Drugs Used in Disorders of Coagulation

Question 1

Now we will go through the drugs used in disorders of coagulation. There are drugs used to reduce clotting and drugs used to treat bleeding. First we will discuss the drugs used to reduce clotting. The first set of drugs are the platelet aggregation inhibitors. What is the action of these drugs?

Answer 1

Decrease formation or action of chemical signals that promote platelet aggregation

Question 2

Again the first set of drugs are the platelet aggregation Inhibitors. First lets talk about the COX inhibitor Aspirin, what is the MOA of Aspirin?

Answer 2

Aspirin inhibits TXA2 synthesis

–by irreversible acetylation of the enzyme COX

Question 3

What is the use of Aspirin?

Answer 3

Prophylactic treatment of transient cerebral ischemia

–reduce the incidence of recurrent MI and to decrease mortality in post MI patients

Question 4

Next in the platelet aggregation inhibitors are the ADP receptor blockers. Clopidogrel and Ticlopidine. What is their MOA?

Answer 4

Irreversibly inhibit P2Y12

–Subtype of ADP receptor on the platelet surface

Question 5

What is the use and side effects of Clopidogrel and Ticlopidine?

Answer 5

Prevent cerebrovascular and CVS and peripheral vascular disease
Irreversible platelet inhibitors
–therefore increased risk of blood for 5-7 days after drug cessation
Side Effect:
–neutropenia (ticlopidine)
–thrombocytopenic purpura (Both drugs)
–inhibit cytochrome P450

Question 6

Clopidogrel is used over ticlopidine, why?

Answer 6

Fewer adverse side effects and dosing requirements

Question 7

Clopidogrel is a prodrug that is converted to an active metabolite, mainly by CYP2C19. Therefore what happens if a patient is a poor metabolizers?

Answer 7

CYP2C19 poor metabolizers
–have lower plasma levels of the active metabolite
Alternative treatments need to be considered for these patients

Question 8

What drug should be avoided in patients taking clopidogrel and why?

Answer 8

Drugs that interfere with CYP2C19

–Omeprazole is a CYP2C19 inhibitor, that reduces plasma levels of the clopidogrel

Question 9

What is the use of clopidogrel?

Answer 9

Reduce the rate of stroke, MI and death in patients with recent MI or stroke

Question 10

Next drug group in the platelet aggregation inhibitors are the phosphodiesterase inhibitors. Dipyridamole and Cilostazol. What is the action of Dipyridamole?

Answer 10

Coronary vasodilator used to treat angina

–increases cAMP levels by inhibiting phosphodiesterase and/or blocking uptake of adenosine

Question 11

Dipyridamole needs to be used with what other drug to have any effect?

Answer 11

By itself little to no effect

• -give with warfarin to prevent postoperative thromboembolic complications of cardiac valve replacement
• -give with aspirin and use the extended release version for secondary prophylaxis of CVS disease

Question 12

Cilostazol is the other phosphodiesterase inhibitor, what is the action and use?

Answer 12

Phosphodiesterase inhibitor

• -promotes vasodilation and inhibition of platelet aggregation
• -treats intermittent claudication

Question 13

The last set of drugs under the platelet aggregation inhibitors are blockers of platelet GPIIb/IIIA receptors. What is their use?

Answer 13

Reduce the rate of thrombotic CVS events in (NSTE-ACS)
IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor
–activation of this receptor is the final pathway for platelet aggregation
–persons lacking this receptor have a bleeding disorder called Glanzmann’s Thrombasthenia

Question 14

There are three drugs that are GPIIb/IIIa receptors. What are they?

Answer 14

Abciximab
--binding is irreversible 
Eptifibatide
--reversible antagonist 
Tirofiban
--reversible antagonist

Question 15

Moving on to the next set of drugs used to reduce clotting are the Anticoagulants. There are four groups of drugs. First group are the indirect thrombin and factor X inhibitors. The main drug in this class is heparin. There is unfractionated and low molecular weight heparins, what is the difference between the two?

Answer 15

LMWHs are free of some of the drawbacks associated with UFH
–therefore they are replacing UFH in many clinical situations
LMWHs
–same efficacy but superior bioavailability, longer half life and less frequent dosing requirements

Question 16

Now to discuss the MOA of heparin. The anticoagulant effect of heparin is due to what?

Answer 16

Consequence of binding to antithrombin III

• -which inhibits clotting factor proteases: thrombin, IXa and Xa
• • a critical sequence of five carbohydrate residues in heparin is needed for binding to antithrombin III once this happens there is an acceleration in the process. Heparin functions as a cofactor for the antithrombin-protease reaction without being consumed. Once the antithrombin-protease complex is formed heparin is released intact.

Question 17

To catalize most efficiently the inactivation of thrombin by antithrombin III a molecule of heparin must bind simultaneously to both thrombin and antithrombin, forming a ternary complex. In contrast, to catalize inactivation of factor Xa by antithrombin III the heparin molecule must bind only to antithrombin. Therefore which heparin is best for this reaction?

Answer 17

LMWH
–efficiently inhibits Xa but have less effect on thrombin
UFH
–efficiently inactivates both thrombin and factor Xa

Question 18

Monitoring of UFH therapy is important for maintaining the anticoagulant effect. How is monitoring performed??

Answer 18

Partial Thromboplastin Time (aPTT) assay

–test of the integrity of the intrinsic and common pathways of coagulation

Question 19

LMWH monitoring is different, how?

Answer 19

Results in predictable plasma levels in patients with normal renal function
–not necessary to monitor levels unless patient has renal insufficiency, obesity, and pregnancy
Potency of LMWH can be assessed with anti-factor Xa assay
(LMWH is excreted in the kidneys)

Question 20

What are the uses of heparin?

