Haem Pharmacology Flashcards
What is the MoA of Ticagrelor and Clopidogrel?
P2Y12 inhibitor
Prevents ADP from binding to P2Y12 receptor → prevent activation of GPIIb/IIIa receptors, platelet recruitment and aggregation
Is ticagrelor reversible? What about clopidogrel?
Ticegrelor is reversible, clopidogrel is irreversible
True or false:
Ticagrelor has a longer duration than clopidogrel
False
Duration of ticagrelor is 2-3 days, whereas duration of clopidogrel is 7-10 days
ADRs of ticagrelor and clopidogrel
Bleeding, bronchospasm, dyspnea, hypotension
Ticagrelor is metabolised by ____ while clopidogrel is metabolised by ______
Ticagrelor: CYP3A4
Clopidogrel CYP2C19
DDIs
List some examples of CYP inhibitors and inducers of ticagrelor
CYP3A4 Inhibitors: clarithromycin, ritonavir, ketoconazole, itraconazole
CYP3A4 inducers: dexamethasone, phenobarbital, phenytoin, carbamazepine, rifampicin
DDIs
List some examples of CYP inhibitors and inducers of clopidogrel
CYP2C19 inhibitors: PPI, ketoconazole, fluxetine
CYP2C19 inducers: rifamycin
True or false
CYP2C19 inhibitors reduces clopidogrel’s antiplatelet effect, while CYP2C19 inducers increases antiplatelet effect
True
This is due to the CYP enzymes effect on metabolising clopidogrel to its active metabolite. (Clopidogrel is a prodrug)
True or false:
Ticagrelor can be used in pregnancy and lactating mothers
False!
Is contraindicated
What is the reversal agent of Ticagrelor?
A. Bentracimab
B. Andexanet alfa
C. Idarucizumab
D. Vitamin K
A
Note that bentracimab is not available in SG
What are some contraindications of ticagrelor and clopidogrel? There may be more than 1 answer
A. Hypersensitivity
B. Asthma
C. Varient alleles of CYP2C9
D. Moderate to severe hepatic impairment
E. Thrombocytopenia
F. Pregnancy and lactation
Ans: A, D, F
C: should be CYP2C19 instead
F: Is in drug points for ticagrelor, but no data for clopidogrel currently
What is the MoA of Aspirin?
Irreversible COX inhibitor (COX-1 > COX-2)
COX1i: inhibit production of TXA2, which promotes platelet aggregation (7-10 days)
COX2i: inhibit production of PGI2, which inhibits platelet aggregation (3-4 days)
True or false:
Duration of aspirin is 7-10 days
True
(COX1) Formation of new platelets and thus production of TXA2 takes 7-10 days
(COX2) Synthesis of new COX enzyme and thus production of new PGI2 takes 3-4 days
True or false
Aspirin has vasodilaiton side effects such as headache, hypotension, dizziness, and flushing
False
Dipyridamole is the only antiplatelet that has vasodilation side effects, due to inhibiting adenosine reuptake and PDEs in vascular smooth muscle
What is the MoA of Dipyridamole? (including off-target effect)
- Adenosine uptake inhibitor → ↑plasma adenosine activation of A2 receptors on platelets
- PDE3 inhibitor → ↓cAMP degradation
Both ↑cAMP within platelets → prevent degradation to AMP → inhibit platelet activation and aggregation
Off-target: Vasodilator (inhibit adenosine reuptake and PDEs in vascular smooth muscle)
DDI
Interaction of dipyridamole with adenosine causes _______ and, and interaction with cholinesterase inhibitors cause _______
Adenosine: ↑cardiac adenosine levels and effects
Cholinesterase inhibitors: aggrevate myasthenia gravis
What is the MoA of warfarin? Include what coagulation factors it inhibits.
Inhibits Vitamin K Epoxide Reductase (VKOR), thus inhibiting reactivation of oxidised vit K, and inhibit the production of factors 2, 7, 9, 10, and anticoagulant proteins C and S
Active vit K activate factors 2, 7, 9, 10 in a step coupled to carboxylation of glutamic acid residues on those coagulation factors
What is the duration of warfarin? What determines this duration?
Duration: 2-5 days
Due to long half-life of factor 2 (42-72hrs)
Note: factor 7 has shortest half-life (4-6hrs)
Explain what is the hypercoagulable state when initiating warfarin. What is done to prevent this?
