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blood CA > pharmacology > Flashcards

pharmacology Flashcards

1
Q

overview of all the drugs

A

1) antiplatelets: dipyridamole, aspirin, clopidogrel, ticagrelor
2) anticoagulants: OAC, warfarin, dabigatran, rivaroxaban, heparin
3) fibrinolytics: alteplase

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2
Q

MOA of dipyridamole

A

1) increase cAMP within platelet -> inhibit platelet activation and aggregation

  • adenosine reuptake inhibitor: increase plasma adenosine activation of A2 receptor
  • phosphodiesterase 3 (PDE3) inhibitor: reduce cAMP degradation within platelet

2) vasodilation

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3
Q

PK of dipyridamole

A
  • fast onset after oral
  • short duration of action (need modified release)
  • fast reversal: useful for haemorrhage/bleeding risk
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4
Q

dipyridamole AE

A

headache, hypotension (vasodilation), dizzy, flushing, GI (N/V/D)

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5
Q

dipyridamole CI/caution

A
  • CI hypersensitivity
  • caution hypotension/severe CAD
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6
Q

dipyridamole DDI

A

1) increase cardiac adenosine levels = trigger reflex tachycardia
2) decrease cholinesterase inhibitor = aggravate myasthenia gravis
3) bleeding risk (+ other anticoagulant/antiplatelet esp heparin)

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7
Q

aspirin MOA

A

irreversible COX inhibitor (COX-1 > COX-2)

  • inhibit platelet production of thromboxane A2
  • platelet X nucleus = X synthesis of new COX enzyme = lesser COX-1 producing thromboxane A2 = lesser platelet aggregation
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8
Q

why lower dose of aspirin more effective than higher dose?

A

higher dose block PGI2 production longer, ideally low enough dose to irreversibly inhibit COX-1 then cleared form body so won’t inhibit COX-2 as much

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9
Q

aspirin AE

A

1) upper GI

  • inhibit COX-1 production of protective PG in stomach
  • gastric ulcer, bleeding

2) increased risk of bleeding and bruising

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10
Q

aspirin CI/caution

A
  • pt w platelet/bleeding disorder
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11
Q

aspirin DDI

A

caution when combine w other antiplatelet/anticoagulant

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12
Q

clopidogrel MOA

A

ADP P2Y12 inhibitor: irreversibly bind to ADP binding site of P2Y12 receptor

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13
Q

clopidogrel PK

A
  • delayed onset and interindividual variability: CYP2C9
  • effect last 7-10 days (lifespan of platelet)
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14
Q

clopidogrel AE

A
  • hemorrhage, bleeding
  • bruising, dyspepsia, bronchospasm, dyspnea, hypotension
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15
Q

clopidogrel CI/caution

A
  • hypersensitivity
  • active pathologic bleeding
  • bleeding risk
  • variant alleles (CYP2C9)
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16
Q

clopidogrel DDI

A

1) warfarin, NSAID, salicylate increase risk of bleeding
2) macrolides reduce antiplatelet effect
3) strong-moderate CYP2C19 inhibitor (PPi, fluoxetine, ketoconazole)
4) rifamycin: increase antiplatelet effect

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17
Q

ticagrelor MOA

A

ADP P2Y12 inhibitor: reversibly bind to different binding site to inhibit G protein activation and signalling

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18
Q

ticagrelor AE

A

haemorrhage, bleeding, bradycardia, dyspnoea, cough

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19
Q

ticagrelor CI

A

1) hypersensitivity
2) severe hepatic impairment
3) breastfeeding, intracranial haemorrhage, active pathologic bleeding

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20
Q

ticagrelor caution

A

bleeding risk, elderly, moderate hepatic failure

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21
Q

ticagrelor DDI

A

1) anticoagulant, fibrinolytic, long term NSAID increase bleeding risk
2) aspirin < 100 mg/day reduce ticagrelor effect but increase bleeding risk
3) CYP3A4 inducer (dexamethasone, phenytoin): decrease serum conc and antiplatelet effect
4) CYP3A4 inhibitor (clarithromycin, ketoconazole) increase serum concentration and AE

