drugs (antiplt, anticoag, fibrinolytics) Flashcards
(106 cards)
1
Q
antiplts target
A
block plt aggregation and 1* haemostasis (step 2)
- to prevent activation of clotting factors, fibrin formation
2
Q
classes of antiplt
A
adenosine uptake, PDE3i (dipyridamole)
COX1 i (aspirin)
ADP (P2Y12) receptor i (clopi, ticag)
glycoprotein IIb/ IIIa inhibitor (eptifibatide)
3
Q
dipyridamole MOA
A
- inhibit PLT activation and aggregative by incr cAMP within plt
1) Adenosine reuptake inhibitor
* Incr plasma adenosine
* activation of A2 receptors on PLT, incr cAMP
2) PDE3 inhibitor
* Reduce cAMP degradation within PLT, les activation of PLT
- vasodilator
- limite adenosine reuptake and PDEs in vascular smooth muscle
4
Q
dipyridamole uses
A
Adjunct antiplt in combi with others antiplt (aspirin), anticoag (warfarin)
Infused IV for myocardial perfusion imaging – good vasodilator
5
Q
dipyridamole PK
A
Dose-limiting ADR limit clinical antiplt efficacy
Fast onset after PO: 20-30mins
Peak: 2-2.5hrs
DOA: short, 3hrs (Require modified-release prep)
6
Q
ADR of dipyridamole
A
Headache, hypotension (vasodil)
Dizzy, flush, GIT disturbances, NVD
7
Q
CI, caution of dipyridamole
A
- Hypersensitive to drug
- Hypotension
- severe coronary artery disease
- Reflex tachy lead to angina pectoris, ECG abnormality, MI
8
Q
DDI of dipyridamole
A
Incr adenosine
* Incr cardiac adenosine lvls, effect
Decr cholinesterase inhibitor
* Aggravate myasthenia gravis
Bleeding
* When combined with heparin, other anticoag, antiplt
9
Q
aspirin MOA
A
Irreversible COX1 inhibitor
COX1 > COX2 inhibitor effect at lower dose
Acetylsalicylic acid blocks production of thromboxane A2 in PLT. New plt formed 7-10d
but COX2 have prostacyclin (inhibit plt aggregation)
10
Q
COX action in body
A
COX 1on PLT – produce thromboxane A2
* Stimulate production of ADP, other mediators
* Promotes plt aggregation
COX 2 on endothelial cells – produce prostaglandins I2
* But PGI2 inhibit plt aggregation
* Restored by synthesis of new COX enzyme, 3-4hrs
11
Q
dosing of aspirin
A
OD daily more effective than 4-6hrs
- new plt formed in 7-10d, longer lasting effect dose regiments to approach SScs
- freq dose, incr COX2 inhibiton of PGI2, counter anti-PLT effect
12
Q
low dose of aspirin is __
A
Low dose 75-325mg loading or 40-160mg daily (OD)
13
Q
indication for aspirin
A
ACS, CCS, PAD
fibrinolytic reperfusion
AIS
2nd stroke prevention
14
Q
ADR of aspirin
A
1) Upper GIT (gastric ulcers, bleed)
- inhibit COX1 protective PGI in stomach (mucus secretion, blood flow, bicarbonate)
- low dose, OD will cause 2-4x incr in UGI events
2) Bruising, bleeding
15
Q
aspirin caution
A
PLT and bleeding disorders
Combi with other antiplt, anticoag
16
Q
P2Y12 receptor inhibitors
A
(irreversible/ reversible) prevent ADP binding
- Blocks the ADP (P2Y12) receptor
- Further reduce expression of (glycoprotein 2b, 2a receptor)// (a2b 3 integrin)
= Less PLT recruitment and aggregation
loading dose regimens needed to accelerate approach to SS
17
Q
clopidogrel
A
- Prodrug with active metabolite
- Delayed onset (6-hr peak)
- Interindividual variability
○ CYP2C19 metabolism (activation)
