Anti-Coagulants (LOOK AT TABLES IN PPT)

Question 1

Aspirin MOA

Answer 1

Irreversibly inhibits cox-1

Question 2

Which is the only irreversible NSAID?

Answer 2

Aspirin

Question 3

What is a low does of aspirin used for?

Answer 3

MI and TIA

Question 4

What is a high dose of aspirin used for?

Answer 4

Anti-inflammatory

Question 5

Side effects of aspirin

Answer 5

Increases GI bleeding

Question 6

Dipyridamole MOA

Answer 6

Phosphodiesterase inhibitor
Inhibits adenosine uptake in the RBC, thereby increasing adenosine levels in the blood
Adenosine binds to platelet adenosine A2 receptor, activating adenylyl cyclase –> increasing cAMP
Increased cAMP reduces platelet aggregation
Dipyridamole also inhibits cGMP phosphodiesterase activity, increasing cGMP and causing vasodilation

Question 7

What must dipyridamole be used in combination with?

Answer 7

Aspirin
For treatment of TIA
Alone, it has no effect

Question 8

Cilostazol

Answer 8

cAMP phosphodiesterase III (PDEIII) inhibitor

Increased cAMP leads to inhibition of platelet aggregation and increased vasodilation

Question 9

What is cilostazol used for?

Answer 9

Intermittent claudication (Leriche syndrome)

Question 10

ADP receptor blockers MOA

Answer 10

Ticlopidine, clopidogrel

Irreversibly inhibits the binding of ADP to its receptors on platelets (no platelet activation)

Question 11

Side effects of ADP receptor blockers

Answer 11

Bleeding
Leukopenia
Thrombocytopenic purpura

Question 12

What are ADP receptor blockers used for?

Answer 12

Alternatives to ASA in TIAs, post MI and unstable angina

Question 13

How is clopidogrel activated?

Answer 13

It is a prodrug and must be activated by p450 CYP2C19.

Patients with polymorphism of this ensue have decreased effectiveness of clopidogrel

Question 14

Why is clopidogrel preferred over ticlopidine?

Answer 14

Ticlopidine has an increased chance of causing thrombotic thrombocytopenia purpura and requires a high dose

Question 15

GP IIb/IIIa receptor blockers MOA

Answer 15

Inhibit the final common pathway of platelet aggregation

Question 16

Which are the most effective anti platelet drugs

Answer 16

GP IIb/IIIa receptor blockers

Question 17

Which drugs are GP IIb/IIIa receptor blockers?

Answer 17

Monoclonal antibody: Eg. Abciximab

Fibrinogen analog: Eptifibatide and Tirofiban

Question 18

What are GP IIb/IIIa receptor blockers used for?

Answer 18

Only in acute coronary syndromes (MI) and angioplasty and postangioplasty

Question 19

Heparin MOA

Answer 19

Biological

Heparin increases antithrombin III activity to degrade XIIa, XIa, Xa, IXa, IIa, by 1000x

Question 20

LMWH and Fondaparinaux act on:

Answer 20

Xa

Question 21

Does heparin cross the BBB? What about the placenta?

Answer 21

No and no –> safe to use in pregnancy

Question 22

How are heparins metabolized?

Answer 22

Highly acidic –> can be neutralized by protamine
Metabolized in macrophages and endothelial cells; high doses are also cleared by the kidneys
Half life = 2h

Question 23

When are heparins used?

Answer 23

Used for rapid anticoagulation for thrombosis, emboli, unstable angina, DIC and open heart surgery

Question 24

Pathogenesis of heparin induced thrombocytopenia

Answer 24

1-5% incidence
Body produces antibodies against platelet factor 4 bound with heparin
IgG+antibody+heparin+PF4 binds to the Fc receptor of platelets, activating them –> platelet microparticles form and a blood clot develops

Question 25

Signs of HIT

Answer 25

New thrombosis Platelet count drops >30% Occurs 5-10 days after beginning heparin therapy

Question 26

How do you treat HIT

Answer 26

Monitor platelet count frequently | Discontinue heparin and switch to DTI or fondaparinux

Question 27

Side effects of heparin

Answer 27

HIT Increases bleeding --> hemorrhagic stroke Hematoma formation Reversible alopecia Osteoporosis (use for 5-8 months - incidence 2-5%. May be due to inhibit cytokine-related osteoblast maturation)

Question 28

What is the antidote for hemorrhagic stroke?

Answer 28

Protamine

Question 29

When is heparin contraindicated?

Answer 29

``` Heparin allergy Bleeding disorders (hemophilia, thrombocytopenia, ulcerative lesions of the GIT) Brain, eye or spinal cord surgery Intracranial hemorrhage Infective endocarditis Severe HTN Active TB ```

Question 30

How does protamine sulphate affect LMWH

Answer 30

Protamine sulfate is only partially effective in reversing it’s anticoagulant effect

Question 31

Which are the LMWH drugs?

Answer 31

Enoxaparin, dalteparin, tinzaparin

Question 32

Why is LMWH better than heparin?

Answer 32

``` LMWH has higher bioavailability and longer duration of action (Enoxaparin T1/2 4.5h) Relatively safe, subcutaneous injection, lower dose, less frequently, do not need aPTT monitoring. Less HIT (0.8% by LMWH vs 1-5% by heparin) LMWH more effective than heparin in high risk setting (eg. Trauma, orthopedic surgeries). ```

Question 33

When is LMWH unsafe to use?

