CPR 9.11 Pharmacology of Coagulation Factor Dysfunctions

Question 1

What are the 3 types of Indirect thrombin inhibitors?

Answer 1

(a) Heparin (UFH): glycosaminoglycan from secretory granules of mast cells.
(b) Enoxaparin (Lovenox): LMWH
(c) Fondaparinux (Arixtra): Synthetic Pentasaccaride end of heparin (smallest functional unit of heparin)

Question 2

Describe the MOA for heparins. Which Coag factors are affected by the various types

Answer 2

Heparin binds to antithrombin via its pentasaccharide sequence→ This induces a conformational change in the reactive center loop of antithombine that accelerates antithrombin interaction with factor Xa. The tail of UFH also binds and inhibits Thrombin (Factor II) LMWH has a decreased ability to inhibit Factor II along with X, and Fondaparinux can only affector factor X.

Question 3

What are the side effects of the different heparins?

Answer 3

High risk for bleeding from Heparin Induced Thrombocytopenia (HIT) with UFH and some risk with LMWH. Bleeding especially prevalent in pts with renal disease. Hypersensitivity, Osteoporosis, Mineralcorticoid deficiency in chronic use.

Question 4

Describe the ADME of UFX vs. LMWH and Fondaparinux

Answer 4

UFH given in IS unit. LMWH and Fondaparinux dosed in mg. Need to monitor via aPTT, Protamine sulfate antagonizes Heprain to counter bleeding (UFH>LMWH» Fondaparinux (doesn’t work).

Question 5

How drug can used in heparin reactions?

Answer 5

5. Protamine (actually a Heparin antagonist; attenuates the enhanced bleeding) great for heparin, some for Enoxaparin, not at all for Fondaparinux)

Question 6

Name the most common Direct Factor Xa Inhibitor

Answer 6

Rivaraoxaban (Xarelto)

Question 7

Describe the MOA and Indications for Rivaraoxaban (Xarelto)

Answer 7

(a) MOA: inhibits factor Xa.

(c) Indications: Hip and knee surgery, DVT, non-valvular atrial fibrillation.

Question 8

Describe the ADME and Side effects for Rivaraoxaban (Xarelto)

Answer 8

(b) ADME: Short half-life, given PO, Excreted by kidney (affected by renal disease).
(d) Side Effects: Expensive, Competitive drug-drug interactions due to P-glycoprotein transport.

Question 9

What are the 2 most common direct thrombin Inhibitors?

Answer 9

Argatroban and Dabigatran (Pradaxa)

Question 10

Describe the MOA, ADME, Indications, and Contraindications for Argatroban

Answer 10

(a) MOA: bind directly to active site of thrombin and inhibit its function.
(b) ADME: parenteral continuous infusion. Monitor via aPPT
(c) Indications: Primarily used in pateints with HIT, without liver disease.
(d) Contraindications: Liver disease.

Question 11

Describe the MOA, ADME, and Side effects for Dabigatran

Answer 11

(a) MOA: bind directly to active site of thrombin and inhibits its function.
(b) ADME: oral, predictable pharmacokinetics and bioavailability, less monitoring needed.
(c) Side Effects: Thrombosis risk with premature discontinuation. Spinal/Epidural hematoma in pts. Receiving neuraxial anesthesia or spinal puncture. Bleeding. GI effects.

Question 12

Describe the MOA, ADME (including baseline testing), Side effects, and Indications for Warfarin

Answer 12

(a) MOA: inhibits Vitamin K epoxide which blocks reduction of Vitamin K back to active form. Factors II, VII, IX, X and C/S all use vitamin K.
(b) ADME: racemic mixtrue (S 4x as potent). CYP3A4 and lots of SNP’s affected leads to 30x variation of effect.
(1) Basline testing: PT/INR and aPTT, CBC (PLTS), Serum Creatinine (GFR), LFTs, Urine pregnancy.
(2) Vitamin K1/K2 can reverse adverse effects of warfarin.
(c) Side Effects: Bleeding, teratogenic, Thrombocytopenia, Early hypercoaguability (from Protein C and S inhibition). Drug-Drug interactions.
(d) Indications: one of most commonly prescribed anticoagulant.

Question 13

What are the 2 most common anti platelet agents?

Answer 13

aspirin and Clopidogrel (plavix)

Question 14

Describe the MOA, Indications, Side effects, and Contrainidications for Aspirin

Answer 14

1. MOA: Inhibits Prostaglandin synthesis by inhibiting COX1 and COX2. (COX 1 is responsible for production of thrombaxonae A2 in platelets, which normally causes them to change change shape, release granules, and adhere.
2. Indications: MI prophylaxis.
3. Side effects: Gastric irritation.
4. Contraindications: Hemophiliacs.

Question 15

Describe the MOA, ADME, indications, and Side effects for Clopidogrel (Plavix)

Answer 15

1. MOA: inhibits ADP-induced platelet aggregation.
2. ADME: It is a prodrug that must be activated by CYP2C19
3. Indications: NSTEMI, STEMI, unstable angina. Often in Combination with ASA.
4. Side Effects: Drug-Drug interactions, SNP in CYP2C19 that slows activation.

Question 16

What is the most common Fibrinolytic agent used?

Answer 16

tPA

Question 17

Describe the MOA, indications, and Side effects of tPA

Answer 17

1. MOA: activates the zymogen plasminogen into plasmin (when plasminogen is bound to fibrin). Activated plasmin can then digest clots.
2. Indications: acute ischemic stroke, Acute MI, PE, DVT.
3. Side effects: excessive bleeding.

Question 18

What are 2 examples of fibrinolytic inhibitors?

Answer 18

1. Tranexamic acid (Cyklokapron) and Aminocaproic acid (Amicar)

Question 19

Describe the MOA, Indications, and Side effects of Tranexamic acid (Cyklokapron) and Aminocaproic acid (Amicar)

Answer 19

2. MOA: competitively inhibits plasminogen activation. (Amicar blocks t-PA/urokinase; Cyklokapron blocks blood activators)
3. Indications: Hemophilia and post surgical bleeding.
4. Side effects: Inravascular thrombosis. Contraindicated in DIC.

Question 20

How can Vitamin K be used in treatment of bleeding disorders?

Answer 20

B. Vitamin K (K1 foods and K2 gut flora)

1. MOA: reverses warfarin toxicities. Coagulation factors II, VII, IX and X are all K dependent