25,26 - Anticoagulant, Antiplatelet, Thrombolytic, Anti-thrombolytic Therapy: Pharmacology

Question 1

hematological pharmacology problem and strategy

Answer 1

Question 2

Important hematological drugs - overview

Answer 2

Question 3

Platelet adhesion, activation and aggregation - mechanistic process

Answer 3

Question 4

Mechanism of antiplatelets

Answer 4

Platelet adhesion and aggregation. GPVI and GPIb are platelet receptors that bind to collagen and vWF, causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR-1 and PAR-4 are PARs that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and COX-1 to promote platelet aggregation and secretion. TxA2 is the major product of COX-1 involved in platelet activation. Prostacyclin (PGI2), synthesized by endothelial cells, inhibits platelet activation.

Question 5

mechanism of ANTICOAGULANTS

Answer 5

Major reactions of blood coagulation. Shown are interactions among proteins of the “extrinsic” (TF and factor VII), “intrinsic” (factors IX and VIII), and a “common” (factors X, V, and II) coagulation pathways that are important in vivo. Boxes enclose the coagulation factor zymogens (indicated by Roman numerals); the rounded boxes represent the active proteases. Activated coagulation factors are followed by the letter a: II, prothrombin; IIa, thrombin.

Question 6

mechanism of THROMBOLYTICS/ FIBRINOLYTICS

Answer 6

Fibrinolysis. Endothelial cells secrete t-PA at sites of injury. t-PA binds to fibrin and converts plasminogen to plasmin, which digests fibrin. PAI-1 and PAI-2
inactivate t-PA; α2-AP inactivates plasmin.

Question 7

pharmacological intervention stratgeies for antiplatelets

Answer 7

Question 8

ANTIPLATELET AGENTS - Cyclooxygenase Inhibitors, mechanism and drugs

Answer 8

General Mechanism—Inhibit platelet cyclooxygenase, thereby blocking thromboxane A2 generation and inhibiting platelet granule release reaction and platelet aggregation

Aspirin:
MOA info
The inhibitory effect is rapid, and aspirin-induced suppression of thromboxane A2 and the resulting suppression of platelet aggregation last for the life of the platelet, which is approximately 7 to 10 days.

Clinical Applications:
Prophylaxis against transient ischemic attack, myocardial infarction, and thromboembolic disorders

Contraindications
Bleeding disorders such as hemophilia, von Willebrand’s
disease, or immune thrombocytopenia

Therapeutic Considerations
Use cautiously in patients with GI lesions, impaired renal function, hypoprothrombinemia, vitamin K deficiency,
thrombotic thrombocytopenic purpura, or hepatic
impairment.

Question 9

ANTIPLATELET AGENTS - Phosphodiesterase Inhibitors - mechanism and drugs

Answer 9

Mechanism—Inhibit platelet cAMP degradation and thereby decrease platelet aggregability

Drugs:
Cilostazol and Dipyridamole

Question 10

ANTIPLATELET AGENTS - ADP Receptor Pathway Inhibitors - mechanism and drugs

Answer 10

Mechanism—Inhibit platelet ADP receptor, thereby preventing receptor signaling and inhibiting ADP dependent platelet activation pathway.

Drugs:
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Tricagrelor

Ticlopidine, clopidogrel, and prasugrel covalently modify the receptor, while ticagrelor and cangrelor are reversible inhibitors.

Question 11

Answer 11

Ticagrelor

Ticlopidine, clopidogrel, and prasugrel covalently modify the receptor, while ticagrelor and cangrelor are reversible inhibitors.

Question 12

ANTIPLATELET AGENTS -
GPIIb–IIIa Antagonists - mechanism and drugs

Answer 12

Mechanism—Bind to platelet receptor GPIIb–IIIa and thereby prevent binding of fibrinogen and other adhesion ligands

Drugs:
Abciximab
Eptifibatide
Tirofiban

Question 13

ANTIPLATELET AGENTS
Thrombin Receptor (PAR-1) Antagonists
mechanism and drugs

Answer 13

Mechanism—Competitive inhibitor of protease-activated receptor 1 (PAR-1), one of the major thrombin receptors expressed on platelets

Drugs:
Vorapaxar

Question 14

all the antiplatelet drugs we need to know + their mechanism

Answer 14

Question 15

coagulation cascade

Answer 15

Question 16

coagulation cascade + protein C and fibrinolytic system

Answer 16

Question 17

anticoagulants, antiplatelets and their mechanisms

Answer 17

Question 18

ANTICOAGULANTS
hepatic epoxide reductase/vitamin K inhibitors mechanism and drugs

Answer 18

Mechanism—Inhibits hepatic epoxide reductase that catalyzes the regeneration of reduced vitamin K, which is required for synthesis of biologically active coagulation factors II, VII, IX, and X and anticoagulant proteins C and S

Drugs:
Warfarin

Question 19

ANTICOAGULANTS
Unfractionated Heparin and Low-Molecular-Weight (LMW) Heparins
mechanims and drugs

Answer 19

Mechanism
Unfractionated heparin: combines with antithrombin III and inhibits secondary hemostasis via nonselective inactivation of thrombin (factor IIa), factor Xa, factor IXa, factor XIa, and factor XIIa.

