Heme/Onc Part 2 Flashcards
Role of ADP, TxA2, PGI
TxA2 and ADP activate platelets by binding to P2Y1 and P2Y12 which inhibit adenylyl cyclase which decreases cAMP which decreases PKA activity which increases platelet activities
-PGI has the opposite effects
White (arterial) thrombus vs Red (Venous) thrombus
- Arterial thrombus can be prevented by anti platelet drugs
- Venous thrombus can be prevented by anticoagulants and existing thrombosis can be treated with thrombolytics
Antiplatelet drugs
Inhibit aggregation of platelets thus reducing risk of thrombus in arterial circulation.
COX-1 inhibitors
Inhibit COX-1 which leads to decreased TxA2 levels
Phosphodiesterase inhibitors
- dipyridamole
- PDE inhibits cAMP degradation which leads to increase PKA activation and causes decreased aggregation
- Combined with fixed dose of aspirin to reduce risk of stroke
Clopidogrel
- ADP receptor antagonist
- prodrug (CYP2C19)
- Binds irreversibly to P2Y12 ADP receptor subtype and prevents activation of GPIIB/IIIA
- Effects last 7 days (time to synthesize new platelets
- PK: orally effective with anti platelet action beginning in 2 days and reach max at 8-11 days (loading dose to reach maximum effect in 2 hours)
- USES: reduces rate of CVA, MI, and death in atherosclerotic patients -or- in combo w/ aspirin to prevent coronary stent thrombosis
- Failure in patients w/ loss of CYP2C19
- TTP rare but life threatening
- Avoid in patients with bleeding disorders
Abciximab
- GPIIB/IIIA Antagonists
- Fab fragment of a monoclonal antibody blocks fibrinogen binding
- IV 48hr half life due to irreversible binding of antagonist
- Most effective drug but it’s expensive
- Used short-term in combo w/ heparin to prevent ischemic events in ACS or PCI
- AE: GI and cerebral bleeds, reversed by infusion of donor platelets -or- anaphylaxis and thrombocytopenia due to antibodies against chimeric protein (risk increases with subsequent doses within short time frame)
Anticoagulant drugs
- Inhibit one or more of various steps in coagulation cascade to suppress formation of fibrin clots and reduce risk of venous thrombosis
- Decrease risk of DVT/PE, MI, and ischemic stroke
Heparin (unfractionated)
- Unfractionated
- Heterogenous mix of sulfated mucoploysaccharides that is highly (-) charged and extracted from porcine intestinal mucosa
Enoxaparin
- LMWH
- Prepared from heparin by gel filtration chromatography
Fondaparinux
-Synthetic pentasaccharide that contains the minimum # of heparin SO4 groups to bind antithrombin
Heparins (ALL OF THEM) MOA and PK
-MOA: Accelerate normal rate of inactivation by antithrombin by serving as a catalytic surface for antithrombin and proteases that make antithrombin more active
-Inhibits only circulating clotting factors and onset is rapid
-Heaprin (IIa and Xa equally) LMWH (Xa) Fonadparinux (Xa w/o effects on IIa)
PK: IV infusion and cleared by reticuloendothelial system
-Binds plasma proteins, mononuclear, and endothelial so drug levels = inconsistent and activity must be monitored (PTT)
-LMWH Fondaparinux given SC and cleared by kidneys NO MONITORING
Heparins (AE and USES)
USES: Initial treatment of DVT/PE
-During PCI, open heart surgery, renal hemodialysis to prevent thrombi
-Used in Combo with anti platelet agents for acute coronary syndromes
-LMWH and Fondaparinux have replaced heparin and are used in outpatient
-CAN BE USED DURING PREGNANCY
AE: Bleeding can be combated with protamine sulfate that binds to anionic heparin to form an inactive complex (inactive against fondaparinux)
-Heparin induced thrombocytopenia in first 5-14 days when IgG antibodies bind to heparin platelet factor 4 complex (IgG tail binds IIa receptors on platelets causing aggregation) this risk in higher in fondaparinux and LMWH
-Alternative anticoagulant is needed while heparin is withdrawn (fondaparinux and bivalirudin but not warfarin )
