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Pharmacology > Anticoagulants and Thrombolytic Drugs > Flashcards

Anticoagulants and Thrombolytic Drugs Flashcards

1
Q

What patient population has an especially high chance of venous thrombosis leading to death?

A

Cancer patients (2nd leading cause)

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2
Q

What is primary vs secondary hemostasis?

A

Primary - platelets adhere to damaged endothelium to form platelet plug

Secondary - thombin converts fibrinogen to fibrin -> mortar is added to the platelet plug

Hemostasis in general forms thrombi to maintain integrity of circulatory systems after vascular damage

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3
Q

What is Factor V Leiden?

A

Clotting disorder in which factor V is mutated, leading to increased risk of developing blood clots

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4
Q

What is paroxysmal nocturnal hemoglobinuria (PNH)?

A

Defect in complement regulatory proteins, which leads to destruction of red blood cells (hemolytic anemia) and formation of blood clots

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5
Q

What are the treatments for PNH?

A
  1. Allogeneic bone marrow transplant - risky

2. Eculizumab - antibody against C5, reduces need for blood transfusions and thrombosis risk

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6
Q

What is the primary side effect of Eculizumab?

A

Defect in complement activation -> susceptible to fatal infections by encapsulated bacteria like N. meningitidis

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7
Q

What two processes are simultaneously activated in order to form a thrombus?

A
  1. Circulating platelets are recruited to site of injury and adhere
  2. Intrinsic / extrinsic coagulation pathways lead to factor X activation of prothrombin to thrombin, and subsequent formation of cross-linked fibrin layer
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8
Q

What is the activation stimulus for the coagulation cascade?

A

Collagen or von Willebrand factor act like glue to platelets, which allows them to stick via specific integrin glycoprotein receptors

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9
Q

What protein interacts with fibrin to “cross-link” it?

A

Glycoprotein IIb/IIIa complex -> attaches to fibrin

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10
Q

Other than acting as scaffolding, what do platelets do to facilitate the clotting process? What is the negative regulator?

A

Secretion of vasoconstrictors and platelet activators, i.e. ADP, TXA2, and 5-HT.

Negative regulator: Prostacyclin (PGI2) - a vasodilator

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11
Q

What is responsible for busting a clot in vivo?

A

Plasmin -> digests fibrin
Plasminogen is made and liver, and endothelial cells will release t-PA (tissue plasminogen activator) to convert plasminogen to plasmin

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12
Q

What are the three major classes of anticoagulants?

A
  1. Parenteral indirect thrombin inhibitors
  2. Parenteral direct thrombin inhibitors
  3. Oral anticoagulants
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13
Q

What is antithrombin III (AT3)?

A

An endogenous inhibitor of both factor Xa and thrombin if both of them are brought in close proximity of AT3

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14
Q

What are the three main heparin preparations?

A
  1. High molecular weight heparin
  2. Low molecular weight heparin
  3. Fondaparinux - synthetic pentasaccharide
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15
Q

What is the primary difference between the three heparins?

A

A pentasaccharide unit found on all heparin preparations is required for binding of AT3

Only HMWH has the additional 13 residues to bring thrombin in close proximity to AT3

All three are able to bring factor Xa in close proximity to inactivate it

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16
Q

Are heparins safe in pregnancy?

A

Yes -> they do not cross the placenta and are the preferred anticoagulant in pregnancy (vs warfarin)

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17
Q

What are high and low molecular weight heparin indicated for?

A

Both: Venous thrombosis, pulmonary embolism, surgery, disseminated intravascular coagulation
HMWH: Acute MI
LMWH: Unstable angina

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18
Q

Why might LMWH be used over HMWH?

A

LMWH has more predictable pharmacokinetics and thus does not require laboratory monitoring. Can be given subcutaneously

Also has lower bleeding / thrombocytopenia risk

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19
Q

What is fondaparinux used for?

A

Thromboprophylaxis of patients undergoing hip / knee surgery, or for PE / DVT prophylaxis

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20
Q

What lab value must be monitored for HMWH?

A

activated partial thromboplastin time (aPTT)

21
Q

What are the risks of heparin toxicity?

A
  1. Major bleeding

2. Heparin-induced thrombocytopenia (HIT)

22
Q

What is the antidote for heparin overdose and how does it work?

A

Protamine sulfate - basic polypeptides which are positively charged, tightly bind heparin and neutralize its anticoagulant effect

-> used after cardiac surgery

23
Q

What is the prototype direct thrombin inhibitor? How does it work?

A

Hirudin, other drugs with -rudin ending (no int’rudin)
Also -gator- from sketchy: argatroban

Irreversible inhibitor of thrombin which was isolated from leech saliva

24
Q

When are direct thrombin inhibitors used?

A

In cases where heparin is not well tolerated, as in heparin-induced thrombocytopenia

25
Q

What is the toxicity of concern with direct thrombin inhibitors?

A

Patients may develop anti-hirudin antibodies which exacerbate renal failure and cause major bleeding
-> aPTT monitoring is recommended

26
Q

What is warfarin and how does it work?

