anticoagulants

Question 1

what is the maintenance of blood fluidity by?

Answer 1

the endothelial lining is non-thrombogenic.

balace between procoagulants:

Thrombin
Tissue factor 
Thromboxane
Adenosine diphosphate (ADP) 
Serotonin (5-hydroxytryptamine)

and

Anticoagulants:
Heparan sulfate
Prostacyclin
Nitric oxide
Antithrombin
Proteins C and S

Heparan sulfate is found on the surface of endothelial cells and in the extracellular matrix - Interacts with circulating antithrombin to provide a natural antithrombotic mechanism

Question 2

what are the drug targets for this?

Answer 2

platelets clump (initial clot) (prevention of this is by antiplatelet drugs) —coagulation cascade—> fibrin forms a mesh around platelet clot (prevent coagulation by blocking a single or multiple steps in the coagulation cascade with anticoagulant drugs (parenteral and oral) —–> clot dissolves (firbinolysis)(prevent ischemic damage by dissolving the clot with fibrinolytic drugs (emergency treatment)

Question 3

what are the 4 drug classes?

Answer 3

1. Antiplatelet agents
   aspirin, clopidogrel
2. Heparin & derivatives
   stimulate natural inhibitors of coagulant proteases (antithrombin)
3. Oral anticoagulants
   warfarin, newer oral anticoagulants (e,g, dabigatran)
   block single or multiple steps in the coagulation cascade
4. Fibrinolytic agents
   streptokinase, tissue plasminogen activator
   lyse (break) formed thrombi

Question 4

what intiates the coagulation cascade?

Answer 4

tissue factor

Question 5

what is the platelet function?

Answer 5

disruption of endothelium —> platelet adhesion —> platelet activation (proaggregatory mediationes: thrombin (from prothrombin)—-> platelet release -(serotonin, ADP, thromboxane, Con Willebrand factor, platelet factor 4) ——> platelet aggregation

Question 6

clopidogrel and ticlopidine do?

Answer 6

Clopidogrel and ticlopidine block the platelet purinergic P2Y receptors for ADP and increase cyclic AMP (which prevents clotting)

Question 7

what does Aspirin do?

Answer 7

Aspirin irreversibly inhibits platelet cyclooxygenase and prevents formation of thromboxane from arachidonic acid

Question 8

Eptifibatide, Abcixmab, Tirofiba do what?

Answer 8

Eptifibatide, abciximab and tirofiban block the GpIIb-IIIa receptor for fibrinogen on platelets and prevent platelet aggregation

Question 9

what does dipyridamole do?

Answer 9

inhibits phosphodiesterase and prevents breakdown of cAMP.

Question 10

what is a good summary for actions of anti-platelet drugs?

Answer 10

Aspirin irreversibly inhibits platelet cyclooxygenase and prevents formation of thromboxane from arachidonic acid
Clopidogrel and ticlopidine block the platelet purinergic P2Y receptors for ADP and increase cyclic AMP
Dipyridamole inhibits platelet phosphodiesterase and prevents breakdown of cyclic AMP
Eptifibatide, abciximab and tirofiban block the GpIIb-IIIa receptor for fibrinogen on platelets and prevent platelet aggregation

Question 11

what are the therapeutic uses of aspirin? what are the contraindications?

Answer 11

Prophylaxis for myocardial infarction (MI) - 80 mg/day
Post MI – 160 to 325 mg/day
Prophylaxis for transient ischemic attacks (TIA) or post TIA – 80 to 325 mg/day

Aspirin – Contraindications (not to be used in these conditions):
Vitamin K deficient patients
Hemophilia of any type
Hypoprothrombinemia
Pregnancy & Childbirth

Question 12

for the coagulation cascade: sites of action of anticoagulant drugs, what does heparin do?

Answer 12

Heparin activates antithrombin III (ATIII) which then:

inhibits XIIa, XIa, IXa, X.

It also inhibits low molecular weight heparins which stops Xa, and it inhibits hirudin which stops it from forming IIa.

Question 13

what is heparin?

Answer 13

Heparin is a negatively charged molecule
Cannot cross cell membranes easily (therefore safe during pregnancy)
Avg mol. wt – 13,500 daltons
Found in mast cells - storage of histamine & proteases

Question 14

what’s the mechanism of action of heparin?

Answer 14

Antithrombin III circulates in the plasma - rapidly inhibits activated clotting factors: IIa (thrombin), Xa, IXa, XIa and XIIa. This reaction goes 1000 to 3000 times faster with heparin (acts as a catalyst).

Question 15

what is the worry with heparin toxicity?

Answer 15

Hemorrhage – especially in patients with recent surgery, trauma, peptic ulcer disease, platelet dysfunction
Severe bleeding – antidote - protamine sulfate (original source sperm of salmon, now produced by recombinant technology) - administered by slow iv infusion

Question 16

what is heparin-induced thrombocytopenia (HIT)?

