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pr3154 > ic3 - pharmacology of hematological drugs > Flashcards

ic3 - pharmacology of hematological drugs Flashcards

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
Q

relate role of ADP and glycoprotein IIb/IIIa in platelet aggregation

A

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

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26
Q

what is the moa of clopidogrel and ticagrelor

A

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

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27
Q

what is the specific moa of clopidogrel

A

prodrug with an active metabolite metabolised by 2C19 that irreversibly binds to ADP binding site on P2Y12 receptor

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28
Q

what are some details of the PK of clopidogrel

A

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

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29
Q

how long does effects of clopidogrel last

A

life span of platelets (7-10d)

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30
Q

what are the c/i for clopidogrel

A

hypersensitivity, active pathological bleeding like peptic ulcer

caution in risk of bleeding (intracranial hemorrhage, trauma, surgery)

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31
Q

what are the ddi for clopidogrel

A

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

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32
Q

what does rifamycin treat

A

abx for e coli, used to treat traveller’s diarrhea

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33
Q

what is the moa of ticagrelor

A

ticagrelor and its metabolites reversibly binds to a binding site different to ADP binding site to inhibit G protein activation and signalling

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34
Q

what are some details on the PK of ticagrelor

A

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

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35
Q

what are the s/e of ticagrelor

A

bleeding, easy bruising, bradycardia, dyspnea, cough

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36
Q

what are the c/i of ticagrelor

A

hypersensitivity, active pathological bleeding, hx of intracranial hemorrhage, breastfeeding, severe hepatic impairment

caution in moderate hepatic impairment, risk of bleeding, elderly

37
Q

what are the ddi of ticagrelor

A

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
Q

list examples of anticoagulants and classify them according to routes

A

OACs: warfarin, dabigatran, rivaroxaban, apixaban

parenteral: heparin (UFH and LMWH eg. enoxaparin)

39
Q

classify the OACs according to moa

A

VKA - warfarin

DOACs: factor IIa inhibitor (thrombin) - dabigatran
DOACs: factor Xa inhibitor - apixaban, rivaroxaban

40
Q

what is the general moa of anticoagulants

A

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
Q

which clotting factors does warfarin, dabigatran, rivaroxaban, LMWH and heparin block

A

warfarin blocks II, VII, IX, X

dabigatran blocks II

rivaroxaban blocks X

heparin blocks IX, X, XI, XII

LMWH block II, X

42
Q

which components rely on vitamin K

A

clotting factors II, VII, IX, X and protein C,S

43
Q

relate conversion of vitK to moa of warfarin

A

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
Q

relate conversion of vitK to moa of warfarin

A

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
Q

does warfarin have a reversal agent, if yes what is it

A

yes, excess vitamin K

44
Q

does warfarin have a reversal agent, if yes what is it

A

yes, excess vitamin K

44
Q

does warfarin have a reversal agent, if yes what is it

A

yes, excess vitamin K

44
Q

does warfarin have a reversal agent, if yes what is it

A

yes, excess vitamin K

45
Q

does warfarin have a reversal agent, if yes what is it

A

yes, excess vitamin K

46
Q

what are some details about the PK of warfarin

A

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
Q

why does warfarin have a relatively long duration of action

A

because some of the clotting factors affected by warfarin has a long half life (eg. factor II has half life of 50h)

48
Q

what are the monitoring parameters for warfarin

A

INR and PT

49
Q

what are the s/e of warfarin

A

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
Q

what are the signs of bleeding patients should look out for

A

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
Q

what are the c/i for warfarin

A

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
Q

what are the c/i for warfarin

A

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
Q

what is endocarditis, pericarditis and pericardial effusion

A

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
Q

what is the ddi and fdi of warfarin

A

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
Q

what is the prodrug of dabigatran

A

dabigatran extexilate

55
Q

what is the moa of dabigatran

A

dabigatran and its acyl glucoronide metabolites are competitive reversible non peptide antagonist of thrombin aka factor IIa inhibitor

56
Q

does dabigatran have a reversible agent, if yes what is it and how does it exert its effect

A

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
Q

what is the moa of rivaroxaban

A

competitive reversible factor Xa antagonist

58
Q

recall what does factor Xa do

A

convert prothrombin to thrombin

59
Q

does rivaroxaban have a reversal agent, if yes what is it

A

andexanet alfa which is a recombinant modified human factor Xa decoy protein for reversal of -xabans

60
Q

compare the PK between the DOACs (dabigatran and rivaroxaban)

A

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
Q

compare the s/e and ddi between the DOACs (dabigatran and rivaroxaban)

A

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
Q

what is the moa of heparin and LMWH

A

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
Q

what is the selectivity of LMWH

A

more selective for Xa than IIa

64
Q

does heparin have a reversal agent, if yes what is it and what does it do

A

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
Q

what are the s/e of heparin

A

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
Q

how might heparin induced thrombocytopenia occur

A

heparin binds to platelet factor 4 (PF4) on activated PLT which triggers formation of IgG Ab against heparin-PF4 complex

67
Q

how is the risk of heparin induced thrombocytopenia affected if swap from heparin to LMWH

A

lower risk if use LMWH

68
Q

what is the c/i for heparin

A

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
Q

is heparin c/i in pregnancy

A

no bc not found to cross placenta and not assoc with fetal malformations

70
Q

what is the ddi and fdi for heparin

A

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
Q

compare the PK between parenteral anticoagulants (heparin and LMWH)

A

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
Q

list examples of fibrinolytics

A

alteplase and kinases (streptokinase, urokinase-type plasminogen activator)

73
Q

how do clots breakdown physiologically

A

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
Q

what is the moa of fibrinolytics

A

to breakdown fibrin crosslinking to reverse clot stabilisation

75
Q

what happens if fibrin meshwork is broken down to rapidly

A

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
Q

when are fibrinolytics indicated

A

to treat pre existing clots that are causing imminent risk of irreversible damage or death eg. stroke/ PE

77
Q

are fibrinolytics indicated for clots in DVT

A

no, DVT clots are allowed to degrade more slowly by physiological actions of endogenous tPA

78
Q

what type of tPA is alteplase

A

a recombinant tPA (r-tPA) produced by recombinant DNA technology

79
Q

how does r-tPA differ from tPA

A

differ in terms of r-tPA having longer plasma half lives that allow convenient IV dosing

80
Q

does fibrinolytic agents have reversal agents, if yes what is it and what does it do

A

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
Q

what are the s/e of alteplase

A

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
Q

what are the c/i for alteplase

A

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
Q

what are the ddi for alteplase

A

antiplatelets (esp dipyridamole and aspirin), anticoagulants (esp warfarin and heparin) incr risk of bleeding

nitroglycerin decr alteplase levels

84
Q

compare the difference in specificity between -teplases vs kinases

A

-teplases has preference over clot-associated plasminogen thus activating plasmin at the clot

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