Drugs To Treat Clotting Disorders Flashcards
(121 cards)
1
Q
Drugs that decrease clotting
A
Anticoagulants
Antiplatelet drugs
Thrombocytes
2
Q
Systemic coagulants
A
Vitamin K Replacement factors Aminocaproic acid (Fibrinogen conc., prothrombin complex conc.) Tranexamic acid DOAC antidotes
3
Q
DOACs and their antidotes
A
Direct oral anticoagulants:
- Dabigatran (direct thrombin inhibitor)
- -> idarucizumab (Praxbind)
- rivaroxoban, apixaban, edoxaban (direct Xa inhibitors)
- Warfarin toxicity
- ->vit k
- Heparin
- -> protamine sulfate
4
Q
Anticoagulants
A
Inhibit formation of arterial and venous fibrin clots
5
Q
Vitamin E Epoxide Reductase Inhibitor
A
Warfarin
6
Q
Indirect Thrombin Inhibitors
A
Heparin (unfractionated)
LMWH
7
Q
Low Molecular Weight Heparin
A
Enoxaparin
Dalteparin
Tinzaparin (off market in 2011)
8
Q
Direct Thrombin Inhibitors (DTI)
A
Dabigatran
Argobatran
Bivalirudin
Desirudin
9
Q
Direct Xa inhibitors
A
-all oral
Rivaroxoban
Apixaban
Edoxaban
10
Q
Indirect Xa inhibitors
A
-antithrombin II or III mediated inhibition of Xa
Fondaparinux (injectable)
Indraparinux (longer acting, withdrawn from market)
11
Q
Antiplatelet agents
A
Inhibition of platelet aggregation
Important in pathological artery occlusion
12
Q
COX inhibitors
A
Aspirin
Others exist but none indicated by FDA for clotting disorders
13
Q
Platelet P2Y12 receptor antagonists
ADP inhibitors
A
Cangrelor Clopidogrel Prasugrel Ticagrelor Ticlopidine HCl
14
Q
PDE/Adenosine uptake inhibitors
A
Dipyridamole
15
Q
Glycoprotein IIb/IIIa inhibitors
A
Abciximab
Eptifibatide
Tirofiban HCl
16
Q
Thrombolytics
A
Tx of arterial or venous thrombi (after formed)
17
Q
Plasminogen activators
A
Alteplase recombinant
Reteplase recombinant
Tenecteplase recombinant
18
Q
Thrombolytic enzyme
A
Urokinase
19
Q
Human protein C
A
Protein C Conc. (Human)
- used in severe congenital protein C deficiency
20
Q
Common coagulation studies
A
PT, aPTT, INR
Used to diagnose coagulation abnormalities or monitor effectiveness of anticoagulantion therapy
- when used to assess drug therapy, achieving a value outside the reference range is therapeutically desirable
21
Q
aPTT
A
Activated patient thromboplastin time
- measures the intrinsic clotting system
- Factors VII, IX, XI, and XII, and factors in common pathway (II, X, V)
- used to monitor unfractionated heparin therapy
- reference range 20-39s
22
Q
PT
A
Prothrombin Time
- directly measures activity of clotting factors VII and X, prothrombin (Factor II), and Fibrinogen
- reference range 10-14s
23
Q
International Normalized Ratio
A
- Recommended method to monitor anticoagulant therapy
- Variable sensitivity of thromboplastin reagents to decreases in specific clotting factors causes a lack of reliability when used at onset of warfarin therapy and in screening for a coagulopathy
24
Q
ACT
A
Activated Clotting Time
- used before, during, after medical procedures that require blood clotting to be suppressed
- measures the immediate effect of heparin but not the level of heparin
- sometimes DTI
- “bedside coagulation monitoring”
25
How is warfarin supplied
Oral tablets
| -iv discontinued and off market
26
Warfarin mech of action
Vitamin k Reductase inhibitor, leads to depletion of vit k dependent clotting factors
- II (60h), VII (6h), IX (24h), X (40h), protein C, protein S
27
Bridge therapy
- Administration of short acting anticoagulant (LMWH, Unfractionated Heparin) while long acting anticoagulant (warfarin) is withheld before surgery
- Subsequently given after surgery as well until long acting anticoagulant is in target therapeutic range
- also applies to new start long acting anticoagulant therapy
28
Indications for warfarin
- MI: STEMI, afib, CHADS2>/=2, mechanical valve, VTE, hypercoagulable disorder
- Thromboembolic complications prevention and/or tx assoc. w afib and/or cardiac valve replacement
- Venous Thrombosis/PE
29
Warfarin Dosing
- 3 ranges of expected MD depending on combination of VKORC1 and CYP2C9 genotype
- traditional means of coumadinization where pt takes 2-5mg daily
- LD of 10mg for 2 days sometimes used, but not recommended for elderly or pts recovering from Heparin induced thrombocytopenia (HIT)
- css in ~5 days
30
Warfarin Absorption
Completely absorbed after oral admin. W peak conc. Generally attained within first 4 hours
31
Warfarin Distribution
- relatively small - 0.14L/kg
- dist. Phase lasting 6 to 12h after oral admin. of aq soln.
