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Year 3 - Biotech (2nd half) > 2 - Anticoagulants > Flashcards

2 - Anticoagulants Flashcards

1
Q

What does warfarin do?

A
  • Anticoagulant -> inactivates clotting factors VII, IX, X, and thrombin (II)
  • Vitamin K antagonist -> inhibits vitamin K1 2,3-epoxide reductase (VKOR)
  • Not a direct antagonist of any clotting factors (doesn’t fit into the active site of any of the clotting factors)
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2
Q

Uses of warfarin

A
  • Prevention of VTE
  • Tx of A. fib
  • Prevention of clotting w/ prosthetic heart valves (and indwelling central venous catheters)
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3
Q

Does warfarin have an effect on existing clotting factors?

A
  • No, clotting factors that are already carboxylated remain active
  • Warfarin reduces gamma-carboxylation of clotting factors
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4
Q

How long does it take for full anticoagulant effect of warfarin?

A

5 days

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5
Q

Warfarin side effects

A
  • Bleeding (major)
    • Intracranial bleeding (most important)
    • Incidence increases as tx duration and INR increase
    • Antidote different depending on INR
  • Skin necrosis (rare)
  • Allergy
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6
Q

Warfarin monitoring

A
  • INR = international normalized ratio
  • Ratio of px prothrombin time (PT) to a control
  • Typical tx target between 2-3; > 5 = overdose
    • Normal untreated INR = 1
  • Need > 5 doses to reach target INR
  • Antidote = vitamin K or plasma (has clotting factors)
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7
Q

Is the S or R form of warfarin more potent?

A

S (3 to 5 fold more potent)

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8
Q

Describe S-warfarin metabolism

A
  • Major inactive metabolite = 7-hydroxywarfarin
  • CYP 2C9 responsible for > 80% of the metabolism of S-warfarin
  • All metabolites are inactive
  • Phase 2 conjugation is primarily glucuronides of the hydroxywarfarins
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9
Q

Activity of CYP 2C9 *2 on warfarin metabolism

A

Inactive

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10
Q

Activity of CYP 2C9 *3 on warfarin metabolism

A

Inactive

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11
Q

Activity of CYP 2C9 *4 on warfarin metabolism

A

Decreased activity

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12
Q

Activity of CYP 2C9 *5 on warfarin metabolism

A

Decreased activity

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13
Q

Activity of CYP 2C9 *6 on warfarin metabolism

A

Inactive

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14
Q

What genotype of CYP 2C9 results in EM for warfarin?

A

*1 / *1

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15
Q

What genotypes of CYP 2C9 results in IM for warfarin?

A
  • *1 / *2

- *1 / *3

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16
Q

What genotypes of CYP 2C9 results in PM for warfarin?

A
  • *2 / *2
  • *2 / *3
  • *3 / *3
17
Q

What can polymorphisms in VKORC1 cause?

A

Changes in warfarin PD

18
Q

Describe VKORC1 -1639 G>A

A
  • *Recall that sign indicates SNP is upstream or 5’ to the transcriptional start site
  • SNP is in the promoter region of the gene, which can reduce transcription factor binding and thereby reduce expression
  • This SNP doesn’t interfere w/ transcription factor binding but does decrease VKORC1 expression
  • VKORC1 mRNA expression is decreased w/ the SNP -1639A allele; decreased mRNA leads to less VKORC1 protein
  • Reduction in the expression of VKORC1 has the effect of reducing the ED50 of warfarin for VKORC1
  • Px who have 1 or 2 copies of the VKORC1 -1639G>A allele require less warfarin to achieve the same effect
19
Q

Warfarin DI or other factors increasing warfarin toxicity

A
  • Decrease platelet function (ASA)
  • GI ulceration (NSAIDs)
  • Decreased gut vitamin K synthesis (antibiotics)
  • Altered warfarin metabolism (co-trimoxazole)
  • Interference w/ vitamin K cycle (acetaminophen doses > 2 g/day)
20
Q

Describe the active sites of thrombin (IIa) inhibitors and what binds to each

A
  • Exosite 1 -> binds fibrinogen
  • Exosite 2 -> positively charged binds fibrin and negatively charged heparin
  • Thrombin active site -> cleavage recognition sequence favours arginine on the N-terminal side of the peptide bond that is cleaved
21
Q

Dabigatran etexilate (Pradaxa)

A
  • Direct thrombin (IIa) inhibitor
    • Competitive inhibitor that binds to thrombin active site and prevents conversion of fibrinogen to fibrin
  • Binds to free and fibrin bound thrombin
  • Reduces platelet activation
  • Starts to work soon after dose
  • Has to be in pro-drug form for oral absorption
    • Dabigatran etexilate –> dabigatran by carboxylesterase 1 (CES1) and other esterases
22
Q

Dabigatran etexilate absorption

A
  • In intestine
  • Pro-drug form only absorbs if pH < 3
  • Capsules formulated w/ tartaric acid to lower pH and increase absorption
  • Dabigatran etexilate (not dabigatran) substrate for P-gP-1
23
Q

Dabigatran etexilate monitoring and antidote

A
  • Not generally needed (has predictable PK)
  • Antidote:
    • Idarucizumab Ab against dabigatran
    • Recombinant factor VIIa (rFactor VIIa), activated charcoal, dialysis
24
Q

Dabigatran interactions

A
  • Other drugs affecting clotting (major) -> warfarin, heparin, rivaroxaban
  • Antiplatelet aggregation (major) -> aspirin, NSAIDs, clopidogrel
  • CI in pregnancy and breastfeeding (major)
25
Q

Dabigatran uses

A
  • Prevent venous thromboembolism following hip or knee replacement
  • Prevent atrial thrombus and subsequent stroke in A. fib
  • Alternative to warfarin, especially if risk of stroke is high
26
Q

Dabigatran SE

A
  • Dyspepsia (GI intolerance)

- Bleeding/ hemorrhage

27
Q

Carboxylesterase 1 CES1

A
  • One of the ubiquitous esterases
  • Important for metabolizing dabigatran etexilate to dabigatran, once absorbed
  • Has several SNPs
  • SNP happens in an intron region -> likely reduces expression of CES1
28
Q

Describe the effect of CES1 polymorphisms and dabigatran

A
  • CES1 22466G > T
  • Individuals w/ at least 1 CES1 22466G > T allele had a lower risk of bleeding w/ dabigatran
  • Heterozygous individuals have a 15% reduction in their dabigatran trough concentration
    • Dabigatran trough concentration predicts bleeding
  • Homozygous CES1 22466G>T individuals have a 30% reduction in their dabigatran trough concentration
29
Q

ABCB1/P-gP and dabigatran

A
  • ABCB1 gene encodes for P-gP (drug efflux pump that uses ATP)
  • Dabigatran etexilate (not dabigatran) is a substrate
  • *ABCB1 inhibitors increase dabigatran BA by 10% to 20%
  • ABCB1 SNP 184516G>A associated w/ peak concentration increase of ~12% in heterozygous individuals
  • *No correlation w/ bleeding events
  • Is in linkage disequilibrium w/ the C3435T SNP

Year 3 - Biotech (2nd half) (7 decks)

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