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22
Q

how Vit K works

A
  • active form activate II, VII, IX, X -> oxidise to inactive form
  • Vit K reductase activate inactive form
  • Vit K cofactor involved in post-translational carboxylation of prothrombin to prothrombin by GGCX
  • meanwhile Vit K hydroquinone converted to Vit K epoxide in presence of O2 & CO2
  • epoxide reduced by VKOR(C1) to Vit K and is converted back to Vit K hydroquinone by VKR
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23
Q

MOA of warfarin

A
  • inhibit Vit K reductase
  • good at blocking extrinsic pathway
  • S-enantiomer active stereoisomer
  • act on VKOR and possibly VKR
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24
Q

warfarin PK

A
  • onset depends on how much active Vit K available
  • hypercoagulable state4-5 days (protein C & S prevent blood clotting but inhibited by warfarin)
  • highly plasma protein bound
  • hepatic CYP2C9 metabolism (genetic polymorphism = variability)
  • urine and shit excretion
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25
Q

warfarin AE

A

1) haemorrhage/bleeding

  • blood in stool/urine, bruising, petechiae, persistent oozing from superficial wound, excess menses
  • regular INR monitoring and dose adjustment required

2) hepatitis
3) cutaneous necrosis & infarction of breast, butt, extremities

  • reduced blood flow to adipose tissue
  • 3 - 5 days after initiation
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26
Q

warfarin CI

A
  • hypersensitivity
  • active bleed, bleed risk, recent major surgery
  • severe/malignant HTN
  • severe renal/hepatic disease
  • pregnancy
27
Q

warfarin caution

A

breastfeeding women

28
Q

warfarin drugs that increase bleeding risk

A

1) long term paracetamol (> 2 wks) at high dose (> 2g/day)
2) allopurinol, NSAID, salicylate, PPi, metronidazole

29
Q

warfarin food that increases bleeding risk

A

gingko, ginseng, reishi mushroom, cranberry juice

30
Q

drugs that reduce efficacy of warfarin

A

barbiturate, corticosteroid, spironolactone, thiazide diuretics

31
Q

warfarin interaction w Vit K containing stuff

A

supplement, green tea, food

32
Q

warfarin interaction w antimicrobials

A
  • higher biome load = metabolise more warfarin = need higher dose of warfarin, INR decrease
  • inflammation = metabolise less warfarin = INR increase
  • bactrim (Sulfamethoxazole/trimethoprim), ciprofloxacin = INR decrease by 25%
33
Q

diseases that affect warfarin

A

1) liver disease

  • decrease clotting factor synthesis & warfarin metabolism
  • INR increase

2) fluid retention

  • liver congestion (decrease liver function), gut malabsorption of warfarin
  • INR increase then decrease

3) fever

  • increase metabolism of clotting factors
  • increase INR

4) thyroid disease

  • HYPERthyroid = increase clotting factor turnover = increase INR
  • hypothyroid = decrease clotting factor turnover = decrease INR
34
Q

lifestyle factors and warfarin

A

1) alcohol

  • CYP450 inhibitor = increase INR

2) chronic alcoholism

  • induce CYP450 = decrease INR

3) sudden increase in physical activity

  • increase metabolism = decrease INR

4) smoking

  • CYP450 inducer = decrease INR
35
Q

genetic polymorphism for warfarin

A

1) CYP2C9

  • increase metabolism = higher dose of warfarin

2) VKORC1

  • increase susceptibility of enzyme to warfarin-induced metabolism = lower dose of warfarin
36
Q

indication for Pgx for warfarin

A

1) existing clot (left ventricular thrombosis)
2) outpatient commencement of warfarin
3) DDI present
4) questionable adherence

37
Q

INR monitoring for warfarin

A
  • dependent on clotting factors II, XII, X
  • why take after 3 days of initiation? factor II take 3 days to reach optimal level
38
Q

loading warfarin

A
  • achieve ideal INR faster
  • load with enoxaparin to reduce hypercoagulable state
39
Q

dabigatran etexilate general

A
  • non Vit K antagonist
  • good at blocking common pathway
  • prodrug metabolised to dabigatran
40
Q

dabigatran etexilate MOA

A
  • competitively and reversibly inhibit thrombin (Factor IIa)
41
Q

reversal of dabigatran etexilate

A

idarucizumab

  • reverse dabigatran for emergency surgery/urgent procedure/life-threatening or uncontrolled bleeding
  • MOA: bind to dabigatran and acyl glucuronide metabolite with higher affinity than dabigatran to thrombin
42
Q

dabigatran etexilate PK

A
  • large excreted unchanged
  • low F so use enteric coated (swallowed whole)
  • only DOAC that is dialysable cuz not very protein bound
43
Q

dabigatran etexilate AE

A
  • bleeding, GI symptoms (dyspepsia)
44
Q

dabigatran etexilate DDI

A

rifampicin, carbamazepine, St, John’s Wort (reduce dabigatran levels, switch to warfarin)