- ~99% bound to plasma proteins
32
Warfarin Metabolism
- Metabolized by CYP450 enzymes to hydroxylated metabolites and by reductases to warfarin alcohols
- inhibits VKOR, which reduces regen. Of vit k from vit k Epoxide
- polymorphs in VKORC1 gene associated w variable warfarin dose requirements
33
Warfarin Excretion
- terminal half life @ ~1 week
- effective half life ranges from 20-60h, mean 40h
- urinary excretion as metabolites
34
Warfarin duration of therapy
Indication dependent
- indefinitely: afib, >2 documented DVTs or PE
- 3 months: ant. MI w LV thrombus, high risk for LV thrombus, bioprosthetic valves in mitral position
35
Warfarin for the elderly
Lower initiation and MD recommended
| "Start low and go slow"
36
Warfarin w renal impairments
No dosage adjustment necessary
| Incr. risk of bleeding complications
37
Warfarin w hepatic impairment
Response to oral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis, cirrhosis
INR should be monitored closely
38
Warfarin w Asian patients
May require lower initiation and MD
39
Warfarin monitoring
- Daily INR monitoring until pt in therapeutic range
- periodic INR monitoring during maintenance (every 1-4 weeks), plus after exchange of products, when other meds are initiated, discontinued, or taken irregularly
- PT, hct, INR, consider genotyping prior to therapy
40
Warfarin common ADRs
- minor and major bleeding episodes
- dermatological rxns
- hypersensitivity
- chills, vasculitis
- tracheal/ tracheobronchial calcification
41
Warfarin antidote
Vit K injection (phytonadione)
- indicated in coagulation disorders due to faulty factor II, VII, IX, X formation when caused by vit k deficiency or interference w vit k activity
- - anticoagulant induced prothrombin deficiency, hemorrhagic diseases of the newborn, hypoprothrombinemia
42
Warfarin food interactions
- Anticoagulant effects may be decreased if taken with foods rich in vit k
- vit E may increase warfarin effect
- Cranberry juice may increase warfarin effect
43
Warfarin contraindications
- pregnancy, hemorrhagic tendencies, malignant hypertension, known hypersensitivity
44
Warfarin Use in pregnancy
Category D: contraindicated except in pregnant women with mechanical heart valves at high risk of thromboembolism
- risk of teratogenicity
- crosses the placenta, concentrations in fetal plasma similar to maternal, teratogenic effects may include Coumadin embryopathy
- LMWH generally used if necessary
45
An I coagulant/DTIs
```
Unfractionated heparin (UFH, high molecular weight)
LMWHs: enoxaparin (lovenox), Dalteparin (fragmin), tinzeparin (off market)
```
46
UFH supply
Injection of widely varied strengths
- used for anticoagulation
- used to maintain latency of IV devices
- not to be used for systemic anticoagulant therapy (heparin lock flush soln.)
47
UFH mechanism of action
- binds to antithrombin III via its pentasaccharide sequence
- - inhibits factor Xa, which normally activate thrombin
- large enough to simultaneously bind antithrombin and thrombin III
48
LMWH mechanism of action
Pentasaccharide sequence bind antithrombin III, potentiating factor Xa inhibition
- cannot simultaneously bind thrombin
49
Fondaparinux mechanism of action
Classified as an indirect Xa inhibitor
| - synthetic pentasaccharide which accelerates only factor Xa inhibition by potentiating of antithrombin III
50
UFH indications
- prophylaxis and tx of thromboembolic disorders
- off label: interstitial cystitis, STEMI as adjuncts to fibrinolytic tx
- unstable angina and non STEMI
- Anticoagulant during percutaneous coronary intervention
- following DVT, PE, superficial vein thrombosis, pts w afib undergoing cardioversion, nonbacterial thrombotic endocarditis and systemic or pulmonary emboli, cerebral venous sinus thrombosis, acute arterial emboli or thrombosis
51
UHF administration
- can be given SC, by cont. iv, by heparin lock
- do not give IM
- CVCs must be flushed w heparin soln when inserted, daily, and after blood withdrawal or transfusion, and after infusion w injectable cap
52
UFH absorption
Oral, rectal: erratic at best
| Subcutaneous: also erratic, but acceptable for prophylaxis
53
UFH metabolism
Hepatic, may be partially metabolized in the reticuloendothelial system
54
UFH excretion
Urine (small amts as unchanged drug)
| Half life eliminate: short and affected by various conditions
55
UFH time to onset
IV: immediate
SC: ~20-30m
56
UFH special pops
Renal function impairment: half life may be increased
Hepatic function impairment: half life may be incr. or decr.
