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Pharmacology > Antiplatelets, anticoagulants and thrombolytic drugs > Flashcards

Antiplatelets, anticoagulants and thrombolytic drugs Flashcards

1
Q

What is primary haemostasis?

A

Arrest of blood loss from a damaged blood vessel

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2
Q

What does vessel damage lead to?

A

Local vasoconstriction

Adhesion, activation and aggregation of platelets at site of injury - platelet aggregation brings more platelets and they activate to form a haemostatic plug (bands of fibrinogen-linked platelets)

Activation of blood clotting and formation of a stable clot (by FIBRIN)

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3
Q

How does damaged blood vessel initiate haemostasis?

A

Damage to endothelial wall exposes sub-endothelial matrix, containing COLLAGEN and TISSUE FACTOR (TF, thromboplastin)

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4
Q

Steps in primary haemostasis, leading to activation of platelets?

A
  1. Exposed collagen binds von Willebrand factor (vWF), to which glycoprotein Ib receptors on platelets also bind
  2. Binding of platelet is stabilised by DIRECT platelet-collagen interaction, via α2β1 and glycoprotein VI receptors - this results in platelet ACTIVATION
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5
Q

What does the activated platelet do in primary haemostasis?

A
  1. Activated platelet:

Changes shape (extsnds pseudopodia) - allows platelets to interact with one another

Synthesises thromboxane A2 from oxidation of arachidonic acid, mediated by the enzyme cyclo-oxygenase

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6
Q

Steps following platelet activation?

A
  1. Thromboxane A2 binds to platelet GPCR TXA2 receptors causing:
    Mediator Release
    5-hydroxytryptamine (AKA serotonin) and ADP are released from dense granules
    vWF and factor V from α-granules

Direct and indirect vasoconstriction; indirect via release of 5-hydroxytryptamine and direct as 5-HT itself is a vasoconstrictor

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7
Q

Functions of ADP released via platelet activation?

A

ADP binds to platelet GPCR P2Y12 RECEPTORS to:

Activate other platelets

Increase expression of glycoprotein IIb and IIIa receptors that bind fibrinogen (this aggregates platelets into a “soft” plug)

Exposing acidic phospholipids on platelet surface - facilitates clot formation

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8
Q

Pivotal event in coagulation?

A

Complex cascade that involves proenzymes are converted to active enzymes, e.g: X to Xa

Pivotal event is the production of the protease THROMBIN (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot

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9
Q

Phases of coagulation?

A

Initial phase
Amplification phase
Propagation phase

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10
Q

Describe the initial phase of coagulation

A
  1. Cells bearing tissue factor (TF, thromboplastin), in the subendothelial matrix, are exposed to factor VIIa from the plasma, forming a COMPLEX (TF:VIIa)
  2. TF:VIIa complex activates factor X, to Xa, which, in combo with its co-factor, Va, converts prothrombin (factor II) to thrombin (factor IIa)
  3. Now amplification can occur on platelet surfaces
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11
Q

Describe the amplification phase of coagulation

A

Occurs at platelets:

  1. Thrombin (factor IIa) activates further platelets and causes the release of factor V from the α-granules of the platelet cytoplasm, so Va forms
  2. Thrombin also liberates factor VIII from vWF (to which it is normally bound) and activates it at the platelet membrane, to form VIIIa
  3. Now propagation can occur
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12
Q

Describe the propagation phase of coagulation

A
  1. Factor XIa (activated by thrombin), or TF:VIIIa, activate factor IX - forms a complex with factor VIIIa which powerfully activates factor X (more so than TF:VIIa); the complex that activates factor X is termed tenase at the platelet membrane
  2. Factors Xa ad Va as a complex bind to prothrombinase at the platelet membrane (converting prothrombin, factor II, to thrombin or factor IIa)
  3. Thrombin cleaves fibrinogen, forming fragments that spontaneously polymerise to form fibrin
  4. Factor VIIIa (activated by thrombin) cross-links the polymer to form a fibrin fibre network and a solid clot
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13
Q

What is thromboses?

A

PATHOLOGICAL haemostasis - a haemostatic plug formed in the absence of bleeding

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14
Q

Predisposing factors to thrombosis?

A

Virchow’s triad:
Injury to vessel wall, e.g: ruptured atheromatous plaque

Abnormal blood flow, e.g AF can cause blood flow stasis

Increased coagulability of blood, e.g: due to some contraceptive pills and also in pregnancy

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15
Q

2 types of thrombus?

