ic3 - pharmacology of hematological drugs Flashcards
list examples of antiplatelets
dipyridamole, aspirin, clopidogrel, ticagrelor, eptifibatide
classify the antiplatelets according to their types (moa)
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
what does ADP and TXA2 cause
when released, they cause an increase in expression of PLT on glycoprotein IIb/IIIa receptors
compare the difference between anticoagulants and antiplatelets
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
how do platelets adhere to damaged blood vessel walls
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)
what is the function of adenosine
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
what is the property of PDE3
PDE3 known to increase contractility
what is the moa of dipyridamole
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
what is the indication for use of dipyridamole
adjunct therapy with other antiplatelets and/or other anticoagulants
what are some details of the PK of dipyridamole
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)
what is the benefit of a shorter duration of action of dipyridamole
rapid reversal
what are the s/e from taking dipyrimadole
headache, hypotension, dizziness, flushing **related to vasodilator effects
GIT (N/V/D)
what are the c/i of dipyridamole
hypersensitivity to dipyridamole, caution in hypotension or severe coronary artery disease
what are the ddi for dipyridamole
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
what is myasthenia gravis
a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles
compare what platelets produce and what endothelial cells produce and what is the function
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
what is the moa of aspirin
aspirin works as an irreversible cyclooxygenase inhibitor that inhibits both COX1 and COX2, but inhibits COX1 more than COX2
how long does aspirin’s effect last and why (compare to endothelial cells)
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
why is aspirin a better antiplatelet at lower doses
it becomes nonselective at higher doses of 500mg-1g vs when it is 75-325mg LD or 40-160mg daily
what is the s/e of aspirin
upper GI events of bleeding, gastric ulcers etc and increase risk of bruising and bleeding
why might aspirin cause upper GI events
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
what is the c/i for aspirin
caution in patients with platelet and bleeding disorders
what is the ddi for aspirin
caution for bleeding if patient on other antiplatelets or anticoagulants
what subtype are ADP receptors on platelets
P2Y12 subtype
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
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
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
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
how long does effects of clopidogrel last
life span of platelets (7-10d)
what are the c/i for clopidogrel
hypersensitivity, active pathological bleeding like peptic ulcer
caution in risk of bleeding (intracranial hemorrhage, trauma, surgery)
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
what does rifamycin treat
abx for e coli, used to treat traveller’s diarrhea
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
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
what are the s/e of ticagrelor
bleeding, easy bruising, bradycardia, dyspnea, cough
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
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
list examples of anticoagulants and classify them according to routes
OACs: warfarin, dabigatran, rivaroxaban, apixaban
parenteral: heparin (UFH and LMWH eg. enoxaparin)
classify the OACs according to moa
VKA - warfarin
DOACs: factor IIa inhibitor (thrombin) - dabigatran
DOACs: factor Xa inhibitor - apixaban, rivaroxaban
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
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
which components rely on vitamin K
clotting factors II, VII, IX, X and protein C,S
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
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
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
does warfarin have a reversal agent, if yes what is it
yes, excess vitamin K
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
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)
what are the monitoring parameters for warfarin
INR and PT
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
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
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)
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)
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
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
what is the prodrug of dabigatran
dabigatran extexilate
what is the moa of dabigatran
dabigatran and its acyl glucoronide metabolites are competitive reversible non peptide antagonist of thrombin aka factor IIa inhibitor
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
what is the moa of rivaroxaban
competitive reversible factor Xa antagonist
recall what does factor Xa do
convert prothrombin to thrombin
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
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
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
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
what is the selectivity of LMWH
more selective for Xa than IIa
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)
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)
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
how is the risk of heparin induced thrombocytopenia affected if swap from heparin to LMWH
lower risk if use LMWH
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)
is heparin c/i in pregnancy
no bc not found to cross placenta and not assoc with fetal malformations
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
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%
list examples of fibrinolytics
alteplase and kinases (streptokinase, urokinase-type plasminogen activator)
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
what is the moa of fibrinolytics
to breakdown fibrin crosslinking to reverse clot stabilisation
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
when are fibrinolytics indicated
to treat pre existing clots that are causing imminent risk of irreversible damage or death eg. stroke/ PE
are fibrinolytics indicated for clots in DVT
no, DVT clots are allowed to degrade more slowly by physiological actions of endogenous tPA
what type of tPA is alteplase
a recombinant tPA (r-tPA) produced by recombinant DNA technology
how does r-tPA differ from tPA
differ in terms of r-tPA having longer plasma half lives that allow convenient IV dosing
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
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)
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
what are the ddi for alteplase
antiplatelets (esp dipyridamole and aspirin), anticoagulants (esp warfarin and heparin) incr risk of bleeding
nitroglycerin decr alteplase levels
compare the difference in specificity between -teplases vs kinases
-teplases has preference over clot-associated plasminogen thus activating plasmin at the clot
