Sketchy Pharm - Anticoagulants and Thrombolytics

Question 1

Explain the MOA of heparin.What is heparin used for?

Answer 1

• Heparin is a large negatively charged molecule and due to its large size it is able to inhibit multiple clotting factors
• Unfractioned Heparin forms a complex with antithrombin III -> antithrombininactivates factor IXa, Xa, XIa, and XIIa by forming stable complexes with them.
• Most of the effects come from irreversibly binding to and inhibiting Factors Xa and II (thrombin).
  Clinical Use:
• For DVT, PE and acute MI
• PTT measures heparin activity (since it measures the intrinsic and common pathway). PTT is monitored in patients taking heparin.
• Heparin can only be used to prevent further clotting and prophylactically – it is NOT a thrombolytic. Should be used for acute treatment of embolus (DVT & PE) before later switching to warfarin, since heparin is fast acting, in these cases IV heaprin is used.

Question 2

What are the side effects of heparin?What can be used to reverse the adverse effects of heparin?

Answer 2

• Bleeding
• Heparin Induced thrombocytopenia (HIT), it is the most common cause of thrombocytopenia in hospitalized patients. Ab’s against heparin bound to platelet Factor IV -> thrombocytopenia// the Ab’s not only cause platelet destruction but also cause their activation (fragments of destroyed platelets may activate remaining platelets activation) -> hypercoagulable state w/ thrombocytopenia). Can cause hypoaldosteronism, there is a toxic effect of heparin on adrenal cortex cells -> this leads to Hyperkalemia (T4 RTA).
• Osteoporosis. Heparin decreases bone formation leading to osteoporosis
  Protamine sulfate can be used to reverse the adverse effects of heparin such as HIT.

Question 3

Explain the MOA of protamine sulfate.

Answer 3

Protamine Sulfate = (+) charged peptide that binds to unfractionated (big) heparin (-charge). It reverses the anticoagulant effect of unfractioned heparin

Question 4

Explain the MOA of LMWH, its indications and its side effects.

Answer 4

• LMWH (-parin) – binds antithrombin III but is a shorter polypeptide -> complex inhibits Factor Xa with less effect on thrombin (basically, can’t bind both at once).
• Has a greater bioavailability and longer half-life than heparin.
• Does not require routine monitoring; cannot be monitored by PTT -> need to use a Xa assay to assess activity.
• Less likely to induce HIT (but still possible) and is preferred over heparin for pregnancy.
• Heparin is SAFE in pregnancy. Though LMWH is preferred in pregnancy.

Question 5

How is heparin and LMWH excreted?

Answer 5

Heparin is excreted via liver whereas LMWH is excreted via kidneys, so renal insufficiency can increase the half life of LMWH.

Question 6

Fondaparinux.Explain the MOA and indications of Fondaparinux and also that of direct thrombin inhibitors.

Answer 6

Fondaparinux:
* Binds Antithrombin III and inhibits Factor Xa with high specificity (does not affect F.II). Has the lowest risk of HIT
* Cannot be inhibited by protamine sulfate.
Direct thrombin inhibitors:
Bivalirudin is a direct thrombin inhibitor. Use in cases of HIT.
Argatroban &Dabigatran: direct thrombin inhibitor. Use in cases of HIT.
Rivaroxaban and Apixaban – direct Factor Xa inhibitors. Especially convenient – can be given as fixed oral doses. No need for routine blood tests. Good for use as stroke prophylaxis in cases of A-Fib.

Question 7

Explain the MOA of warfarin.Does it exhibit a rapid or delayed effect?

Answer 7

Inhibits vitamin K enzyme epoxide reductase which is responsible for converting vitamin K to its active form, this reaction happens in the liver.Vitamin K dependent factors are 2, 7, 9, 10, C, and S – VitK acts as a cofactor for an enzyme that gamma carboxylates them (at their glutamic acid residue) during synthesis of these proteins. So Warfarin will only effect synthesizing factors, not currently existing ones -> Warfarin displays a delayed effect.Factor VII is the first one to ‘go down’ since it has the shortest half life of all the coagulation factors.