45
Q

rivaroxaban MOA

A
  • competitively reversible antagonist of activated factor X
46
Q

reversal of rivaroxaban

A

andexanet alfa (Factor Xa decoy)

47
Q

rivaroxaban PK

A

hepatic metabolism (CYP3A4), excreted mainly in urine

48
Q

rivaroxaban AE

A

bleeding

49
Q

rivaroxaban DDI

A

1) antiplatelet, thrombolytics, anticoagulant, PGPi, CYP3A4i (macrolides): increase bleeding risk

2) PGP inducer, CYP3A4 inducer (Rifampicin), St. John’s Wort: reduces rivaroxaban levels

50
Q

heparin and LMWH MOA

A
  • heparin inactivate thrombin (IIa), factor IXa, Xa, XIIa
  • LMWH inactivate factor Xa and IIa (lesser extent)
  • both best at blocking intrinsic pathway
51
Q

reversal of heparin and LMWH

A

protamine sulfate IV

  • highly basic peptide stably bind to negatively charged heparin -> neutralised
  • incomplete reversal of LMWH
52
Q

LMWH PK

A
  • higher F and longer t1/2
  • mostly excreted in urine
53
Q

heparin and LMWH AE

A

1) LMWH lesser chance of thrombocytopenia
2) bleeding

  • anticoagulation effect disappear after few hours
  • increased risk of epidural/spinal hematoma & paralysis in pt receiving epidural/spinal anesthesia/spinal puncture
  • heparin induced thrombocytopenia
    ** bind to PF4 on activated platelet surface
    ** form IgG antibody against complex
54
Q

heparin and LMWH special population

A

X for pregnancy cuz cross placenta

55
Q

heparin and LMWH CI

A

hypersensitivity, active major bleeding, thrombocytopenia

56
Q

heparin and LMWH caution

A

elderly, risk of bleeding, renal insufficiency

57
Q

heparin and LMWH interactinos

A

1) increase risk of bleeding

  • antiplatelet, anticoagulant, fibrinolytics, NSAID, SSRIs
  • chamomile, fenugreek, garlic, ginger, gingko, ginseng
58
Q

MOA alteplase

A
  • act as tPA for resolution of clot
59
Q

reversal of alteplase

A

tranexamic acid, aminocaproic acid

  • compete for lysine binding site on plasminogen & plasmin -> block interaction with fibrin
60
Q

alteplase vs endogenous tPA

A
  • longer t1/2 = more convenient dosing
  • bind preferentially to clot-associated plasminogen -> Activate platelet at clot
61
Q

alteplase AE

A
  • haemorrhage, bleeding
  • ventricular arrhythmia, hypotension, oedema
  • cholesterol embolisation, venous thromboembolism
  • hypersensitivity (recombinant protein), anaphylaxis
62
Q

alteplase CI

A
  • active bleeding
  • prior intracranial haemorrhage
  • recent (within 3 months) intracranial/intraspinal surgery, serious head injury/stroke
63
Q

alteplase caution

A

1) if fibrin meshwork breakdown too quickly -> clot break up too fast in clumps instead of gradual release of trapped stuff -> risk fragments circulating in blood -> embolus/block other small vessels

  • ONLY used to treat pre-existing clots causing imminent risk of irreversible death/damage
  • other clots degrade slowly with endogenous tPA

2) major surgery within 10 days
3) risk of bleeding
4) cerebrovascular disease
5) mitral stenosis
6) atrial fibrillation
7) acute pericarditis
8) subacute bacterial endocarditis

64
Q

alteplase DDI

A
  • increase risk of bleeding w antiplatelet (esp dipyridamole, aspirin) or anticoagulant (esp warfarin, heparin)
  • nitroglycerin reduce levels of alteplase

blood CA (9 decks)

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