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Pharm Block 2 > Anti-coagulants, thrombolytics > Flashcards

Anti-coagulants, thrombolytics Flashcards

1
Q

What is the difference between venous and arterial thrombosis?

A

Venous: has to do with RBCs in a meshwork of fibrin, looks like red thrombi. Most occur in deep or superficial veins of leg. DVT happens in larger veins at or above knee, can embolize to lungs -> pulmonary infarction. DVTs associated with hypercoaguable states.

Arterial: has to do with platelets with little fibrin or RBCs, looks like white thrombi. Usually occurs after erosion or rupture of atherosclerotic plaque. Leads to cardiac ischemia and stroke.

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2
Q

Synthesis of which factors are Vitamin K dependent?

A

Factor 2, 7, 9, 10

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3
Q

Physical properties of heparin?

A

Heterogenous mixture of sulfated polysaccharides
Highly sulfated/negatively charged
15kDa
40 monosaccharide units

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4
Q

Antithrombin is a ______ (type) substrate for different ACTIVATED/INACTIVATED coagulation factors, especially ______

A

suicide, activated

factors 9a, 10a, 11a, 12a

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5
Q

Explain how antithrombin inactivated coagulation factors. How does heparin affect this process?

A

ACTIVATED coagulation factors, especially thrombin, 9a, 10a, 11a, and 12a, attack Arg-Ser peptide bond in Antithrombin. It becomes trapped and inactivated.

Heparin increases this reaction by 1000x fold via specific pentasaccharide sequence in heparin, causing a conformational change in antithrombin making the active site more accessible to the proteases.

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6
Q

How does low molecular weight heparin compare to heparin?

A

Low molecular weight heparin does NOT catalyze the inhibition of thrombin by antithrombin.
*They both catalyze the inhibition of 10a by AT, though.

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7
Q

Physical property of low molecular weight heparin?

A

Less than 18 monosaccharide units

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8
Q

How is heparin administered? Why?

A

IV or Sub-Q

It is large and charged/polar so it is not absorbed by GI tract.

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9
Q

Can you give a pregnant woman heparin?

A

Yes! Anti-coagulant of choice since it does NOT cross the placenta.

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10
Q

How/where is heparin cleared and degraded?

A

By the reticuloendothelial system (monocytes and macrophages in reticular connective tissue) and liver

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11
Q

A patient on heparin has an aPTT time of 120 seconds. Is this normal? Why or why not?

A

No; normally a clot forms within 26-33 seconds. If a person is on heparin, a therapeutic aPTT would be 1.5-2.5x that or 50-80 seconds.

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12
Q

How do you prepare a sample to test for aPTT?

A

Take blood sample, add citrate to plasma to inactivate calcium and prevent clotting.

Add:

  • Negatively charged phospholipids
  • Particulate substance (like aluminum sulfate/Kaolin)
  • Calcium
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13
Q

A patient has venous thromboembolism; how would you administer heparin? Cardiopulmonary bypass? As a prophylatic to prevent venous thrombosis?

A

Venous thromboembolism: bolus injection, followed by continuous IV. Look for 1.8-2.5x normal, which is good enough for therapeutic/decreased recurrence if within 24 hours.

Cardiopulmonary bypass: Very high dose, aPTT prolonged indefinitely

Prophylaxis to prevent venous thrombosis: Sub-q, low dose, no effect on aPTT

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14
Q

Major adverse effect of heparin? Other effects?

A
  • BLEEDING in 1-5% patients treated for venous thromboembolism -> treat with antagonist, protamine sulfate
  • Can also cause thrombocytopenia
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15
Q

Contraindication of heparin use?

A

Active bleeding
Severe uncontrolled hypertension
Recent surgery of eye, brain, spinal cord

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16
Q

What are the low molecular weight heparins? How big are they and how are they administered?

A

Enoxaparin
Dalteparin
15 monosaccharide units
Sub-q/parenteral injection

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17
Q

Is heparin or LMWH absorbed more uniformly?

A

LMWH

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18
Q

How does half life compare between heparin and LMWH?

A

LMWH > Heparin

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19
Q

How does elimination differ between heparin and LMWH?

A

Heparin: reticuloendothelial system and liver
LMWH: renal elimination -> risk in pts with renal disease

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20
Q

Adverse effects of LMWH? Contraindications?

A

Lower risk of bleeding and thrombocytopenia compared to heparin
Contraindications:
- Same as heparin; active bleeding, severe uncontrolled hypertension, recent surgery of eye/brain/spinal cord
- Renal impairment

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21
Q

Therapeutic uses of LMWH?

A

Similar to unfractionated heparin:

  • Acute DVT
  • Acute unstable angina and MI
  • Prophylaxis of DVT
  • Hip replacement surgery, during and following
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22
Q

What are the direct thrombin inhibitors?