Question 8

Explain the MOA of Protein C and Protein S.

Question 9

How can we measure the extent of activity of warfarin to determine therapeutic dose?What are its indications?

Answer 9

Warfarin is good for long-term anticoagulation in A-Fib (1st line for long-term prophylaxis), DVT and PE. But during acute event, use heparin! Then switch to warfarin later due to its delayed effects.

• Warfarin can be taken orally and has a long half-life. It is good for long-term therapy.
• Need monitoring of PT (prothrombin time) levels (extrinsic measure d/t being used to measure Factor VII specifically*).
• INR is also used to assess warfarin activity. Recommended value for therapeutic levels is INR 2-3 (we normally have INR around 1).

Question 10

What are the side effects of warfarin?How can we reverse the adverse effects caused by warfarin?

Answer 10

• CAUTION: Warfarin is teratogenic – can cause neonatal hemorrhage and abnormal bone formation (by inhibiting important carboxylation reactions).
• Risk of bleeding – contraindicated in patients with cerebral hemorrhage!
• Warfarin-induced skin necrosis is also possible! - d/t a hypercoagulable state in the first few days of therapy, leads to blanche infarction of superficial tissue – This is due to Anticoagulant Protein C activity being reduced early in warfarin therapy (Protein C has a short half-life, so its inhibited synthesis will show effects sooner than most of the other factors) -> co-administer heparin during the first few days of warfarin therapy to prevent the early hypercoagulable state. *This can also be seen in patients with underlying Protein C deficiency.
• One of the most concerning side effects of warfarin is precipitation of cerebral hemorrhage.
• Warfarin anticoagulation can be reversed with Vitamin K – but it will be a delayed effect since new factors will still need to be synthesized. Fresh Frozen Plasma provides immediate coagulation factors for immediate warfarin reversal which is much faster than administering vitamin K.
• Warfarin is metabolized by CYP450. So it has numerous interactions with other drugs

Question 11

Explain some of the agents that promote platelet adhesion and aggregation.

Answer 11

• ADP assists in platelet aggregation by binding to P2Y12 receptors. ADP also induces GpIIb/IIIa expression for cross-linking to Fibrinogen for further aggregation.
• 5-HT (serotonin) assists in platelet aggregation and acts locally as a vasoconstrictor.
• TXA2 (thombaxane A2) -> recruits nearby platelets by causing them to change shape, aggregate, and degranulate. TXA2 also acts as a local vasoconstrictor. (Arachadonic Acid (AA) made into TXA2 by COX-1 in the platelet).

Question 12

What is the MOA and side effects of aspirin.

Answer 12

ASA (Acetylsalicylic acid) inhibits COX-1 and COX-2. Low levels will affect COX-1 more. Aspirin irreversibly inhibits COX1/2 via Acetylation -> lasts for the lifetime of the platelet, inhibits synthesis of thromabaxane.ASA is associated with pseudo-allergy may occur due to excess Leukotriene synthesis, it is a pseudoallergy since it is not IgE mediated -> use ADP inhibitor instead.

Question 13

Name ADP receptor antagonists, their indications, MOAand side effects.

Answer 13

Thienopyridines, ADP receptor P2Y12 inhibitor: ticlopidine, clopidogrel and prasugrel. These agents reduce platelet aggregation by inhibiting the ADP pathway of the platelets.

