Hematopoietics, Anticoag, Antiplatelets and Thrombolytic Drugs Flashcards
HEMATOPOIETICS
Recombinant growth factors
3 types:
- Erythropoietin Stimulating Agent
- increase RBC production (Epoetin) - Granulocyte Stimulating Agents
- increase myeloblast cells (G-CSF, GM-CSF) - Platelet Stimulating Agents
- increases platelet production (thrombocytes)
ESAs
Epoetin, Procrit, Darbepoetin given IV or SQ
Uses: Anemia: renal disease
Onset of Action
- 2 to 6 weeks (take a while to work)
- 8-26 days to actually increase RBC numbers
Monitoring
- hemoglobin
- iron levels
G-CSF
Increases WBCS-neutrophils
Filgrastim, Pegfilgrastrim
IV, SQ or patch
Uses:
-treats neutropenia complications in cancer pt.
Pegfilgrastim needs to be given once
Filgrastrim is daily
Monitoring: absolute neutrophil count (ANC)
GM-CSF
Increases WBC production (neutrophils, eosinophils, basophils and mast cells) and RBCs
Sargramostin
Uses:
- acute myelogenous leukemia
- bone marrow transplant
Monitoring: CBC with differential
TPO Receptors
Increase platelet production
Romipolstim(outside of receptor) Eltrombopag (inside of receptor)
MOA:
-binds to and activates human thrombopoetin receptor
OOA:
-increased platelet production in a week
Uses: chronic immune thrombocytopenia
Drugs to combat CLOT FORMATION
1: ANTICOAGULANTS
2: ANTI-PLATELETS
3: THROMBOLYTICS
ANTICOAGULANTS
- prevent further propagation of clots
- disrupt clotting cascade
- best for treatment of arterial and venous clots
- inhibit activity of clotting factors
- inhibit synthesis of clotting factors
HEPARIN, LMWH, FONDAPARINUX, WARFARIN, DIRECT THROMBIN AND DIRECT Xa INHIBITORS
Heparin UNFRACTIONATED MOA
MOA: enhance the activity of antithrombin
- inhibit factor Xa and thrombin equally
- inhibits the change of fibrinogen to fibrin
A mixture of long polysaccharide chains
Active section is a pentassaccharide sequence found randomly along the chain
Metabolized by the LIVER
Bolus dose
Indications: treatment and prevention of thrombosis
Bodies own way of responding to clot is ENHANCED by heparin
- First binds with Antithrombin + causes a conformational change
- Then binds to factor 10 (Xa) and thrombin EQUALLY
- THIS DISRUPTS FINAL STEP OF FIBRINOGEN TO FIBRIN
UPH Monitoring
Monitoring efficacy
- aPTT (more common) or anti-Xa
- checked usually every 4-6 hours until stable
APPT and ANTI XA SHOULD BE HIGHER WITH HEPARIN
APTT test
Activated partial thromboplastin
- measures the time it takes for the blood to clot
- higher aPTT=more anticoagulation effects
We want high aPPT when on heparin
-but not too high or too low
Anti-Xa
Measures the amount of Xa not bound by heparin
Higher the level=more anticoagulation effects
UPH Adverse Effects
BLEEDING (10%)
- must monitor for:
- blood loss
- decreased BP
- increased HR
- black tarry stools
- red colored urine
- headache
- somnolence
- abdominal pain
UFH Side Effects
Spinal epidural hematoma
Heparin-Induced Thrombocytopenia (HIT)
-DECREASE IN PLATELETS
-Type 1: usually 1-2 days after exposure
(transient drop in platelets, will recover)
-Type 2: 4-7 days after exposure WORSE
(>50% drop in platelets over time, worry about thrombosis)
(COULD cause a secondary clot)
HIT
Body develops antibodies to heparin-PF4 (platelet factor 4) complex
-results in new thrombosis development
Confirm by ordering HIT antibody test with SRA assay
Treatment
- discontinue heparin
- initiate ARGATROBAN (antidote) - different drug that causes clot formation
Reversing bleeding with UFH
Antidote: PROTAMINE(+)
-Binds with Heparin(-)—>no longer able to bind to anti-thrombin—>CAUSES CLOTS, prevents heparin from working
- neutralization occurs immediately and last for 2 hours
- little roll for protamine if the heparin infusion was discontinued over 4 hours agin
- give plasma or blood (if Hg<7 or hypotension) in addition to protamine if necessary
PROTAMINE
First isolated from fish sperm
Highly positive charged molecule (binds with heparin-negatively charged)
Sequesters heparin so it cannot bind with antithrombin
Low-molecular weight heparins
LMWH
Smaller pieces of polysaccharides -cannot hug thrombin
MOA:
-bind to antithrombin and inactivate Factor Xa (only)
Indications: treatment and prevention of thrombosis
Onset: 1-2 hours QUICKER; SQ (Patient can be treated outpatient!