Warfarin
- Vitamin K antagonist that inhibit VKORC 1 (which turns epoxide back to reduced form)
- II VII IX X all depend on vitamin K for carboxylation
- W/O carboxylation these factors have decreased activity
- C and S also depend on vit K so this may create a hyper coagulable state b/c C has the shortest half life of all factors
Warfarin: PK USEs and Pharmacogenetics
PK: 99% bound to albumin and metabolized by 2C9
-Target INR 2-3
USES: Long term prophylaxis of venous thrombosis
-Prevent progression or recurrence of DVT/PE following an initial course of heparin
-Prevent thromboembolism in pts with prosthetic heart valves, a fib, or post MI
-NOT FOR EMERGENCIES
Pharmacogenetics:
-2C9 *2 and *3 = reduced warfarin clearance
-VKORC1 haplotype A = reduced enzyme activity and achieve target INR more rapidly (substantial dose reduction)
Warfarin: Adverse effects and Drug interactions
Adverse Effects:
-Bleeding if INR is too high (intracranial)
-Vitamin K (phytonadione) restores hepatic synthesis of clotting factors when INR > 10 and reduces INR within 24-48 hrs
-With life threatening hemorrhage infusion of 4-factor prothrombin complex concentrate or fresh frozen plasma
-Teratogen,
-Skin necrosis especially in protein C or S deficiency
-Purple toe (cholesterol emboli
-anaphylaxis/hypersensitivity
Drug Interactions:
–Drugs that inhibit 2C9, displace from albumin, broad spectrum antibiotics (less vitamin K), and anything that promotes bleeding –> bleeding
-Inducers of CYP and excessive intake of vitamin K reduce warfarin efficacy and lead to thrombosis (low INR)
Bivalirudin
- Direct inhibitor of Thrombin (IIa) and Factor (Xa)
- recombinant peptide of leech saliva
- Binds reversibly to catalytic and substrate recognition sites of thrombin to prevent it from activating fibrinogen
- IV and monitor by aPTT
- Inactivated by proteases and excreted by kidneys
- Used during PCI with anti platelet drugs and HITT
Dabigatran Etexilate
Oral thrombin inhibitor
- prodrug that is metabolized to competitive inhibitor of thrombin (binds only active site)
- Onset 2-3 hrs excreted renally, shorter t1/2 makes missing a dose a big deal
- Taken 2x/day w/o INR
- Approved for prevention of Stroke in Pts with non-valvular atrial fib (NOT PROSTHETIC HEART VALVES)
- Predictable response
- Bleeding side effect which is less severe than warfarin but no specific antidote
Thrombolytic Agents
- Used to lyse pre-exisiting clots and restore vessel patency in MI, pulm embolism, and stroke
- MUST BE GIVEN WITHIN first 3-6 hrs after event
- Administered via arterial catheter directly to the site of occlusion to lyse large venous thrombus
t-PA (alteplase)
- Thrombolytic
- Recomb. human serine protease
- inactive plasminogen –> plasmin that digests fibrin confines fibrinolysis to clots
- IV w/ T1/2 5 min
- AE produce systemic lytic state that can result in hemorrhage and can also dissolve necessary clots
Ferrous Sulfate
-IRON DEFICIENT ANEMIA
-Oral preparation but all formulas vary in amount of elemental iron
-150-200 mg/day spaced between 3X to avoid GI effects
-Therapy is for 3-6 months after the anemia is corrected or prophylaxis during pregnancy
AE:
-GI disturbances: Naseau, heartburn, constipation, and diarrhea (fade with time)
-Iron toxicity: Hepatic failure, and pulmonary edema, usually in kids, Treat with deferoxamine
-Interactions: antacids reduce absorption and decreases absorption of tetracycline
Iron Dextran
- Iron Deficient Anemia
- Rate of response = ferrous sulfate
- Given when oral iron is intolerable or can’t replenish iron supply fast enough
- W/ Chronic use it’s important to monitor ferritin levels to prevent Iron overload
- Anaphylaxis fro dextran may occur (rare)
B12 deficiency anemia
- Megaloblastic anemia due to impaired DNA synthesis
- Nerve demyelination (can’t be reversed with Folic acid) recovery is slow
