Issar Anticoagulants, Antiplatelets And Antithrombolic Agents

Front 1

Unfractionated Heparin

Back 1

Class:
Indirect thrombin inhibitor

Mechanism:
- binds to antithrombin via its pentasaccharide sequence inducing a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa.
- to potentiate thrombin inhibition, drug must simultaneously bind to antithrombin and thrombin. With a mean molecular weight of 15kDa, virtually all of the drug chains are long enough to do this.

Drug characteristics:
- mixture of highly electronegative acidic mucopolysaccharides consisting of repeating disaccharide units composed of glucosamine and either L-iduronic acid or D-glucosamine. Naturally present in secretory granules of circulating basophils and mast cells.

SE:
Heparin-induced thrombocytopenia (HIT). 2 types:
- Type 1: common, 25% of pt population. Mechanism - direct interaction between heparin and platelets --> platelet aggregation
- Type 2: rare, FATAL. Mechanism includes IgG antibodies vs heparin - platelet factor 4 complexes. Complex binds to Fc gamma IIa receptors --> platelet aggregation and release of more platelet factor 4 and thrombin

Contraindications:
- Ulcerative GI lesions
- Recent brain, spinal cord or eye surgery
- Threatened abortion
- Pts with preexisting bleeding tendencies
- Severe hypertension
- Bacterial endocarditis


Extra Note:
Give pt protamine to neutralize heparin if pt is bleeding too much

Front 2

Dalteparin

Back 2

Class:
Indirect thrombin inhibitor, Low Molecular Weight Heparin (LMWH)

Mechanism:
- no intrinsic anticoag activity
- bind to antithrombin (AT-III) and accelerate the rate at which it inhibits various coag proteases.
-Too short to bridge AT III to thrombin so there is a higher specificity to 10a than thrombin.

Metabolism:
liver heparinase
End stage renal disease or cirrhotic liver can reduce the heparin clearance, so adjust dose

Uses:
subcu delivery as prophylactic therapy for DVT.

Advantages:
Less bleeding, longer half life, no lab monitoring

SE:
BBW: for LMWH only, can cause spinal/epidural hematomas
Heparin-induced thrombocytopenia (HIT). 2 types:
- Type 1: common, 25% of pt population. Mechanism - direct interaction between heparin and platelets --> platelet aggregation
- Type 2: rare, FATAL. Mechanism includes IgG antibodies vs heparin - platelet factor 4 complexes. Complex binds to Fc gamma IIa receptors --> platelet aggregation and release of more platelet factor 4 and thrombin

Contraindications:
- Ulcerative GI lesions
- Recent brain, spinal cord or eye surgery
- Threatened abortion
- Pts with preexisting bleeding tendencies
- Severe hypertension
- Bacterial endocarditis

Extra Note:
Give pt protamine to neutralize heparin if pt is bleeding too much

Front 3

Enoxaparin

Back 3

Class:
Indirect thrombin inhibitor, Low Molecular Weight Heparin (LMWH)

Mechanism:
- no intrinsic anticoag activity
- bind to antithrombin (AT-III) and accelerate the rate at which it inhibits various coag proteases.
- Too short to bridge AT III to thrombin so there is a higher specificity to 10a than thrombin.

Metabolism:
liver heparinase
End stage renal disease or cirrhotic liver can reduce the heparin clearance, so adjust dose

Uses:
subcu delivery as prophylactic therapy for DVT.

Advantages:
Less bleeding, longer half life, no lab monitoring

SE:
BBW: for LMWH only, can cause spinal/epidural hematomas
Heparin-induced thrombocytopenia (HIT). 2 types:
- Type 1: common, 25% of pt population. Mechanism - direct interaction between heparin and platelets --> platelet aggregation
- Type 2: rare, FATAL. Mechanism includes IgG antibodies vs heparin - platelet factor 4 complexes. Complex binds to Fc gamma IIa receptors --> platelet aggregation and release of more platelet factor 4 and thrombin

Contraindications:
- Ulcerative GI lesions
- Recent brain, spinal cord or eye surgery
- Threatened abortion
- Pts with preexisting bleeding tendencies
- Severe hypertension
- Bacterial endocarditis

Extra Note:
Give pt protamine to neutralize heparin if pt is bleeding too much

Front 4

Fondaparinux

Back 4

Class:
Indirect thrombin inhibitor, synthetic polysaccharide

Mechanism:
- no intrinsic anticoag activity
- bind to antithrombin (AT-III) and accelerate the rate at which it inhibits various coag proteases.
- Too short to bridge AT III to thrombin so there is a higher specificity to 10a than thrombin.