LMW heparins: combine with antithrombin III and inhibit secondary hemostasis via relatively (threefold) selective inactivation of factor Xa

Drugs:
Heparin
EnoXaparin
Dalteparin
TinZaparin

Question 20

Which must heparin bind to in order to exert its
anticoagulant effect?
* GP IIb/IIIa receptor.
* Thrombin.
* Antithrombin III.
* von Willebrand factor.

Answer 20

antithrombin 3

Unfractionated heparin: combines with antithrombin III and inhibits secondary hemostasis via nonselective inactivation of thrombin (factor IIa), factor Xa, factor IXa, factor XIa, and factor XIIa.

Question 21

ANTICOAGULANTS
Selective Factor Xa Inhibitors
mechanism and drugs

Answer 21

Mechanism:
Fondaparinux: combines with antithrombin III and inhibits secondary hemostasis via highly selective inactivation of factor Xa.

Apixaban and rivaroxaban: competitively inhibit factor Xa by binding to the active site of the enzyme

Drugs:
FondaparinuX
ApiXaban
RivaroXaban
EdoXaban

Question 22

ANTICOAGULANTS
Direct Thrombin Inhibitors
mechanism and drugs

Answer 22

Mechanism
Bind directly to thrombin and thereby inhibit secondary hemostasis

Drugs:
Argatroban
Dabigatran
Lepirudin
Desirudin
Bilva*rudin

Question 23

A 70-year-old female is diagnosed with nonvalvular
atrial fibrillation. Her past medical history is significant for
chronic kidney disease, and her renal function is moderately diminished. All of the following anticoagulants would be expected to require a reduced dosage in this patient except:

• Apixaban.
• Dabigatran.
• Rivaroxaban.
• Warfarin.

Answer 23

apixaban is typically not significantly affected by renal impairment, and a reduced dosage may not be necessary in patients with moderate renal dysfunction. However, the other options (dabigatran, rivaroxaban, and warfarin) may require dosage adjustments in patients with impaired renal function

Question 24

ANTICOAGULANTS
Recombinant Activated Protein C (r-APC)
mechanism and drugs

Answer 24

Mechanism
Proteolytically inactivates factors Va and VIIIa; may also exert anti-inflammatory effect by inhibiting tumor necrosis factor production and blocking leukocyte adhesion to selectins

Drugs:
rAPC

Question 25

THROMBOLYTIC AGENTS mechanism and drugs

Answer 25

**Mechanism** *Proteolytically activate* plasminogen to form plasmin, which digests fibrin to fibrin degradation products Drugs: **Streptokinase** **Alteplase** **Tenecteplase** **Reteplase** | Alteplase = recombinant tissue-type plasminogen activator, rt-PA

Question 26

THROMBOLYTIC AGENTS Serine-Protease Inhibitor mechanism and drugs

Answer 26

**Mechanism** Inhibits serine proteases, including plasmin, t-PA, and thrombin Drugs: **Aprotinin**

Question 27

ANTI-THROMBOLYTIC AGENTS/ ANTI-FIBRINOLYTIC AGENTS Lysine Analogues mechanism and drugs

Answer 27

**Mechanism** Analogues of lysine that bind to and inhibit plasminogen and plasmin Drugs: **Tranexamic acid** **Aminocaproic acid**

Question 28

Reversal agents for anticoagulants

Answer 28

Question 29

reversal agents for warfarin

Answer 29

Question 30

Reversal agents for heparin

Answer 30

Question 31

reversal agents for direct oral anticoagulants

Answer 31

Question 32

Answer 32

Sulfamethoxazole/trimethoprim can increase the anticoagulant effect of warfarin by displacing warfarin from protein-binding sites, leading to an elevated concentration of free, active warfarin in the bloodstream. Therefore, the correct option is: * Sulfamethoxazole/trimethoprim will increase the anticoagulant effect of warfarin.

Question 33

Answer 33

The most appropriate agent for reversing the anticoagulant effects of heparin is Protamine sulfate.

Question 34

(Multiple Choice) Mouse/human chimeric monoclonal antibody -- blocks IIb/IIIb platelet receptor A) ticlopidine B) timolol C) abciximab D) eicosapentaenoic acid E) streptokinase

Answer 34

C) Abciximab

Question 35

T/F: Unfractionated heparin and low-molecular-weight heparins (LMWH) directly inhibit thrombin in the coagulation cascade.