Elderly: plasma levels may be higher
57
UFH monitoring
- aPTT/ antifactor Xa activity levels, ACT when high dose heparin w procedures where clotting is suppressed
- platelet counts when HIT risk
58
Common UFH ADRs
- Heparin Induced thrombocytopenia (HIT)
- Hypersensitivity
- Local rxns: erythema, hematoma, irritation, pain, ulceration
- Misc.: cutaneous necrosis, delayed transient alone is, osteoporosis
- elevations of ALT and AST
59
Heparin Induced Thrombocytopenia
Drug induced immunologic rxn
- incidence of 1-2%
- leading complication is thromboembolism
- type 1: presents 2d post admin, then platelet count normalizes
- type2: 4-10d and can cause life threatening thrombotic event
- skin lesions, chills, fever, dispensing and chest pain after IV
- Probability det. by 4 Ts
60
Management of HIT
- discontinue heparin, replace w anticoagulant that doesn't cause HIT (bivalirudin, argatroban, fondaparinux)
- renal insuff.--> argatroban
- hepatic impairment --> fondaparinux
- both--> low dose argatroban or bivalirudin
61
Transition to warfarin post HIT
- do not use as initial anticoagulant after HIT, may increase risk of gangrene by rapid lowering of protein C
- should be started only after:
- - pt is antioagulated w alternative anticoagulant
- - platelet count of at least 150k/microL
- min 5 days overlapping therapy
62
UFH hypersensitivity
Heparin are porcine products
| Fondaparinux is synthetic w lower risk of hypersensitivity
63
UFH antidote
Protamine Sulfate
- binds to long part of heparin molecules, neutralizes
- - only partially works on LMWHs
- minimal dose should be used to avoid anticoagulant effects: 1mg for every 100 units heparin
64
UFH in pregnancy
Category C: does not cross placenta. May be used for prevention and tx of TE in pregnancy, but LMWH is preferred
65
LMWHs
Enoxaparin, Dalteparin
66
LMWH metabolism/excretion
- primarily metabolized in the liver by desulfurization and/depolymerization
- total renal clearance of active and inactive enoxaparin fragments represents 40% of the dose, w 10% active fragments
67
Dalteparin special pop
Pts w chronic renal insuff requiring hemodialysis--> expect greater accumulation
68
Enoxaparin special pop
- Renal insuff: antifactor Xa exposure @css marginally increased in mild and moderate renal insuff, significant in severe renal insuff.