- Effect on plt last 7-10d
18
Q
clopidogrel indication and doses
A
ACS/ CCS 300-600mg LD –> 75mg OD
(6h - 2h onset)
ischaemic stroke/ TIA
300-600mg LD –> 75mg OD
PAD 75mg OD
19
Q
clopidogrel PK
A
LD: 300mg (6h), 600mg (2h)
time to plt aggregation SS w/o LD: 5-6d
M: 2 step activation (CYP3A4, IA2, 2C19)
E: t1/2: 1.9hr
50% urinary, 50% fecal
DDI: 2C19, 3A, PGP substrate
stop for surgery: 5 days
20
Q
clopidogrel renal and hepatic
A
renal: no dose adj
hepatic: no dose adj, CI in severe impairment
21
Q
clop BF and preg
A
BF: no known if present, risk & benefit
preg: no assoc of ADR. discontinue 5-7d prior to labour
22
Q
clopidogrel SE
A
Haemorrhage, bleeding (intracanal bleed, bruise)
headache, dizzy, ND, C, ab pain
hypotension
23
Q
clopidogrel CI, cautions
A
- Hypersensitive
- Active pathologic bleeding (Peptic ulcer)
- At risk of bleeding
- Intracranial haemorrhage
- Trauma
- Surgery
- thrombotic thrombocytopenia purpura
- Variant alleles of CYP2C19
- Reduced active metabolites, less antiplt response
24
Q
CYP2C9 LoF alleles ares
A
2* or 3*
use ticagrelor instead (reduced ischemic events)
25
DDI of clopidogrel
* Incr risk of bleeding
* Warfarin, aspirin, NSAIDs, salicylates, OACs
* Reduce antiplt effect
* Macrolides
* Strong-mod CYP2C19i, reduce antiplt effect
* PPI, fluoxetine, ketoconazole
* Incr antiplt effect
* Rifamycin
26
DHI clopidogrel
incr antiplt effect
ginseng (antiplt)
vit E (> 400 IU/Day, antiplt)
omega 3 (>2g/day, antiplt)
27
monitor for clopidogrel
1. sign of bleed
2. Hb, Hematocrit
- DAPT: 1,3,6 mnth
- mono: TCU
3. PLT function
28
stop for surgery
min 5 days
29
ticagrelor MOA
ADP receptor P2Y12 inhibitor (reversible)
* Binds to diff site not ADP binding site
* Inhibit G protein activation and signalling
More potent
30
ticagrelor dose and indication
180mg LD (2h)
90mg BD (12mn) --> 60mg BD (extended therapy)
CYP2C19 LoF, ACS, AIS
2nd stroke prevention (large vessel disease)
31
ticagrelor onset
* Faster onset and peak effect > clopidogrel
* Recovery of PLT is 2-3days (depend on serum conc & active metabolites)
Faster offset too
32
ticagrelor PK
time to plt aggregation SS (no LD):2 days
- recovery from stopping TICA 2x rapid as Clopido
M: no biotransformation (not affected by CYP2C9, ABCB1 poly)
- hepatic CYP3A4 --> metabolite
E: parent 7h, metabolite 9h
33
stop for surgery
2-3day
34
ticagrelor ADR
Haemorrhage, bleeding (intracanal bleed, bruise)
Cough, dyspnea, Bradycardia
(incr Adenosine lvl in lungs > cardiac musc)
35
ticagrelor CI and cautions
* Hypersensitive, SEVERE hepatic impairment, breastfeeding
* Active pathologic bleeding
* Peptic ulcer
* Hist of intracranial hemorrhage
* At risk of bleeding
* Peptic ulcer
* Trauma
* Surgery
* Elderly
* Moderate hepatic failure
36
ticagrelor DDI
* Incr risk of bleeding
* Anticoag, fibrinolytics, LT NSAIDs use
○ Aspirin >100mg/day decr ticagrelor effect, incr bleed risk
* CYP3A4 inducer, decr antiplt
* Dexamethasone, phenytoin
* CYP3A4i Incr antiplt effect
* Clarithromycin, ketoconazole
37
glycoprotein IIb/ IIIa inhibitor (eptifibatide) MOA
reversible GP 2b3a receptor inhibitor
38
eptifibatide indication and dose
