Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PR3154 Haematology & Musculoskeletal > Haematology - Pharmacology > Flashcards

Haematology - Pharmacology Flashcards

1
Q

What are the classes of drugs in haematology?

A

Antiplatelets, Anticoagulants, Fibrinolytics (thrombolytics)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the common antiplatelets?

A

Dipyridamole, Aspirin, Clopidogrel, Ticagrelor, Prasugrel, Ticlopidine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the common anticoagulants?

A

Warfarin, Direct thrombin inhibitors (Dabigatran), Anti-Xa inhibitors (Rivaroxaban, Apixaban, Edoxaban), Heparin (UFH, LMWH)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the common fibrinolytics?

A

r-TPA (Alteplase), Tenecteplase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the MOA of dipyridamole?

A

Inhib adenosine reuptake into inactivated platelets & rbc. Increased plasma adenosine activation of A2 rece on inactivated platelets. Adenosine inhib platelet activation & aggreg.

Additionally inhib PDE-3 in inactivated platelets (which break down cAMP–> AMP). More surviving cAMP to further inhib platelet activation & aggreg/

Inhib of adenosine reuptake & PDE-3 in vascular SM –> vasodil

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the indications for dipyridamole?

A

Adjunct antiplatelet in combi w other antithrombotics.
IV infusion as alt to exercise for myocardial perfusion imaging

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the PK of dipyridamole.

A

A:
- Onset fast after PO admin (20-30min).
- Peak effect: 2-2.5h

E:
- Duration of action: ~3h (usually a MR preparation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the S/E associated w dipyridamole?

A

Dose limiting vasodilation
Headache
Hypotension
Dizziness
Flushing
GI disturbances
Diarrhoea
NV

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the DDI associated w dipyridamole?

A

Increases adenosine
Decreases cholinesterase inhib (may aggrevate myasthenia gravis)
Heparin, and other antithrombotics: Increased bleeding risk

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the CI w dipyridamole?

A

Hypersensitivity to drug
Hypotension
Severe CAD (induction of acute hypotension, reflex tachycardia, angina pectoris, ECG abnormalities MI)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the MOA of aspirin?

A

Irreversible COX-1 inhib > COX-2 inhib
Inhib of COX-1 in platelets:
- Decrease pdtn of TXA2 which promotes platelet aggreg –> Decreased platelet aggreg
- Takes 7-10d to reverse

Inhib of COX-2 in endothelial cells:
- Decreased pdtn of PGI2 which inhib platelet aggreg –> increased platelet aggreg
- Restoration within 3-4h w clearance of low dose aspirin

Effect dep on ratio of COX-1: COX-2 inhib

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why is low dose aspirin favoured over high dose aspirin in antiplatelet indications?

A

Low dose aspirin favours inhibition of platelet aggregation by action of COX-1 inhib prevailing over COX-2 inhib of endothelial cell PGI2 pdtn

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Describe the PK of aspirin.

A

A:
- Clinically sig antiplatelet effect onset: 3-4h
- Max antiplatelet effect onset: 2-3d (cont admin)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the S/E associated with aspirin?

A

Upper GI events (ulcer, bleeding): inhib of COX-1 pdtn of PG in stomach, low dose aspirin cardioprotective prop assox w 2-4x increase in UGI

Bleeding (when combi w other antithrombotics)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the DDI associated with aspirin?

A

Other antithrombotics: bleeding risk

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the special considerations or CI with aspirin?

A

CI in bleeding or platelet disorders

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Describe the MOA of the P2Y12i? (Clopidogrel, Ticagrelor, Prasugrel)

A

Binds to the ADP P2Y12 rece on platelets. Prevents release of ADP from platelets, prevents xp of GpIIb/IIIa rece complex on platelets. Decrease platelet activation and aggregation.

Clopidogrel: irreversible, competitive
Ticagrelor: reversible, non-competitive (recovery 2-3d upon discontinuation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Describe the PK of Clopidogrel vs Ticagrelor

A

M:
- Clopi: CYP2C19 (polymorphism) but most activated by CYP3A4, 2B6, 1A2 > 2C9, 2C19
- Tica: CYP3A4 substrate, P-gp transporter inhib

E:
- Clopi: t1/2 -1.9h, 50% urinary, 46% faecal
- Tica: t1/2 - 7h (tica), 9h(active metabolite), 26% urinary, 58% faecal

Onset:
- Tica faster than clopi

Tmax:
- Clopi: 1h vs Tica: 1.5h(tica), 2.5h(active metabolite)

Time to platelet aggreg SS (no LD):
- Clopi: 5-6d vs Tica: 2d

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the S/E associated w P2Y12i?