Metabolism:
-liver heparinase
-End stage renal disease or cirrhotic liver can reduce the heparin clearance, so adjust dose

Uses:
- subcu delivery as prophylactic therapy and tx for DVT
- prophylactic tx to prevent clotting in arterial and heart surgery, abdominal or hip replacement surgeries, during blood transfusions, and in renal dialysis and blood sample collection

SE:
Heparin-induced thrombocytopenia (HIT). 2 types:
- Type 1: common, 25% of pt population. Mechanism - direct interaction between heparin and platelets --> platelet aggregation
- Type 2: rare, FATAL. Mechanism includes IgG antibodies vs heparin - platelet factor 4 complexes. Complex binds to Fc gamma IIa receptors --> platelet aggregation and release of more platelet factor 4 and thrombin

Contraindications:
- Ulcerative GI lesions
- Recent brain, spinal cord or eye surgery
- Threatened abortion
- Pts with preexisting bleeding tendencies
- Severe hypertension
- Bacterial endocarditis

Extra Note:
Give pt protamine to neutralize heparin if pt is bleeding too much

Front 5

List all Indirect Thrombin Inhibitors

Back 5

Unfractionated Heparin
Enoxaparin (LMWH)
Dalteparin (LMWH)
Fondaparinux (Synthetic polysaccharide)

Front 6

Lepirudin

Back 6

Class:
Direct thrombin inhibitors

Mechanism:
- Directly bind to thrombin to prevent thrombin-medicated activation of fibrinogen and factor XIII
- Why for is this drug highly effective?
because it inhibits both free and fibrin bound thrombin. And the binding to thrombin is irreversible.

Drug characteristics:
- short T1/2

Use:
- HIT

Front 7

Desirudin

Back 7

Class:
Direct thrombin inhibitors

Mechanism:
Directly bind to thrombin to prevent thrombin-medicated activation of fibrinogen and factor XIII

Use:
Prophylaxis against DVT in pts undergoing hip replacement

Front 8

Bivalirudin

Back 8

Class:
Direct thrombin inhibitors

Mechanism:
- Directly bind to thrombin to prevent thrombin-medicated activation of fibrinogen and factor XIII
- thrombin slowly cleaves an arginine-proline bond in this drug (this could cause a reduction in efficacy)

Use:
- Pts undergoing coronary angiography and angioplasty and may reduce rates of bleeding relative to heparin for this indication

Extra note:
very slow cleavage by thrombin, slowly inactivating the drug and therefore decreasing efficacy over time

Front 9

Agatroban

Back 9

Class:
Direct thrombin inhibitors

Mechanism:
Binds only to the active site of thrombin - does not interact with exosite.

Uses:
tx for pts with HIT.

Metabolism:
Biliary - CYP3A4 dependent metabolism. Therefore ok to give in renal insufficiency

Front 10

Dabigatran

Back 10

Class:
Direct thrombin inhibitors

Mechanism:
Prodrug. Binds only to the active site of thrombin - does not interact with exosite.

Use:
- prevention of thromoembolsm in pts with non-valvular AFib

Front 11

List the Direct Thrombin Inhibitors

Back 11

Lepirudin
Desirudin
Bivalirudin
Agatroban
Dabigatran

Front 12

Warfarin

Back 12

Class:
Oral anticoagulant (OA)

Mechanism:
1) acts on carboxylation pathway, not by inhibiting the carboxylase directly, but by blocking the epoxide reductase that mediates the regeneration of reduced vitamin K
2) Depletion of reduced vitamin K in the liver prevents carboxylation reaction that is required for the synthesis of biologically active coagulation factors

Metabolism:
CYP2C9

Use:
- prophylaxsis and
tx for DVT and prevention of PE
- prevention of systemic embolism from rheumatic valvular disease and artificial heart valve.
- heparin is often given together with this drug for the first 2-7days until prothrombin time (PR)

Why for onset delay?
action of oral anticoags parallels the half life of coag factors in circulation (specifically: II, VII, IX, and X). Factor VII has the shortest half life (6hrs). Therefore the effect of single dose is not felt for ~18-24hrs (3-4 times the half life of VII). No other anticoag has this onset delay!

