Treatment of Hemostasis Disorders

Question 1

What is the MOA of aspirin

Answer 1

Inhibits the synthesis of TXA2 by irreversibly inhibiting COX1

Question 2

Ticlodipine MOA, indications and its side effects

Answer 2

• Inhibits ADP receptor P2Y12 which inhibits GPIIB-IIIA, inhibiting platelet aggregation.
• Used for TTP.
  AE:
• Nausea, dyspepsia, diarrhea, hemorrhage
• Rare cases of severe bone marrow toxicity leading to leukopenia, granulocytopenia and aplastic anemia

Question 3

Clopidogrel.

Answer 3

• Similar MOA to ticlodipine but less AE, used for stroke, recent MI or for patients who are on stents.
• Requires to be activated by CYP2C19 so it has many drug drug interactions
• If drug interactions are difficult to manage then use Ticlodipine

Question 4

Abciximab.What is the MOA of Tirofiban and Eptifibatide?

Answer 4

• Human monoclonal antibody against GP2B3A
• Given IV to patients undergoing coronary angioplasty
  Tirofiban and Eptifibatide has similar MOA in that they target GP2b3a

Question 5

Explain properties of Phosphodiesterase inhibitors.

Answer 5

Dipyridamole
* A coronary vasodilator that also inhibits platelet aggregation
In combination with warfarin, inhibits embolism from prosthetic heart valves (main use)
* In combination with aspirin, reduces thrombosis in patients with thrombotic disease
Cilostazol
* Antithrombotic, antiplatelet and vasodilatory action
* Inhibits phosphodiesterase type III, and thereby, increases cAMP levels
* Used for intermittent claudication and peripheral vascular disease
Anagrelide
* Reduces elevated platelet counts in patients with essential thrombocytosis (too many platelets)
* Inhibits megakaryocyte development in the late post mitotic stage
* Approved for the treatment of thrombocytocytosis secondary to myeloproliferative disorders, such as, polycythemia vera and chronic myelogenous leukemia to reduce the risk of stroke and myocardial infarction Inhibits formation of platelets

Question 6

Explain the MOA of calcium chelators, heparins, rudins and coumarin.

Question 7

Can you give heparin orally or via IM?

Answer 7

No, its not well absorbed orally and if given IM there is a risk of development of hematoma at the site of injection

Question 8

Explain the properties of heparin.

Answer 8

MOA
* The protease inhibitor, antithrombin III , forms a 1:1 complex with clotting factor protease
* This interaction is slow, but is stimulated 1000-fold by heparin, which binds to antithrombin III
* The heparin-antithrombin III complex inactivates factor IIa (thrombin); main mechanism
* The heparin-antithrombin III complex also inactivates factor Xa, which occurs earlier in the cascade Common Pathway heparin-antithrombin III
Standard Heparin
* Endothelial cell/protein binding:
* Extensive (sticky molecule) Clearance is dose-dependent becauseplasma levels of heparin increase considerably once binding sites are saturated Dose-dependent pharmacokinetics Therapeutic goal:Prolong Partial Thromboplastintime (PTT) to 1.5 to 2.5 times normal (measured just before next dose for intermittent therapy) Most drugs have dose-independent pharmacokinetics
Contraindications
* Bleeding disorders and disorders that predispose to bleeding (e.g., hemophilia, thrombocytopenia), hemorrhage and several other diseases
* Patients with advanced liver or kidney disease, severe hypertension and certain infections (active tuberculosis, infective endocarditis)
* Preferable to other anticoagulants during pregnancy due to lack of placental transfer (contrast to warfarin)
Adverse Effects
* Bleeding/hemorrhage
* Bleeding is minimized with careful monitoring of PTT and platelet counts
* Allergic reaction (heparin is an animal product)
* Osteoporosis (long-term therapy)
* Transient and occasionally severe heparin-induced thrombocytopenia ( HIT):
Type I = Transient and rapidly reversible.
* Antibodies are generated against platelets.
* Results in a decrease in platelet count. Type II = Severe
* Antibodies decrease platelet count.
* The antibodies also activate platelets.
* This may produce a thromboembolism, which may be life- threatening.
Antidote - Protamine sulfate
* Protamine is a basic peptide that binds to heparin (anion/cation interaction)
* Excessive antidote must be avoided because protamine itself is an anticoagulant
* Protamine is much less capable of reversing the effects of LMWH

Question 9

What are some examples of LMWH.

Answer 9

Enoxaparin, Dalteparin and Tinzaparin

Question 10

LMWH

Question 11

Compare and contrast heparin and LMWH.