ACS (PCI before use of potent antiPLT)
IV (double bolus) 180ug/kg
10min interval f/b
infusion 2ug/kg/min for 72h
39
classes of anticoagulants
PO :
- vit K antagonist
- DOAC (dabigatran DTI + Xa inhibitor RAE)
IV: UFH, LMWH (enoxaparin), DTI
40
anticoagulants target
2nd hemostasis (step 3)
* Prevent fibrinogen --> fibrin
* Prevent polymerisation
* Prevent activation of clotting factors, tissue factors, XIIa, Xa, IIa (thrombin)
41
warfarin, vit K antagonist MOA
* Ext (10A)
* Int (2A, 9)
* Common pathway
1. Inhibit Vit K reductase enzyme (VKORC1) that reactivate oxidized vit K
2. Active --> inactive vit K
* Oxidation process
* Coupled to carboxylation of glutamic acid residues on coagulation factors II,VII,IX,X (2,7,9,10) = activation
42
indication for warfarin
SPAF
LV thrombus
mechanicla/ prosthetic heart valves, mitral stenosis
APS
VTE/ DVT
favoured in renal, hepatic impairment (INR monitor)
43
warfarin initation
LD --- hypercoagulability (prot C,S)
start with fasting anticoag, admin 5days w/ warfarin, until INR >2
monitor INR 2-3 day after change/ initiate
1) LMWH
2) UFH (if renal impair <30ml)
44
warfarin doses
5mg OD (if not expected to be sensitive)
2.5mg (for pt expected to be sensitive)
- elderly, frail, hypoalbumin, hepatic/ renal impair, acute ill, HASBLED
- concomittant drug that decr warfarin metabolism (incr INR)
- race
45
monitor warfarin for initation
pre-initiation:
- Base INR/ PT
- renal panel
optional: LFT, pgx
46
warfarin monitoring
INR 2-3
higher (2.5-3.5): mitral mechanical valves
47
freq of FU for monitoring
- inpt: daily INR
- after discharged from hosp: 1-3 day (unstable) 3-5d (stable)
- outpt: 3-5d
1wk (first mnth) --> 2wks --> 3wks --> 3mnths (v stable)
48
reverse of warfarin
1) VITAMIN K CAN REVERSE
(PO 1-2mg --> IV 5-10mg)
- not use iV as pt can be at risk of thrombosis
2) PCC
3) fresh frozen plasma
49
overcorrection
delayed re-anticoagulation, hard to reverse back to INR range
50
PK of warfarin
* PO: 24-72hrs ,rapid absorption
* Peak: 2-8hr
* Full effect: 5-7d
* Need deplete endogenous vit K
* DOA: 2-5d
* Long t1/2 (36-42) as some coag factors II = 50hrs
* Metabolised: 99% protein bind = hepatic, CYP2C9, 3A
no pgp bind
* Elimination: 20-60hrs, variable among indiv
* excreted : urine and feces
51
genetic polymorphism for warfarin metabolism in 2 genes
○ CYP2C9 (main metaboliser of S-warfarin)
○ vit K reductase complex subunit 1 (target MOA)
so need to monitor INR, prothrombin + titrate dose
52
when to pgx
1) existing clot (LV thrombus)
2) outpt initiation
3) complex DDI
4) questionable adherence
benefit: =/<21mg/wk or =/>49mg/wk
NO NEED if alr know maintenance dose, no indication for dosing
53
warfarin ADR
* Haemorrhage/ bleeding
* Blood ins tool, urine, melena, excess bruise, petechiae, persistent ooze from superficial injury, excess menstrual bleed
* Hepatitis
* >60yr, M, warfarin < 1mnth
* Cutaneous necrosis
* infarction breast, buttocks, extremities
* Reduce blood supple to adipose tissue
* 3-5d after initiate tx
54
ABSOLUTE CI for warfarin
* Hypersensitive
* Active bleed
* Risk of pathologic bleeding
* recent traumatic surgery of enclosed palce (eye, CNS, heart)
* blood dyscrasias (bleed, thrombocytopenia)
* inability to monitor tx
55
relative CI of warfarin
- link to HASBLED
* mild/ mod hypertension
* Severe renal, hepatic disease
* Subacute bacterial endocarditis, pericarditis, pericardial effusion
* PUD < 3mnths, chronic alcohol abuse, bariatric surgery
* thrombophilia (deficient in prot C,S)
56
cautions for warfarin
pts with
* Diverticulitis, colitis
* Mild, mod hypertension
* Mild, mod renal, hep disease
* Drainage tube in orifice (any)
57
speical pop in warfarin
hepatic impairment (no specific guidelines)
renal impairment (start 10-20% lower dose, monitor INR)
breastfeeding: little risk of harm
elderly: more sensitive
preg --> LMWH: CI unless prosthetic mechanical valve
58
preg absolute CI for warfarin
PREG
* Teratogenic 1st trimester
* 2-4 wks before delivery
* threat
* 48h postpartum
* threatened abortion, preeclampsia
exception: women with mechanical heart valve, hgih risk for thromboembolism
59
DDI for warfarin
* Incr bleed
* Paracetamol LT > 2wk, high dose >2g/day
* Risk of bleed
* NSAID, antithrombotics, SSRI
* CYP2C9 Inhibitors (Incr warfarin effect )
○ Amiodarone, isoniazide, SMX, voriconazole, metronidazole, fenofibrate, quercetin, MACROLIDES
60
decr efficacy of warfarin DDI
Barbiturates, CS, spironolactone, thiazide diuretics
* CYP2C9 Inducers (Decr warfarin effect)
○ Carbamazepine, rifampin, st John's wort, phenobarbital
61
antimicrobials effect on warfarin
○ Microbiome, produce menadione (type of vit K)
-Antimicrobials, decr vit K, incr INR
○ adj of warfarin
-Preemptive: SMX/TMP, ciprofloxacin, metronidazole
- No adj: macrolide, amox/calv, doxycycline
62
pre-emptive dose adj of warfarin
(decr dose)
amiodarone
fluconazole
metronidazole
SMX-TMP, ciprofloxacin
(incr dose)
rifampin
63
DFI with warfarin
○ Med, herb, suppl. Food
○ alcohol (rise INR, chronic decr)
○ incr INR: Gingko, ginseng, reishi mushroom, jamu, cranberry juice
○ omega-3, vit E, alcohol
○ (decr INR, decr efficacy): vit K rich foods -- green tea, kale, spinach
64
drug-lifestyle interaction
smoke: CYP450 induction, incr warfarin metabolism =(DECR INR)
incr physical activity: incr warfarin meta = (DECR INR)
65
drug disease interaction
liver impairment (decr CF synthesis, warf meta) = INCR
infection (fever/ sepsis) (incr metabolism, clotting factor turnover faster) =INCR
hyperthyroid (incr CF turnover) = INCR
preeclmpsia (coagulability state) = DECR
HF (oedematous gut DECR) (liver, clotting factor =INCR)
renal impair (low albumin) = INCR
66
DOAC - dabigatran MOA
DTI
* Intrinsic pathway (2A)
* Common pathway
Prodrug (dabigatran) are competitive reversible non-peptide antagonists of thrombin (factor IIa)
67
dabigatran reversal
1) Reversed with Idarucizumab $1000
- humanised Mab fragment that binds dabigatran and acyl glucuronide metabolites with greater affinity than dabi-thrombin
2) hold, renal CL or dialysis
68
PK of dabigatran
* PO, rapid onset, 3-7% bioavail
* Peak action: 3h
* T1/2: 12-17h
* Metabolism: largely excreted unchanged (80% renally cleared)
* Excretion: urine
69
ADR of dabigatran
Bleeding
GIT sx (dyspepsia, discomfort)
hypotension, headache
70
