Drugs Used in Disorders of Coagulation

Question 1

Platelet Aggregation Inhibitor general MOA

Answer 1

Decrease synthesis or action of chemical signals that promote platelet aggregation

4 types:

• COX inhibitors
• ADP receptor blockers
• phosphodiesterase inhibitors
• blockers of platelet GPIIb/IIIa receptors

Question 2

Aspirin MOA

Answer 2

Platelet Aggregation Inhibitor

TXA2 causes platelets to normally degranulate and aggregated –> Aspirin inhibits TXA2 synthesis by irreversible acetylation of COX enzyme –> Anulcear platelets cannot synthesise new enzyme during its 10-day lifetime

Question 3

Aspirin Uses

Answer 3

1) Prophylatic treatment of transient cerebral ischemia
2) To reduce incident of recurrent MI
3) To decrease mortality in post MI patients

Question 4

ADP receptor blockers

Answer 4

Clopidogrel

Ticlopidine

Question 5

Clopidogrel MOA

Answer 5

Irreversible inhibition of P2Y12 - one of the two subtypes of ADP receptors on the platelet surface –> inhibits platelet aggregation

Clopidogrel is preferred over ticlopidine as it has fewer side effects

Question 6

Clopidogrel PK

Answer 6

Prodrug - converted to active metabolite mainly by CYP2C19

Patients who are poor metabolisers have low plasma levels of the active metabolite so alternative treatment should be considered

Concurrent use of clopidogrel and CYP2C19 inhibitors (e.g. omeprazole) should be avoided as they will reduce the plasma level of active metabolite

Question 7

Ticlopidine MOA and AE

Answer 7

Irreversible inhibition of P2Y12 - one of the two subtypes of ADP receptors on the platelet surface –> inhibits platelet aggregation

Clopidogrel is preferred over ticlopidine as it has fewer side effects

Most serious side effect is neutropenia

Question 8

Clopidogrel Uses

Answer 8

Similar to those of aspirin:

To reduce rate of stroke, MI and death in patients with recent MI, stroke or acute coronary syndrome

Question 9

Dipryidamole MOA and use

Answer 9

Phosphodiesterase inhibitor –> inhibits platelet aggregation

Used for stroke prevention

Question 10

Cilostazol MOA and use

Answer 10

Phosphodiesterase inhibitor –> promotes vasodilation and inhibits platelet aggregation

Used for intermittent claudication

Question 11

Abciximab, Eptibatide, Tirofiban MOA

Answer 11

Blocks platelet GP IIb/IIIa receptor –> inhibits platelet aggregation

Complex is a receptor for fibrinogen –> fibrinogen is a bivalent ligand which binds to two receptors and forms bridges between adjacent platelets activation of this receptor is the final common pathway for lately aggregation

Question 12

Tirofiban MOA and use

Answer 12

Blocks platelet GP IIb/IIIa receptor –> inhibits platelet aggregation

Adjuncts to PCI (percutaneous coronary intervention) for prevention of cardiac ischemic complications

Question 13

Indirect thrombin and factor Xa inhibitors

Answer 13

Unfractionated heparin (UFH)
Low-molecular-weight-heparins (LMWH)
Fondaparinux

Question 14

Route of administration of heparins

Answer 14

Heparin is an injectable, rapidly acting anticoagulant

Can not be given orally

Question 15

Heparins MOA

Answer 15

Heparin’s anticoagulant effect is a consequence of binding to antithrombin III.

Antithrombin III is an a-globulin. It inhibits clotting factor proteases, especially thrombin, IXa and Xa, by forming equimolar stable complexes with them. In the absence of heparin, these reactions are slow.

Heparin acts as a catalyst to antithrombin III which which allows it to interact more rapidly with the clotting factors.

Question 16

Structural differences between UFH and LMWH

Answer 16

Both are mixture of straight, chain, sulphated mucopolysaccharides isolated from bovine lung or porcine intestinal mucosa

UFH - molecular weight range of 5000-30000

LMWH (Enoxaparin) - produced by depolymerisation of UFH. Molecular weights range from 1000-5000

Question 17

Difference in MOA of heparins

Answer 17

Both accelerate antithrombin III activity via binding of specific pentasaccharide sequence

UFH efficiency inactivated both thrombin (IIa) and factor Xa –> forms a ternary complex with ATIII and IIa

LMWH efficiently inhibit Xa only as they are too short to form ternary complex. Not very good at inhibiting thrombin but there is little acceleration of thrombin inactivation indirectly by ATIII.