- elderly: antifactor Xa exposure 15% greater @ day 10 than day 1
- weight: antifactor Xa exposure increased in low weight pts
69
LMWH monitoring
- periodic CBC incl. platelet count and hct or hgb
- closely monitor Thrombocytopenia
- no special blood clotting time monitoring needed
- monitor for signs of bleeding in pts w low body weigh, risk for renal disfunction, pregnancy
- monitor for thromboembolism in obese pts
70
LMWH in pregnancy
Category B: does not cross placenta, fetal bleeding or teratogenicity not reported
- recommended over UFH for treatment of acute VTE in pregnancy
71
LMWH and UFH interactions
- avoid combination w other anticoagulants and antiplatelet agents, may enhance effect (apixaban, Dabigatran)
- Other agents w antiplatelet properties: clopidogrel, NSAIDs, SSRIs
- hormones can increase coagulopathy risk and diminish efficacy
- vit E, herbals, supplements can increase risk of bleeding
72
LMWH and UFH contraindications
- hypersensitivity to LMWHs, heparin a, pork products, or any component of the formulation
- active major bleeding
- epidural or spinal hematoma so may occur in pts who are anticoagulated w LMWHs or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture
73
Direct Thrombin Inhibitors
Dabigatran (Pradaxa) - PO
Argatroban - IV
Bivalirudin (Angiomax) - IV
Desirudin (Ipravask) - SC
74
Direct Factor Xa inhibitors
Rivaroxoban (Xarelto) - PO
Apixaban (Eliquis) - PO
Edoxaban (Savaysa) - PO
75
Indirect Factor Xa inhibitors
Fondaparinux (Arixtra) - IV
- accelerates only factor Xa inhibition by antithrombin
- lower HIT risk compared to LMWHs,higher bleed risk
76
DTI monitoring
- monitor for symptoms of blood loss
- aPTT is generally used, but dose response is not linear and reaches a plateau
- INR increased by all DTIs (variably)
- aPTT more than 2.5 may indicate over anticoagulation
- monitor renal function
77
DTI common ADRs
- Bleeding is major adverse effect
- hemorrhage may occur at virtually any site
- - risk dependent on multiple variables: intensity of anticoagulation, concurrent use of a glycoproteins IIb/IIIa inhibitor (bivalirudin), and pt susceptibility
78
DTIs drug interactions
Dabigatran is a substrate of P-glycoprotein
| G-protein inhibitors would decrease absorption
79
DTIs contraindications
- Hypersensitivity to active ingredients
- active major bleeding
- Mechanical prosthetic heart valve (Dabigatran only)
80
DTIs in pregnancy
```
Category B: argatroban, bivalirudin
Category C: Dabigatran, Desirudin
Insufficient data to evaluate safety of DTIs in pregnancy
Avoid use of oral agents
Unknown if excreted in breast milk
```
81
DTI antidote
Idarucizumab (Praxbind)
- reversal of Dabigatran (Pradaxa)
- Humanized monoclonal antibody fragment (Fab) derived whose target is Dabigatran
- for use in urgent/ emergent life threatening bleeds
- 5g IVx1, repeat if necessary
82
Direct and Indirect Xa inhibitor monitoring
- periodically monitor for blood loss, periodic cbc and stool occult tests recommended during tx
- frequently monitor for neurological impairment, renal function prior to initiation and when clinically indicated (at least annually)
- monitor hepatic function
- antifactor Xa assay may be helpful in guiding clinical decisions
83
Apixaban metabolism/ transport effects
- Minor substrate of: BRCP, CYP1A2, CYP2C19, CYP2C8, CYP2C9
- Major substrate of CYP3A4
- substrate of P-glycoprotein
- weak inhibitor of CYP2C19
84
Edoxaban metabolism/transport effects
Substrate of P-glycoprotein
85
Rivaroxoban metabolism/transport effects
- Minor substrate of CYP2J2
- Major substrate of CYP3A4
- substrate of P-glycoprotein
86
Direct and Indirect Xa inhibitor Drug-disease interactions
- impaired renal function + rivaroxaban + drugs that are weak to moderate CYP3A4 and P-gp inhibitors may have increases in Rivaroxoban exposure
- grapefruit juice may increase levels / effects of apixaban and rivaroxaban
87
Direct and Indirect Xa inhibitor contraindications
- hypersensitivity
- active, major bleeding
- Fondaparinux: severe renal impairment (
88
Direct and Indirect Xa inhibitors in Pregnancy
Category B: apixaban, Fondaparinux
Category C: rivaroxaban, edoxaban
-may increase risk of pregnancy related hemorrhage
-anticoagulant effect cannot be easily monitored or reversed. Prompt clinical evaluation is warranted w any unexplained decrease in Hb, hct, BP, or fetal distress
89
Direct and Indirect Xa inhibitor antidote
There are none
- also not dialyzable
- Protamine and vit k do not affect anticoagulant activity
- Therapy for severe hemorrhage may include prothrombin complex (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa
- potential use of activated charcoal if ingestion of apixaban within 2-6h of presentation
90
Antiplatelet agents
- COX inhibitors
- PDE/adenosine uptake inhibitors
- aggregation inhibitors/ platelet P2Y12 receptor antagonists (ADP inhibitors)
- aggregation inhibitors/ PDE III inhibitor
- glycoproteins IIb/IIIa inhibitors
91
COX inhibitors
Aspirin (PO) 75-500mg
92
PDE/ adenosine uptake inhibitors
Dipyridamole (PO)
93
ADP inhibitors (platelet P2Y12 receptor antagonists)
- Cangrelor
- Clopidogrel (Plavix)
- Prasugrel (effient)
- Ticragrelor (Brillinta)
- Ticlopodine HCl (Ticlid)
94
PDE III inhibitor
Cilostazol (pletal)
95
Glycoprotein IIb/IIIa inhibitors
- Abciximab (ReoPro) - IV
- Eptifibatide (integrilin) - IV
- Tirofiban HCl (Medicure) - IV
96
Aspirin (ASA) indications
- Prevention of recurrence of stroke, TIA, MI
- Revascularization procedures
- Acute coronary syndromes: do not use ext. release or enteric coated form
97
Aspirin dosage (STEMI and unstable angina/ non-STEMI)
Initial: 162-325 mg on presentation
Maintenance: 81mg/d, same if taken w Ticagrelor
- doses over 150mg makes little difference in CV outcomes, but increases bleeding risk
Concomitant: in combination w clopidogrel or Ticagrelor (or w an IV GPIIb/IIIa inhibitor if invasive strategy for Unstable Angina/non-STEMI
98
Aspirin onset of action
Immediate release: platelet inhibition within 1 hour
| Enteric coated: delayed (but within 20 mins if chewed)
99
Aspirin duration
IR: 4-6h
| - platelet inhibition lasts lifetime of platelet be of irreversible inhibition of platelet COX1
100
Aspirin Absorption
IR: rapidly absorbed in stomach and upper intestine
XR: dependent upon food, alcohol, and gastric pH
101
Aspirin distribution
VD 10L, readily into most body fluids and tissues
| Protein Binding: Concentration dependent, inverse to salicylate concentration
102
Aspirin Metabolism
Hydrolysis to salicylate (active) by esterases in GI mucosa, RBCs, synovial fluid, and blood
- metabolism of salicylate occurs primarily by hepatic conjugation
- metabolic pathways are saturable
103
Aspirin Excretion
Urine
Half life:
- parent drug: 15 to 20 minutes
- salicylates: 3h at lower doses, 5-6h after 1g, 10h with higher doses
104
Aspirin contraindications
- Hypersensitivity to NSAIDS
- Allergic cross reactivity for salicylates
- ADR
105
Aspirin in pregnancy
- salicylates cross placenta, can cause mortality, intrauterine growth retardation, salicylate intoxication, bleeding abnormalities, neonatal acidosis
- use close to delivery may cause premature closure of ductus arteriosus
- may be used in 2nd and third trimesters in women w prosthetic valves
106
Aspirin interactions
- Any drug that has anticoagulant effect - incr. bleed risk
- NSAIDs suppress glomerular filtration, may cause toxicity in drugs that rely on renal excretion
- NSAIDs can elevate BP an antagonize hypertensive meds
- very sensitive to pH changes: Ammonium chloride and acetazolamide may increase. Serum conc. And Sodium bicarbonate alkalizer urine, leading to enhanced excretion
107
Dipyridamole indications
Adjunct to Coumadin anticoagulants
| Prevention of stroke or TIA
108
Dipyrimadole absorption/distribution
- 75 min to peak conc. After oral dose
| - alpha half life of 40 mins, beta half life is 10h
109
Dipyridamole metabolism and excretion
Metabolized in liver, conjugated as a glucuronide and excreted in bile
110
Dipyridamole contraindications
- hypersensitivity
- elevation in hepatic enzymes
- headache (has vasodilatory effect)
111
Dipyridamole in pregnancy
Category B
Excreted in human milk
Not used in pregnancy much
112
Dipyridamole drug interactions
Inhibits P-glycoprotein
113
Dipyridamole monitoring
Signs and symptoms of bleeding
| FDA doesn't recommend any labs
114
Dipyridamole fun facts
Not used much
| Short acting might lead to increased risk of cardiac ischemia when used by patients using dipyridamole to prevent MI
115
Cilostazol indications
- Intermittent claudication
| - - reduction of symptoms as indicated by walking distance
116
Cilostazol distribution
Protein binding: Cilostazol 95-98%; active metabolites 66-97%
117
Cilostazol metabolism
Hepatic
Major: CYP2C19, CYP3A4
Minor: CYP1A2, CYP2D6
118
Cilostazol excretion
Urine (74%), feces (20%) as metabolites
| Half life elimination: 11-13h
119
Cilostazol onset
Effect on walking distance:2-4 weeks, may require up to 12 weeks
120
Cilostazol special pops
Renal function impairment - increases metabolic concentrations and alters protein binding of parent drug
Dialysis- unlikely that it can be removed efficiently bc of protein binding
Smokers - decreases exposure by 20%
121
Cilostazol monitoring
Periodic white blood cell and platelet counts
