Anticoagulants Pharmacology Flashcards
Role of the following
- PFA100
- Thromboxane A2
- ADP receptor
- GpIIb/IIIa
- PFA100: measure of platelet function
- Thromboxane A2 (vasoconstrictor)produced by activated platelets using COX1
- ADP receptor: Platelet aggregation & activation
- GpIIb/IIIa used to bind to fibrinogen &vWF factor
Three main targets for antiplatlets
COX inhibitors
ADP receptor inhibitors
GpIIb/IIIa receptor inhibitor
2 drugs that are COX inhibitors
- Asprin (irreversible)
2. NSAIDS (reversiable)
Aspirin
Indications
NOT indicated for
Mechanism
Kinetics
SE
Indications
• 1 & 2 prevention of peripheral arterial thrombosis
• Placental insufficiency
• Prevention of venous thromboembolism
• CAD/angina/MI
• + warfarin: patients with mechanical heart valves
• Afib in patients who can’t take warfarin
Not indicated for
• Stroke prevention in atrial fibrillation & mechanical heart valves
Mechanism • Thromboxane A2 derived from arachidonic acid using COX protein important for platelet aggregation using • Aspirin irreversibly acetylates COX o Can’t produce TXA2 o Inhibits platelet aggregation
Kinetics
• Short half-life but
• Since irreversible binding you have to wait 7-10 days to replace your platelets
• Stop 10 days before surgery
SE
• GI distress
• Bleeding
NSAIDS
- Hw long until peak effect?
- Which has longer half life naproxen or ibuprofen
- When is platelet function restored
- SE
- Peak effect 1-2 hours after dose
- Ibuprofen shorter hl so stopped 1-2 days before surgery
- Naproxen longer hl so stopped many days before surgery
- Restore platelet function when drug is cleared
- Excreted in urine within 24 hours
SE
• GI distress
• Bleeding
2 big categories of ADP receptors
THIENOPYRIDINES & TICAGRELOR
2 types of thienopyridines
Clopidogrel & prasugrel
3 benefits of prasugrel over clopidogrel
- Less drug resistance
2. Reach peak effect & steady state sooner
Mechanisms of thienopyridines (clopidergrel & prasugrel)
How is it different from ticagrelor
- Irreversible inhibition of ADP receptor mediated platelet aggregation
- Prodrug
Ticagrelor - Reversable
Clopidogrel
- Indications
Prassugrel
- Indications
Clopidogrel
• 2 prevention arterial thrombosis
• Prevention of coronary stent thrombosis
• Transient cerebral ischemia
• Recurrent arterial Thromboemboli despite treatment with aspirin
Prassugrel (only after acute coronary syndroms)
• Acute coronary syndromes with percutaneous coronary interventions
• Prevent coronary stent thrombosis
Clopidogrel metaobilism inhibited by
atovastatin
Side effect unique to clopidergrel
SE unique to prasugrel
SE common to clopidegral & prasgrel
SE unique clopidogrel
• Rash & diarrhea
• Drug resistance
SE unique to prasugrel
• Increased risk of stroke so contraindicated in patient with TIA and strike
Common SE
• Bleeding worse with aspirin
• Thrombotic thrombocytopenic purpura (TTP)
Ticagrelor
Indications Mechanism (how is it different from thienopyridines)
Unique SE
Indication
• Acute coronary syndromes
Mechanism
• Reversible inhibition of ADP receptor mediated platelet aggregation
Prodrug and metabolites effective
• Reversible
SE
• Gynecomastia (swelling of breasts)
• Bleeding
• Dyspnea & bradycardia
Role of GpIIb/IIIa
3 example drugs: Abcixmab,
Indications
SE
GpIIb/IIIa receptor on platelets used to bind to fibrinogen &vWF factor
Abicixmab- monoclonal antibody
Epitifibatide - cyclic heptapeptide
Tirofiban - Small molucule
SE
Eptifibatide and tirofiban: severe thrombocytopenia
Name 3 big classes of annticoagulants and how the
DIfference in Warfin & Heparin
- Use
- Mechanism
- What is monitored
Heprarin, warfin & PARENTERAL DIRECT THROMBIN INHIBITORS
Heparin - acute
Warfin - Longterm chronic use
Heparin: Factor X antagonist
Warfin: Inhibits synthesis of factor 2, 7, 9, 10 & protein C & S
Monitor
HMW: aPTT
LMW: Anti-Xa (aPTT)
Warfarin: INR/PT between 2-3
Benefits of LMW heparin
- Increased bio availability
- SubQ
- Fixed dose
- Limited lab monitoring need
- Treat patients at home for DVT since SubQ