Answer 20

Initiate treatment of venous thrombosis and pulmonary embolism
–continued for about 5 days until warfarin kicks in
Initial management of unstable angina or acute MI
Used during coronary balloon angioplasty to prevent thrombosis
DO NOT cross the placenta (so use in pregnancy)

Question 21

What are the adverse effects of heparin?

Answer 21

1. Bleeding
2. Hypersensitivity reaction
3. Heparin induced Thrombocytopenia (HIT): type I and type II
   - -type II: more serious leads to a systemic hypercoagulable state in patients treated with UFH for a min of 7 days. caused by antibodies that recognize complexes of heparin and a platelet protein, platelet factor 4. results in thrombocytopenia (Due to platelet consumption) and thrombosis
   - -patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor or fondaparinux
4. Mild elevated liver transaminases in plasma
5. Osteoporosis after chronic use

Question 22

How would heparin be reversed?

Answer 22

Discontinuance of the drug

–agonist such as protamine sulfate (will not reverse fondaparinux though)

Question 23

The other drug besides heparin in the indirect thrombin and factor Xa inhibitors is Fondaparinux. What is the make up, use, MOA of this drug?

Answer 23

Pentasaccharide that contains the sequence of five carbohydrates needed for binding antithrombin III
Selective, indirect, inhibitor of factor Xa
Prophylaxis and treatment of DVT
Need to be assessed with an anti-Xa assay

Question 24

The next anticogulation class are the direct thrombin inhibitors (DTIs). How do they exert their action?

Answer 24

Directly binding to the active site of thrombin

Question 25

There are parenteral and oral direct thrombin inhibitors. First lets start with the parenteral thrombin inhibitors. Three drugs fall under this, with the first being Lepirudin. What is the use, make and MOA?

Answer 25

Thrombin Inhibitor
–recombinant form is called lepirudin
Inactivates both free and fibrin-bound thrombin in developing clots
Excreted in kidneys so be careful in renal failure patients
No antidote
Indicated for use in patients with heparin induced thrombocytopenia (HIT)
Monitored via aPTT

Question 26

The next parenteral thrombin inhibitor is Bivalirudin, what is the use, make and MOA?

Answer 26

Bivalent Inhibitor of Thrombin
–inhibits platelet activation
Monitored by aPTT
Use in patients undergoing percutaneous coronary intervention (PCI)

Question 27

The last parenteral thrombin inhibitor is Argatroban. What are some features?

Answer 27

Thrombin Inhibitor

• -prophylaxis or treatment of thrombosis in patients with HIT
• -patients at risk for HIT undergoing percutaneous coronary intervention (PCI)
• -monitored by aPTT

Question 28

The only oral parenteral thrombin inhibitor is Dabigatran Etexilate. What are some features?

Answer 28

Reversibly blocks the active site of thrombin
No routine monitoring needed
Tx of thromboembolic stroke in patients with non valvular atrial fibrillation
No antidote

Question 29

The next anticoagulant drugs are the direct factor Xa inhibitors, Apixaban and Rivaroxaban. What are the features?

Answer 29

Oral direct factor Xa inhibitors

• -no coagulation monitoring
• -no antidote

Question 30

The last anticoagulant drug is a coumarin anticoagulant called Warfarin. What are general features of warfarin?

Answer 30

Administered orally

–antagonize the cofactor function of vitamin K

Question 31

What is the MOA of Warfarin?

Answer 31

Factors II, VII, IX and X
–all undergo a vitamin K dependent post translational modification
Warfarin inhibits vitamin K epoxide reductase now you have inactive clotting factors
Coagulation factors have long half lives so results arent usually seen until starting at about 24 hours but peak effects is usually 72 to 96 hours
Give patient Vitamin K to overcome the effects of warfarin however this takes about 24 hours

Question 32

How are warfarin levels monitored?

Answer 32

Narrow therapeutic index so monitoring is needed
—performed with prothrombin time (PT): tests the integrity of the extrinsic and common pathways of coagulation
PT prolonged: levels of fibrinogen, factor V, or the vitamin K dependent factors II, VII or X are decreased
PT measurement is expressed as the International Normalized Ratio (INR): of the prothrombin time

Question 33

What are the uses for warfarin?

Answer 33

1. Prevent the progression or recurrence of acute DVT or pulmonary embolism following an initial course of heparin
2. Prevents venous thromboembolism in patients undergoing orthopedic or gynecological surgery, recurrent coronary ischemia in patients with acute MI and systemic embolization in patients with prosthetic valves or a-fib
3. For venous thromboembolism, heparin, LMWH and fondaparinux is continued for about 5 says after warfarin is begun or until the INR is in therapeutic range

Question 34

What are the adverse effects of warfarin?

Answer 34

Hemorrhage
–whole blood, frozen plasma or plasma concentrates of blood factors may be employed to arrest hemorrhage
Cutaneous Necrosis
–due to reduced activity of protein C sometimes occurs in the beginning of therapy.
Warfarin crosses the placenta
–hemorrhagic disorder in the fetus .

Question 35

Finally there are a number of drug interactions that potential or attenuate the anticoagulant effects of warfarin. Lets start with drugs that inhibit warfarin metabolism (thus potentiating anticoagulation). Aka inhibitors of P450, drug is reaching toxic levels aka bleeding

Answer 35

Cimetidine 
Chloramphenicol 
Disulfiram 
Metronidazole 
Phenylbutazone 
Sulfinpyrazone 
Trimethoprim-Sulfamethoxazole

Question 36

Finally what drugs stimulate warfarin metabolism (thus reducing anticoagulation)? Inducers of P450, drug is below therapeutic levels so patient is throwing clots.

Answer 36

Barbiturates
Carbamazepine
Phenytoin
Rifampin