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Cardiovascular & Respiratory Pharmacology (Karen) > Drugs affecting coagulation > Flashcards

Drugs affecting coagulation Flashcards

1
Q

Thrombus forms

A

in vivo

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2
Q

Clot forms

A

in vitro (operating table, test tube)

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3
Q

Coagulation is

A

formation of a fibrin thrombus/clot in blood vessel

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4
Q

Thrombosis

A

formation of a haemostatic plug in a blood vessel in the absence of blood loss

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5
Q

arterial thrombus

A
  • white
  • platelets + white blood cells in a fibrin mesh
  • usually associated with atherosclerosis
  • can embolize, leading to vessel obstruction and infarction
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6
Q

venous thrombus

A
  • red
  • fibrin, platelets, red blood cells
  • usually associated with blood stasis (DVT)
  • can embolize leading to pulmonary or cerebral emboli
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7
Q

What does blood vessel damage trigger?

A
  • vasoconstriction
  • platelet adhesion and activation (primary) + fibrin formation (secondary)
    • leads to development of a thrombus
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8
Q

What is the mechanism of vasoconstriction in haemostasis?

A
  • collagen from damaged vessel is exposed to tissue factor
  • leads to adhesion of platelets, causing them to activate
  • ADP and 5-hypoxytryptomine (serotonin) are released from platelets
    • serotonin is a powerful vasoconstrictor
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9
Q

What is the mechanism of platelet activation and adhesion in haemostasis?

A

*activation is target of number of drugs*

  • activated platelets release ADP
    • induces other platelets to activate and change shape
  • granules secreted (ADP, 5-HT)
  • activates other platelets
  • synthesize mediators (thromboxane)
  • platelets aggregate
  • adhere by fibrinogen bridging between glycoprotein GPIIb/IIIa receptors
  • = formation of soft plug
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10
Q

How does platelet activation trigger thromboxane production?

A
  • activation of platelets results in activation of phospholipase A2
  • PLA2 liberates arachidonic acid from the membrane
  • COX –> thromboxane
  • thromboxane then stimulates further platelet activation
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11
Q

What are some stimuli for platelet activation?

A
  • collagen
  • thrombin
  • thromboxane
  • ADP
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12
Q

What is the mechanism of fibrin deposition in haemostasis?

A
  • fibrinogen (soluble) –> fibrin (insoluble) by thrombin (protease)
    • thrombin produced by activation of prothrombin, it is not present in plasma like fibrinogen
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13
Q

How is prothrombin activated?

A
  • via the coagulation cascade (secondary haemostasis)
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14
Q

What is the intrinsic pathway of the coagulation cascade?

A
  • occurs in vitro (test tube)
  • intrinsic to the blood
    • exposed collagen or other material, negative charges (e.g. glass) induce clotting
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15
Q

What is the extrinsic pathway of the coagulation cascade?

A
  • extrinsic - in vivo
  • extrinsic to the blood, involving the vessel rather than the blood itself
    • exposed collagen activates tissue factor (thromboplastin)
  • fewer steps (therefore faster) than intrinsic pathway
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16
Q

What is the common pathway of the coagulation cascade?

A
  • extrinsic and intrinsic pathways lead to the formation of Xa from X
  • this activates prothrombin to thrombin
  • thrombin cleaves fibrinogen to fibrin to form the stable clot
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17
Q

How is blood coagulation controlled?

A
  • inhibition of thrombin and factor Xa by antithrmobin
  • fibrinolysis by plasmin
    • formed from activation of plasminogen through inactivation of its imhibitor activated protein C
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18
Q

What are the 3 factors that contribute to haemostasis and thrombosis?

A
  • hypercoaguability
  • blood stasis
  • vessel damage
19
Q

What are examples of blood stasis promoting thrombosis?

A
  • atrial fibrillation
    • cerebral or renal embolism
  • DVT
    • pulmonary embolism
20
Q

What are the anticoagulation drug targets?

A
  • coagulation (fibrin formation)
  • platelet adhesion and activation
  • fibrinolysis
21
Q

Vitamin K

A
  • procoagulant
  • essential for formation of clotting factors:
    • II, VII, IX, X (2, 7, 9, and 10 - Melbourne TV stations)
    • all require glutamate carboxylation after syntehsis
      • reduced Vit K is a cofactor
  • inhibited by coumarin derivatives (warfarin) that inhibit vitamin K reduction
22
Q

Heparin

A
  • injectible anticoagulant
  • acute, short-term use
  • targets fibrin formation by enhancing activity of antithrombin III
  • large, negatively charged
23
Q

Warfarin

A
  • oral anticoagulant
  • prolonged therapy
  • targets fibrin formation
  • coumarin derivative
  • inhibits reduction of vitamin K
    • tf inhibits carboxylation of glutamate and production of 2, 7, 9, and 10
  • only active in vivo
  • delated onset of action bc factor half-lives are long
  • overdoes tx with Vit K
24
Q

Low molecular weight heparins

A
  • e.g. Clexane
  • same effect on Xa, lesser effect on thrombin
  • similar anticoagulant effects
  • longer half life
    • can be used daily, at home
  • can be teratogenic in combination with warfarin
25
Q

Clexane

A

LMW Heparin (injection)

26
Q

How is heparin anticoagulation monitored?

