Antithrombotic pharmacotherapy

Question 1

for each disease, name the thorombus location:

• atrial fibrillation
• myocardial infarction
• DVT/PE
• Stroke

-Critical limb ischemia

Answer 1

• atrial fibrillation: atrial appendage
• myocardial infarction: coronary artery
• DVT/PE: deep vein (femoral)/ pulmonary artery
• Stroke: CNS circulation

-Critical limb ischemia: peripheral circulation (legs)

Question 2

What are two critical elements in thrombus formation? what element is critical for thrombolytics? List the drugs for each.

Answer 2

Fibrin–> anticoagulants:

• heparin
• warfarin
• direct thrombin inhibitors
• factor 10 inhibitors

Activated platelets –> antiplatelets

• aspirin
• ADP blockers
• IIb/IIIa inhibitors
• PDE inhibitors

Thrombolytics

-tPA

Question 3

Different disorders = different Rx

Acute MI:

Answer 3

antigocagulants:

heparin, direct thrombin inhibitors

antiplatelets:

aspirin, IIb/IIIa

** Thrombolytics **

Question 4

Different disorders = different Rx

A fib

Answer 4

anticoagulant: heparin

Question 5

Different disorders = different Rx

Stroke

Answer 5

Anticoagulants: heparin

Antiplatelets: aspirin

thrombolytics

Question 6

Different disorders = different Rx

DVT/PE

Answer 6

anticoagulant: heparin

thrombolytics

Question 7

Different disorders = different Rx

limb ischemia

Answer 7

anticoagulant: heparin

thrombolytics

Question 8

Different disorders = different Rx

chronic/prevention

coronary disease

Answer 8

antiplatelet: aspirin

Question 9

Different disorders = different Rx

Chronic/prevention

A fib

Answer 9

Anticoagulant: warfarin

Question 10

Different disorders = different Rx

Chronic/prevention

Stroke

Answer 10

antiplatelet: aspirin, clopidogrel (ADP blockers)
anticoagulant: warfarin

Question 11

Different disorders = different Rx

chronic/prevention

DVT/PE

Answer 11

anticoagulant: warfarin

Question 12

Different disorders = different Rx

chronic/prevention

Peripheral vascular disease

Answer 12

antiplatelet: aspirin

Question 13

“white” vs “red” thrombus

Answer 13

Red: more fibrin than platelets

venout clots (DVT, PE) —> antithrombotics

White: more platelets than fibrin

arterial clots (MI, Stroke) –> antiplatelets

Question 14

extrinsic vs intrinstic pathway

Answer 14

extrinsic: need to add tissue factor (factor VII)
intrinsic: TF exposed to bloodstream when endothelial damage (silica added, starts with factor X)

Question 15

drugs related to the factor that converts prothrombin (II) to thrombin (IIa)

Answer 15

Factor X related drugs:

• unfractionated heparin (indirect)
• low molecular weight heparin (indirect)

fond aparinux

rivaroxaban (direct inhibitors po)

apixaban (direct inhibitor, po)

Question 16

What do indirect Factor X related drugs target?

Answer 16

activate/amplify anti thrombin III

anti thrombin III blocks prothrombin and factor Xa activation

Question 17

direct thrombin inhibitors and uses

Answer 17

hirudin, lepirudin, bivalirudin

uses: pt with heparin-induced thrombocytopenia (HIT) or A fib

Question 18

If you administer someone with UF heparin and the PPT does not elevate as it should, what is a possible expalantion? (recall PTT measures intrinsic pathway)

Answer 18

Anti-thrombin deficiency –blunted response to heparin

(UF heparin activates AT III)

Question 19

UF Heparin:

• administration of drug
• action, effect
• uses
• side effects

Answer 19

• IV drug, acute onset
• increases PTT
• lots of binding to plasma proteins, cells
• highly variable response, dose must be adjusted to reach goal PTT
• acute management: DVT/PE, Mi, stroke, prophylaxis for DVT in hospitalized pts
• side effects: bleeding, thrombocytopenia, osteoporois, mild increased AST/ALT

Question 20

Heparin Induced Thrombocytopenia

Answer 20

severe- immune mediated reaction, binds platelet factor 4

Question 21

LMWH (low molecular weight heparin), Enoxaparin

-similarities/differences to UFH

Answer 21

• works just like UFH
  distinction: does NOT inhibit 2–>2a (note that UF heparin and LMWH activate AT III, which inhibits 10–>10a and 2—>2a)
• more predictable effects (dose based on weight, no titrating, reduced binidng to plasma proteins and cells)
• given subcutaneously
• not reverseible, meanwhile UFH is

Question 22

protamine

Answer 22

reverses effects of UF heparin

Question 23

what do you check if monitoring LMWH?