- Lower heparin induced thrombocytopenia
- More predictable response
- Less HIT
Disadvantages of LMW heparin
- Don’t prolong aPTT
- Test amount with Anti-Xa assay
- Renal excretion so patients in renal failure will actually bleed because drug concentrated
- Longer half lives
Heparin
- Indications
- Mechanisms
- Kinetics (HMW & LMW)
- Reversal ( HMW & LMW)
- Dosing HMW & LMF
- SE
Indications
• “Treatment” after acute arterial venous thromboembolism
• 1 prevention of acute arterial & venous thrombosis
Mechanism
• Inhibits activity of PREFORMED coagulation factors
• Does not breakup existing clot
• Endogenous fibrinolytic system clears the clot
• Prevents thrombus propagation & clot formation
Kinetics HMW • Cleared in 2 phases o Rapid: Binding to endothelial cells, plasma proteins & macrophages o Slow: Renal • HL is dose dependent
Kinetics LWM
Renal excretion
Reversal
HMW: • Protamine sulfate
LMW: Nothing
Dosing
HMW
IV
• Used acutely in bolus
• Individual variability to bioavailability
• Binds to plasma proteins
• Adjust dose based on prolongation of aPTT in common pathway
LMW SubQ • Prophylaxis • Poor bioavailability • 2-3 doses per day • Monitor Anti Xa levels but aPTT is not prolonged
SE Bleeding HMW: Heparin Induced Thrombocytopenia (HIT) Osteoporosis Skin lesions Hyperaldosteronism
Warfarin
- Indications
- Mechanism
- Kinetics
- Reversal
- Dosing
- Contraindications
- SE
Indications
• 1 & 2 prevention of venous thromboembolism
• 1 & 2 prevention of arterial thrombosis
o Stroke prevention after Afib, heart valves, failure of antiplatelet
• Used in conjunction with antiplatelet therapy
Mechanism • Inhibits synthesis of vitamin K dependent coagulation factors o 2, 7, 9, 10, C, S & Z o Target epoxide reductase • Inhibits gamma carboxylation • Superwarfarins get around resistant
Kinetic • Not affected by renal dysfunction • Crosses placenta so can't use in pregancy • 33 hour half-life so steady state takes 7-10 days to have an effect so not used for acute treatment • Liver metabolism • Metabolism decreases with age • Food slows absorption • Genetic polymorphisms alter metabolism
Reversal
• Plasma
• Vitamin K
• Prothrombin complex concentrates
Dosing
• Dose with aim of getting INR(PT) between 2-3
• Since slow acting, start concurrent therapy with heparin until target INR is reached
• INR/PT used for monitoring because factor 7 1st to show decline (shortest half-life)
• Can induce hypercoagulable state (C and S are vitamin dependent)
Contraindications • Medications • Food rich in vitamin K • Medical conditions o Liver o CHF o Malnutrition o Hyper-metabolic states (fever, hyperthyroidism) • Warfarin resistance o Gastric bypass o Pharmacogenomics
Side Effecrs
Bleeding
Skin necrosis (worse in patients with protein C and S because will actually will be pro-coagulation leading to thrombosis)
Teratogenic during fetal development
Which anticoagulant safe in pregnancy why?
Heparin - does not cross BBB
What are pareteral direct thrombin inhibitors
Name 3
What do you monitor?
Method of delivary?
Sythetic molecules used in place of heparins
- Argatroban, bivilirudin & lepirudin
- Monitor aPTT (targeted 45-90s)
- Continues IV infusion
Name 2 mechanisms of fibrinolytic agents and name drugs in each class
- Mechanism 1: convert plasminogen to plasmin with synthetic plasminogen activators (rTPA, Alteplase)
- Mechanisms 2: Binds plasminogen to degrade fibrin: Streptokinase
Herbs & supplements that are antiplatelet & anticoagulants
- SSRI
- Gingko
- Garlic
- Ginger
- Fish oil
- PC-SPES
What are the targets in ththe anticoagiulation paththway
DABIGATRAN
RIVAROXABAN
APIXABAN
Longest half life
Benefits of Target specific oral agents
DABIGATRAN - IIa (thrombin)
RIVAROXABAN - Xa
APIXABAN - Xa
Longest half life - DABIGATRAN
Benefits • Treatment and prevention of arterial and venous thrombosis • Direct inhibitors so work quickly • Renal excretion • No antidote but have a short half life • No lab monitoring • Uniform dosing across patients • Few drug and food interactions
