E1: Anticoagulants Flashcards
This covers Dr. Potter's slides on anticoagulants
Heparin
SAR
Indication
Pharmacology
ADR
DI
Monitoring
Reversal agent
SAR: heterogenous mixture of polysaccharide chains derived from cows/pigs
Indication: clot prevention, DVT
Pharmacology:
1. heparin binds to antithrombin III (AT-III-Thrombate) and produces a conformation change that ↑ AT-III binding to thrombin (IIa) and Stuart factor (Xa) *Initial 5 saccaride sequence important w/SULFATE groups that help form strong bonds to ANTITHROMBIN III
2. AT-III inhibits serine proteases on specific activated clotting factors: AT-III activity slow and gradual by itself
3. main clotting factors inhibited (IIa, Xa)
4. after AT-III binds to the clotting factors, heparin dissociates and binds to different AT-III’s over and over
5. heparin inhibits IIa and Xa, has NO fibrinolytic activity
ADR: HIT, transient thrombocytopenia, hemorrhage, allergy (bovine/porcine sources
DI: Antithrombotic agents (ASA»_space; NSAIDS, ↑ risk of bleeding because inhibit platelet aggregation)
Monitoring: aPTT (activated partial thromboplastin time)
Reversal agent: protamine sulfate IV
When is reversal not required for heparin/LMWH
Prophylactic doses
Enoxaparin
Class
Advantages over heparin
Greatest effect on which clotting factor(s)
Indication
Pharmacology
DI
Monitoring
Reversal agent
Class: Low molecular weight heparin (LMWH)
Advantages over heparin:
A. ↓ non-specific binding to plasma proteins
B. less binding to platelets (↓HIT)
C. more predictable response and ↓ need to monitor
D. longer T1/2 than heparin; less frequent dosing; QD to BID ***fragments of UH created by enzymatic separation that have more homogenous chain mixtures (saccharide length os 10-20)
Greatest effect on which clotting factor(s): IIa, not so much Xa
Indication: DVT, PE, unstable angina, AMI
Pharmacology: 1. Activate AT-III which bind Xa and to a lesser extent bind IIa causing inactivation
–inhibiting 1 activated clotting factor X will inhibit generation of roughly 50 thrombin molecules
DI: other antithrombotic drugs
Monitoring: platelet count only
Reversal agent: protamine sulfate IV
Fondaparinux (Arixtra)
Class
SAR
Pharmacology
Monitoring
Class: Indirect Xa inhibitor
SAR: synthetic “pentasaccharide:
Pharmacology:
1. Indirect Xa inhibitor
a. inhibits ONLY xa
-no direct binding to Xa; only activates AT-III
- AT-III acquires faster recognition and inactivation of clotting factor Xa
Monitoring: unneccessary to routinely monitor coagulation
Apixaban (Eliquis) and Rivaroxaban (Xarelto)
Advantages
Indication
Pharmacology
Caution note
Reversal agents
Advantages:
A. routine coagulation monitoring not required
B. oral agents quicker onset as pt transitions from hosp to outpatient
C. These agents better than warfarin at establishing therapeutic blood
Indication:
1. Venous thromboembolism prophylaxis following knee or hip surgery/prevent Pulmonary embolism (PE)
2. (PSAF) prevention of stroke (emboli formation) in patients w/A. Fi
Pharmacology
Direct Xa inhibitors
-inhibit both bound and free Xa reversibly
Caution note
Caution:
-rivaroxaban and apixaban: discontinuing abruptly without initiating some other anticoagulation (↑ risk of stroke)
-rivaroxaban and apixaban: caution/avoid w/dual inhibitors of CYP3A4 and P-gp ( ↑ exposure and risk of bleeding; ↓ dose or avoid (ketoconazole, itraconazole, ritonavir, or clarithromycin)
-caution/avoid w/ strong dual inducers of CYP 3A4 (↓ exposure and ↑ risk of strong (rifampin, carbamazepine, phenytoin, St. John’s wort)
Reversal agents:
Andexanet (AndexXa)
4 factor PCC (Kcentra), activated PCC (FEIBA)
Andexanet (AndexXa)
Indication
Pharmacology
ADR
Price?