Formulations: Enoxaparin, Tinzaparin, and Dalteparin
Monitoring: anti Xa (level)
-rental cleared (cannot use in patients with acute kidney injury or hemodialysis
PREFERRED OVER UFH to treat and prevent venous thrombosis
-quicker, no hospital stay, can self administer, don’t have to monitor, rare to cause HIT
LMWH Adverse Events
Bleeding (less common that UFH)
Spinal /epidural hematoma
Thrombocytopenia (similar to HIT)
- antibody mediated, less likely with LMWH
- discontinue medication, treat with Argatroban
LMWH Reversal of Bleeding
Antidote: PROTAMINE can be used, not as effective
- binds 80% of LMWH
- can give within 12-24 hours after last done of LMWH
- give plasma or blood (if Hg<7 or hypotension) in addition to PROTAMINE if necessary
- protamine cannot bind to LMWH, less of a negatively charged tail present for protamine to bind to
Fondaparinux MOA
-inhibits Factor Xa by binding to antithrombin
Only contains the essential pentasaccharide
DVT/PE treatment and prevention
Administration: SQ -once a day
Renally eliminated, cannot use in acute kidney injury or hemodialysis
Can be used in patients with a history of HIT
Fondaparinux Adverse Events and Reversal
Adverse events:
- bleeding
- similar to UFH and LMWH
Antidote: None
- give plasma or blood (if Hg<7 or hypotensive)
- cannot give PROTAMINE, drug is too small and will not bind to protamine
Vitamin K Antagonist
WARFARIN
Treats and prevents thrombosis
MOA: inhibits clotting factor synthesis that require vitamin K
- inhibits vitamin K epoxide reductase complex 1 and vitamin k reductase
- inhibit production of: Prothrombin (Factor II), VII, IX, X, Protein C and S (FACTORS 2, 7, 9, 10 and PROTEIN C and S)
- conversion of fibrinogen to fibrin will not occur
Warfarin (cont.)
Extensively bound to albumin
Metabolized by the liver CYP2C9
OOA: DELAYED! takes approx 2 days to start decreasing clotting factors
-usually takes several days to achieve full therapeutic effect
(Half life of factor II=90hours)
-if drug is stopped, effects linger
- Must BRIDGE with another anticoagulant to treat the clot in the meantime!
- bridge while receiving SQ or IV anticoagulants for active clots
Warfarin Monitoring and Goals
Monitoring:
- International Normalized Ratio (INR)
- prothrombin time (PT)
INR measures decrease in clotting factor caused by warfarin
INR=higher=more anticoagulation with warfarin
- want it around 2-3
- INR>3-4=HIGH RISK OF BLEEDING
Warfarin Adverse Effects and Reversal
BLEEDING
Reversal of uncontrolled bleeding:
- antidote: Phytonadione (Vitamin K) -takes a while
- takes at least 2-6 hours to start reversing effects
- total effect within 24 hours
- MUST give plasma or prothrombin complex concentrate (PCC) or factor VII (novoseven) in the meantime to treat the bleeding right away-gives you all the factors that warfarin inhibits (2, 7, 9, 10) quicker
- can give blood in addition based on HgB
Warfarin Interactions
INCREASED
Bactrim Amidarone Cimetidine Acetaminophen Metronidazole Anole Antifungals
Example: Give warfarin while a patient is on bactrim treating a UTI
- bactrim will inhibit metabolization of warfarin
- warfarin will accumulate in the blood
- INR=too higher, depleted too many clotting factors =HIGH BLEEDING RISK
- more warfarin, inhibits anticoagulant factors, not metabolized=toxic effects
Warfarin Interactions
DECREASED
Phenobarbital
Rifampin
Phenytoin
Carbamazepine
*Anticoagulants and antiplatelets can have an added pharmacodynamic effect to increase rates of bleeding
Direct Thromin Inhibitors
MOA:
- inhibit thrombin (IIa) to prevent conversion of fibrinogen to fibrin