Resistance:
the VKORC1 is the site of genetic resistance, and depending on the VKORC1 haplotype, pts may be more or less sensitive to the drig and may required increase or decrease in dose.

Drug characteristics:
~100% absorbed orally
t1/2 = 36hrs, onset delay = 8-12hrs
Highly protein bound to plasma (99%)

SE:
- bleeding = most serious and most common
- nausea, vomiting, diarrhea
- skin necrosis due to widespread thrombosis in microvasculature
- overdose tx = vitamin K (IV) or fresh frozen plasma or prothrombin complex concentrates (PCC)

Contraindications:
similar to heparin. Never administered to pregnant ladies because it can cross placenta and cause baby hemorrhage or have congenital defects.

Front 13

Aspirin (ASA)

Back 13

Class:
Antiplatelet agent

Mechanism:
Irreversible inhibitor of COX-1 in platelets (covalently aceylates serine residue at active site or COX enzyme)
- In case you forgot like I did, COX-1 converts AA --> TxA2 and therefore other platelets can't be activated
- High dose --> inhibition of COX-1 in endothelial cells -x-> PGI2 (vasodilator)

Uses:
- prevent MI or stroke
- prevent recurrence or TIA or stroke

SE:
GI discomfort or bleeding. Take with food

Front 14

Ticlopidine

Back 14

Class:
ADP inhibitor - thienopyridines

Mechanism:
irreversibly inhibits platelet ADP receptors. Act to covalently modify and inactivate the platelet P2Y (ADP) receptors (also known as P2Y12)

Drug characteristics:
- oral, 1st gen, prodrug
- 8-11day onset delay (shorten with aspirin)

Metabolism:
Liver converts prodrug --> active thiol metabolite

SE:
BBW - hematological: neutropenia/agranulocytosis, thrombotic thrombocytopenia purpura, aplastic anemia. Monitor WBC for 1st 3mos

Extra Note:
More effective than aspirin because ADP is a stronger stimulus of platelet activation and aggregation

Front 15

Clopidrogrel

Back 15

Class:
ADP inhibitor - thienopyridines

Mechanism:
irreversibly inhibits platelet ADP receptors. Act to covalently modify and inactivate the platelet P2Y (ADP) receptors (also known as P2Y12)

Drug Characteristics:
- oral, 2nd gen, prodrug

Metabolism:
CYP2C19 and CYP450

SE:
- BBW - poor metabolizer treated with clopidogrel show higher rates of CV events
- neutropenia, thrombocytopenia purpura (but less of these than ticlopidine)

Drug interactions:
- statins, proton-pump inhibitors (drugs metabolized by CYP450)

Extra Note:
More effective than aspirin because ADP is a stronger stimulus of platelet activation and aggregation

Front 16

Prasugrel

Back 16

Class:
ADP inhibitor - thienopyridines

Mechanism:
irreversibly inhibits platelet ADP receptors. Act to covalently modify and inactivate the platelet P2Y (ADP) receptors (also known as P2Y12)

Drug characteristics:
- 3rd gen, prodrug

Metabolism:
- more effectively metabolized by CYP3A4 therefore higher [active form] and more complete inhibition of P2Y ADP receptor

SE:
- BBW - bleeding risk (because they are so good at inhibiting P2Y ADP), contraindicated in conditions like active pathological bleeding, hx of transient ischemic attacks/stroke

Extra Note:
More effective than aspirin because ADP is a stronger stimulus of platelet activation and aggregation

Front 17

Ticagrelor

Back 17

Class:
ADP inhibitor - thienopyridines

Mechanism:
REVERSIBLY interacts with P2Y12 ADP receptor to prevent signal transductionand platelet activation