Indication:
1. Recombinant modified human factor Xa decoy protein
2. Indicated for toxicity of patients treated with Xa inhibitors (for apixaban and rivaroxaban OVERUSE)
Pharmacology:
1. Modified recombinant derivative of factor Xa which acts as a decoy receptor
2. Higher affinity to Xa inhibitor than natural Xa
3. Xa inhibitor binds to andexanet rather than to endogeous Xa
ADR:
1. DVT
2. Ischemic stroke
3. Cardiac arrest
4. Sudden death
Price: $$$$$$$$$$$$$$$
Use 4 factor PCC instead
Dabigatran etexilate (Pradaxa)
Indication
Kinetics
Pharmacology
Warning
General info/Monitoring
Reversal agent
Indication: ↓ stroke and systemic embolism in patients w/ A fib
KineticsProdrug converted to active dabigitran by serum esterases (NO monitoring)
Pharmacology: Binds directly to activated thrombin (IIa)
a. bound to fibrin in clot
b. circulating in blood
Warning:
1. has potential for severe bleeding in patients w/ ↓ renal function (CrCl 30ml/min)
2. Boxed warning: d/c abruptly w/out initiating some other anticoagulation can ↑ risk of stroke
General info/Monitoring:
1. Routine coagulation monitoring unnecessary
2. Predictable pharmacokinetics, faster onset, therapetuic onset in 2hr
3. less potential for drug-drug interactions
4. Capsules expire 120 days after bottle is opened (store in original container, remove one pill at a time
Reversal agent:
Idarucizumab (Praxbind)
Idarucizumab (Praxbind)
General information/Indication
Pharmacology
How to determine if need reversal?
General information/Indication:
1. Reversal agent indicated in patients treated w/ Dabigatran-Pradaxa
2. REVERSAL of the anticoagulant effects of dabigatran
3. for emergency surgery/urgent procedures
4. in life-threatening or uncontrolled bleeding
Pharmacology:
Humanized monoclonal antibody fragment (FaB)
Binds 350x higher affinity for dabigatran than thrombin
How to determine if need reversal? If last dose >51-85 hr ago
Warfarin-Coumadin
Class
General information
Indication
Pharmacology
ADR
Toxicity
Genetic considerations
DI
Monitoring
Reversal agent
Class: Vitamin K antagonist
General information:
-onset of action: 24-48hr
-days to effect and duration of action
-patients need strict compliance
Indication:
1. post-MI and venous thrombosis
2. prophylaxis of embolism in patients w/a. fib
Pharmacology:
1. Inhibits VKORC1
2. induces state of vitamin K deficiency in liver (oxidized vit K can’t be converted to reduced vit K that is used to activate clotting factors)
3. ↓vitamin K available as a cofactor for activation of vit K dependent clotting factors
4. ↓ production of vit k dependent clotting factors (prothrombin II and factors VII, IX, and X) by synthesizing biologically inactive clotting factors)
5. pcol effect delayed due to clotting factor t1/2 (6 to 60hr)
6. Does NOT dissolve preexisting thrombus yet does prevent further thrombi formation
ADR: bleeding
Toxicity: purple toe syndrome
Genetic considerations: CYP2C9 poor metabolizers have ↓ warfarin degradation and ↑ risk of bleeding
DI:
1. 99% PPB
2. Drugs that also cause bleeding (higher doses of ASA, nonselective NSAIDS)
3. herbals: wolfberry
4. Substrate for P450 CYP1A2, CYP2C9 (even opthalmic erythromycin ↑INR, cephaolsporins/penicllins ↑ risk of bleeding)
FOOD: rich vit K food ↓ warfarin effect; alcohol in acute excess ↑ warfarin effect, in chronic ingestion↓ effect by ↑ metabolism of anticoagulant; liver failure ↓ clotting factor synthesized –> ↑bleeding
Monitoring: 1. narrow therapeutic index drug/high alert medi
2. Prothrombin time (PT) measured then normalized
3. International normalized ration (INR)
–therapeutic efficacy of warfarin measured by INR; goal 2-3
Reversal agent:
1. 4-factor Prothrombin complex concentrate (4-F PCC, KCentra) or activated PCC (FEIBA)
2. d/c warfarin
3. Vitamin K (phytonadione)
4-factor Prothrombin complex concentrate (4-factor PCC)
Indication
Pharmacology
Black Box Warning
Indication:
1. Reversal agent for Warfarin
2. In life-threatening or uncontrolled bleeding (intracranial bleeding, major GI bleeding)
Pharmacology: Contains non-activted factors II, VII, IX, X
Black Box Warning: Arterial and venous thromboembolic complications
When is Warfarin Reversal required
INR greater than or equal to 1.4 (outside of normal INR)