A

Arterial thrombus

Venous thrombus

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16
Q

Describe an arterial thrombus

A

WHITE thrombus - mainly platelets in a fibrin mesh (few rbcs)
Forms an embolus if it detatches from its site of origin and often lodges in a brain artery (stroke), or other organ

Tend to arise in left heart, carotid artery etc

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17
Q

Describe a venous thrombus

A

RED thrombus - white head, jelly-like red tail, FIBRIN RICH

If it detaches, forms an embolus that usually dislodges in the lung (PE)

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18
Q

Differences in treatment of arterial and venous thrombi?

A

Arterial - ANTI-PLATELETS mainly

Venous - ANTI-COAGULANTS mainly

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19
Q

How are many clotting factors activated?

A

Clotting factors II (prothrombin), VII, IX and X are glycoprotein precursors of the active factors II a (thrombin), VIIa, IXa and Xa that act as SERINE PROTEASES

Remember: the precursors that are formed are inactive and require a post-translational modification (γ-CARBOXYLATION OF GLUTAMATE RESIDUES) for subsequent function of the active factors

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20
Q

General equation for γ-carboxylation?

A

O2 + CO2 + glutamic acid residues (in factors II, VII, IX and X)

Converted to

γ-carboxyglutamic acid residues (in II, VII, IX and X - these precursors are still inactive)

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21
Q

Role of vitamin K in activation of clotting factors?

A

Carboxylase enzyme that mediates γ-carboxylation REQUIRES VITAMIN K, in its REDUCED form, as an ESSENTIAL CO-FACTOR

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22
Q

How does warfarin work on vitamin K?

A

BLOCKS VIT K REDUCTASE

So, vitamin K’s oxidised form (epoxide) is not reduced to hyroquinone (the reduced form)

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23
Q

What are anti-coagulants used for?

A 
Used widely in prevention/treatment of VENOUS THROMBOSIS and embolism, e.g:
DVT
Prevention of post-operative thrombosis
Patients with artificial heart valves
AF
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24
Q

Risk of anti-coagulants?

A

All carry risk of HAEMORRHAGE

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25
Q

Mechanism of action of warfarin?

A

Coumarin derivative (structurally related to Vit K) and competes the Vit K for binding to hepatic vit K reductase - prevents conversion of epoxide to the active hydroquinone

Blocks coagulation IN VIVO, and not in vitro

26
Q

Which factors does warfarin render inactive?

A

Factors II, VII, IX, and X

27
Q

Administration of warfarin and dosing?

A

Orally administered and is well-absorbed

Has a long, and variable, half-life (usually around 40 hours) - so, it may take a days to reach steady state (5 half-lives)

28
Q

Onset of action of warfarin and why this length?

A

SLOW onset of action (2-3 days), whilst inactive factors replace active γ-carboxylated factors (slowly created from plasma

HEPARIN may be added for rapid anti-coagulant effect

29
Q

Warning with warfarin and monitoring?

A

Difficult to strike balance between desired anti-coagulant effect and haemorrhage - low TI

Must be monitors regularly using INR

30
Q

Factors that potentiate warfarin action (risk of haemorrhage increased)?

A

Liver disease – decreased clotting factors

High metabolic rate – increased clearance of clotting factors

Drug interactions:
Agents that inhibit hepatic metabolism of warfarin (consult BNF as many interactions possible)
Drugs that inhibit platelet function (e.g. aspirin, other NSAIDs)
Drugs that inhibit reduction, or decrease the availability, of vitamin K

31
Q

Factors that lessen warfarin action (risk of thrombosis increased)?

A

Physiological state:
Pregnancy (increased clotting factor synthesis)
Hypothyroidism (decreased degradation of clotting factors)

Vitamin K consumption

Drug interactions:
Agents that increase hepatic metabolism of warfarin (consult BNF as drug interaction are numerous)

32
Q

How to treat warfarin overdosage?

A

Administration of VITAMIN K, or concentrate of plasma clotting factors

33
Q

Role of anti-thrombin III?

A

AT III - important inhibitor of coagulation which neutralises all serine protease factors in the coagulation cascade, by binding to their active site in a 1:1 ratio

34
Q

Mechanism of action of heparin?

A

Heparin binds to AT III, increasing its affinity for serine protease clotting factors (particularly Xa and IIa, (thombin), to greatly increase the rate of their inactivation

35
Q

Binding of heparin to cause inactivation?

A

Heparin must bind to BOTH AT III and IIa to inhibit IIa

Heparin need BIND ONLY to AT III to inhibit Xa, as Xa is closely linked to AT III

36
Q

What are LMWHs?

A

Low molecular weight heparins - naturally occurring sulphated glycosaminoglycan of variable molecular size (unfractionated heparin)

Extracted from beef lung, or hog intestine

37
Q

How are LMWHs specified?

