25,26 - Anticoagulant, Antiplatelet, Thrombolytic, Anti-thrombolytic Therapy: Pharmacology Flashcards
hematological pharmacology problem and strategy
Important hematological drugs - overview
Platelet adhesion, activation and aggregation - mechanistic process
Mechanism of antiplatelets
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.
mechanism of ANTICOAGULANTS
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.
mechanism of THROMBOLYTICS/ FIBRINOLYTICS
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.
pharmacological intervention stratgeies for antiplatelets
ANTIPLATELET AGENTS - Cyclooxygenase Inhibitors, mechanism and drugs
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.
ANTIPLATELET AGENTS - Phosphodiesterase Inhibitors - mechanism and drugs
Mechanism—Inhibit platelet cAMP degradation and thereby decrease platelet aggregability
Drugs:
Cilostazol and Dipyridamole
ANTIPLATELET AGENTS - ADP Receptor Pathway Inhibitors - mechanism and drugs
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.
Ticagrelor
Ticlopidine, clopidogrel, and prasugrel covalently modify the receptor, while ticagrelor and cangrelor are reversible inhibitors.
ANTIPLATELET AGENTS -
GPIIb–IIIa Antagonists - mechanism and drugs
Mechanism—Bind to platelet receptor GPIIb–IIIa and thereby prevent binding of fibrinogen and other adhesion ligands
Drugs:
Abciximab
Eptifibatide
Tirofiban
ANTIPLATELET AGENTS
Thrombin Receptor (PAR-1) Antagonists
mechanism and drugs
Mechanism—Competitive inhibitor of protease-activated receptor 1 (PAR-1), one of the major thrombin receptors expressed on platelets
Drugs:
Vorapaxar
all the antiplatelet drugs we need to know + their mechanism
coagulation cascade
coagulation cascade + protein C and fibrinolytic system
anticoagulants, antiplatelets and their mechanisms
ANTICOAGULANTS
hepatic epoxide reductase/vitamin K inhibitors mechanism and drugs
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
ANTICOAGULANTS
Unfractionated Heparin and Low-Molecular-Weight (LMW) Heparins
mechanims and drugs
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
Which must heparin bind to in order to exert its
anticoagulant effect?
* GP IIb/IIIa receptor.
* Thrombin.
* Antithrombin III.
* von Willebrand factor.
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.
ANTICOAGULANTS
Selective Factor Xa Inhibitors
mechanism and drugs
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
ANTICOAGULANTS
Direct Thrombin Inhibitors
mechanism and drugs
Mechanism
Bind directly to thrombin and thereby inhibit secondary hemostasis
Drugs:
Argatroban
Dabigatran
Lepirudin
Desirudin
Bilva*rudin
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.
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
ANTICOAGULANTS
Recombinant Activated Protein C (r-APC)
mechanism and drugs
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
THROMBOLYTIC AGENTS
mechanism and drugs
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
THROMBOLYTIC AGENTS
Serine-Protease Inhibitor
mechanism and drugs
Mechanism
Inhibits serine proteases, including plasmin, t-PA, and thrombin
Drugs:
Aprotinin
ANTI-THROMBOLYTIC AGENTS/ ANTI-FIBRINOLYTIC AGENTS
Lysine Analogues
mechanism and drugs
Mechanism
Analogues of lysine that bind to and inhibit plasminogen and plasmin
Drugs:
Tranexamic acid
Aminocaproic acid
Reversal agents for anticoagulants
reversal agents for warfarin
Reversal agents for heparin
reversal agents for direct oral anticoagulants
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.
The most appropriate agent for reversing the anticoagulant effects of heparin is Protamine sulfate.
(Multiple Choice) Mouse/human chimeric monoclonal
antibody – blocks IIb/IIIb platelet receptor
A) ticlopidine
B) timolol
C) abciximab
D) eicosapentaenoic acid
E) streptokinase
C) Abciximab
T/F: Unfractionated heparin and low-molecular-weight heparins (LMWH) directly inhibit thrombin in the coagulation cascade.
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.
T/F: Fondaparinux is a pentapeptide activator of antithrombin III.
False. All heparins are mucopolysaccharides, not polypeptides. Fondaparinux is similar in structure to the pentasaccharide sequence within heparin that binds to antithrombin III.
T/F: Warfarin readily crosses the placenta
True. Warfarin can cause fetal abnormalities and, unless essential, should not be given in early or late pregnancy.
T/F: Warfarin prevents the synthesis of vitamin K-dependent clotting factors.
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.
T/F: The activity of warfarin is inhibited by broad-spectrum antibacterial agents.
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.
T/F: Clopidogrel has its antithrombotic action by enhancing the action of ADP on platelets.
**False. **Clopidogrel and related drugs prevent the platelet aggregatory action of ADP by blocking its purinergic (P2Y 12 ) receptors.
T/F: Aspirin is a reversible inhibitor of cyclooxygenase type 1 (COX-1).
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.
T/F: Aspirin inhibits platelet aggregation at doses below those needed for an antiinflammatory effect.
**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.
T/F: Tenecteplase is a modified form of t-PA with a longer half-life than alteplase.
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.
T/F: Apixaban is a direct inhibitor of factor Xa.
True. Apixaban, edoxaban and rivaroxaban are orally active direct inhibitors of factor Xa.
T/F: Tranexamic acid enhances plasminogen activation.
False. Tranexamic acid is an antifibrinolytic agent that inhibits plasminogen activation, reducing fibrin degradation and the risk of bleeding.
Review of important anticoagulants, thrombolytic agents, platelet inhibitors, and treatments of bleeding
Dipyridamole clinical applications and therapeutic considerations
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
Ticlodipine, clopidogrel, Prasugrel, Tricagrelor, Cangrelor mechanism and PK considerations
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
Warfarin PK consideration
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.