A

Common: Epistaxis, gum bleeding, easy bruising, dyspnoea, dizziness, syncope, hypotension, bradycardia, diarrhoea, nausea, cough

Severe: Melena, fresh blood with stools, haemoptysis, haematemesis, haematuria, sudden severe headache, bleeding lasting >15min, ICH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the DDI associated w Clopidogrel?

A

Warfarin, NSAIDs, salicylates: Increased bleeding risk
Strong to moderate CYP2C19 inhib (PPI, fluoxetine, ketoconazole): Decreased antiplatelet effect

CYP3A4 inducers: ASMs, Rifampin
CYP3A4 inhib: itraconazole, fluconazole, ketoconazole, voriconazole, ritonavir, clarithromycin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe the transporters and enzyme implications w P2Y12i.

A

Clopi:
- Meta by CYP3A4, 2B6, 1A2 > 2C9, 2C19
- P-gp inhibitor

Tica:
- Meta by CYP3A4
- P-gp inhibitor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the drug disease interaction with ticagrelor?

A

Gout: raises uric acid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What are the DDI associated w Ticagrelor?

A

Antithrombotics, fibrinolytics, long term NSAIDs: Increased bleeding risk

CYP3A inducers
- ASMs, ritonavir

CYP3A inhib
- Itraconazole, ketoconazole, fluconazole, posaconazole, ritonavir, clarithromycin

P-gp substrates
- Digoxin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What are the special considerations w P2Y12i?

A

PGx
Loss of fn mutation 2/3 alleles for CYP2C19 precludes the use of clopidogrel in ACS as they are assoc w increased risk of MACE. Ticagrelor and prasugrel preferred for those with loss of fn mutation.

Aspirin doses >100mg/day: Decrease ticagrelor effect but increase bleeding risk

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What are the CI w P2Y12i?

A

Severe:
Lacation
Severe hepatic impairment
Hypersensitivity to drug
Hx of ICH
Active pathological bleeding

Caution:
Mild-mod hepatic impairment
Risk of bleeding
Elderly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Describe the time to .. for P2Y12i.

A

Time to recovery:
- Clopi: 7-10d
- Tica: 2-3d

Time to surgery:
- Clopi: 5d
- Tica: 3d

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Describe the MOA of warfarin.

A

Inhib vitamin K reductase (VKORC1). Reduced reactivation of vit K, reduced activation of clotting factor II, VII, IX, X.

28
Q

What are the S/E assoc w warfarin.

A

Common: Epistaxis, gum bleeding

Severe: Melena, fresh blood with stools, haemoptysis, sudden severe headache, bleeding lasting >15min

Hepatitis - greatest risk in older males durg early treatment >60y, on warfarin <1mo

Cutaneous necrosis (~ 1 in 10 000), infarction of breast, buttocks & extremities - 3-5d after ini treatment

Low BMD

29
Q

Describe the PK of warfarin.

A

A:
- PO rapid & complete

M:
- Hepatically metabolised. S-enantiomer by CYP2C9 (affected by polymorphisms), R-enantiomer by CYP3A4, 1A1, 1A2

E:
- t1/2: 20-60h (high inter pt var)
- Urine & faeces
- 92% renally cleared as metabolites

Onset:
- Action (PO): 24-72h(lag for endogenous reserves of active vit K depleted)
- Time to peak, plasma (PO): 2-8h
- Full thera effect: 5-7d

Duration of action: 2-5d (long t1/2 of some coag factors)

30
Q

What are the special considerations w Warfarin?

A

CYP2C9 loss of fn mut, polymorphism: Reduced clearance of warfarin, reduced dosage requirements

VKORC1 polymorphism: increased sensitivity to warfarin, reduced dosage requirement

CANNOT interchange brands

If miss dose and rmb within 6-8h, take missed dose. Otherwise miss the dose and take as per normal the next day. Do not double dose.

Look out for illness, particularly if close to next blood draw

Keep diet consistent (vit K)

Avoid smoking: CYP450 induction
Avoid alc:
- Binge: CYP450 inhib
- Chronic alcoholism: CYP450 indution

31
Q

What are the benefits of genotyping for warfarin initiation?