- binds directly to thrombin and inhibit conversion of
Oral and IV available
- Diabigatran (PO)
- Argatroban (IV)
- Bivalirudin (IV)
Dabigatran (Pradaxa)
Indications:
- prophylaxis for non-valvular afib
- Treatment of DVT/PE
Rapid onset, prodrug converted by blood esterases
Renally eliminated and dose adjusted for CKD
(Cannot use in hemodialysis patients)
Treat life threatening bleed with PRAXBIND (can remove drug with hemodialysis)
-sequesters Dabigatran
-give plasma or blood in addition if needed
Argatroban
Indications:
-HIT treatment
Metabolized by liver
-dose adjustment needed for chronic liver disease
Monitoring: aPTT
Will artificially increase INR
Adverse events: BLEEDING
- no antidote
- give plasma plus or minus blood if necessary
Bivalirudin
For patients going to the cath lab
Eliminated by the kidneys
-dose adjustment needed for renal dysfunction
Monitoring: aPTT
Adverse events: BLEEDING
- no antidote
- give plasma plus or minus blood if needed
Direct Xa Inhibitors
Bind directly to Xa and inhibit conversion of fibrinogen to fibrin
No monitoring values
Rapid onset
Oral agents only
- Rivaroxaban
- Apixaban
- Edoxaban
- Betrixaban
Antidote: Andexxa IF BLEEDING OCCURS
HD does not remove drug
Can give blood with or without plasma as needed
Apixaban (Eliquis)
Indications:
- DVT/PE treatment
- stroke prophylaxis in non-value afib
- post op DVT prophylaxis
Dose Adjustments
-for afib, if 2 or 3 are met: Age>80, Scr>1.5, or Wt. <60kg
Drug Interactions
- strong CYP 3A4
- PGP inhibitors or inducers
Rivaroxaban (Xarelto)
Indications:
- DVT/PE treatment
- stoke prophylaxis in non-valve afib
- post op DVT prophylaxis
Dose Adjustments:
-renal insufficiency
Drug Interactions:
- strong CYP 3A4
- PGP inhibitors or inducers
Edoxaban (Savaysa)
Indications:
- DVT/PE treatment
- stroke prophylaxis in non-valve afib
Dose adjustments:
-renal insufficiency
Drug Interactions:
- strong CYP3A4
- PGP inhibitors or inducers
Betrixaban (Bevyxxa)
Indications:
-prophylaxis for VTE
Dose adjustments:
-renal insufficiency
Drug Interactions:
-strong PGP inhibitors
ANTIPLATELETS
Used to prevent arterial thrombosis by
- cox inhibition
- increased plasma adenosine
- phosphodiesterase-3 (PDE-3) inhibition
- P2Y12 ADP inhibition
- glycoproteins IIb/IIIa inhibition
*used to treat arterial clots rather than venous clots
COX Inhibitors
Cause irreversible inhibition cyclooxygenase 1 and 3
-enzyme responsible for making Throboxane A2 (TXA2) which causes platelets to aggregate
Aspirin only medication in this class
Effects last for duration of platelet (7-10 days)
IRREVERSIBLE: Inhibits enzyme cyclooxygenase for its whole life
-Aspirin (a cox inhibitor) binds to cycooxygenase 1 and 2 and prevents formation of thromboxane, platelets won’t clot=PREVENTS CLOTS
P2Y12 Inhibitors
Prevent platelet activation by inhibiting ADP binding to P2Y12 receptor
Monitoring: platelet assay tests
Irreversible and reversible
REVERSIBLE: patient cannot stop taking the medication
- decreases platelet stickiness and coagulation but has the reverse if the drug is not taken
- beneficial for those who need to undergo heart/emergency surgery because the drug will wear off, if the bleeding occurs during surgery normal clotting will occur
Clopidogrel (Plavix)
Type of Inhibition:
IRREVERSIBLE
Prodrugs: Metabolized to active drug by CYP2C19 (genetic variance)
Clopidogrel Adverse Effects and Reversal
Bleeding
Thrombocytopenia (TTP)
No antidote to reverse
-give platelets
Many drug interactions with CYP2C19
-Genetic factors: poor metabolizes
Hold 5 days prior to major surgery/procedure