A

Lepirudin

Bivalirudin

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23
Q

What is the direct Factor Xa inhibitor?

A

Fondaparinux

24
Q

How are direct thrombin inhibitors administered?

A

Lepirudin and Bivalirudin are through IV

25
Q

How is Fondaparinux administered?

A

Sub-q

26
Q

How does aspiring work as an anti-platelet drug?

A

Low doses of aspirin acts to irreversibly inhibit COX-1 in platelets. Platelets use COX-1 to make PGH2 -> TXA2 (thromboxane), which promotes platelet aggregation.
*You still retain endothelial cells -> PGH2 -> PGI2 production (inhibits platelet aggregation)

27
Q

How long does a single dose of aspirin act as an anti-platelet drug?

A

About 10 days - enough time for the platelet to replicate since it does not have a nucleus for new protein synthesis

28
Q

What are the therapeutic uses of aspirin?

A
  • Prophylaxis of MI, stroke
  • Acute phase of ischemia stroke
  • Alone or with thrombolytics in acute MI
  • Unstable angine/acute coronary syndrome
29
Q

What is dipyridamole? Mechanism of action? Therapeutic uses?

A

Anti-platelet drug and vasodilator
- Inhibits both PDE3 and PDE5 to increase cAMP, which inhibits platelet aggregation and vasodilation.

Therapeutic use:

    • Warfarin: Primary prophylaxis of thromboemboli in patients with prosthetic heart valves
    • Aspirin: secondary prevention of MI or Transient Ischemic Attack
30
Q

How does ADP affect platelet aggregation? Which drugs affect ADP’s effect on platelet aggregation? Reversible, irreversible?

A 
ADP acts via P2Y1 and P2Y12 receptors to activate platelets. The drugs below antagonize ADP's effect. 
"Tic, Tic, Clumped Platelets"
Ticagrelor - reversible
Ticlodipine  - irreversible
Clopidogrel - irreversible
Prasugrel - irreversible
31
Q

What is the difference between P2Y-1 and P2Y-12 receptors?

A

P2Y-1 is a GPCR associated with Gq -> PLC -> increase Ca2+

P2Y-12 is a GPCR associated with Gi -> inhibit adenylate cyclase -> less cAMP -> decrease PKA

32
Q

“Tic Tic Clumped Platelets”; describe their pharmacokinetics

A

Ticagrelor
Ticlodipine** - Prodrug to active via CYP2C19
Clopidogrel - Prodrug to active via CYP2C19
Prasugrel* - Prodrug to active via esterase hydrolysis and CYP3A4/2B6

Orally administered

  • Prasugrel has most predictable effects out of them all
  • *Ticlodipine rarely used
33
Q

What are the adverse side effects of anti-platelet drugs?

A

All - bleeding
Ticagrelor - dyspnea
Ticlodipine - neutropenia

34
Q

What is unique about clopidogrel metabolism?

A

It’s a prodrug that is activated via CYP2C19 but 3-20% of the population have polymorphisms -> poor metabolizers so there is LESS active drug in system

Also patients who are on aspirin and clopidogrel complain of GI irritation. So you prescribe omeprazole (PPI) but that is also a CYP2C19 substrate -> even less active clopidogrel in system.

35
Q

Explain how abciximab works.

A

It’s a monoclonal chimeric antibody (Fc is human, Fab is murine)

Binds to GP IIb/IIIa on platelets, inhibits binding of fibrinogen, vW factor and inhibits platelet crosslinking. It binds to a site DIFFERENT from the direct RGD binding site so it exerts its effects noncompetitively.

36
Q

What is eptifibatide? How is it different from abciximab?

A

It’s a cyclic heptapeptide anti-platelet drug that is derived from disintegrins - proteins from snake venom that inhibit platelet aggregation.

It has a KGD (lysine, glycine, aspartate) motif that makes it specific for GP IIb/IIIa on platelets to prevent it from binding fibrinogen.

Competitive, reversible; Abciximab is NON-competitive

37
Q

Which antiplatelet drugs are giving through IV?

A

Abciximab and Eptifibatide

38
Q

Pharmacokinetic differences between Abciximab and eptifibatide?

A

Abciximab: Quick onset, delayed clearance, effective up to 7 years
Eptifibatide: Quick onset, quick clearance (platelet aggregation back to normal within 8 hours), renal clearance

39
Q

What is the role of alpha2-antiplasmin?

A

Keeps free plasmin inactive so it doesn’t break down other clotting factors other than fibrin

40
Q

Explain how plasminogen turns into plasmin

A

Cleaving of Arg560-Val561 bond by t-PA (endogenous) or Alteplase (exogenous), leading to a two chain disulfide molecule.

