Pharm: Heparin Anticoagulants

Question 1

Describe where heparin is found naturally within the body

Answer 1

Found in mast cell granules with histamine and serotonin

Question 2

Describe the chemical structure of heparin

Answer 2

Strongly acidic mucopolysaccharide with repeating units of sulfated glucuronic acid and sulfated glucosamine

Question 3

Describe the size of heparin

Answer 3

Heterogenous

Molecular weight varies between 2kDa and 40kDa

Question 4

What is the mechanism of action of heparin?

Answer 4

Inhibits action of Xa, IIa, XIIa, Xia (2,10,11,12)

by binding to ATIII and increasing ATIII affinity for these factors

Question 5

What are the actions of heparin?

Answer 5

Plasma clearing
Neutralization of vascular lining
Release of tissue factor pathway inhibitor (TFPI)

Question 6

What is the route of administration of heparin?

Answer 6

IV or subcutaneous

Not absorbed orally or rectally

Question 7

How is heparin therapy monitored?

Answer 7

Heparin therapy is carefully monitored using APTT

Target APTT is 2-2.5x baseline

Question 8

How is heparin metabolized?

Answer 8

25% excreted in urine
Some metabolized in liver by heparinases
Mast cells take up heparin
Endothelium binds heparin

Question 9

Describe the pharmacokinetics of heparin

Answer 9

PK of heparin is dose dependent

Higher doses, longer half life

Question 10

What are the endogenous modulators of heparin action?

Answer 10

ATIII
Heparin cofactor II
Tissue factor pathway inhibitor (TFPI)
Platelet factor 4 (PF4)

Question 11

What are the side effects of heparin?

Answer 11

Hemorrhagic complications
Heparin induced thrombocytopenia
Osteoporosis –> fracture risk
Alopecia (loss of hair)

Question 12

What are the clinical uses of heparin?

Answer 12

Therapeutic, surgical and prophylactic ANTICOAGULATION
Unstable angina
Adjunct therapy with thrombolytic drugs
Thrombotic and ischemic strokes

Question 13

What is the antagonist of heparin?

Answer 13

Protamine: very basic protein derived from fish sperm
Combines with heparin to form stable salt with no anticoagulant activity
1:1 antagonism

Question 14

Describe the structure of chemically synthesized heparin

Answer 14

Composed of pentasaccharide

Mimics the sequence repeats found in natural heparin in order to maintain ATIII interaction

Question 15

How does the bioavailability of LMW heparin differ from native heparin?

Answer 15

LMW heparin has 100% bioavailability unlike native heparin which has ~30% bioavailability

Question 16

What are the clinical advantages of LMW heparin

Answer 16

Better bioavailability, longer duration of action, less bleeding, lesser thrombocytopenia

Question 17

What are the clinical uses of LMW heparin

Answer 17

DVT: Prophylaxis and treatment
Acute coronary syndromes management
Anticoagulation during procedures

Question 18

What are antithrombin concentrates clinically used for?

Answer 18

Congenital antithrombin deficiency

Sepsis and DIC

Question 19

What is hirudin?

Answer 19

A thrombin inhibitor derived from leaches

Used for anticoagulation in thrombocytopenic patients

Question 20

What is argatroban?

Answer 20

A synthetic anti-thrombin agent used as an anticoagulant alternative to heparin for patients with heparin induced thrombocytopenia

Question 21

What is bivalirudin?

Answer 21

A synthetic antithrombin that is a combination of hirudin and a tripeptide
used for anticoagulation during stent placement and angioplasty

Question 22

What is fondaparinux?

Answer 22

Pentasaccharide
Complexes with ATIII in order to inhibit factor Xa
Used for management of DVT

Question 23

What is the most common side effect of heparin and related drugs?

Answer 23

Bleeding

Question 24

What is the mechanism of action of argatroban, bivalirudin and hirudin?

Answer 24

Directly inhibits IIa (thrombin)

Question 25

What is the main oral anticoagulant prescribed in the US?

Answer 25

Warfarin

Question 26

What are the clinical uses of warfarin?

Answer 26

Prophylaxis for thrombotic disorders | Treatment of established thrombus

Question 27

What class of drugs does warfarin belong to?

Answer 27

Vitamin K antagonists (VKAs)

Question 28

What coagulation factors does warfarin act on?

Answer 28

II, VII, IX, X

Question 29

Warfarin is an analogue of _________

Answer 29

Vitamin K | Warfarin and Vit K have similar chemical structures

Question 30

What is the mechanism of action of warfarin?

Answer 30

Inhibit II, VII, IX, X by preventing carboxylation of glutamic acid, thus preventing Ca2+ binding

Question 31

What is the route of administration for warfarin?

Answer 31

Oral

Question 32

Is warfarin plasma bound?

Answer 32

Yes, 97% bound to albumin | This gives warfarin a long half life

Question 33

How is warfarin metabolized?

Answer 33

Liver: hydroxylated in hepatic ER into inactive compound

Question 34

What lab test is used to monitor warfarin therapy?

Answer 34

PT is used to monitor warfarin and its effect on the extrinsic pathway

Question 35

How is INR calculated?

Answer 35

INR is a normalized PT value | INR = PT_patient / PT_normalcontrol

Question 36

What factors effect the dose of oral anticoagulants?

Answer 36

Nutrition, anemia, liver disease, biliary obstruction, drugs

Question 37

What are the main drug-drug mechanisms leading to potentiation of warfarin's effect?

Answer 37

``` Causing vit K deficiency (ABX) Displacing warfarin from albumin Decreasing clotting factor synthesis Decreasing metabolism Antiplatelet aggregating properties ```

Question 38

What are the main drug-drug mechanisms leading to inhibition of warfarin's effect?

Answer 38

Decreasing absorption of warfarin | Increasing metabolism of warfarin

Question 39

What are the main side effects of warfarin?

Answer 39

Bleeding due to hypoprothrombinemia (ecchymoses, purpura, hematuria, hemorrhage)

Question 40

Is warfarin safe to give to pregnant women?

Answer 40

No. Warfarin passes the placental barrier and can cause fetal malformation

Question 41

How does warfarin cause necrosis?

Answer 41

Impaired functionality of protein C due to inhibition of gamma carboxylation of glutamic acid

Question 42

What is the treatment of warfarin overdose?

Answer 42

- Replacement of factors II, VII, IX, X via whole fresh blood infusion or frozen plasma - Recombinant factor VIIa - Vitamin K

Question 43

What are the therapeutic uses of vitamin K?

Answer 43

- Antidote for drug-induced hypoprothrombinemia - Intestinal disorders and surgery - Hypoprothrombinemias in newborns

Question 44

What are the anti-Xa drugs?

Answer 44

Apixaban Edoxaban Rivaroxaban

Question 45

What are the interactions with anti-Xa drugs?

Answer 45

Anti-Xa drugs are potent CYP3A4 inhibitors

Question 46

What is the target of Dabigatran?

Answer 46

Factor IIa (thrombin)

Question 47

Do the new oral anticoagulants require coagulation monitoring?

Answer 47

No.

Question 48

What is a contraindication for dabigatran?

Answer 48

Renal failure | Dabigatran is 100% cleared by the kidney

Question 49

What class of drugs does dabigatran interact with?

Answer 49

Proton pump inhibitors

Question 50

What are the indications for the anti-Xa drugs?

Answer 50

Stroke prevention in AFib patients | Prophylaxis of DVT

Question 51

What is the indication for dabigatran?

Answer 51

Stroke prevention in AFib patients