
  • Tenase - combination of IXa and VIIIa

* Prothrombinase - combination of Xa and Va

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13
Q

What is the purpose of thrombin? What are points of drug intervention to inhibit coagulation cascade?

A
  • Thrombin converts fibrinogen into fibrin causing formation of solid clot
  • Inhibit action of Xa or IIa (thrombin)
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14
Q

What is thrombosis? What are predisposing factors for thrombosis?

A
  • Pathological haemostasis - innaproapriate activation of coagulation cascade
  • Virchow’s triad - endothelial injury, turbulent flow, hypercoaguability of blood
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15
Q

What are features of an arterial thrombus? (2)

What are arterial thrombi treated with?

A
  • 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
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16
Q

What are features of a venous thrombus? (2)

What are venous thrombi treated with?

A
  • RED thrombus - white head, red tail, fibrin rich due to high % of erythrocytes
  • Forms an embolus that usually lodges in the lung (PE)
  • Anticoagulants
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17
Q

What is the site of action of Warfarin? Rivaroxiban? Heparin? Dabigatran?
What are these drugs classed as?

A
  • 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

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18
Q

What are clotting factors II, VII, IX and X? How do they produce active factors?

A
  • 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
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19
Q

Why is vitamin K essential for coagulation cascade?

A

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

20
Q

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?

A
  • Epoxide
  • Hydroquinone
  • Reduced form
  • Vitamin K reductase
21
Q

How does Warfarin block modification of factors X and II?

A
  • Warfarin nhibits vitamin K reductase, which means hydroquinone cannot be formed
  • Hydroquinone required for y-carboxylation of precursors to form active factors
22
Q

What are anticoagulants used to treat/prevent? Examples? What is the risk of using anticoagulants?

A
  • 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
23
Q

What is the effect of Warfarin? Can it be used both in vivo and in vitro? How is it administered?

A
  • renders factors II, VII, IX and X inactive
  • Blocks coagulation in vivo but not in vitro
  • Administered orally + is v well absorbed
24
Q

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?

A
  • 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
25
Q

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)

A
  • 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
26
Q

What do factors that potentiate warfarin action do? Examples? (5)

A

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
27
Q

What do factors that lessen warfarin action do? Examples? (4)

A

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
28
Q

What is antithrombin III? What does Heparin do?

A
  • 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
29
Q

How does heparin inhibit IIa? Xa? What do LMWHs do?

A
  • 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)
30
Q

What is heparin? What is it extracted from?

A
  • Naturally occurring sulphated glycosaminoglycan of variable molecular size
  • Extracted from animal offal
31
Q

What are generally preferred over heparin? Examples? When can they not be used?

A
  • 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)
32
Q

What agents act similarly to LMWHs? How is heparin administered? (2)
How are LMWHs administered?

A
  • Fondaparinux and idabriotaparinux
  • IV for immediate onset or SC (delayd 1 hr onset)
  • LMWHs given SC
33
Q

How is optimum dosage of heparin (NOT LMWHs) determined? What is the elimation of heparin? HMWHs?

A
  • In vitro clotting test
  • Heparin - zero order
  • HMWHs - first order
34
Q

What are adverse effects of heparin and LMHWs? (4)

A
  • haemorrhage – discontinue drug, if necessary administer protamine sulfate IV (inactivates heparin)
  • osteoporosis (long term treatment)
  • hypoaldosteronism
  • hypersensitivity reactions
35
Q

What are orally active agents that act as direct inhibitors of thrombin? Xa? What are the advantages of these agents? (2) Major disadvantage??

A
  • Thrombin inhibitors - dabigatran etexilate
  • Xa - rivaroxaban
  • Convenience of administration
  • Predictable degree of coagulation
  • Major disadvantage - NO agent available to reduce haemorrhage in overdose D:
36
Q

What are rivaroxiban and dabigatran etexilate used for?

A

To prevent venous thrombosis in patients undergoing hip and knee replacements

37
Q

What are actions of anti-platelet drugs? (4)

A
  • 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

38
Q

What are anti-platelet drugs used for? What is aspirin? What does it do? (2)

A
  • 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)
39
Q

Why does TXA2 synthesis not recover for 7-10 days once treatment with aspirin is stopped?

A
  • Endothelial cells can synthesise new COX enzyme whereas platelets cannot
  • TXA2 synthesis does not recover until affected platelets are replaced (7-10 days)
40
Q

How is aspirin administered? What patients is it used in? Adverse effects? (2)

A
  • Orally
  • Thromboprophylaxis in patients at high cardiovascular risk
  • GI bleeding and ulceration
41
Q

What does clopidogrel do? What patients used for? Administered how? What happens when used in combo with apsirin?

A
  • Links to P2Y12 receptor by a disulphide bond producing irreversible inhibition
  • Patients intolerant to aspirin
  • Orally
  • When combined with aspirin has a synergistic action
42
Q

How is tirofiban administered? Used in what patients? With what other drugs?

A
  • IV
  • Prevent MI in high risk patients with unstable angina
  • Used with heparin and aspirin
43
Q

What cascade opposes coagulation cascade? Explain cascade (2)

A

Fibrinolytic cascade

  • Plasminogen activated to form plasmin by endogenous tissue plasminogen activator (tPA)
  • Plasmin breaks down fibrin into fibrin fragments resulting in clot lysis
44
Q

What are fibinolytics used for? (2) Administered? What can give an additive beneficial effect?

A
  • To reopen occluded arteries in acute MI or stroke
  • Less frequently in PE or venous thrombosis
  • IV
  • If combined with aspirin
45
Q

What are examples of fibrinolytic drugs? (3) What do they do?

A
  • Streptokinase, alteplase and duteplase

* Activate plasminogen

46
Q

What is streptokinase? What is it used for? Administered? What are the problems with streptokinase?

A
  • 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)
47
Q

What are alteplase and duteplase? Administered? Advantage over streptokinase? Adverse effects??

A
  • 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)

Cardiovascular (28 decks)

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