Cleavage exposes Kringle sites; 5 disulfide bond loops on the N-terminal side with Lysine binding sites (Kringle) that can bind to specific residues on the polymerized fibrin. Plasmin cleaves fibrin.

N-terminal = Heavy chain with the Kringle sites
C-terminal = Light chain with the catalytic activity
41
Q

Where is t-PA synthesized? How does t-PA concentration change during clot formation?

A

Synthesized from endothelial cells
In early stages of clot formation there is little t-PA; t-PA inhibitor called t-PAI or PAI-1 and PAI-2 keep t-PA inactive so that the clot can actually form

42
Q

What is alteplase? How is it administered and why?

A

Glycoprotein that is made from cDNA for natural human tissue t-PA via DNA recombinant technology

It has a very short half life so it is given through IV

43
Q

Thrombolytic therapy such as alteplase has a lower risk of bleeding when used for treatment of an acute MI compared to a pulmonary embolism/DVT. True or false? Why or why not?

A

True; it has to do with dose and duration

Remember that pulmonary embolism requires an initial bolus and continous IV

44
Q

Thrombolytic therapy, like alteplase, is used therapeutically for: (3 things)

A

Acute MI (STEMI) (reduce infarct size, often given heparin or aspirin)
Treatment of pulmonary embolism/DVT
Stroke within first 3 hours

45
Q

What drug is used to block plasminogen and plasmin mediated fibrinolysis? Mechanism?

A

Aminocaproic acid

- Lysine analogue that binds to lysine binding sites of plasminogen and plasmin

46
Q

What is the therapeutic use of aminocaproic acid?

A

If there is too much fibrinolysis, it can inhibit it further.

Aminocaproic acid is also found 100x higher in the urine than in the plasma so it’s useful for treating urinary tract bleeding

47
Q

What are some advantages of the new oral anticoagulants compared to warfarin?

A 
Rapid onset/offset
No food interactions
Fewer drug interactions
Limited hepatic metabolism
Wider therapeutic window
Lower risk of intracranial hemorrhage
Lower risk of bleeding complications 
Reduce need for antidote
48
Q

What are some disadvantages of the new oral anticoagulants compared to warfarin?

A

Severe chronic kidney disease can’t use or need to lower dose
More expensive
No specific antidote yet, compared to warfarin (K+, fresh plasma)

49
Q

What are the therapeutic uses of heparin?

A

DVT (remember how it was administered)
Pulmonary embolism
Initial management of unstable angina or MI
Coronary angioplasty or stent replacement
In vitro uses - hemodialysis, blood samples drawn for lab
***drug of choice for anticoagulation in pregnancy

50
Q

Describe protamine sulfate. Side effects?

A

Chemical antagonist; low MW, + charged so it binds heparin 1:1 to make an inactive complex

Use:

  • Combat heparin overdose that cant be stopped by just stopping heparin
  • Reverse heparin following cardiopulmonary bypass

Side effects:

  • if used alone, it can actually act as an anticoagulant
  • anaphylactic reaction (fish hypersensivity, previous exposure to insulin products since they could have had protamine)
  • severe pulmonary hypertension
51
Q

Warfarin is a structural analogue of _____ and a derivative of _______

A

Vitamin K

Fat soluble derivative of 4-hydroxycoumarin

52
Q

Lepirudin is a recombinant form of ____, which is a polypeptide derived from _____.

A

Hirudin

Leeches

53
Q

What is the mechanism of action of lepirudin and bivalirudin? How is it excreted?

A

Binds 1:1 to thrombin at the catalytic site AND exosite 1

Renal excretion

54
Q

When would you use lepirudin or bivalirudin?

A

It’s an alternative to heparin in patients who have had heparin-induced thrombocytopenia

55
Q

Describe fondaparinux, excretion, administration, adverse effect, contraindications, therapeutic uses:

A 
Synthetic pentasaccharide
Renal excretion
Sub-q
Hemorrhage side effect
Contraindication like others: active bleeding, recent surgery of eye brain spinal cord, renal impairment
Uses:
- To prevent DVT in patients undergoing surgery
- Treat acute PE
- Treat acute DVT w/o PE
56
Q

How do you know Warfarin is working? What is the prep?

A

Look at prothrombin time (aPTT is for heparin)

  • add citrate to blood to inactive calcium and prevent clotting
  • Add thromboplastin (saline brain extract that has tissue factor and phospholipids)
  • Clots within 12-14 seconds, INR of 0.8-1.2
  • If warfarin is working, PT should be 15-26 seconds, INR of 2-3
57
Q

Why use INR? What does it mean?

A

Because variability of thromboplastin used.
INR: international normalized ratio; ratio of patient PT to a control PT that wouldve been obtained using a WHO primary standard thromboplastin

Pharm Block 2 (7 decks)

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