A
  • APTT test (activated partial thromboplastin time)
    • time to clot formation in citrated plasma after addition of Ca, contcat activator, and phoshoplid
    • measure of intrinsic pathway
27
Q

What are the adverse effects of heparin?

A
  • haemorrhage (increased risk of bleeding and CVAs)
  • thrombocytopaenia (platelet deficiency)
  • osteoporosis
28
Q

What are the adverse effects of warfarin?

A
  • haemorrhage
    • titrate dose, determine dose w/INR
    • can be reversed w/Vit K, fresh frozen plasma
29
Q

Why is warfarin considered a ‘moody drug’?

A
  • orally active and rapidly absorbed
  • but strongly bound to plasma protein (99%)
    • unbound form is active
    • changes with changes in blood plasma levels
  • tf levels and anticoagulant effects are very labile
    • diet high in Vit K will outcompete warfarin
30
Q

What causes increased warfarin activity?

A
  • vitamin K deficiency
  • hepatic disease (impaired synthesis of clotting factors and plasma proteins)
  • hypermetabolic states (increased metabolsim of clotting factors)
  • drug interactions:
    • impaired platelet aggregation (aspirin)
    • competition for plasma protein binding (NSAIDs)
    • competition for Cyt-p450 pathway reduces clearance (cimetidine - H2 blocker for gastric ulcers, alcohol)
31
Q

What causes decreased warfarin activity?

A
  • pregnancy
  • drug interactions
    • induction of liver enzymes (barbituates, alcoholism increases clearance)
    • vit K supplements
32
Q

How is warfarin activity monitored?

A
  • prothrombin time (PT)
    • time to clot formation of plasma after addition of Ca2+ and tissue factor/thromboplastin
    • measures extrinsic pathway
  • INR
    • ratio of patient PT to normal PT
    • varies with disease (++synthetic valves, +DVT)
33
Q

Clopidogrel

A
  • ADP receptor antagonist
  • oral administation, as a prodrug
  • prevents binding of ADP to its receptor on platelets
    • prevents activation of glycoprotein IIb/IIIa complex
    • this inhibits platelet aggregation
  • more routinely used as an antiplatelet drug than abciximab which is more expensive and has to be given IV
34
Q

platelet activation and adhesion

Aspirin

A
  • inhibits COX, thereby inhibiting thromboxane synthesis
    • this inhibits platelet aggregation
35
Q

What are the drugs used to affect platelet activation and adhesion?

A
  • ADP receptor antagonists (clopidogrel)
  • thromboxane synthesis inhibitors (COX inhibitors e.g. aspirin)
  • glycoprotein IIa/IIIb receptor antagonists (tirofiban, abciximab)
36
Q

Tirofiban

A
  • glycoprotein IIb/IIIa receptor antagonist
  • stop platelet aggregation by blocking binding of fibrinogen to the receptor
37
Q

Abciximab

A
  • glycoprotein IIb/IIIa receptor antagonist
  • stop platelet aggregation by blocking binding of fibrinogen to the receptor
  • IV use (large molecular weight) in high risk acute coronary syndromes (v. expensive)
38
Q

What are the guidelines for use of drugs affecting platelet activation and adhesion?

A
  • indicated in less severe anticoagulative states than warfarin e.g. arterial stent or increased risk of DVT
  • adjunctive therapy with aspirin
  • in patients intolerant to aspirin
  • post iscahemic heart disease
  • atrial fibrillation (stroke prevention)
39
Q

What is the mechanism of low-dose aspirin therapy?

A
  • low dose because 90% eliminated first pass (liver) tf readily absorbed
    • binds to platelets at portal vein before entering liver for metabolism
  • reduces thromboxane syntehsis from platelets in portal vein by inhibition of COX-1
    • decreases platelet aggregation and decreases vasoconstriction
  • retained PGI2 (prostacyclin) from endothelium (COX production not affected)
    • inhibits platelet aggregation and promotes vasodilation
40
Q

What are the fibrinolytic drugs?

A
  • streptokinase
  • alteplase
41
Q

What is the general mechanism of fibrinolytic drugs?

A
  • plasminogen is activated in the presence of activated protein C
  • yields plasmin, a protease that destroys the clot (fibrinolysis)
  • tf streptokinase and alteplase activate plasmin to promote fibrinolysis
42
Q

Streptokinase

A
  • activates plasminogen –> plasmin
  • IV administration (large molecular weight)
  • derived from streptomyces (streptococcus) bacterium
    • tf it is antigenic and stimulates the immune system to produce Abs
    • tf it can only be used once though it is cheap and effective
43
Q

Alteplase

A
  • human recombinant tissue plasminogen activators (hrtPA)
  • not antigenic tf given to pt who have had streptokinase
  • IV administration (short half-life)
  • active on fibrin-bound plasminogen
    • it is tf considered ‘clot selective’
  • very expensive, ~$1000/vial, need ~2 for a 70kg pt

Cardiovascular & Respiratory Pharmacology (Karen) (15 decks)

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