Answer 35

**False.**Heparins first form a complex with antithrombin III; the complex then inactivates thrombin and other clotting factors, including factors IXa, Xa and XIa. Complexes of LMWH with antithrombin have a more selective action on factor Xa.

Question 36

T/F: Fondaparinux is a pentapeptide activator of antithrombin III.

Answer 36

**False.** All heparins are mucopolysaccharides, not polypeptides. Fondaparinux is similar in structure to the pentasaccharide sequence within heparin that binds to antithrombin III.

Question 37

T/F: Warfarin readily crosses the placenta

Answer 37

**True.** Warfarin can cause fetal abnormalities and, unless essential, should not be given in early or late pregnancy.

Question 38

T/F: Warfarin prevents the synthesis of vitamin K-dependent clotting factors.

Answer 38

**True.** Warfarin inhibits vitamin K epoxide reductase (VKOR); this reduces the regeneration of the active (hydroquinone) form of vitamin K required for gamma-carboxylation of clotting factors II (prothrombin), VII, IX and X in the liver.

Question 39

T/F: The activity of warfarin is inhibited by broad-spectrum antibacterial agents.

Answer 39

**False.** Vitamin K is produced by gut bacteria, and their elimination by broad-spectrum antibacterials reduces vitamin K formation. This further impairs the synthesis of vitamin K-dependent clotting factors and enhances the anticoagulant activity of warfarin.

Question 40

T/F: Clopidogrel has its antithrombotic action by enhancing the action of ADP on platelets.

Answer 40

**False. **Clopidogrel and related drugs prevent the platelet aggregatory action of ADP by blocking its purinergic (P2Y 12 ) receptors.

Question 41

T/F: Aspirin is a reversible inhibitor of cyclooxygenase type 1 (COX-1).

Answer 41

**False.**Aspirin (acetylsalicylic acid) irreversibly inhibits COX-1 by acetylating its active site. At low doses, this produces a selective antiplatelet action, as the platelet is nonnucleated and unable to replace the COX-1 enzyme by gene transcription and protein synthesis.

Question 42

T/F: Aspirin inhibits platelet aggregation at doses below those needed for an antiinflammatory effect.

Answer 42

**True. ** Thromboxane A 2 (TXA2) required for platelet aggregation is synthesised by COX-1, whereas prostaglandins are synthesised during inflammation predominantly by induced cyclooxygenase type 2 (COX-2). Aspirin is 160 times more active at inhibiting COX-1 than COX-2, so it has no antiinflammatory effect at the low doses required to inhibit TXA 2 synthesis.

Question 43

T/F: Tenecteplase is a modified form of t-PA with a longer half-life than alteplase.

Answer 43

**True.** Alteplase is identical to the naturally occurring t-PA, whereas tenecteplase has been modified for greater fibrin specificity and a longer duration of action.

Question 44

T/F: Apixaban is a direct inhibitor of factor Xa.

Answer 44

**True.** Apixaban, edoxaban and rivaroxaban are orally active direct inhibitors of factor Xa.

Question 45

T/F: Tranexamic acid enhances plasminogen activation.

Answer 45

**False.** Tranexamic acid is an antifibrinolytic agent that inhibits plasminogen activation, reducing fibrin degradation and the risk of bleeding.

Question 46

Review of important anticoagulants, thrombolytic agents, platelet inhibitors, and treatments of bleeding

Answer 46

Question 47

Dipyridamole clinical applications and therapeutic considerations

Answer 47

dipyridamole is an antiplatelet agent, specifically a phosphodiesterase inhibitor that inhibits platelet cAMP degradation and thereby decreases plately aggregability. **clinical applications:** prophylaxis against thromboembolic disorders **Therapeutic considerations:** Weak antiplatelet effect Usually administered in combination with warfarin or aspirin

Question 48

Ticlodipine, clopidogrel, Prasugrel, Tricagrelor, Cangrelor mechanism and PK considerations

Answer 48

ANTIPLATELET AGENTS ADP Receptor Pathway Inhibitors Mechanism—Inhibit platelet ADP receptor, thereby preventing receptor signaling and inhibiting ADP-dependent platelet activation pathway. Ticlopidine, clopidogrel, and prasugrel covalently modify the receptor, while ticagrelor and cangrelor are reversible inhibitors. **MOA considerations:** Ticagrelor and Cangrelor bind to the P2Y_12 ADP receptor in a reversible manner. **PK considerations:** Clopidogrel is a prodrug and as such activated by CYP450 enzymes in the liver

Question 49

Warfarin PK consideration

Answer 49

ANTICOAGULANTS Warfarin Mechanism—Inhibits hepatic epoxide reductase that catalyzes the regeneration of reduced vitamin K, which is required for synthesis of biologically active coagulation factors II, VII, IX, and X and anticoagulant proteins C and S PK consideration: Warfarin readily crosses the placental barrier.