Antiplatelet and coag vs. thrombolytics
Antiplatelet and coag - inhibit formation of clots
Thombolytics - lyse clots
Antidepressants and platelets
Increased serotonin release so can lead to risk of bleeding
Aspirin MOA
Irreversible inhibitor (of mostly COX1) COX1 constitutive in platelets INhibits TXA2 formation No TXA2 can stimulate TP receptor Inhibits platelet aggregation for the life of the platelet
Other NSAIDs
Are reversible…may compete with aspirin and decrease its effectiveness
Uses of aspirin and route of delivery
Oral
Acutely in patients (MI or PCI)
Prophylaxis to prevent primary or secondary CV events
Other aspirin uses
Antipyretic
Analgesic
Anti-inflammatory
All at higher doses
Aspirin adverse effects and contraindications
Profound bleeding and bruising
Increased risk of heartburn and PUD due to inhibited gastric PG synthesis (less at lower dose)
Hypersensitivity of ASA or asthma
Aspirin PK
Half life short
Therapeutic effect 7-10 days
Clopidogrel MOA and use
Prodrug
Irreversible antagonist of ADP receptor P2Y12
Prevents ADP induced decrease in cAMP and thus prevents aggregation
similar to aspirin use
Clopidogrel metabolism and PK
CYP2C19 metabolized...2 steps Don't use with CYP2C19 inhibitors (omeprazole) Therapeutic is 7-10 days Oral Genetic variation of CYP2C19
Adverse effects of clopidogrel
Bruising and bleeding
Vorapaxar MOA and therapeutic use
Antagonist of protease activated receptor 1 (PAR1) thus prevents platelet activation by thrombin via this receptor
Only in patients with history of peripheral artery dz or previous MI…use with aspirin and/or clopidogrel
Vorapaxar adverse effects, contraindicated, and drug interactions
Increased bleeding
Patients with history of hemorrhage or TIA (transient ischemic attacks)
NSAIDs, SSRIs, SSNIs, and strong CYP3A4 modifeiers
Abciximab MOA and route
IV
GP2B/3A antagonist block platelet aggregation by preventing fibrinogen from binding platelets and consolidating platelet plug
Prevents platelet adhesion and aggregation by ANY stimulus
Prevents prothrombin from binding to platelets —– decreases thrombin formed—-anticoagulant
Monoclonal AB
Uses of abciximab
Emergency tx of acute coronary syndromes
During PCI
Crisis situations
Adverse effects and PK of abciximab
Bleeding
Half life of about 30 minutes
Gp2b/3a bound for 18-24 hours
PLatlet function back in 48 hours
Heparin route and MOA
IV, SC
Complex with AT and increases activity
Inactivates factors 2, 9, and 10 as suicide substrate
How to monitor heparin
Anti-10a assay (or aPTT) and platleet count…alters intrinsic pathway
Heparin advewrse affects
Bleeding
HIT
Heparin sensitivyt
Osteoporosis
Antidote for heparin
Protamine sulfate
Enoxaparin MOA and route
Complexes with AT3 and increases activity…only inactivates 10a
IV, SC
Fondaparinux MOA and route (with PK)
Only SC
Accelerates activity of AT3 against F10
More predicatble with 17 hour halflife
Adverse effects of heparin and derivitives
Bleeding problems…patient education…less with fondaparinux
Monitoring of heparin and derivatives
Heparin - must be monitored by Anti 10a (.3-.7 is goal)
Others - Anti 10a if needed
PK of heparin and deriviates
Hep and LMWH - SC or IV
Fonda - only SC
Hep and LMWH - given IV at hospital for acute conditions due to rapid onset
All good for SC for long term outpatient use
Heparin is dose dependent (1/2 = 30-150 min)
Enox - 3-6 hr
Fonda - 17hr
DO NOT CROSS PLACENTA SO SAFE FOR PREG
Use of heprain and deriv
Usually initial short term rx and transition to oral meds
Can also use with antiplatelet therapy in more urgent situations
Bivalirudin MOA and route
Direct irreversible inhibitor of thrombin
IV infusion
T1/2 = 25 minutes
Bivalirudin uses
Patients who need heparin but have HIT
Microvascular surgery to reattach digits
Warfarin route and MOA
Oral
Antagonist of VKOR…inhibits synthesis of factors 2,7,9,10 and protein C and S
Onset of action is 8-12 days with full effect in 3 days
Alters both intrinsic and extrinsic pathways
Warfarin uses
Tx of thrombosis/embolisms
Metal prosthetic valves
Warfarin PK
Oral
99% plasma protein bound
CYP metabolized
therapeutic half life long
Warfarin adverse effects
Bleeding
NOT GOOD WITH PREG
Warfarin induced skin necrosis - use heparin brdige to prevent
Purple toe syndrome
Warfarin antidotes
Vit K1
FFP
Prothrombin complex
F7a
Dabigatran etexilate advantages
Direct action on thrombin (rapid effect)
Prodrug activated by plasma esterases, NOT CYP
More effective with less drug interactions and little impact on anything but clotting
MOA of dabigatran and route
Prodrug
Competitive inhibitor of thrombin activity on both fibrinogen and platelets decrasing both platelet and coag activity
Oral
Dabigatran uses
Prevent strokes
DVT and PE
Dabigatran adverse effect, antidote, and PK
Bleeding
Idarucizumab
Prodrug cleaved by esterases
Dose adjustment needed in renal dz and in combination with drugs that compete for the P glycoprotein efflux transporter which transports active drug into renal tubular fluid
Rivaroxaban route, MOA, uses, PK
Oral
Directly inhibits factor 10a (not through AT3 like LMWH)
Same uses as dabigatran
Oral, once a day
Rivaroxaban warnings and antidotie
Bleeding, monitor renal function
Andexanet alpha
Alteplase MOA and PK
Binds to clot bound fibrin and converts plasminogen to plasmin which degrades fibrin
Recombinant tPA
IV only with short half life
When to use alteplase
Acute stroke
MI
PE
DVT
Adverse effects of alteplase
Lyse all physiologic thrombi as well
Contraindications of alteplase
Surgery, trauma within 10 days
Serious GI bleeding in last 3 months
Hypertension
Activebleeding or threat
Antidoes for fibrinolytic therapy
Epsilon aminocaproic acid - PO, IV…inhibits fibrinolysis
Tranxenamic acid - topical, PO…inhibits plasminogen activity…can also be used as rinse to reduce bleeding