Drugs Used in the disorders of Coagulation Flashcards
3 Types of drugs used to reduce clotting?
Platelet Aggregation Inhibitors
Anticoagulants
Thrombolytics
4 types of platelet aggregation inhibitors?
CYCLOOXYGENASE INHIBITORS
ADP RECEPTOR BLOCKERS
PHOSPHODIESTERASE INHIBITORS
BLOCKERS OF PLATELET GP IIb/IIIA RECEPTORS
Describe Cyclooxgenase inhibitor
ASPIRIN
• Thromboxane A2 causes platelets to
degranulate and aggregate.
• Aspirin inhibits TXA2 synthesis by irreversible
acetylation of the enzyme COX.
• The anuclear platelet can’t synthesize new
proteins.
• Therefore it can’t synthesise new enzyme
during its 10-day lifetime.
Uses of Aspirin
Prophylactic treatment of transient cerebral
ischemia
• To reduce the incidence of recurrent MI
• To decrease mortality in post MI patients.
2 ADP receptor blockers?
CLOPIDOGREL & TICLOPIDINE
Describe ADP receptor blockers?
• Irreversible inhibitors of P2Y12, one of the two
subtypes of ADP receptor on the platelet surface.
• Clopidogrel has fewer adverse effects than
ticlopidine.
• Clopidogrel is preferred over ticlopidine.
Describe Clopidogrel metabolism?
Clopidogrel is a prodrug converted to an active
metabolite, mainly by CYP2C19.
• Patients who are CYP2C19 poor metabolizers
have lower plasma levels of the active
metabolite.
• Alternative treatments should be considered
for CYP2C19 poor metabolizers
concomitant use of clopidogrel with what type of drugs should be avoided, give example?
The concomitant use of clopidogrel and
CYP2C19 inhibitors should be avoided.
• Omeprazole, a CYP2C19 inhibitor, reduces
plasma levels of the active metabolite of
clopidogrel.
• Concurrent use of clopidogrel and
omeprazole should be avoided.
Uses for Clopidogrel?
Indicated to reduce the rate of stroke, MI, and
death in patients with recent MI or stroke or
acute coronary syndrome.
What are the two PHOSPHODIESTERASE INHIBITORS? What is each used for?
DIPYRIDAMOLE - Used for stroke prevention
CILOSTAZOL - Used for intermittent claudication
BLOCKERS OF PLATELET GP IIb/IIIa RECEPTORS and their use?
ABCIXIMAB EPTIFIBATIDE TIROFIBAN Adjuncts to PCI for prevention of cardiac ischemic complications.
What are the 4 types of anticoagulants?
Indirect Thrombin and Factor Xa inhibitors
• Vitamin K Antagonists
• Direct Thrombin Inhibitors
• Direct Factor Xa Inhibitors
3 types of INDIRECT THROMBIN AND FACTOR XA INHIBITORS?
- Unfractionated heparin (UFH)
- Low-molecular-weight heparins (LMWH)
- Fondaparinux
What is Heparin?
UNFRACTIONATED &
LOW-MOLECULAR-WEIGHT HEPARINS weight ranges?
• Heparin is an injectable, rapidly acting
anticoagulant, used to interfere with formation of
thrombi.
Unfractionated heparin (UFH) has a molecular
weight range of 5,000 - 30,000.
• Low-Molecular-Weight Heparins (Enoxaparin)
are produced by depolymerization of UFH. Their
molecular weights range from 1,000 – 5,000.
LMWH vs UFH difference in bioavailability, half-life, and dosing requirements?
LMWH have equal efficacy to UFH, higher
bioavailability, longer half-life, and less frequent
dosing requirements.
• LMWH are replacing UFH in many clinical
situations.
Herparin MOA?
• Antithrombin III inhibits clotting factor
proteases: thrombin, IXa and Xa.
• In the absence of heparin, antithrombin III
inhibits them very slowly.
• Binding of heparin to antithrombin III accelerates
the inhibition.
• Heparin functions as a cofactor for the
antithrombin-protease reaction.