A

Faster time to therapeutic range
Req fewer dose titration durg first two weeks, fewer follow up
Assoc w INR stability in >=70y.o. absence of chronic disease
Assoc w INR stability in CHF, DM and target range for INR >=3.0

32
Q

How to predict maintenance dose for warfarin?

A

BSA, Age, Target INR, race, current thrombosis, amiodarone use, smoking status

PGx
- Limited use since time lag/turnaround of gene testing, pt already sent home. Beneficial for those req
- <=21mg/week or 8mg/day
- >=49mg/week or 7mg/day

Local maintenance dose: 3-4mg vs Indians/Caucasians: 8-10mg

33
Q

How can the effects of warfarin be reversed?

A

Fresh Frozen Plasma
Prothrombin Complex Concentrates
Vit K

34
Q

What are the DDI w warfarin?

A

Other antithrombotics: Increased bleeding risk

CYP2C9 inhib (amiodarone, fluconazole, voriconazole, cotrimoxazole, metronidazole, PPI): Increase warfarin levels, increase bleeding risk
- Amiodarone: pre-emptively adjust maintenance dose by 30-50%
- In PUD, pre-emptively adjust maintenance dose of warfarin by 35%

CYP2C9 inducers (CBZ, PB, rifampin): Decrease warfarin level, therapeutic efficacy

Abx: Decreased bacterial pdtn of menadione (vit K), increase warfarin effect. If unadjusted increases INR. Pre-emptively adjust dose of warfarin for bactrim (by 25-50%) and ciprofloxacin (by 20-30%). No adjustment needed macrolides, augmentin, doxycycline.

Paracetamol: long term thera (>2 weeks) @ high doses (>2g/day) increased bleeding

Traditional meds: gingko biloba, ginseng, reishi mushroom, cranberry - increase risk of bleeding

Food - CYP2C9, 3A4 inhib (cranberry juice, pomegranate juice, grapefruit juice, tumeric

35
Q

What are the CI w warfarin?

A

Hypersensitivity to drug
Severe renal or hepatic disease
Subacutre bact endocarditis, pericarditis, pericardial effusion
Pregnancy
Active pathological bleeding, risk of pathological bleeding
Severe or malignant HTN
After recent major surgery

Caution:
Breastfeeding
Diverticulitis, colitis
Mild - mod HTN
Mild - mod renal or hepatic disease
Drainage tubes in any orifice

36
Q

Describe the MOA of direct thrombin inhibitors (dabigatran).

A

Competitive reversible non-peptide antagonist of thrombin (factor IIa)
Dabigatran etexilate is a prodrug of dabigatran

37
Q

What are the S/E assoc w DTI?

A

Common: Epistaxis, gum bleeding

Severe: Melena, fresh blood with stools, haemoptysis, sudden severe headache, bleeding lasting >15min

Dyspepsia, abdo discomfort

38
Q

Describe the PK of DTI.

A

A:
- F 3-7% (v low compared to rivarox)
To enhance absorption in small intestine, admin as enteric coated prep

M:
- Largely xcre unchanged

E:
- Urine
- t1/2: 12-17h
Revesal on discontinuation 3-5d

Onset:
- Rapid
- Peak action: 3h

39
Q

What are the special considerations of DTI?

A

Must control HTN - otherwise high risk of ICH

40
Q

What are the DDI assoc w DTI?

A

Anticoag, fibrinolytics, antiplatelets: ↑ bleeding risk

Long term NSAIDs: ↑ bleeding risk

P-gp & CYP3A4 inducers:↓ rivarox levels, ↓ anticoag effect (subtherapeutic)
- CBZ, PHT, PB, Valproic acid (1st gen ASMs)
- [CI] Rifampin, rifampicin: ↓ dabigatran level by 1/2, anticoag effect
- Consider alt

PPI: ↓ absorption of dabigatran
St John’s wort: P-gp/BCRP, CYP3A4 induction. -Shld be avoided

Garlic: Mild CYP3A4 inhib

Ginger, ginseng: Anticoagulation/antiplatelet

Gingko biloba, Green tea: P-gp inhib, anticoagulation/antiplatelet effect

41
Q

What are the CI w DTI?

A

Active pathological bleeding
ICH

42
Q

How can the effects of DTI (dabigatran) be reversed?