Ternary complex not necessary to accelerate inactivation of Xa by ATIII

Question 18

Monitoring heparin levels

Answer 18

Using aPTT assay –> activated partial thromboplastin time –> test of integrity of intrinsic and common pathways of coagulation

Dosing of LMWH results in predictable plasma levels so it is not usually necessary to monitor LMWH blood levels.

Potency of LMWH can be assessed by anti-factor Xa assays

Question 19

Uses of heparins

Answer 19

Prevention and treatment of DVT, pulmonary embolism and MI

Drug of choice during pregnancy as it does not cross placenta and not associated with fatal malformations unlike warfarin

Question 20

Heparin AE

Answer 20

Bleeding

Hypersensitivity reactions

Heparin-induced Thrombocytopenia (HIT)

Type II HIT:
Caused by antibodies that recognise complexes of heparin and a platelet protein, Platelet Factor 4. IgG binds to PF4/heparin complex forming immune complexes –> IgG binding to Fc receptors on platelets –> Fc activation leading to platelet degranulation and aggregation –> activated platelets release more PF4 –> new immune complexes form –> can result in thrombocytopenia and thrombosis that range from mild to life-threatening.

Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor (argatroban or bivalirudin) or fondaparinux.

Question 21

Reversal of heparin action

Answer 21

Discontinuance of drug if excess anti-coagulation occurs

If bleeding occurs –> give protamine sulfate

Question 22

Fondaparinux MOA

Answer 22

Smallest heparin –> synthetic pentasaccharide that binds to antithrombin III –> specific inhibitor of Xa

Has negligible activity against thrombin (IIa)

Question 23

Fondaparinux Uses

Answer 23

Prevention and treatment of DVT

Question 24

Warfarin MOA

Answer 24

Antagonizes cofactor function of vitamin K by inhibiting vitamin K epoxide reductase –> results in production of inactive clotting factors.

Factors II, VII, IX and X and proteins C and S undergo a vitamin K-dependent post- translational modification, whereby a number of their glutamic acid residues are carboxylated to form gamma-carboxy-glutamic acid residues –> enzyme gamma-glutamyl carboxyl required vitamin K in reduced form as co-factor.

Question 25

Warfarin anticoagulant effects

Answer 25

Coagulation factors involved have half-lives ranging from 6-60 hours: 60 hours for factor II and 6 hours for factor VII

Anticoagulant effect is apparent within 24 hours of administration –> peak effect may take 72-96 hours

Duration of action of a single dose of warfarin is 2 to 5 days

Question 26

Reversal of warfarin action

Answer 26

Anticoagulant effects can be overcome by giving vitamin K –> reversal takes approx 24 hours

Question 27

Monitoring warfarin levels

Answer 27

Has narrow TI and many drug-drug interactions are involved –> effects must be monitored regularly (every 2-4 weeks)

Monitoring by assessing prothrombin time (PT) –> tests integrity of extrinsic and common pathways of coagulation –> results are expressed as INR

Question 28

Warfarin uses

Answer 28

Prevention and treatment of DVT, pulmonary embolism , following an initial course of heparin

Prevention and treatment of thromboembolic complication associated with atrial fibrillation

Question 29

Warfarin AE

Answer 29

Hemorrhage

Cutaneous necrosis: due to reduced activity of protein C –> is an anticoagulant factor –> in some people protein C levels drop faster than the clotting factors so there is over-coagulation –> blood clots block the blood vessels in skin and cause necrosis

Teratogenic: crosses placenta and can cause hemorrhagic disorder in fetus and serious birth defects

Question 30

Warfarin contraindications

Answer 30

Pregnancy category X –> crosses placenta and can cause hemorrhagic disorder in fetus and serious brith defects

Many drug interactions that can potentiate or attenuate anticoagulant effects as it metabolised by P450 enzymes (more potent S-warfarin by CYP2C9)

Question 31

Direct thrombin inhibitors MOA

Answer 31

Directly bind to active site of thrombin –> anticoagulant effect

Question 32

Desirudin MOA and use

Answer 32

Parenteral DTI –> directly binds to active site of thrombin –> anticoagulant effect

Monitered by aPTT assay

Indicated for thromboprophylaxis in patients undergoing elective hip replacement surgery