Difference in anticoagulant activity of UFH and LMWH?
UFH efficiently inactivates both thrombin and
factor Xa
LMWH efficently inhibit Xa but have less
effect on thrombin.
Why do LMWH have little efficacy on thrombin?
LMWH molecules are of insufficient length to form the ternary complex and thus catalyze inhibition of
thrombin. In contrast, UFH efficiently inactivates both thrombin and factor Xa
How are Heparin levels monitored?
Monitoring is performed with the activated partial
thromboplastin time (aPTT) assay.
• The aPTT is a test of the integrity of the intrinsic
and common pathways of coagulation.
Difference in LMWH monitoring of Heparin levels?
• Dosing of LMWH results in predictable plasma
levels.
• It is not usually necessary to monitor LMWH
blood levels.
• The potency of LMWH can be assessed with
anti-factor Xa assays.
What is Heparin used for?
- DVT
- Pulmonary embolism
- MI
- DOC during pregnancy
AE of Heparin?
- Bleeding
- Hypersensitivity reactions
- Heparin-induced Thrombocytopenia (HIT)
Describe Heparin induced thrombocytopenia type 2 and alternative treatment>
It is caused by antibodies that recognize complexes of
heparin and a platelet protein, Platelet Factor 4 (PF4). IgG binds to the PF4/heparincomplex forming immune complexes. Then IgG binds to the Fc receptor on platelets. Fc activation leads to platelet degranulation & aggregation. The activated platelets release more PF4. New immune complexes form. This can result in thrombocytopenia (due to platelet consumption) and thrombosis that range from mild to life-threatening. The result can be deep vein thrombosis, pulmonary embolism, or even a heart attack or stroke. Platelet counts can drop 50% or more. Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor (argatroban or bivalirudin) or fondaparinux.
Reversal of Heparin?
• Excessive anticoagulant action of heparin is
treated by discontinuance of the drug.
• If bleeding occurs protamine sulfate is given.
Describe FONDAPARINUX?
• Synthetic pentasaccharide.
• Sequence of five carbohydrates that bind to
antithrombin III.
• Specific inhibitor of Xa.
• Negligible antithrombin activity.
• Approved for prevention and treatment of DVT.
Warfarin MOA?
• Warfarin antagonizes the cofactor function of
vitamin K.
• Warfarin inhibits vitamin K epoxide reductase.
• Treatment with warfarin results in the production
of inactive clotting factors, because they lack the
gamma-carboxyglutamyl side chains.
Describe Warfarin monitoring?
• Warfarin has a narrow TI and participates in
many drug–drug interactions.
• The effects of warfarin therapy must be
monitored regularly (every 2 - 4 weeks).
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• Monitoring is performed with the prothrombin
time (PT).
• This is a test of the integrity of the extrinsic and
common pathways of coagulation.
• The results are expressed as INR.
Warfarin uses and AE?
Uses:
• Prevention and treatment of DVT and PE,
following an initial course of heparin.
• Prevention and treatment of thromboembolic
complications associated with AF(atrial fibrillation).
AE of Warfarin?
• Warfarin crosses the placenta and can cause
a hemorrhagic disorder in the fetus and serious
birth defects.
• Warfarin should never be administered
during pregnancy.
• Pregnancy category X.
• Hemorrhage
• Cutaneous necrosis due to reduced activity of
protein C.
How do DTI exert their effect?
• They exert their anticoagulant effect by directly
binding to the active site of thrombin.
Two types of DTIs?
- PARENTERAL DTIs
* ORAL DTIs
PARENTERAL DTIs, list 3, how are they monitored, and their use?
DESIRUDIN BIVALIRUDIN ARGATROBAN • Monitored by the aPTT. • Used in patients undergoing PCI (percutaneous coronary intervention).
ORAL DTIs? Name one, monitoring, and use?
DABIGATRAN ETEXILATE
• Prodrug converted to dabigatran.
• Produces a predictable anticoagulant response.
• Routine monitoring is unnecessary.
• Used for prevention and treatment of DVT and PE.