A

Withhold 1-2d if renal fn normal, non life-threatening bleed

Idarucizumab
- Humanised mab fragment
- Binds dabigatran & its acyl glucuronide metabolites w higher affin than binding affin of dabigatran to thrombin
- Indicated in reversal for emergency surgery/urgent procedures, lifethreatening or uncontrolled bleeding
- Reverses effects in min but cos $2000, only avail in certain hospitals

Dialysis
- Likely dialysable, highly renal CL dep
- Will take time, req catheter

43
Q

Describe the MOA of factor Xa inhibitors?

A

Direct, competitive, selective reversible antagonist of factor Xa.
Inhib conversion of prothrombin to thrombin
Inhib conversion of fibrinogen into fibrin –> inhib fibrin clot formation

44
Q

What are the S/E assoc w Xa inhibitors?

A
  • Common:
  • Nose bleeding
  • Gum bleeding
  • Easy bruising
  • Bleeding from small cuts for 10-15min even w P
  • Heavier menstrual bleeding
  • NV
  • Abdo pain
  • Rare, but serious:
  • Hematuria
  • Hemoptysis
  • Hematemesis
  • Melena
  • Fresh red blood w stools
  • ICH
  • Sudden, severe headache
  • Spinal or epidural hematomas
45
Q

Describe the PK of rivaroxban.

A

A:
- F: 80-100%
- Tmax: 2-4h (adult)

D:
- High protein binding (>90%)

M:
- Hepatic, CYP3A, 2J2
- 18% CYP3A4 substrate
- Substrate of P-gp & BCRP

E:
- Urine (66%) & faeces (28%)
- Active metabolite dep on kidney for CL –> renal impairment some impact on dosing
- t1/2: 5-9h
Shorter than dabi. Reversal on discontinuation 1-2d

Onset:
- Rapid
- Peak action: 2.5-4h

46
Q

Describe the PK of apixaban.

A

A:
- F: 50%
- Tmax: 3-4h

D:
- High protein binding (87%)

M:
- Hepatic, CYP3A>CYP1A2, 2C8, 2C9, 2C19, 2J2
- 25% CYP3A4 substrate
- Substrate of P-gp & BCRP

E:
- Renal 25% (unlikely dialysable)
- t1/2: 12h (8-15)

47
Q

Which of the DOACs are cleared renally?

A

Dabigatran (80%), Rivaroxaban (66%), Apixaban (25%)

Edoxaban not reliant on either renal or hepatic CL.

48
Q

Which of the DOACs are cleared hepatically?

A

Dabigatran largely excre unchanged

Rivaroxaban, Apixaban (75%)

Edoxaban not reliant on either renal of hepatic CL.

49
Q

What are the enzyme/transporter concerns assoc w the DOACs?

A

Dabigatran: Plasma esterases, P-gp
Rivaroxaban: CYP3A4, P-gp, BCRP
Apixaban: CYP3A4, P-gp, BCRP
Edoxaban: Minimally CYP3A, P-gp

50
Q

What are DDI assoc w Xa inhib?

A

P-gp & CYP3A4 inhib: ↑ antiXa levels, ↑ bleeding risk
Strong: Ketoconazole, Itraconazole, voriconazole, posaconazole, ritonavir
- Pre-emptively reduce dose
Apix 5mg BD –> 2.5mg BD, 2.5mg BD –> avoid use
Weak: Clarithromycin, erythromycin
- Consider alt

P-gp & CYP3A4 inducer: ↓ antiXa levels, ↑ clotting risk
Strong: DVT/PE treatment - X use, SPAF/VTET - no dose adj, monitor
- ASM: PHT, CBZ, PB
- Rifampicin[CI] : ↓ antiXa level by 1/2, anticoag effect

St John’s wort: Use w caution
Garlic: Mild CYP3A4 inhib
Ginger, ginseng: Anticoagulation/antiplatelet
Gingko biloba, Green tea: P-gp inhib, anticoagulation/antiplatelet effect

51
Q

What are the CI w Xa inhib?

A

Active pathological bleeding, PUD, Hepatic disease w coagulopathy, Mod-severe mitral stenosis, mechanical heart valve

52
Q

How can the effects of Xa inhibitors be reversed?

A

Withhold 1-2d if renal fn normal, non-life threatening bleed

Prothrombin complex concentrates
- Caution in fluid restriction since low [ ] may req large loading to ensure suff clotting factors admin

Andexanet alfa
- Recombinant modified human factor Xa decoy protein

53
Q

How can swapping bet DOAC and warfarin for TB pts be done?