A

Preparation have variable potency and are specified in UNITS OF ACTIVITY, rather than by mass

38
Q

Why are LMWHs preferred?

A

Such as enoxaparin and dalteparin, as they do not require an in vitro clotting test, in order to determine optimum dosage as heparin does

NOT PREFERRED IN RENAL FAILURE

39
Q

How do LMWHs work?

A

Inhibit factor Xa, but not thrombin IIa

Fondaparinux works similarly

40
Q

Difference between heparin and LMWHs administration?

A

Heparin is administered either intravenously (immediate onset of action), or subcutaneously (onset delayed by 1 hour)

LMWHs are given subcutaneously

41
Q

Elimination of heparin and LMWHs?

A

Heparin - shows 0 order kinetics

LMWHs - 1st order kinetics and via renal excretion; this is why HEPARIN, which has alternative excretion pathways, is PREFERRED in RENAL FAILURE

42
Q

Adverse effects of heparin and LMWHs?

A

Haemorrhage – discontinue drug, if necessary administer protamine sulfate (inactivates heparin); LMWHs effects cannot be reversed

Rarely:
Osteoporosis (long-term treatment)
Hypoaldosteronism
Hypersensitivity reactions

43
Q

How do orally active inhibitors work?

A

Newer ORALLY ACTIVE agents act as DIRECT INHIBITORS OF THROMBIN, e.g: dabigatran, or inhibit factor Xa, e.g: Rivaroxaban
Way to remember: RivaroXaban

Advantages - convenient administration and predictable degree of anti-coagulation (nut no specific agent to reduced haemorrhage in overdose)

44
Q

When are orally active inhibitors used?

A

To prevent venous thrombosis in patients undergoing hip and knee replacements

45
Q

When are anti-platelet drugs used?

A

Used mainly in arterial thrombosis treatment

46
Q

Mechanism of action of aspirin?

A

IRREVERSIBLY BLOCKS CYCLOXYGENASE in platelets, preventing TXA2 synthesis

Also, stop COX in endothelial cells from inhibiting production of anti-thrombotic protaglandin I2 - balance shifted in favour of an anti-thrombotic effect because endothelial cells can synthesis new COX enzyme, whereas enucleate platelets cannot (TXA2 synthesis does not recover until affected platelets are replaced over 7-10 days)

47
Q

What is aspirin used for?

A

Main anti-platelet agent; used orally, mainly for thromboprophylaxis in patients with high CV risk

48
Q

Side effect of aspirin?

A

GI bleeding and ulceration

49
Q

Mechanism of action of Clopidogrel?

A

Links to PSY12 receptor, via a disulphide bond, producing irreversible inhibition

50
Q

When is Clopidogrel used?

A

Most often used in patients intolerant of aspirin (cost is an issue)

Administered orally, when combined with aspirin has a synergistic action

51
Q

Clinical use of Tirofiban?

A

Given intravenously in short term treatment to prevent MI in high risk patients with unstable angina (with aspirin and heparin)

52
Q

Which cascade opposes coagulation cascade?

A

Fibrinolytic cascade exists endogenously and opposes coagulation cascade

53
Q

Describe the fibrinolytic cascade

A

Plasminogen is converted to plasmin, by endogenous tissue plasminogen activator (tPA)

Plasmin converts fibrin to fragments, resulting in clot lysis

54
Q

What are fibrinolytics used for?

A

To DISSOLVE CLOTS

To reopen occluded arteries in acute MI, or stroke
Less frequently are used in life-threatening venous thrombosis or PE

55
Q

Administration of fibrinolytics?

A

Administered i.v within as short a period as possible of the event
Percutaneous coronary intervention (PCI) is superior if available promptly

Have an additive beneficial effect with aspirin

56
Q

Examples of fibrinolytics?

A

Streptokinase
Alteplase
Duteplase

All activate plasminogen

57
Q

What is streptokinase?

A

NOT AN ENZYME - protein extracted from streptococci cultures

58
Q

What is streptokinase used for?

A

Reduces mortality in acute M.I. but action blocked after 4 days by the generation of antibodies; further doses not to be given after this time

May cause allergic reactions ( and should not be given to patients with recent streptococcal infections)

59
Q

What are alteplase and duteplase?

A

Recombinant tissue plasminogen activator (rt-PA)

More effect on fibrin-bound plasminogen than plasma plasminogen and show selectivity for clots

Do not cause allergic reactions

Short half-life so given I.V

60
Q

Major adverse effect of fibrinolytics?

A

Haemorrhage that may be controlled by tranexamic acid, which inhibits plasminogen activation

Pharmacology (17 decks)

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