Prasugrel (Effient)
Type of Inhibition:
IRREVERSIBLE
Prodrug converted by the liver
No antidote
Hold 5 days prior to surgery
Avoid use in patients who are over 75, or have a history of stroke or TIA
Dose adjust if patients weighs over 60
Prasugrel (Effient) Adverse effects and reversals
Bleeding, angioedma (rare)
- avoid using in patients who are over 75 with a history of stroke or TIA
- dose adjust if patient weights less than 60kg
No antidote
-give platelets or blood
Hold 5 days prior to surgery
Tricagrelor (Brilinta)
Type of Inhibition:
REVERSIBLE
Significant drug interactions: aspirin, Digoxin, CYP3A4 inhibitors
Don’t used if concerned about medication adherence
Hold 1 day prior to surgery
Tricagrelor (Brilinta) Adverse Effects and Reversal
Adverse effects:
- bleeding
- dyspnea
- ventricular pauses
Sig. Drug Interactions:
- aspirin dose >100mg/day , make the drug less effective
- CYP3A4 inhibitors/inducers
- do not exceed over 40mg a day of simvastatin or lovastatin
- Digoxin levels may increase (PGP inhibitor)
No antidote available
-give platelets, wears off fathers
Don’t use if concerned about medication adherence
Hold 1 day prior to surgery
Cangrelor (Kengreal)
Type of inhibition:
REVERSIBLE
Adverse events: bleeding
-treat with platelets or blood
Same thing as Ticagrelor but IV form
-only in IV formulation
GP IIB/IIIA Inhibitors
Block the final receptors where fibrinogen should bind to
IV only
Cause reversible blockade
Available agents: Abciximab, Eptifbatide and Tirofiban
Adverse events: bleeding
- no antidote available
- give platelets or blood
Dipyridamole
MOA: Inhibits platelets by increasing plasma levels of adenosine
Always given in combo with aspirin (Aggrenox)
Adverse effects: bleeding, dyspepsia
No antidote available
-give platelets or blood
Cilostazol (Pletal)
MOA: PDE-3 Inhibitor
Full onset of action: 12 weeks -takes a while!
Adverse effects: horrible headache
Contraindication to use: patients with heart failure
Drug interactions: Inhibitors of CYP3A4
No antidote
-give platelets of blood
Good for people with intermittent clot risks
Pentoxyifylline (Trental)
MOA: Increases cAMP in RBCs, leading to increased RBC flexibility and decreased Viscosity-less likely to clot
Adverse Events:
- nausea, vomiting, leukopenia
- no sig. bleeding risk
THROMBOLYTICS
Given to remove thrombi that have already formed
CLOT BUSTERS
- these drugs augment plasminogen conversion to plasmin
- plasmin degrades fibrin, breaks up the clot
Used emergency
Contraindications to using (relative and absolute)
3 formulations:
- Alteplase (tPA)
- Tenecteplase
- Reteplase
Example: have an MI, but don’t have access to a catheter lab, you would give a thrombolytic to break up the clot
-used in rural areas
Alteplase (Activase or tPA)
MOA: binds with plasminogen to form an active complex
- complex catalyze the conversion of other plasminogen molecules into plasminogen
- digests the fibrin meshwork
Alteplase
Drug binds with plasminogen to form an active complex
Ischemic stroke, MI, acute massive PE (cant get to cath lab in time)
Adverse events: bleeding, angioedema (swelling of lips/tongue
Reversal:
-no antidote, give plasma or blood
Tenecteplase (TNkase)
Only indicated to treat a heart attack (AMI)
-rural area, no access to cath lab
Single dose
Longer half life
Adverse events:
-bleeding
Reversal:
-no antidote, give plasma or blood
Reteplase (Retavase)
Only indicated to treat AMI
Short half life -give 2 intermittent injections
Complex dosing schedule, not as favorable as others
Adverse events:
-bleeding
Reversal:
-no antidote, give plasma or blood