Drug characteristics:
oral, both parent and active metabolite have same activity in vivo

Use:
- prevent thrombosis in percutaneous coronary intervention
- given as ASA + Clopid or prasugrel for 1yr
- alternative to ASA for prophylaxis MI, TIA or previous stroke

Extra Note:
More effective than aspirin because ADP is a stronger stimulus of platelet activation and aggregation

Front 18

Name all of the ADP inhibitors - the thienopyridines

Back 18

Ticlopidine
Clopidrogrel
Prasugrel
Ticagrelor

Front 19

Abciximab

Back 19

Class:
Platelet gylocoprotein IIB//IIIA receptor blocker

Mechanism:
- GP IIB/IIIA can be expressed on the platelet surface, the expression activated by thrombin, ADP, collagen, and TxA2. GPIIB/IIIA is an integrin receptor for fibrinogen and von Willebrand factor (vWF).
- bind to the GP IIb/IIIA receptors on surface of platelets, preventing interaction with fibrinogen. Powerful inhibitors of platelet aggregation

Drug characteristics:
- chimeric mouse-human monoclonal antibody directed against human GP IIb/IIIA receptor. -Irreversible binding.
- reverse effects by giving fresh platelets

Front 20

Tirofiban

Back 20

Class:
Platelet gylocoprotein IIB//IIIA receptor blocker

Mechanism:
- GP IIB/IIIA can be expressed on the platelet surface, the expression activated by thrombin, ADP, collagen, and TxA2. GPIIB/IIIA is an integrin receptor for fibrinogen and von Willebrand factor (vWF).
- bind to the GP IIb/IIIA receptors on surface of platelets, preventing interaction with fibrinogen. Powerful inhibitors of platelet aggregation

Drug characteristics:
non-peptide tyrosine analogue that reversibly antagonizes fibrinogen binding to platelet GP IIb/IIIIa receptors

Front 21

Eptifibatide

Back 21

Class:
Platelet gylocoprotein IIB//IIIA receptor blocker

Mechanism:
- GP IIB/IIIA can be expressed on the platelet surface, the expression activated by thrombin, ADP, collagen, and TxA2. GPIIB/IIIA is an integrin receptor for fibrinogen and von Willebrand factor (vWF).
- bind to the GP IIb/IIIA receptors on surface of platelets, preventing interaction with fibrinogen. Powerful inhibitors of platelet aggregation

Drug characteristics:
reversible inhibitor of platelet aggregation

Front 22

List all the platelet glycoprotein IIb/IIIa receptor blockers

Back 22

Abciximab
Tirofiban
Eptifibatide

Front 23

Dipyridamole

Back 23

Class:
Phosphodiesterase inhibitor

Mechanism:
1) interferes with platelet function by increasing cellular [cAMP], mediated by inhibition of cyclic nucleotide phosphodiesterases
2) blockade of uptake of adenosine, which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase and cellular cAMP

Drug characteristic:
- oral
- weak antiplatelet effect so give with aspirin (reduce chance of thrombus in pts with thrombotic diathesis) or warfarin (inhibits thrombus formation on prosthetic heart valves)
- vasodilatory properties

SE:
- vasodilatory properties could cause angina in pts with CAD because blood is shunted to dilated vessels, decreasing blood supply to other parts of heart (CORONARY STEAL)

Front 24

Cilostazol

Back 24

Class:
Phosphodiesterase inhibitor

Mechanism:
selective inhibitor of phosphodiesterase III (PDE III) that causes accumulation of cAMP in many cells including blood platelets

Contraindicated:
- pts with CHF of any severity

Front 25

Alteplase
Tissue plasminogen activator (t-PA)

Back 25

Class:
Thrombolytic (fibrinolytic) drug

Mechanism:
- binds to newly formed thrombi with high affinity, causing fibrinolysis at the site of thrombus. Once bound to the fresh thrombus, drug undergoes a conformational change that renders it a potent activator of plasminogen. In contrast, drug is a poor activator of plasminogen in absence of fibrin-binding.