Warfarin inhibits production of natural anticoagulant proteins C and S. Protein C has a half life of 9hrs, while protein S has a half-life of 60hrs. Hence there would be a hypercoagulable state of approx 4-5 days.
Bridge with LMWH/ enoxaparin to prevent this hypercoagulable state.
Germ: pls help edit this explanation if needed arigatouu
Which enzymes metabolises warfarin?
CYP2C9 (S-enantiomer) and CYP3A4 (R-enantiomer)
DDI
Which drugs have a DDI with warfarin? (can think if they are inducers or inhibitor)
Metronidazole
Clarithromycin
Ritonavir
St John’s Wort
Bactrim
Omeprazole
Ciprofloxacin
Carbamezapine
Sodium valproate
Atorvastatin
Fluconazole
Amoxicillin
Ciprofloxacin
Phenobarbital
Furosemide
Rifampicin
Doxycycline
Amiodarone
Digoxin
CYP inhibitors: metronidazole, -azoles, PPIs
Adjust preemptively: bactrim, ciprofloxacin
CYP inducers: rifampicin, ritonavir, carbamazepine, barbiturates, St John’s Wort
What drugs need to be preemptively adjusted when taken with warfarin? State what the adjusted dose is too.
Bactrim/ Co-trimox (25-50% reduction)
Ciprofloxacin (20-30% reduction)
DDI
Which drugs have a DDI with apixaban? (can think if they are inducers or inhibitor)
Metronidazole
Clarithromycin
Ritonavir
St John’s Wort
Bactrim
Omeprazole
Ciprofloxacin
Carbamezapine
Sodium valproate
Atorvastatin
Fluconazole
Amoxicillin
Ciprofloxacin
Phenobarbital
Furosemide
Rifampicin
Doxycycline
Amiodarone
Digoxin
CYP3A4 and P-gp inhibitors: -azole, ritonavir
CYP3A4 and P-gp inducers: carbamazepine, phenytoin, phenobarbital, St John’s Wort, rifampicin
Note: for CYP3A4 and P-gp inducers, avoid use in DVT/PE. For SPAF/ VTEP, no adjustments needed, monitor.
Which increases and which decreases INR?
Hyperthyroidism
Hypothyroidsim
Fluid retention due to oedematous gut
Fluid retention from HF
Fever
Liver impairment
Alcohol binge
Chronic alcoholism
Smoking
Grapefruit juice
Increase INR: liver impairment, fluid retention from HF (liver congestion), fever, hyperthyroidism, alcohol binge, grapefruit juice
Decrease INR: fluid retention due to oedematous gut (gut malabsorption), hypothyroidism, chronic alcoholism, smoking
True or false:
Warfarin cannot be used for all 3 trimesters in a pregnant woman
False
Warfarin C/I in 1st trimester.
Use LMWH for 1st trimester, switch to warfarin after 1st trimester, switch to LMWH 1 week before delivery
Does warfarin have renal and liver impairment dose adjustments?
Only for renal, hepatic don’t have
Renal: lower dose in eGFR < 60, HD, and PD. Avoid use in Concurrent chemoradiotherapy (CCRT) and Prolonged Intermittent Renal Replacement Therapy (PIRRT)
Hepatic: NIL, monitor INR closely
What is the MoA of dabigatran, rivaroxaban, apixaban, and edoxaban?
Dabigatran: reversible direct thrombin inhibitor
Riva, apix, edo: competitive reversible factor Xa inhibitor
True or false:
All DOACs undergo hepatic metabolism
False
Dabigatran: mainly renally cleared
Rivaroxaban, Apixaban: CYP3A4
Edoxaban: Minimally hepatically and renally cleared
True or false:
Apixaban can be used in Child-Pugh Score C patients
False
Contraindicated!
True or false:
DOACs cannot be used in pregnancy and lactation
True
Which is the order in which DOACs are most renally cleared, in ascending order.
(legend: D = dabigatran, R = rivaroxaban, A = apixaban, E = edoxaban)
A. D < R < A < E
B. R < D < E < A
C. E < A < R < D
D. E < R < A < D
C
What are the reversal antidotes for DOACs?
Dabigatran: idarucizumab
Rivaroxaban, apixaban, edoxaban: andexanet alfa
What is the MoA of UFH and LMWH?