Answer 23

anti-10a levels (obesity and renal failure pts can have variable response)

Question 24

3 drugs that block deactivated platelet conversion to activated platelet

Answer 24

• aspirin
• ADP receptor blockers
• PDE inhibitors

Question 25

action of aspirin, uses, side effects

Answer 25

- irreversibly inhibits cox - 7-10 day clearance - uses: acute MI, acute stroke, MI/stroke preventions side effects: gastric ulcers, tinnitus, reye's syndrome

Question 26

Reye's Syndrome - effect - symptoms - mechanism

Answer 26

- encephalopathy, liver failure, fatty infiltration - vomiting, confusion, seizures, coma - caused by diffused mitochondrial insult - follows viral illness (varicella, influenza) - associated wiht aspirin use in children (never give ASA to children, exception is Kawasaki disease)

Question 27

Ticlopidine, Clopidrogrel, Prasugrel - mechanism - uses - side effects

Answer 27

ADP receptor blockers (antiplatelets) - irreversible (5 day clearance) - uses: when allergy to aspirin, added to aspirin after coronary stenting or for stroke prevention - side effects: ticlopidine-thrombotic thrombocytopenic purpura

Question 28

Cilostazol, Dipyrimadole: - mechanism - use - side effects

Answer 28

PDE inhibitors (antiplatelet) - inhibits PDE III -----| cAMP + platelets - uses cilostazol: claudication, improves leg pain dipyrimiadel + aspirin (aggrenox): stroke prevention -side effects: vasodilation --\> nausea, headache, flushing, hypotension, abdominal pain

Question 29

Abciximab, Eptifibatide, Tirofoban - type of drug + mechanism - uses - side effects

Answer 29

- antiplatelets - IIb/IIIa (glue) inhibitors - uses: unstable angina, acute MI, after stent implantation - side effects: thrombocytopenia

Question 30

Vitamin K factors:

Answer 30

2, 7, 9, 10 (1972)

Question 31

Warfarin - mechanism - uses - side effects

Answer 31

- antagonist Vit K, lowers all levels of Vit K factors - takes DAYS to reach effective dose - dose ajusted to reach target PT/INR - level affected by diet, drugs (antibiotics increase INR) - crosses placenta - side effects: bleeding, **skin necrosis** - uses: stroke **prevention**, chronic/preventitive A fib, mechanical heart valves, prior DVT/PE

Question 32

Treatment with this drug causes initial protein C deficiency

Answer 32

Warfarin - protein C (anticlotting factor) is also vitamin K dependent -causes brief increased risk of clotting, very low risk, eventually other factors fall

Question 33

For active clot disorders (PVT/PE), always start _____ first for its acute onset one exception: start _____ by itself first for A fib

Answer 33

Heparin first warfrin for A-fib, no active clot, just risk

Question 34

Indications for Chronic Oral Anti-coagulation (3)

Answer 34

1. A-fib 2. mechanical heart valve 3. Prior DVT/PE (Prior standard: warfarin --low cost but required montly blood draws for INR checks)

Question 35

Dabigatrant, Bivalarudin

Answer 35

Direct thrombin inhibitors

Question 36

Novel Oral anticoagulants (NOACs)

Answer 36

warfarin alternatives: - factor 10a inhibitors - direct thrombin inhibitors pros: no INR checks, consistent dose cons: $$, no reversal angets, only provein effect in A-fib

Question 37

Thrombolytics

Answer 37

increase plasmin activation (plasminogen --\> plasmin ---\> breaks down fibrin into degradation products **tPA, streptokinase, urokinase** \*powerful clot busters- use for acute MI, stroke, but serious bleeding risk

Question 38

Lab tests to monitor drug effects: Intrinsic Extrainsic INR 2 rare measurements

Answer 38

**Intrinsic:** activated partial thrombolastin time (PTT) - add plasma to negative charged silica - time to form clot (nl = 30 sec) **Extrinsic:** Prothrombin Time (PT) - add plasma to TP - time to form clot (nl = 10 sec) **INR** = patient PT/control PT (nl = 1, therapeutic = 2-3, higher # = slower clot time) **2 rare measurements: ** thrombin time, bleeding time

Question 39

which test measures heparin? which one measures warfarin?

Answer 39

PTT (intrinsic) = heparin PT/INR (extrinsic) = warfarin

Question 40

Drug reversal treatment and INR protocol

Answer 40

- fresh frozen plasma (FFP) - Vitamin K * INR 3-5: hold warfarin* * INR 5-9: hold warfarin, oral Vit K* * INR \> 9: IV Vit K, FFP*