DIRECT FACTOR Xa INHIBITORS, name one, use, and monitoring?
APIXABAN & RIVAROXABAN
• Oral direct factor Xa inhibitors.
• Do not require monitoring.
• Used for prevention and treatment of DVT and PE.
Which type of drugs are replacing Warfarin, give 3 examples and why and for what?
• The direct oral anticoagulants (DOACs)
dabigatran, apixaban, and rivaroxaban have
equivalent antithrombotic efficacy to warfarin and
lower bleeding rates.
• They have rapid onset of action, predictable
pharmacokinetics, wider therapeutic window, no
monitoring requirements, and fewer drug
interactions.
• They are replacing warfarin for treatment of VTE
or stroke and prevention of embolism in AF.
Describe THROMBOLYTICS (fibrinolytics)?
• Anticoagulants prevent formation of thrombi but
are ineffective against pre-existing clots.
• Thrombolytic drugs lyse blood clots and restore
the patency of obstructed vessels before distal
tissue necrosis occurs.
• Thrombolytic agents act by converting
plasminogen to plasmin.
Name 5 Thrombyltics?
- STREPTOKINASE
- UROKINASE
- ALTEPLASE
- RETEPLASE
- TENECTEPLASE
Describe Streptokinase?
- Protein produced by -hemolytic streptococci.
* Rarely used since the advent of newer agents.
Describe UROKINASE?
• Human enzyme synthesized by the kidney and
found in the urine.
• Approved for lysis of pulmonary emboli.
Describe ALTEPLASE, RETEPLASE & TENECTEPLASE?
• Tissue plasminogen activator (t-Pa) is a serine
protease produced by human endothelial cells.
• t-Pa activates plasminogen bound to fibrin in a
thrombus.
• t-Pa is “fibrin selective“, unlike streptokinase
and urokinase, which are non-fibrin-selective.
ALTEPLASE
• Recombinant t-Pa.
• Indicated for management of acute MI, and acute
ischemic stroke.
RETEPLASE & TENECTEPLASE
• Recombinant variants of t-PA with longer halflives.
Main use of each drug?
Aspirin TIA, MI, ischemic stroke Clopidogrel ACS, Ischemic stroke Dipyridamole Stroke prevention Cilostazol Intermittent claudication GP IIb/IIIa blockers PCI Heparins VTE, ACS, PCI Fondaparinux VTE, HIT Warfarin VTE, AF IV DTIs PCI, HIT Oral DTIs VTE, AF Oral FXa Inhibitors VTE, AF Thrombolytics MI, Ischemic stroke, massive PE
4 drug types used to treat bleeding?
- PLASMINOGEN ACTIVATION INHIBITORS
- PROTAMINE SULFATE
- VITAMIN K
- PLASMA FRACTIONS
Name 2 Plasminogen activation inhibitors?
AMINOCAPROIC ACID & TRANEXAMIC ACID
Describe Plasminogen activation inhibitors and use?
• Inhibits plasminogen activation.
• Uses: adjunctive therapy in hemophilia, and
therapy for bleeding from fibrinolytic therapy.
Describe Protamine Sulfate?
• Chemical antagonist of heparin.
• High in arginine.
• The cationic protein interacts with anionic
heparin to form complex with no anticoagulant
activity.
Describe Vitamin K and its various uses?
• Used to correct the bleeding tendency or
hemorrhage associated with its deficiency.
DRUG-INDUCED HYPOPROTHROMBINEMIA
• Vitamin K is available in oral and parenteral
forms.
• Onset of effect: 6 hours.
• The effect is complete by 24 hours.
• If immediate hemostasis is required, fresh-frozen
plasma should be infused.
Vitamin K use in newborns?
PREVENTION OF VITAMIN K DEFICIENCY
BLEEDING IN NEWBORNS
• All babies should receive vitamin K.
• Standard treatment is with vitamin K1 IM at birth.
Describe PLASMA FRACTIONS?
• Deficiencies in plasma coagulation factors can
cause bleeding.
• Factor VIII deficiency and factor IX deficiency
account for most of the heritable coagulation
defects.