Question 12

Fondaparinux

Answer 12

Fondaparinux
* It is a synthetic pentasaccharide anticoagulant
* Unlike UHF or LMWHs, it has no effect on thrombin (factor IIa)
* It exerts antithrombotic activity as a result of ATIII- mediated selective inhibition of factor Xa
* Given subcutaneously
Uses:
* Venous thromboembolism prophylaxis following orthopedic surgery
* Treatment of pulmonary embolism (PE)
* Treatment of deep venous thrombosis (DVT)
* Treatment of coronary artery thromboembolism; promising but still under study

Question 13

Explain the properties of warfarin.

Answer 13

Warfarin

• Coumarin derivative
• Hemorrhagic substances found in spoiled sweet clover; used as rodenticides
• 100% oral bioavailability
• Inhibits epoxide reductase, Vitamin K is not then converted to its active form Plasma protein binding : – Extensive (>99%), which accounts for: low volume of distribution (albumin space)
• long half-life (36 h)
• lack of urinary excretion of unchanged drug
• Metabolized to inactive metabolites by cytochrome P450 (CYP2C9) in liver, numerous drug interactions
• Resistance - Mutations in vitamin K epoxide reductase confers heritable resistance to warfarin Speed of onset: slow
• Warfarin half-life = 1.5 days –8 to 12 h for initial anticoagulant effect, several days to reach maximum hypoprothrombinemia.
• The delay represents the time to replace normal clotting factors with incompletely γ-carboxylated factors, and the time to reach steady-state levels of drug
• Antidote– Discontinue drug and administer large doses of vitamin K (phytonadione) and fresh, frozen plasma or factor IX concentrates containing prothrombin complex.

Question 14

What are some of the drugs that can either reduce or enhance warfarin’s effect?

Answer 14

There are drugs that can reduce warfarin absorption - cholestyramine
Drugs can induce hepatic CYP450 - St. John’s Wort, Rifampin and anticonvulsants.
Drugs that induce synthesis of clotting factors: vitamin K and estrogen.
Drugs that displace warfarin from albumin - sulfonamides

• Drugs that increase [warfarin] by inhibitng CYP450: Metronidazole and Fluconazole.

Question 15

What are indications, therapeutic goal and limitations of warfarin?

Answer 15

Warfarin Uses
* Heparin and warfarin are both used to treat both arterial and venous thrombi
* Heparin is used for the first 7-10 days, with a 3-5 day overlap with warfarin, which may be continued for up to 6 months
* Warfarin is also used to prevent blood clots in patients with chronic atrial fibrillation
Therapeutic goal
* Prolongation of Prothrombin Time (PT) above normal Therapeutic goal achieved in about one week - Slow onset

Adverse effects:
* Serious and possibly fatal bleeding occurs in brain, pericardium, stomach and intestine
* Pregnancy - Warfarin is contraindicated
Contraindications:
* Pregnancy (risk of fetal hemorrhage/malformation)
* Patients with bleeding disorders
* Liver disease (impaired drug metabolism)

Question 16

Compare and contrast heparin and warfarin.

Question 17

Explain direct thrombin inhibitors.

Answer 17

Direct Thrombin Inhibitors
* Hirudin : the rudins – This is a specific thrombin inhibitor obtained from leeches
Lepirudin is a recombinant yeast-derived form of hirudin – It is approved for anticoagulation in patients with heparin- induced thrombocytopenia (HIT)
Desirudin and Bivalirudin are new recombinant hirudin analogs that may be used instead of heparins in the future
Argatroban is the 2nd agent (1st is lepirudin) approved for HIT
* Intravenous, anticoagulant in patients with HIT or at risk for HIT Unlike lepirudin, it is cleared by liver and can be used in patients with end-stage renal disease

Question 18

Explain the properties of Dabigatran, Riveroxaban and Apixaban.

Answer 18

Dabigatran	
* First oral direct thrombin inhibitor	
* Parent drug and its metabolites are active	
* Excreted in urine	
* No need for monitoring
Rivaroxaban	
* FXa inhibitor	
* Metabolized and inactivated by CYP450	
* Excreted in both urine and feces
Apaxiban	
* FXa inhibitor	
* Excreted in urine and feces

Question 19

Streptokinase

Question 20

Urokinase

Question 21

t-PAs

Question 22

What are the uses of thrombolytic agents?

Question 23

What are some contraindications to thrombolytic therapy?

Answer 23

Contraindications to Thrombolytic Therapy

• Surgery within 10 days
• Serious G.I. bleeding within 3 months
• History of hypertension (diastolic pressure > 110 mm Hg)
• Active bleeding or hemorrhagic disorder
• Previous cerebrovascular accident or active intracranial process
• Aortic dissection
• Acute pericarditis

Question 24

Vitamin K uses.

Question 25

Aminocaproic acid.