A

Synthetic derivative of coumadin from plants, inhibits the vitamin-K dependent gamma-carboxylation (of glutamate) of proteins in the clotting cascade by preventing vitamin K regeneration.

Specifically, it interrupts calcium-dependent clotting factors 7, 9, 10 and prothrombin

27
Q

What does warfarin do to clotting factors?

A

Results in incomplete coagulation factor molecules which are biologically inactive

28
Q

In what conditions is warfarin indicated?

A

Start therapy after acute DVT or pulmonary embolism

Prevent embolism in patients with acute MI, prosthetic heart valves, or atrial fibrillation

29
Q

Why can warfarin not be used in pregnancy?

A

It readily crosses the placenta and can cause hemorrhagic disorder in the fetus

30
Q

Why are the effects of warfarin delayed?

A

Need to wait out the half lives of the affected Vitamin-K dependent clotting factors and anticoagulation proteins, so it takes some time.

Additionally, warfarin has a long half-life

31
Q

What is warfarin resistance and who is it common in?

A

Progression or recurrence of thrombotic event, most common in patients with advanced cancer

32
Q

What drugs increase the anticoagulant effect of Warfarin?

A
  1. Cephalosporins - kill bacteria in GI tract that make vitamin K, and directly inhibit the vitamin K epoxide reductase
  2. Aspirin
  3. Ginseng
  4. Ginkgo biloba
33
Q

What drugs decrease the anticoagulant effect of Warfarin?

A
  1. Barbituates
  2. Rifampin
  3. St. John’s wort
  4. Vitamin K -> the antidote of Warfarin overdose!!
34
Q

What are the newer oral direct inhibitors which are hitting the market?

A

Dibigatran, Rivaroxaban, and Apixaban

“Xa-ban” = Banning factor Xa

They inhibit specifically either factor Xa or thrombin (dabigatran)

35
Q

Why might the newer oral direct inhibitors be preferable to warfarin and how are they inactivated?

A

They are used in prevention of stroke primarily, may be preferable because they do not require as much blood monitoring.

However, they do have a significant bleeding risk (except apixaban) and only dabigatran can be reversed (via monoclonal antibody)

36
Q

What is necessary for t-PA enzymatic activation? What protein is it similar to?

A

Fibrin binding. This will allow it to rapidly activate plasminogen to plasmin

Similar to streptokinase, which activates plasminogen itself

37
Q

What are the derivatives of t-PA now in use and why?

A

Alteplase, Reteplase, Tececteplase

-> longer half life than regular t-PA, so they have more convenient dosing

38
Q

What conditions is t-PA indicated for? What might be more useful?

A

pulmonary embolism, severe DVT, and acute MI

Angioplasty with or without stent placement tends to be superior

39
Q

What is the primary toxicity of t-PA and what might reverse this?

A

A whole body thrombolytic state which can cause bleeding.

Could be reversible via Aminocaproic acid -> inhibitor of fibrinolysis by blocking the interaction between fibrin and plasmin. This might be a problem with problematic clots not being able to be busted by body.

40
Q

What patients should never be given fibrinolytics / thrombolytics?

A

patients with surgery history in <10 days, recent GI bleed (3 months), hypertensive patients, previous CVA or active intracranial process, aortic dissection, or acute pericarditis

41
Q

What is aspirin’s primary antiplatelet mechanism?

A

Blocks platelet aggregation and vasoconstriction by inhibiting synthesis of thromboxane A2, a vasoconstrictor, through permanent acetylation of COX-1

42
Q

How does clopidogrel (Plavix) work?

A

Inhibits platelet activation by antagonizing the platelet ADP receptor

43
Q

How do the glycoprotein inhibitors of platelet aggregation work?

A

They bind Glycoprotein IIb/IIIa, which is a platelet surface integrin which binds to fibrinogen

44
Q

What is clopidogrel an attractive medication and what is it used for?

A

Has a better toxicity profile than aspirin (upper GI bleed, especially in combination with warfarin / clopidogrel), less frequent thrombocytopenia / leukopenia

Used with aspirin after angioplasty, also in patients with recent MI or stroke, peripheral artery disease, or acute coronary syndrome

45
Q

How can glycoprotein inhibitors be reversed?

A

platelet transfusions

46
Q

What drug should aspirin not be taken with?

A

Ibuprofen, due to bloodstream interactions which can mitigate its effectiveness at stopping clotting

47
Q

What is the direct PDE3 inhibitor anti-platelet drug and how does it work?

A

Cilostazol - he lost the ball!
-> acts as a direct arterial vasodilator, especially in arteries supplying to the legs. This decreases platelet aggregation

48
Q

What is the clinical use of cilostazol?

A

Treatment of intermittent claudication, especially calves.

49
Q

Who is cilostazol contraindicated in?

A

Patients with congestive heart failure of any severity -> causes fluid retention and arrhythmias

Pharmacology (54 decks)

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