Answer 16

Thrombocytopenia – more than 50% decrease in platelet count (<150,000/μl) due to an antigen antibody reaction
Occurs in 3-5% of patients, 5 to 10 days after starting heparin therapy
Lower incidence with low mol wt heparin
Can be life-threatening
Stop heparin immediately
Alternative anticoagulants – direct thrombin or factor Xa inhibitors (Avoid low molecular weight heparins)

Question 17

what are the therapeutic uses of heparin?

Answer 17

Not absorbed orally - administered by i.v. infusion or s.c.
In venous thrombosis and pulmonary embolism - rapid onset of action, anticoagulation maintained by oral anticoagulants
Some conditions treated: coronary angioplasty, stent placement, cardiopulmonary bypass surgery
Drug of choice for anticoagulation during pregnancy – does not cross the placenta

A thrombus is a clot attached to the vessel wall
An embolus is a free travelling clot that can lodge in certain organs and obstruct blood flow

Question 18

what is the mechanism of action of low molecular weight heparins?

Answer 18

LMWHs are smaller molecules than heparin (produced by fragmentation of heparin molecules) and have no space to bind thrombin.
LMWHs do not inactivate thrombin (IIa)

However, LMWHs bind to antithrombin III and can inactivate factor Xa which binds directly to antithrombin III

MAJOR DIFFERENCE BETWEEN HEPARAIN AND LMWHs IS THAT THE LMWH DOES NOT INACTIVATE THROMBIN.

Question 19

what are the advantages of LMWHs over heparin? disadvantages?

Answer 19

Advantages of LMWHs over heparin:
Better absorbed - higher bioavailability
Can be given subcutaneously without lab monitoring in an outpatient setting
Lower risks of thrombocytopenia and bleeding
Disadvantages:
More expensive than heparin
Cleared unchanged by kidney (do not use in renal failure!) rather than by the mononuclear phagocyte system

Question 20

for oral anticoagulants, what does coumarins (warfarin) do?

Answer 20

Inhibit vitamin K epoxide reductase in the liver where clotting factors are synthesized
Takes 4-5 days to become effective – active carboxylated factors in plasma need to be cleared before inactive factors from the liver predominate
Small Vd, steep D-R curve – small increase in dose can easily become toxic
Warfarin crosses placenta – is teratogenic – causes birth defects and abortion
Uses: To prevent and treat various thrombo-embolic conditions

Question 21

for warfarin and drug interactions what should I know and what is INR ?

Answer 21

Coumarins (warfarin) are metabolized by CYP1A and CYP2C9
Watch out for drug interactions and bleeding episodes ! Warfarin (Coumarin) overdose - Antidote - excess vitamin K

Efficacy of treatment is measured by INR (International Normalized Ratio), the patient’s PT divided by the PT in pooled plasma

target is 2 - 3

Question 22

comparison of warfarin and newer oral anticoagulants (know this there’s a qusetions about this slide)

Answer 22

warfarin

Slow onset and offset of action – need a rapidly acting anticoagulant at the start

Interindividual variability in anticoagulant effect – variability in dose requirements

Narrow therapeutic index – need to monitor anticoagulant effect

Food and drug interactions – need for anticoagulant activity lab tests

Reduce synthesis of all vitamin K dependent proteins – risk of many side effects

Newer oral anticoagulants

Rapid onset of action – no need for bridging anticoagulant

Predictable anticoagulant effect – no need for frequent lab tests for anticoagulant effect

Specific coagulation enzyme target – low risk of off-target side effects

Low potential for food interactions – no dietary precautions

Low potential for drug interactions – few drug restrictions

WITH WARFARIN YOU NEED TO CONTINUALLY MONITOR THE PROTHROMBIN TIME, EVERY MONTH OR SO.

the new oral anticoagulants (NOAs) have increased therapeutic options and work independent of the vitamin K pathway.
NOAs are limited by their high cost, lack of specific antidotes, and lack of long-term safety data.

Question 23

what is the fibrinolytic process, what does streptokinase do? what does tPA (tissue type plasminogen activator) do?

Answer 23

Streptokinase binds to plasminogen and converts it into active plasmin

tPA binds to fibrin plus plasminogen and converts plasminogen into active plasmin

these lead to fibrin fragmentation (degraded) and lysis of the clot.

The tissue or endothelium releases this tPA

Question 24

what are the indications for streptokinase, when should you not use it?

Answer 24

Indications: Dissolve clots after myocardial infarction, deep vein thrombosis, massive pulmonary emboli
Streptokinase is believed to cause systemic plasmin formation (and not only at sites of clot formation) – this may cause increased bleeding as a side effect
Side effects: Bleeding, allergic reactions, hypotension, fever
DO NOT USE IN: Patients with prior intracranial injuries, known brain vessel lesions, brain tumors, previous stroke, aortic lesions, bleeding tendencies, recent injuries etc.

Question 25

what is tissues plasminogen activator (t-PA)- (alteplase,ACTIVASE) doing?

Answer 25

Activates fibrin bound plasminogen (less systemic plasmin formation) – therefore theoretically it is believed to act only at sites of clot formation and more specific than streptokinase
Clinical trials do not show it to be more specific than streptokinase
Indications: Same as streptokinase
More expensive than streptokinase
Contraindications (do not use): same as with streptokinase