Binds tightly to antithrombin III and causes a conformational change → exposes active site for ↑ interaction → inactivates thrombin/ facotr IIa (which converts fibrinogen to fibrin), and factors IXa, Xa, XIa, XIIIa
True or False:
LMWH is more potent than UFH
True
LMWH has a higher selectivity for factor Xa, longer half-life, and higher bioavailability than UFHs
Do take note that LMWH are less selective of factor IIa/ thrombin as compared to UFHs
What causes heparin-induced thrombocytopenia (HIT)? Does UFH or LMWH have a higher risk for HIT?
Heparin binds to platelet factor 4 (PF4) on activated platelet surface → ↑IgG activation against heparin-PF4 complex → HIT
Lower risk of HIT w LMWH
True of False:
UFH cannot be used for pregnancy, while LWMH can
False
Both can be used in pregnancy
What is the reversal agent for LWMH and UFH?
Extra: What is its MoA?
No reversal agent for LWMH!
Protamine sulfate IV infusion for UFH.
Highly basic peptide stably binds negatively charged heparin and neutralises anticoagulant properties of heparain
True or false:
Drugs that increases risk of bleeding when taken with UFHs and LWMH include fibrinolytics, NSAIDs, and SSRIs
True
What is the MoA of fibrinolytics? (tenectaplase, alteplase)
Recombinant tissue plasminogen activator (r-tPA)
Binds preferentially to clot-associated plasminogen → activating plasmin at the clot → plasma digests firbin, thereby dissolving the clot
What is the reversal antidote for fibrinolytics? There may be more than one answer.
Extra: What is its MoA?
A. Tranexamic acid
B. Bentracimab
C. Fresh frozen plasma transfusion
D. Andexanet alfa
E. Aminocaproic acid
Tranexamic acid and aminocaproic acid
MoA: compete for lysine binding sites on plasminogen and plasmin → block interaction with fibrin
Why are firbinolytics only used in high-risk patients? Think about its high potency and adverse effect on the clots.
Fibrinolytics may cause fibrin meshwork to be broken down too rapidly, resulting in clots breaking down in clumps. This increases the risk of fragments of clots in the bloodstream, thus causes embolism.
Hence avoid fibrinolytics if clot is not stable. Use antiplatelets and anticoagulants to remove unstable clot instead.
Warfarin
What are instructions when taken with CYP inhibitors and inducers? Think which to lower dose preemptively first or monitor first.
CYP inhibitor: lower dose preemptively first and monitor
CYP inducer: monitor first, then dose adjust as needed
True or false:
Apixaban can be used in dialysis
True
Apixaban is the only DOAC that can be used in dialysis
True or false:
Ticagrelor is a prodrug, while clopidogrel is not
False!
Opposite!
Clopidogrel is a prodrug, while ticagrelor is not
List the ADRs of oral/ parenteral iron (Hint: have acute and chronic ADRs)
Acute: constipation, necrotizing gastroenteritis with vomiting, abdominal pain, bloody diarrhoea → f/b lethargy, shock, dyspnea, metabolic acidosis, coma, death
Chronic: haemochromatosis with iron deposited in the heart, liver, pancreas, and other organs → causing organ failure and death
What is used to treat iron overdose?
Parenteral deferoxamine/ oral deferasirox iron chelators
List the ADRs of oral and parenteral vit B12
Photosensitivity
Injection site pain/rxn (when given parenterally)
HTN, hot flushing, tremor, arrhythemias secondary to hypokalemia, GI disturbances, dizziness, paraesthesia, chromaturia, acneiform and bullous eruptions, rash and itching
True or false:
PPIs help increase the absorption of oral Vit B12
False!
PPIs lower their absorption
List the ADRs of folic acid
GI: bitter taste, nausea, abdominal distension, flatulence
Hypersensitivity
Anorexia (rare)
List some DDIs with folic acid
Germ: surely he doesn’t expect us to remember all right…. ded
↓plasma concentration of anticonvulsants (phenytoin, valproic acid, phenobarbital, carbamazepine)
↓effect of methotrexate chemotherapy
↓absorption of sulfasalazine, triamterene
↑effect of lithium
↑elimination of aspirin
Chloramphenicol and bactrim interfere w folate metabolism
What population requires special precautions when taking folic acid?