Question 33

Bivalirudin MOA and use

Answer 33

Parenteral DTI –> directly binds to active site of thrombin –> anticoagulant effect

Monitered by aPTT assay

Used in patient use going PCI

Question 34

Argatroban MOA and use

Answer 34

Parenteral DTI –> directly binds to active site of thrombin –> anticoagulant effect

Monitered by aPTT assay

Used in patient use going PCI

Question 35

Dabigatran etexilate

Answer 35

Oral DTI –> directly binds to active site of thrombin –> anticoagulant effect

Prodrug converted to dabigatran (active metabolite)

Produces a predictable anticoagulant response so routine monitoring is unnecessary

Question 36

Dabigatran etexilate use

Answer 36

Prevention and treatment of DVT and PE

Question 37

Apixaban and rivaroxaban MOA and use

Answer 37

Oral direct factor Xa inhibitors –> newer drugs given now instead of warfarin

Do not require monitoring

Used for prevention and treatment of DVT and PE

Question 38

Choice of oral anticoagulant

Answer 38

Direct oral coagulants dabigatran, apixaban and rivoraxaban have equivalent antithrombotic efficacy to warfarin and lower bleeding rates

Other advantages:

• have rapid onset of action
• predictable pharmacokinetics
• wider therapeutic window
• no monitoring needed
• fewer drug interactions

Are replacing warfarin for treatment of VTE or stroke and prevention of embolism in atrial fibrillation

Question 39

Thrombolytics general MOA abd use

Answer 39

Thrombolytic agents act by converting the inactive zymogen plasminogen to the active protease plasmin. Plasmin is a relatively nonspecific protease that digests fibrin.

Anticoagulants can prevent formation of thrombi but are ineffective against pre-existing clots. Thrombolytic drugs lyse blood clots and restore the potency of obstructed vessels before distal tissue necrosis occurs.

Thrombolytic drugs reduce the mortality of acute myocardial infarction and are used in situations in which PCI (angioplasty) is not readily available.

Question 40

Streptokinase MOA and use

Answer 40

Thrombolytic - activates plasminogen to plasmin which digests fibrin to break down clots

Protein produced by b-hemolytic streptococci

Rarely used since advent of newer agents

Question 41

Urokinase MOA and use

Answer 41

Thrombolytic - activates plasminogen to plasmin which digests fibrin to break down clots

Human enzyme synthesised by the kidney and found in the urine

Approved for lysis of pulmonary emboli

Question 42

Fibrin-selective thrombolytics

Answer 42

Alteplase
Reteplase
Tenecteplase

Question 43

Alteplase, reteplase, tenecteplase MOA

Answer 43

Tissue plasminogen activator (t-Pa) is a serine protease produced by human endothelial cells –> activates plasminogen bound to fibrin in a thrombus –> is a fibrin-selective thrombolytics –> more selective at breaking down clots –> the selectivity of t- Pa for fibrin limits systemic formation of plasmin and the induction of a systemic lytic state

Alteplase - recombinant t-Pa

Reteplase, tenecteplase - recombinant variants t-Pa with longer half-lives

Question 44

Alteplase use

Answer 44

recombinant t-Pa –> thrombolytic

Management of acute MI and acute ischemic stroke

Question 45

Aminocaproic acid & tranexamic acid MOA and use

Answer 45

Inhibit plasminogen activation –> protect integrity of clot –> for treatment of bleeding disorders

Used as adjunctive therapy in haemophilia and therapy for bleeding from thrombotic therapy overdose

Question 46

Protamine sulfate MOA and use

Answer 46

Chemical antagonist of heparin –> high in arginine –> cationic protein that interacts with anionic heparin to form a complex with no anticoagulant activity.

Protamine is most active against UFH and it can partially reverse the anticoagulant effects of LMWHs.

Inactive against fondaparinux.

Question 47

Vitamin K uses

Answer 47

Used to correct the bleeding tendency or hemorrhage associated with its deficiency

Used for drug induced hypoprothrombineia:
Vitamin K is available in oral and parenteral forms –> onset of effect taken 6 hours and effect is complete by 24 hours.

If immediate homeostasis is required, fresh-frozen plasma should be infused in addition

Also given to prevent vitamin K deficiency bleeding in newborns –> all babies should receive standard vitamin K1 IM at birth

Question 48

Plasma Fractions

Answer 48

Deficiencies in plasma coagulation factors can cause bleeding.

Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease or hemophilia B) account for most of the heritable coagulation defects.