Drug characteristics:
- recombinant form of naturally occurring thrombolytic enzyme
- serine protease produced by human endothelial cells - not antigenic

Front 26

Reteplase

Back 26

Class:
Thrombolytic (fibrinolytic) drug

Mechanism:
- has increased fibrin specificity relative to t-PA and is resistant to plasminogen activator inhibitor-1 (PAI-1). Otherwise, same mechanism as t-PA:
- binds to newly formed thrombi with high affinity, causing fibrinolysis at the site of thrombus. Once bound to the fresh thrombus, drug undergoes a conformational change that renders it a potent activator of plasminogen. In contrast, drug is a poor activator of plasminogen in absence of fibrin-binding.

Drug characteristic:
- genetically engineered variant of t-PA

Use:
"accelerated" regimen for coronary thrombolysis
- double bolus given every 30min

Front 27

Tenecteplase

Back 27

Class:
Thrombolytic (fibrinolytic) drug

Mechanism:
- has increased fibrin specificity relative to t-PA and is resistant to plasminogen activator inhibitor-1 (PAI-1). Otherwise, same mechanism as t-PA:
- binds to newly formed thrombi with high affinity, causing fibrinolysis at the site of thrombus. Once bound to the fresh thrombus, drug undergoes a conformational change that renders it a potent activator of plasminogen. In contrast, drug is a poor activator of plasminogen in absence of fibrin-binding.

Drug characteristic:
- genetically engineered variant of t-PA
- longer t1/2 compared to t-PA
- can be given in a single bolus

SE:
- serious hemorrhage, treated by giving a fibrinogen in the form of plasma concentrates or aminocaproic acid - a competitive inhibitor of plasminogen activation

Front 28

List all the Thrombolytic (fibrinolytic) drugs

Back 28

The "plase's"

Alteplase
Reteplase
Tenecteplase

Front 29

Vitamin K1

Back 29

Class:
Hemostatic agent

Mechanism:
- found in food
- essential cofactor in the gamma-carboxylation of multiple glutamate residues of several clotting factors and anticoag proteins.
- adequate bile salts are required for oral absorption

Uses:
- available as prescription
- Administration to all newborns to prevent hemorrhagic disease of vitamin K deficiency, esp common in premies
- IV feeding to pts in ICU with dietary deficiency
- IV in reversing bleeding episodes induced by oral anticoagulants
- IV should be slow. Rapid infusion can cause dyspnea, chest and back pain and even death :(

Front 30

Vitamin K2

Back 30

Class:
Hemostatic agent

Mechanism:
- not available as prescription
- found in human tissues and is synthesized by intestinal flora
- essential cofactor in the gamma-carboxylation of multiple glutamate residues of several clotting factors and anticoag proteins.
- adequate bile salts are required for oral absorption

Uses:
- Administration to all newborns to prevent hemorrhagic disease of vitamin K deficiency, esp common in premies
- IV feeding to pts in ICU with dietary deficiency
- IV should be slow. Rapid infusion can cause dyspnea, chest and back pain and even death :(

Front 31

List the hemostatic agents

Back 31

Vitamin K1
Vitamin K2

Front 32

Aminocaproic acid

Back 32

Class:
FIbrinolytic inhibitor

Mechanism:
- lysine analogue that completes for lysine binding sites on plasminogen and plasmin, blocking the interaction of plasmin with fibrin.

Uses:
- potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis (however thrombi that form during tx with this drug are NOT lysed)
- reduce bleeding after prostatic surgery or after tooth extractions in hemophiliacs

Front 33

Tranexamic acid

Back 33

Class:
FIbrinolytic inhibitor

Mechanism:
- lysine analogue that completes for lysine binding sites on plasminogen and plasmin, blocking the interaction of plasmin with fibrin.

Use:
- controlling heavy menstrual bleeding
- adjust dose with renal impairment

Front 34

List all the FIbrinolytic inhibitors

Back 34

Aminocaproic acid
Tranexamic acid

Front 35

Rivaroxaban

Back 35

Class:
Other agents

Mechanism:
direct inhibition of factor Xa, also inhibits free and clot bound factor Xa

Metabolism:
CYP3A4 and CYP2J2

Uses:
Prevention of DVT in pts undergoing knee and hip replacement