A
  • TB agents induce liver fn, takes min 4 weeks for full induction effects
  • Start at 1.5-2x est maintenance dose of warfarin
  • Perform LFT, PT, INR
  • Repeat TCU over first 4-8weeks
54
Q

Describe the MOA of r-TPA.

A

Recombinant variants of tPA
Longer t1/2 than native (endogenous) tPA
Advantage > urokinase, streptokinase
- Bind preferentially to clot assoc plasminogen, activating plasmin at clot
Plasmin mediates fibrinolysis = depolymerise, breakg down fibrin meshwork that stabilises the thrombus
Cells & platelets trapped in clot to be slowly released back into bloodstream

55
Q

Describe the MOA of UFH.

A
  • UFH int w AT via the pentasaccharide seq of the drug
  • Binding triggers a conformational change at the active centre of AT –> accel int w factor Xa
  • Thereby catalyse inactivation of factor Xa
  • Req formation of ternary heparin antithrombin-thrombin complex
  • At least 18 saccharides units
56
Q

Describe the MOA of LMWH

A

Same as UFH heparin BUT selective blocking of the common pathway (factor Xa & to a lesser xtent IIa)
- Less inhib activity than thrombin

57
Q

What are the S/E assoc w heparin?

A

Haemorrhage (1-5% pts treated w IV heparin)
- Anticoag effect disappears within h of discontinuation

↑ risk of epidural or spinal haematoma & paralysis in pts receiving epidural or spinal anaesthesia or spinal puncture

Heparin induced thrombocytopenia (HIT) = low platelet count
- Heparin binds to platelet factor 4 (PF4) on activated platelet surface
- Trigger IgG against heparin-PF4 complex
- Lower risk w LMWH (1% vs heparin 5%)

58
Q

Describe the PK of heparin.

A

A :
- F: 86-89% (greater F than heparin)

E:
- t1/2: 4h
- Renal xcre

  • MW: ~5000 Da

Note: Longer t1/2 & higher F favours

59
Q

What are the DDI assoc w heparin.

A

Antiplatelets, anticoagulants, fibrinolytics: ↑ bleeding risk
NSAIDs: ↑ bleeding risk
SSRIs: ↑ bleeding risk
Var herbs/foods incl chamomile fenugreek, garlic, ginger, ginkgo, ginseng: ↑ bleeding risk

60
Q

How can the effects of heparin be reversed?

A

Protamine sulfate IV infusion to reverse effects of heparin
- 5kDa cationic polypeptide derived from salmon sperm
- Highly basic peptide stably binds -vely charged heparin & neutralises anticoag prop of heparin
- Only partial reversal for LMWH

Andexanet alfa
- Off label use for reversal
- Recombinant modified human factor Xa decoy protein

61
Q

What are the CI w heparin.

A

Hypersensitvity to heparins
Active major bleeding
Thrombocytopenia or presence of antiplatelet Ig

Caution:
Prosthetic heart valves
Elderly
Risk of bleeding or hematoma incl major surgery, regional or lumbar block anaesthesia, blood dyscrasias, recent childbirth, pericarditis or pericardial effusion, renal insuff (for LMWH)
Pregnancy - UFH & LMWH do not cross placenta & hv not been assoc w fetal malformations

62
Q

What are the S/E assoc w r-TPA?

A

Haemorrhage
Ventricular arrhythmias
Hypotension
Oedema
Cholesterol embolisation
VTE
Hypersensitivity and anaphylaxis

63
Q

Describe the PK of r-TPA.

A

DOA: 20-30min

64
Q

What are the DDI assoc w r-TPA?

A

Antiplatelets (esp dipyridamole, aspirin), anticoagulants (esp warfarin, heparin), fibrinolytics: ↑ bleeding risk

Nitroglycerin: may ↓ alteplase level

65
Q

What are the CI w r-TPA?

A

Active bleeding
Prior intracranial haemorrhage
Recent (3mo) intracranial or intraspinal surgery
Recent srs head injury
Recent stroke

Caution
- Presence of stable clots that cld cause embolism if rapidly fragmented & mobilised
- Major surgery within 10d
- Risk of bleeding
- Cerebrovascular disease
- Mitral tenosis
- AF
- Acute pericarditis
- Subacute bact endocarditis

66
Q

How can the effects of r-TPA be reversed?

A

Tranxemic acid & aminocaproic acid
- Compete for lysine binding sites on plasminogen & plasmin
- Block int w fibrin

PR3154 Haematology & Musculoskeletal (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions