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pr3154 > ic3 - pharmacology of hematological drugs > Flashcards

ic3 - pharmacology of hematological drugs Flashcards

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1
Q

list examples of antiplatelets

A

dipyridamole, aspirin, clopidogrel, ticagrelor, eptifibatide

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2
Q

classify the antiplatelets according to their types (moa)

A

dipyridamole is adenosine reuptake and PDE3 inhibitor

aspirin is a COX1 inhibitor

clopidogrel and ticagrelor are P2Y12 receptor inhibitors

eptifibatide is a glycoprotein IIb/IIIa inhibitor

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3
Q

what does ADP and TXA2 cause

A

when released, they cause an increase in expression of PLT on glycoprotein IIb/IIIa receptors

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4
Q

compare the difference between anticoagulants and antiplatelets

A

anticoagulants slow down clotting and thus prevent clots from forming and growing

antiplatelets prevent platelets from clumping and also prevent clots from forming and growing

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5
Q

how do platelets adhere to damaged blood vessel walls

A

inactive platelets become activated and adhere to collagen at sites of damaged blood vessels and to other platelets via glycoprotein IIb/IIIa receptors (on platelets)

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6
Q

what is the function of adenosine

A

an inhibitory mediator that activates adenosine A2 receptors on inactive platelets to increase cyclic AMP levels within platelets and inhibit platelet activation and aggregation

also a vasodilator through increasing cGMP, which leads to inhibition of calcium entry into the cells (Ca2+ required for muscle contraction), opening of potassium channels, and activation of myosin light chain phosphatase

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7
Q

what is the property of PDE3

A

PDE3 known to increase contractility

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8
Q

what is the moa of dipyridamole

A

dipyridamole acts as both an adenosine reuptake inhibitor and a PDE3 inhibitor

by inhibiting adenosine reuptake, it increases plasma adenosine activation of A2 receptors thus increasing cAMP to prevent platelets from activating and aggregating

by inhibiting PDE3, reduces cAMP degradation within platelets

as a result, dipyridamole also acts as a vasodilator since it would inhibit adenosine reuptake and PDEs in vascular smooth muscle

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9
Q

what is the indication for use of dipyridamole

A

adjunct therapy with other antiplatelets and/or other anticoagulants

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10
Q

what are some details of the PK of dipyridamole

A

fast onset after PO of 20-30mins, peak effect in 2-2.5hrs, short duration of action of approx 3hrs (thus given as a modified release preparation)

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11
Q

what is the benefit of a shorter duration of action of dipyridamole

A

rapid reversal

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12
Q

what are the s/e from taking dipyrimadole

A

headache, hypotension, dizziness, flushing **related to vasodilator effects

GIT (N/V/D)

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13
Q

what are the c/i of dipyridamole

A

hypersensitivity to dipyridamole, caution in hypotension or severe coronary artery disease

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14
Q

what are the ddi for dipyridamole

A

caution for bleeding if heparin/ antiplatelets/ anticoagulants

decreases cholinesterase inhibitors which can aggravate myasthenia gravis (cholinesterase inhibitors prevent the breakdown of ACh to help muscle activation and contraction)

increases adenosine which increases cardiac adenosine levels and effects

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15
Q

what is myasthenia gravis

A

a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles

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16
Q

compare what platelets produce and what endothelial cells produce and what is the function

A

platelets express COX1 which produces TXA2 which promotes platelet aggregation while endothelial cells on blood vessel walls expresses COX2 which produces prostacyclin (PGI2) that inhibits platelet aggregation

balance between inhibiting and promoting platelet aggregation in order to keep blood flowing

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17
Q

what is the moa of aspirin

A

aspirin works as an irreversible cyclooxygenase inhibitor that inhibits both COX1 and COX2, but inhibits COX1 more than COX2

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18
Q

how long does aspirin’s effect last and why (compare to endothelial cells)

A

aspirin effects last for lifespan of platelets as platelets are unable to produce new COX (7-10d) while endothelial cells have nucleus thus able to produce new COX and restore production of PGI2 in 3-4h

during the 3-4h, low dose aspirin is largely cleared and thus will not inhibit newly produced COX

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19
Q

why is aspirin a better antiplatelet at lower doses

A

it becomes nonselective at higher doses of 500mg-1g vs when it is 75-325mg LD or 40-160mg daily

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20
Q

what is the s/e of aspirin

A

upper GI events of bleeding, gastric ulcers etc and increase risk of bruising and bleeding

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21
Q

why might aspirin cause upper GI events

A

aspirin inhibits COX1 production of protective PG in stomach that usually helps to decrease acid secretion and increase bicarb and mucus secretion and increase blood flow

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22
Q

what is the c/i for aspirin

A

caution in patients with platelet and bleeding disorders

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23
Q

what is the ddi for aspirin

A

caution for bleeding if patient on other antiplatelets or anticoagulants

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24
Q

what subtype are ADP receptors on platelets

A

P2Y12 subtype

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25
relate role of ADP and glycoprotein IIb/IIIa in platelet aggregation
ADP released from dense granules of platelets binds to ADP P2Y12 receptor and activates glycoprotein IIb/IIIa receptors on platelets which activates platelet recruitment and aggregation ADP -> P2Y12 -> GP IIb/IIIa -> serve as receptors for vWF and fibrinogen for platelet aggregation
26
what is the moa of clopidogrel and ticagrelor
inhibits ADP P2Y12 receptor to block ADP mediated increase in cell surface expression of active glycoprotein IIb/IIIa receptors thus reducing platelets to platelet adhesion and decreases platelet aggregation
27
what is the specific moa of clopidogrel
prodrug with an active metabolite metabolised by 2C19 that irreversibly binds to ADP binding site on P2Y12 receptor
28
what are some details of the PK of clopidogrel
loading dose to accelerate approach to steady state delayed onset and peak effect in 6-8hrs interindividual variability due to 2C19 mediated metabolism to produce active metabolite
29
how long does effects of clopidogrel last
life span of platelets (7-10d)
30
what are the c/i for clopidogrel
hypersensitivity, active pathological bleeding like peptic ulcer caution in risk of bleeding (intracranial hemorrhage, trauma, surgery)
31
what are the ddi for clopidogrel
warfarin, NSAIDs and salicylates like aspirin can increase risk of bleeding macrolides may reduce antiplatelet effect strong to moderate 2C19 inhibitors can reduce antiplatelet effect (PPI, fluoxetine, ketoconazole) rifamycins may increase antiplatelet effect
32
what does rifamycin treat
abx for e coli, used to treat traveller's diarrhea
33
what is the moa of ticagrelor
ticagrelor and its metabolites reversibly binds to a binding site different to ADP binding site to inhibit G protein activation and signalling
34
what are some details on the PK of ticagrelor
LD to achieve faster approach to steady state faster onset and peak effect than clopidogel recovery of PLT function depends on serum concentration of ticagrelor and its metabolites, approx 2-3d
35
what are the s/e of ticagrelor
bleeding, easy bruising, bradycardia, dyspnea, cough
36
what are the c/i of ticagrelor
hypersensitivity, active pathological bleeding, hx of intracranial hemorrhage, breastfeeding, severe hepatic impairment caution in moderate hepatic impairment, risk of bleeding, elderly
37
what are the ddi of ticagrelor
anticoagulants, long term NSAIDs and fibrinolytics can increase risk of bleeding aspirin of dose >100mg/day can decrease antiplatelet effect of ticagrelor thus increasing beleding risk 3A inducers like dexamethasone and phenytoin can decrease ticagrelor levels strong 3A inhibitors like clarithromycin and ketoconazole can increase ticagrelor levels and risk of s/e
38
list examples of anticoagulants and classify them according to routes
OACs: warfarin, dabigatran, rivaroxaban, apixaban parenteral: heparin (UFH and LMWH eg. enoxaparin)
39
classify the OACs according to moa
VKA - warfarin DOACs: factor IIa inhibitor (thrombin) - dabigatran DOACs: factor Xa inhibitor - apixaban, rivaroxaban
40
what is the general moa of anticoagulants
block activation of fibrin polymerisation and secondary hemostasis block coagulation cascade at various levels but ultimately preventing thrombin activation thus inhibiting conversion of fibrinogen to fibrin and subsequent polymerisation of fibrin required to stabilise fibrin in a meshwork
41
which clotting factors does warfarin, dabigatran, rivaroxaban, LMWH and heparin block
warfarin blocks II, VII, IX, X dabigatran blocks II rivaroxaban blocks X heparin blocks IX, X, XI, XII LMWH block II, X
42
which components rely on vitamin K
clotting factors II, VII, IX, X and protein C,S
43
relate conversion of vitK to moa of warfarin
active vitamin K is oxidised into inactive vitamin K in a step coupled to carboxylation of glutamic acid residues on clotting factors II, VII, IX, X (carboxylation activates these clotting factors) vitK reductase enzyme would reactivate the oxidised inactive vitK which warfarin comes in to inhibit the vitK reductase enzyme
43
relate conversion of vitK to moa of warfarin
active vitamin K is oxidised into inactive vitamin K in a step coupled to carboxylation of glutamic acid residues on clotting factors II, VII, IX, X (carboxylation activates these clotting factors) vitK reductase enzyme would reactivate the oxidised inactive vitK which warfarin comes in to inhibit the vitK reductase enzyme
44
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
44
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
44
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
44
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
45
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
46
what are some details about the PK of warfarin
rapid and complete PO absorption onset 24-72h, peak effect 2-8h, full effect 5-7d duration of action 2-5d metabolised by 2C9 halflife 20-60h highly variable eliminated in urine and feces affected by interindividual variability in mutations of VKORC1 and 2C9
47
why does warfarin have a relatively long duration of action
because some of the clotting factors affected by warfarin has a long half life (eg. factor II has half life of 50h)
48
what are the monitoring parameters for warfarin
INR and PT
49
what are the s/e of warfarin
bleeding, hepatitis, cutaneous necrosis and infarction of the breast, buttocks and extremities likely due to reduced blood supply to adipose tissue (typically occurs 3-5d after initiation
50
what are the signs of bleeding patients should look out for
blood in urine (kopi o colour) or stools, melena (black tarry stools), excessive bruising, petechiae (purple spots on skin) , persistent oozing from superficial injuries, heavier menses
51
what are the c/i for warfarin
hypersensitivity, severe or malignant HTN, severe renal or hepatic impairment, active bleeding, risk of pathological bleeding (after recent major surgery), pregnancy, subacute bacterial endocarditis/ pericarditis/ pericardial effusion caution in breastfeeding, mild to moderate HTN, mild to moderate renal or hepatic disease, colitis, drainage tubes in any orifice (nose/ anal)
51
what are the c/i for warfarin
hypersensitivity, severe or malignant HTN, severe renal or hepatic impairment, active bleeding, risk of pathological bleeding (after recent major surgery), pregnancy, subacute bacterial endocarditis/ pericarditis/ pericardial effusion caution in breastfeeding, mild to moderate HTN, mild to moderate renal or hepatic disease, colitis, drainage tubes in any orifice (nose/ anal)
52
what is endocarditis, pericarditis and pericardial effusion
endocarditis is inflamm of the inner lining of the heart chambers and valves pericarditis is inflamm of the tissue surrounding the heart pericardial effusion is fluid buildup in the space around the heart
53
what is the ddi and fdi of warfarin
ddi include: long term (>2w) use of paracetamol at high doses (>2g/day) can incr risk of bleeding 2C9 inhibitors and other antiplatelets and anticoagulants like NSAIDs, PPIs, salicylate, allopurinol, metronidazole can increase risk of bleeding 2C9 inducers like barbiturates, corticosteroids, spironolactone, thiazide diuretics may decrease efficacy of warfarin fdi include: traditional herbs and supplements and food like gingko, reishi mushroom, ginseng, cranberry juice may increase risk of bleeding vitK rich food like green tea may decrease efficacy of warfarin
54
what is the prodrug of dabigatran
dabigatran extexilate
55
what is the moa of dabigatran
dabigatran and its acyl glucoronide metabolites are competitive reversible non peptide antagonist of thrombin aka factor IIa inhibitor
56
does dabigatran have a reversible agent, if yes what is it and how does it exert its effect
yes, idarucizumab which is a humanized MAb fragment that binds dabigatran and its acyl glucoronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin
57
what is the moa of rivaroxaban
competitive reversible factor Xa antagonist
58
recall what does factor Xa do
convert prothrombin to thrombin
59
does rivaroxaban have a reversal agent, if yes what is it
andexanet alfa which is a recombinant modified human factor Xa decoy protein for reversal of -xabans
60
compare the PK between the DOACs (dabigatran and rivaroxaban)
dabigatran vs rivaroxaban target: IIa vs Xa route: PO vs PO onset: rapid vs rapid F: 3-7% (thus enteric coated) vs 80-100% peak: 3h vs 2.5-4h half life: 12-17h vs 5-9h (shorter thus easier for reversal of effects) metabolism: largely excreted unchanged vs hepatic elimination: urine vs 66% urine and 28% feces
61
compare the s/e and ddi between the DOACs (dabigatran and rivaroxaban)
dabigatran: bleeding, GI sx (dyspepsia, abdominal discomfort) rivaroxaban: bleeding dabigatran: anticoagulants, antiplatelets, fibrinolytics, NSAIDs, ketoconazole incr risk of bleeding; rifampin decr levels of dabigatran rivaroxaban: anticoagulants, antiplatelets, NSAIDs, P-gp and 3A4 inhibitors incr risk of bleeding; P-gp and 3A4 inducers decr levels of rivaroxaban
62
what is the moa of heparin and LMWH
potentiates action of antithrombin III (AT III) and thus inactivate thrombin which is needed for conversion of fibrinogen to fibrin and without fibrin the clot formation is impeded active heparin molecules bind tightly to ATIII and cause a conformational cange which exposes AT III's active site for more rapid interaction with proteases and heparin-AT III complex inactivates coagulation factors II, IX, X, XI, XII
63
what is the selectivity of LMWH
more selective for Xa than IIa
64
does heparin have a reversal agent, if yes what is it and what does it do
protamine sulfate (IV infusion) is a 5kDa cationic polypeptide derived from salmon sperm and is highly basic it stably binds to negatively charged heparin and neutralises anticoagulant properties of heparin to reverse its effect (partial but incomplete reversal for LMWH)
65
what are the s/e of heparin
bleeding (but short half life so anticoagulant effects disappears within a few hrs after discontinuation), increase risk of epidural or spinal hematoma and paralysis (if receive epidural or spinal anethesia or spinal puncture), heparin induced thrombocytopenia (low PLT count)
66
how might heparin induced thrombocytopenia occur
heparin binds to platelet factor 4 (PF4) on activated PLT which triggers formation of IgG Ab against heparin-PF4 complex
67
how is the risk of heparin induced thrombocytopenia affected if swap from heparin to LMWH
lower risk if use LMWH
68
what is the c/i for heparin
hypersensitivity to heparin and pork products, active major bleeding, thrombocytopenia or antiPLT Ab caution in elderly and risk of bleeding (prosthetic heart valves, blood dyscrasias, recent childbirth, pericarditis, pericardial effusion, renal impairment for LMWH, major surgery, regional or lumbar block anesthesia)
69
is heparin c/i in pregnancy
no bc not found to cross placenta and not assoc with fetal malformations
70
what is the ddi and fdi for heparin
anticoagulants, antiplatelets, NSAIDs, fibrinolytics, SSRIs can incr risk of bleeding various herbs and foods including gingko, chamomile, garlic, ginger, ginseng incr risk of bleeding
71
compare the PK between parenteral anticoagulants (heparin and LMWH)
heparin vs LMWH routes: IV and SC vs IV and SC size: 15000Da vs 5000Da half life: 1h vs 4h F: 30% vs 86-98% renal excretion: no vs yes thrombocytopenia risk: <5% vs <1%
72
list examples of fibrinolytics
alteplase and kinases (streptokinase, urokinase-type plasminogen activator)
73
how do clots breakdown physiologically
by actions of endogenous tissue type plasminogen activators (tPA) which activates the conversion of plasminogen into plasmin which is an enzyme that mediates fibrinolysis by allowing cells and platelets that are stuck in clots to be slowly released back into the bloodstream
74
what is the moa of fibrinolytics
to breakdown fibrin crosslinking to reverse clot stabilisation
75
what happens if fibrin meshwork is broken down to rapidly
clot can break down too fast in clumps than by gradual release of RBC and platelets that are trapped in clots thus risking fragments of clot to circulate in bloodstream which can cause embolism or blockage of smaller blood vessels elsewhere
76
when are fibrinolytics indicated
to treat pre existing clots that are causing imminent risk of irreversible damage or death eg. stroke/ PE
77
are fibrinolytics indicated for clots in DVT
no, DVT clots are allowed to degrade more slowly by physiological actions of endogenous tPA
78
what type of tPA is alteplase
a recombinant tPA (r-tPA) produced by recombinant DNA technology
79
how does r-tPA differ from tPA
differ in terms of r-tPA having longer plasma half lives that allow convenient IV dosing
80
does fibrinolytic agents have reversal agents, if yes what is it and what does it do
tranexamic acid and aminocaproic acid that act as antidotes and compete for the lysine binding sites on plasminogen and plasmin thus blocking their interaction with fibrin and is used to reverse states of excessive fibrinolysis
81
what are the s/e of alteplase
bleeding ventricular arrythmias, hypotension, edema (can monitor, not major impediments for use) cholesterol embolisation and VTE (due to fragments of clots being mobilised) hypersensitivity and anaphylaxis (rare but srs)
82
what are the c/i for alteplase
active bleeding, prior intracranial hemorrhage or recent (within past 3m) intracranial or intraspinal surgery, serious head injury, stroke caution in pts with major surgery within 10d, risk of bleeding, cerebrovascular disease, mitral stenosis, AF, acute pericarditis or subacute bacterial endocarditis
83
what are the ddi for alteplase
antiplatelets (esp dipyridamole and aspirin), anticoagulants (esp warfarin and heparin) incr risk of bleeding nitroglycerin decr alteplase levels
84
compare the difference in specificity between -teplases vs kinases
-teplases has preference over clot-associated plasminogen thus activating plasmin at the clot

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