DDI of dabigatran
* Incr risk of bleeding
* Antiplt, anticoag, fibrinolytics, NSAID, ketoconazole
* Decr efficacy: Rifampin
* PGPi
71
DOAC rivaroxaban MOA
* Common pathway (10A)
Competitive reversible antagonist of activated factor X (Xa)
72
indication and dose for rivaroxaban
- DVT/ VTE
15mg BD 21d --> 20mg OD --> proph 10mg OD
- SPAF : 20mg OD
crcl 30-50 = 15mg OD
crcl 15-30 = caution
crcl < 15 = CI
-ACS
2.5mg BD (combi w/ aspirin + clopi), continue 1 yr
crcl <3- = avoid use
73
reverse rivaroxaban
1) Andexanet alfa
- recombinant modified human factor Xa decoy protein (NOT SG)
2) renal function to clear, hold for 1-2days
3) prothrombin complex concentrates (incr 2,7,9,10, C,S)
74
PK of rivaroxaban
* PO, rapid onset, 80-100% bioavail
* Peak action: 2.5-4h
* Half-life: 5-9h
* Metabolism: 66% hepatic (CYP3A4, CYP2J2, PGP, BCRP)
* Excretion: urine, faeces
75
CL of rivaroxaban
33% --> renal excretion
33% --> renal elimination of liver metabolite
33% --> fecal elimination of liver metabolite
76
special pop consideration
eldlery, obese (BMI >30) = no dose adj
hepatic: avoid if B & C
77
preg and lact for rivaroxaban
preg: not recomm, (potential fetal bleed, miscarriage)
lact: risk vs benefits
78
ADR of rivaroxaban
bleeding, bruising
gastroenteritis
vomiting
cough
79
rivaroxaban DDI
* Incr risk of bleeding
* Antiplt, anticoag, NSAID, P-glycoprotein inhibitors, CYP3A4i
* Decr efficacy
* CYP3A4 inducers, PGP inducers
80
combined P-gp and CYP3A4 inhibitors (incr bleed)
ARC
PO azoles (ketoconazole), ritonavir, clarithromycin (CYP3A4i, Azi P-gp inhibitor, less interaction)
81
potent CYP3A4 inducers (decr efficacy):
carbamazepine, phenytoin, phenobarbital, rifampin, and St. John's wort
82
potent P-gp inhibitor:
verapamil, quinidine, dronedarone, amiodarone, macrolides (ACE), PO azole, ciclosporins.
83
riva monitoring parameters
baseline: Hb, renal panel
efficacy: s&sx, adherence
84
when to FU for DOAC
1mnth (first)
4mnth
* >75yo (dabi), frail
Every crcl/10 mnths
* Crcl < 60ml/min
Immediately
* Potential impact on renal, hepatic function
* Infection, NSAID use, dehydration
85
compare riva with apixaban and edoxaban
R: OD, high BW
A: BD, low BW, elderly, CKD
SDL
E: OD
not for crcl> 95ml/min (risk of stroke)
86
apixaban PK
F: 66%
tmax: 3h
t1/2: 8-15h
hepatic, protein bind: >80%
(CYP3A, pgp, BCRP)
87
edoxaban PK
F: 62%
1max: 4h
t1/2: 10-14h
protein binding: ~55% (unlikely dialysable)
CYP3A, pgp
88
IV anticoagulant -heparin MOA
* Ext (10A)
* Common pathway
Potentiates action of anti-thrombin (AT III)
Inactivates thrombin (less fibrinogen --> fibrin)
1. Heparin bind to AT III, conformational change
2. Expose ATIII active site with proteases
3. Inactivates coagulation actors
a. Thrombin, Ixa, Xa, Xia, XIIa
b. No fibrin
89
reversal for heparin
Protamine sulfate IV infusion
- 5kDa cationic pp
- bind to -ve heparin, neut properties
incomplete reversal for LMWH
90
PK of heparin
* MW: 15,000
* Bioavail: 30%
* T1/2: 1h
* Excretion: liver
91
ADR of heparin and LMWH
* Bleeding
○ Anticoag effect disappear after 1hr
* Risk epidural or spinal haematoma, paralysis
○ Epidural, spinal anesthesia/ puncture