• Irreversibly inhibits ADP receptors. Can reduce cardiovascular events in patients w/ peripheral artery disease and/or angina. These drugs irreversible bind to the surface ADP receptor, P2Y12 thus inhibiting platelet aggregation
• Use Antiplatelet therapy in cases of acute ST elevation MI - Can be use dual therapy as well (ASA + ADP receptor inhibitor). Dual antiplatelet therapy (consisting of aspirin and ADP receptor blocker) reduces risk of coronary stent thrombosis.
• Antiplatelet therapy is also important in preventing ischemic stroke in patients w/ atherosclerosis or cerebrovascular disease. Need to chew the first dose of aspirin for immediate effect in the case ofSTEMI
• Acute ischemic stroke is also treated with dual antiplatelet therapy
• Tyclopidine (“TY COBB”) – can cause neutropenia and granulocytopenia – monitor using complete WBC’s every 2 weeks. Due to this effect clopidogrel is the first line use as an ADP blocker

Question 14

What test can we use to monitor the activity of anti platelet agents?

Answer 14

Bleeding time,assess platelet function and it can be prolonged via anti platelet therap

Question 15

What are some of the other anti platelet drugs used other than ADP receptor inhibitors?What are their side effects?

Answer 15

• GpIIbIIIa receptor inhibitors – abciximab (“abc” sports broadcasting) – IgG monoclonal antibody – CAUTION: can cause drug induced thrombocytopenia -> prolonged bleeding time. Need to monitor patients platelet count. Eptifibatide and Tirofiban – (“Tied” game) – block fibrinogen binding by blocking GpIIbIIIa receptors. CAUTION: can cause drug induced thrombocytopenia -> prolonged bleeding time. Need to monitor patients platelet count

Question 16

Name the phosphodiesterase inhibitors, thier MOA and side effects.

Answer 16

• Phosphodiesterase inhibitors - -> ↑cAMP -> activation of Protein Kinase A -> impaired platelet function. This impairs platelet aggregation and leads to inhibition of formation of platelet plug.
  Dipyridamole, can be used with aspirin for dual platelet therapy.
  Cilostazol – also causes vasodilation – helpful when treating symptoms of claudication d/t peripheral artery disease. Can cause coronary steal (in patients with coronary artery disease the coronary arteries are already maximally dilated due to localized ischemia, if a vasodilator is given then only peripheral blood vessels will be further dilated, stealing the blood away from coronary arteries, exacerbating ischemia, hence the term coronary steal)

Question 17

Name thrombolytic agents.What is unique about their MOA?

Answer 17

• Alteplase, Reteplase, Tenecteplase – these are recombinant forms of TPA
• Streptokinase
  Fibrinolytics can be administered in acute settings to accelerate clot lysis, all the previous drugs that we talked about were for prevention of clotformation or for prohylaxis, they dont do anything to clots that have already formed.

Question 18

What is the MOA of tPA and streptokinase?What tests can we use to measure their activity?What are their indications and side effects?

Answer 18

• tPA and Streptokinase work by activating Plasminogen (“plasma general”) into Plasmin which degrades fibrin clot - since it is destroying the end-product of the clotting cascade -> it is affecting both PT & PTT. Degradation of fibrin -> D-dimers.
• Fibrinolytics can be administered in acute settings to accelerate clot lysis. Can be used in the setting of ischemic stroke (when a patient is having an acute MI, if he cant receive percutaneous coronary intervention with 3 to 4.5 hours, then it is “fibrinolysis time”, have to do fibrinolytic therapy for acute MI). Can be used for acute treatment of severe DVT and PE and be used in the acute management of MI.
• Primary Percutaneous Coronary Intervention (the stent bat) is the preferred reperfusion option in acute STEMI if available within 2 hours.
• Main adverse effect is increased risk of bleeding (e.g. intracranial hemorrhage, GI hemorrhage, etc.) – don’t use if had recent intracranial surgery or recent head trauma.
• Severe HTN is also a contraindication.
• Streptokinase is antigenic, can cause an allergic reaction and even anaphylaxis.

Question 19

What can be used to reverse the adverse effects of fibrinolysis?

Answer 19

• Aminocaproic Acid – can be used to reverse effects of fibrinolysis – Works by competitively inhibiting plasminogen activation.
• Transexamic Acid – can also be used to reverse fibrinolysis by the same mechanism.
• If needed, clotting factors can be given via Fresh Frozen Plasmaor Cryoprecipitate (“cryo-pac”)