Folate-dependent tumours, haemolytic anaemia, alcoholism
Women w pre-existing DM, obesity, family hx of neural tube defects, prev pregnancy affected by neural tube defect
Children, pregnancy, lactation
What are the contraindications of folic acid?
Untreated cobalamin deficiency (including untreated pernicious anaemia/ lifelong vegetarians), and malignant disease
True or false:
Folic acid has minimal liver metabolism and renal excretion
False
Metabolised in liver, converted to active metabolite 5 methyltetrahydrofolate, undergoes enterohepatic circulation
Excreted via urine
True or false:
Vitamin B12 is excreted mainly by bile and urine
True
What is the MoA of erythropoiesis stimulating agents?
Stimulate division and differentiation of erythroid progenitor cells → reticulocytes are released from bone marrow and mature into erythrocytes → regulating erythropoiesis
True or false
IV epoetin alfa has a shorter half-life than darbepoetin alfa
True
Epoetin alfa t1/2 = 4-13hrs
Darbepoetin alfa t1/2 = 20-25hrs
True or false:
ESAs are mainly metabolised by the liver
False
Limited metabolism occurs
List some of the ADRs that ESAs causes. Also use the ADRs unique to epoetin alfa and darbepoetin alfa each.
HTN, oedema, ↑plasma count, thrombosis, stroke, hyperkalemia, seizures, myalgia, arthralgia, limb pain, GI disturbances
Epoetin alfa: pruritus
Darbepoetin alfa: dyspnoea, cough, bronchitis
Can ESAs be used in pregnancy, lactation, and children?
Yes, use with caution
What are the two contraindications of ESAs?
Uncontrolled HTN, hypersensitivity
What is the MoA of Myeloid Growth Factors? I.e. Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating facotr (GM-CSF)
G-CSF: Stimulates proliferation and differentiation of progenitors (neutrophils). Additionally also activates phagocytic activity and prolong survival of mature neutrophils
GM-CSF: Stimulates proliferation and differentiation of early and late granulocytic, erythroid, and megakaryocyte progenitors
What are some examples of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating facotr (GM-CSF)?
G-CSF: filgrastim, prefilgrastim (longer t1/2)
GM-CSF: sargramostim
Note: G-CSF can be combined with haematopoeitic stem cell mobiliser, plerixafor
True or false:
GM-CSF is better tolerated than G-CSF
False
G-CSF better tolerated than GM-CSF
List some ADRs of G-CSF and GM-CSF
G-CSF: bone pain (reversible)
GM-CSF: fever, malaise, arthralgias, myalgias
Potentially fatal: Severe sickle cell crisis, capillary leak syndrome, respiratory failure, acute respiratory distress syndrome, splenic rupture
List which are contraindications and which require special cautions when taken with G-CSF/ GM-CSF.
A. Pre-malignant/ malignant myeloid condition
B. Acute myeloid condition
C. Chronic myeloid condition
D. Sickle-cell disease
E. Chronic myelodysplastic syndrome
F. Pneumonia/ lung infiltrates
G. Osteoporotic bone disease
Caution: A, B, D, F, G
C/I: C, E
What are some examples of megakaryocyte growth factors? (3)
Oprelvekin (recombinant IL-11)
Romiplostim (Fc-peptide fusion protein thrombopoietin receptor agonist)
Eltrombopag (nonpeptide thrombopoietin receptor agonists)
List some ADRs of megakaryocyte growth factors. Note that one has extra ADRs from the rest.
Thromboembolic events
Oprelvekin: fluid retention, peripheral oedema, dyspnoea on exertion
True or false:
Oprelvekin must be used with caution in patients with chronic HF, at risk of developing HF, and fluid retention
True
True or false:
Megakaryocyte growth factors must be used with caution in cerebrovascular disease only
False
Caution: cerebrovascular disease, and thormboembolism risk factors
Thromboembolism risk factors: advanced age, prolonged immobilisation, malignancies, bleeding, surgery/trauma, obesity, smoking, contraceptives, hormone replacement therapy
True or false: Romiplostim require higher dose for patients with non-East Asian ancestry
False
Should be Eltrombopag instead
What drugs causes immune thrombocytopenia?
Heparin, sulphonamides, carbamazepine, phenytoin, GIIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)