* Heparin induced thrombocytopenia
○ Low PLT
○ Drug-PLT factor 4 on activated PLT surface
○ IgG Ab against heparin-PF4 complex
○ Lower risk with LMWH
92
CI for heparin & LMWH
OK WITH PREG, does not cross placenta, not assoc with fetal malformations
* Hypersensitive to heparin, pork
* Active major bleeding
* Thrombocytopenia, antiPLT Ab
Caution:
* Elderly pt
* Risk of bleeding
* Pt with prosthetic heart valves, major surgery, regional or lumbar block anesthesia, blood dyscrasis, recent childbirth, pericarditis effusion
* RENAL INSUFFICIENCY: LMWH
93
DDI, DFI with heparin & LMWH
incr risk of bleeding
* Drug
○ Antiplt, anticoag, fibrinolytics, NSAID, SSRIs
* Food
○ Chamomile, fenugreek, garlic, ginger, gingko, ginseng
94
LMWH enoxaparin MOA
* Ext (10A)
* Less int (2A)
* Common pathway
Potentiates action of anti-thrombin (AT III)
Inactivates thrombin
More selective for factor Xa (ext, int) > factor IIa (thrombin)
95
PK of LMWH
* MW: 5000
* Bioavail: 86-98%
* T1/2: 4h
* Excretion: renal
96
enoxaparin use
DOC for preg, weight based dosing
bridge for warfarin
bridge for DVT
PCI
97
fibrinolytic
Breakdown fibrin crosslinking to reverse clot stabilisaiton
(step Fibrinolysis)
98
alteplase MOA
1) Binds preferentially to clot-associated plasminogen, --> plasmin at the clot
2) break down clots
acts like Tissue Plasminogen Activator
99
alteplase PK
Longer plasma t1/2 than endogenous tPA
Onset of action: 20-30mins
100
alteplase ADR
□ Haemorrhage/ bleeding
□ Ventricular arrhythmias, hypotension, oedema
□ Cholesterol embolisation, venous thromboembolism
- if break down clot too fast > gradual release
- Fragment of clots circulating = embolism
□ Hypersensitivity, anaphylaxis
101
reverse alteplase
Tranexamic acid, aminocaproic acid
- Compete for lysine binding sites on plasminogen and plasmin
- Block interaction with fibrin and Reverse excess fibrinolysis
102
CI of alteplase
Pt with active bleeding
- Prior intracranial haemorrhage
- Recent (3mnths) intracranial or intraspinal surgery
- Serious head injury
-Stroke
103
caution for alteplase
- Major surgery within 10d
- risk of bleeding (peptic ulcers)
- cerebrovascular disease, mitral stenosis, atrial fib, acute pericarditis, subacute bacterial endocarditis
◊ only use with pre-existing clot that cause imminent risk of irreversible damage or death: thrombotic stroke, or coronary embolism
◊ Prevent dislodge other clots that may be present in pt
104
DDI with alteplase
□ Incr risk of bleeding
- Antiplt (dipyridamole, aspirin), anticoag (warfarin, heparin)
- not used within last 24hr
□ Decr alteplase lvls
- Nitroglycerin
105
inclusion for thrombolytics
diagnosis for AIS
within 4.5hr
CT scan shows AIS diagnosis
no exclusion criteria
106
exclusion criteria for thrombolytics
hx of ICH, IS (3mnths), subarachnoid/ intracranial haemorrhage
- endocardities, aortic arch dissection
- active internal bleeds, GI haemorrhage
- major surgery/ serious trauma in last 14d
- Lumbar puncture in last 7d
- preg
- BP > 185/110
- counts: INR > 1.7, PLT <100,000, glucose < 2.7
- use of DTI, Xa inhibitor in last 48hr
- use of warfarin in last 48hr unless INR < 1.7
- LMWH in last 24hr