Answer 33

LMWH unsafe in pts. with renal insufficiency due to mainly cleared by renal

Question 34

Fondaparinux MOA

Answer 34

Synthetic Inactivates Xa by binding to antithrombin III Half life = 15h

Question 35

How does protamine affect fondaparinux?

Answer 35

It will not reverse it's action

Question 36

Does fondaparinux have heparin structure?

Answer 36

No

Question 37

What does excess protamine cause?

Answer 37

Bleeding (protamine-heparin complex may damage platelet function)

Question 38

Which are the oral direct Xa inhibitors?

Answer 38

Rivaroxaban, apixaban, edoxaban

Question 39

What are direct Xa inhibitors used for?

Answer 39

Non-valvular a-fib, DVT and PE They are preferred over warfarin Do not require monitoring

Question 40

When are direct Xa inhibitors contraindicated?

Answer 40

Liver and renal dysfunction

Question 41

Direct thrombin inhibitors MOA

Answer 41

Directly bind to and irreversibly inhibit thrombin | Monitored by aPTT (oral dabigatran is not monitored routinely)

Question 42

When are DITs used?

Answer 42

In patients with HIT

Question 43

Hirudin

Answer 43

Specific irreversible thrombin inhibitor from leech saliva

Question 44

Which are the DTIs?

Answer 44

Lepirudin, bivalirudin, argatroban, dabigatran

Question 45

What is warfarin used to treat?

Answer 45

``` Used to maintain anticoagulation therapy over long term To prevent thrombosis in patients with: valvular a-fib mechanical heart valves kidney dysfunction liver dysfunction ```

Question 46

What is dicoumarol?

Answer 46

Drug similar to warfarin, but not as effective

Question 47

Warfarin MOA

Answer 47

Inhibits vit k epoxide reductase, reducing the conversion of vit k epoxide (KO) to hydroquinone (KH2), which is the active form. Therefore, warfarin inhibits synthesis of new clotting factors II, VII, IX, X, protein C and protein S. It has no effect on old clotting factors already synthesized.

Question 48

How can effects of warfarin be reversed?

Answer 48

Vitamin K, but it takes time. So immediate remedy is through transfusion of fresh frozen plasma.

Question 49

Can warfarin be used in pregnancy?

Answer 49

NO. Crosses the placenta and produces fetal toxicity because fetal proteins with carboxyglutamate residue in bone may be affected and can cause abnormal bone formation. LMWH are a better alternative.

Question 50

What is the half life and Vd of warfarin?

Answer 50

Half life: 2-5 days Vd: low because it is 99% protein bound Onset is 6-8h Bioavailability is 100%

Question 51

Side effects of warfarin

Answer 51

Bleeding (monitor INR) Skin necrosis due to low protein C (Because of the delay in thrombin suppression, heparin is administered concurrently with warfarin for 4-5 days to prevent thrombus propagation)

Question 52

Which drugs cause increased action of warfarin?

Answer 52

``` Cephalosporins Cimetidine Macrolide antibiotics Ketoconazole Fluconazole Metronidazole Amiodarone Sulfa drugs ```

Question 53

Which drugs cause decreased action of warfarin?

Answer 53

``` Barbiturates Phenytoin Rifampin Vitamin K Cholestyramine St Johns wort ```

Question 54

When should fibrinolytic therapy be started?

Answer 54

ASAP to reestablish blood flow After MI --> within 12h After ischemic stroke --> within 3h Prevention of further clot formation starts with heparin for a week to achieve immediate action, followed by warfarin for 6 months maintenance therapy. Antiplatelet drugs are added to therapy

Question 55

Which are the fibrinolytic drugs?

Answer 55

``` Streptokinase Urokinase Anistreplase Alteplase Reteplase Tenecteplase ```

Question 56

MOA of fibrinolytics

Answer 56

Rapidly lyse the thrombi by catalyzing the formation of plasmin from plasminogen

Question 57

Which fibrinolytic is binds to fibrin more tightly and is approved for treatment of ischemic stroke?

Answer 57

Alteplase

Question 58

When is thrombolytic therapy for ischemic stroke contraindicated?

Answer 58

Use of heparin in the previous 48 hours A platelet count less than 100 000/mm3 Another stroke or a serious head injury in the previous 3 months Major surgery within the preceding 14 days SBP >185mm Hg, DBP > 110 mm Hg Rapidly improving neurological signs Prior intracranial hemorrhage Blood glucose less than 50 mg/dL or greater than 400 mg/dL Seizure at the onset of stroke GI or urinary bleeding within the preceding 21d Recent MI

Question 59

What are the antidotes for tPA?

Answer 59

Epsilon amino caproic acid, tranexamic acid

Question 60

Tranexamic acid MOA

Answer 60

Binds to plasminogen and inhibits plasminogen activation | Used in the treatment of fibrinolytic overdose, hemophilia, postoperative bleeding, etc.

Question 61

Agents used in excessive bleeding:

Answer 61

``` Blood transfusion Fresh frozen plasma Clotting factors and Platelets Protamine sulphate Vitamin K Antifibrinolytics Idarucizumab ```