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MOHDIII - Unit 2 > Anticoagulant Pharmacology > Flashcards

Anticoagulant Pharmacology Flashcards

1
Q

Anticoagulants

A
  • heparin, low molecular weight heparin (LMWH)
  • warfarin
  • direct thrombin inhibitors
  • direct factor Xa inhibitors
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2
Q

Heparin

A
  • natural sulfated glycosaminoglycan (from porcine intestines)
  • unfractionated heparin (UFH)
  • low molecular weight heparin (LMWH)
  • mechanism: enhances inhibition of clotting factors by antithrombin (ATIII or AT)
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3
Q

Molecular targets of heparin (UFH)

A
  • factors IXa, Xa, IIa
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4
Q

Size difference b/w UFH & LMWH

A
  • UFH 3X larger than LMWH
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5
Q

Effect of UFH on inactivation of thrombin and factor Xa

A
  • thrombin: template mechanism (binds AT & thrombin)

- factor Xa: conformation mechanism (only binds AT) which increases affinity for Xa binding

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6
Q

Effect of LMWH on inactivation of thrombin & factor Xa

A
  • thrombin: conformation mechanism (WEAK)
  • factor Xa: conformation mechanism (STRONG)
  • *must use conformation mechanism b/c too small to be able to bind another molecule besides AT**
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7
Q

UFH mechanism

A
  • enhances ability of antithrombin, a serine protease inhibitor (serpin), to inhibit thrombin, factor Xa, and other activated clotting factors
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8
Q

UFH facts

A
  • parenteral administration (IV or SC) – bolus followed by continuous infusion
  • rapid onset of actin & short half life (1-2hrs)
  • requires monitoring by APTT
  • effect can be REVERSED by protamine
  • can be used during pregnancy
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9
Q

Molecular targets of LMWH

A
  • MORE Xa inhibition

- some IIa (thrombin) inhibition

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10
Q

LMWH facts

A
  • SC administration
  • rapid onset w/ short half life (6-12 hrs)
  • monitored by specialized assay, NOT APTT
  • partially reversed by protamine
  • can be used safely during pregnancy
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11
Q

LMWH metabolism

A
  • cleared by kidney

- should not be used in patients w/ impaired renal function

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12
Q

Adverse effects of heparins

A
  • bleeding
  • osteoporosis
  • heparin induced thrombocytopenia: can cause THROMBOSIS
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13
Q

Heparin induced thrombocytopenia (HIT)

A
  • prothrombotic condition mediated by IgG antibodies that bind to platelet factor 4 when complexed w/ heparin
  • surgical patients have higher risk
  • UFH higher risk than LMWH
  • occurs 5-10 days after initiation of heparin
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14
Q

Treatment of HIT

A
  • immediately discontinue all heparins
  • start non heparin anticoagulant drug: fondaparinux (synthetic LMWH), direct thrombin inhibitor (argatroban, lepirudin, bivalirudin)
  • warfarin should not be used until platelet count has recovered to at leas 150,000 per uL
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15
Q

Warfarin

A
  • vitamin K antagonist

- inhibits glutamate carboxylation of vitamin K dependent clotting factors

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16
Q

Molecular targets of warfarin

A
  • activated clotting factors IIa, VIIa, IXa, Xa
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17
Q

Warfarin administration

A
  • ORAL
  • slow onset of action b/c long half lives of clotting factors in plasma
  • action reversed by vitamin K
  • metabolized by liver and kidney
  • monitored by INR of PT
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18
Q

Warfarin drug interactions

A
  • pharmacokinetics: changes absorption, protein binding, or metabolism–metabolism/elimination via cytochrome P450 system
  • pharmacodynamic: alter risk of bleeding or clotting by either effect on platelet aggregation of vitamin K catabolism
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19
Q

Warfarin pharmacogenetics

A
  • R-warfarin & S-warfarin (CYP2C9)

- S warfarin more effective at vitamin K inhibition

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20
Q

Warfarin & genotyping

A
  • genotyping appears to allow you to get INR into the proper range sooner but has not been shown to improve clinical outcomes
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21
Q

Adverse effects of warfarin

A
  • bleeding
  • teratogenicity (contraindicated in pregnancy)
  • warfarin induced skin necrosis
  • purple toe syndrome (cholesterol emobilization)
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22
Q

Limitations of warfarin

A
  • narrow therapeutic index
  • requires frequent monitoring
  • pharmacogenetic testing has not been proven to improve clinical outcomes
  • slow onset–so heparin overlap necessary
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23
Q

Direct thrombin inhibitors

A
  • parenteral: argatroban, lepirudin, bivalirudin

- oral: dabigatran

24
Q

Molecular target of direct thrombin inhibitors

A
  • FACTOR IIa – thrombin
25
Q

Argatroban

A
  • approved for treatment of heparin induced thrombocytopenia
  • administration: continuous IV
  • short half life (1 hour)
  • monitoring: APTT
  • metabolism: HEPATIC
26
Q

Lepirudin & Bivalirudin

A
  • approved for treatment of HIT
  • administration: continuous IV
  • short half life (1-2 hours)
  • metabolism: RENAL
  • *derived from the medicinal leach**
27
Q

New oral target specific anticoagulant drugs

A
  • direct thrombin inhibitors: dabigatran

- direct factor Xa inhibitors: rivaroxaban, apixaban

28
Q

Look at table on page 45

A

DO IT NOW

29
Q

Important features of new oral anticoagulants

A
  • faster onset than warfarin: ~2 hours
  • shorter half life: 7-17 hours
  • monitoring: NOT NEEDED
30
Q

Efficacy of new oral anticoagulants

A
  • stroke prevention in non valvular Afib
  • prevention of VTE in orthopedic surgery
  • treatment of VTE
31
Q

New oral anticoagulants: antidote

A
  • NO ANTIDOTE
  • under development: anti dabigatran monoclondal antibody, inactive Xa analogues (decoys) to neutralize factor Xa inhibitors
32
Q

Anti platelet drugs

A
  • aspirin
  • P2Y12 receptor antagonist (receptor on platelets for ADP)
  • glycoprotein IIb/IIIa antagonists
  • dipyridamole
33
Q

Aspirin: mechanism

A
  • irreversibly inhibits COX 1&2, decreasing synthesis of TXA2 (potent platelet agonist)
  • inhibits platelet function for life of platelets (7-10 days)
  • administration: oral
34
Q

Aspirin: adverse effects

A
  • bleeding
  • GI ulceration
  • allergy/bronchospasm
  • interstitial nephritis, papillary necrosis, proteinuria, renal failure
  • reye’s syndrome (rapidly progressive encephalopathy & hepatic dysfunction) in children w/ viral illness*
35
Q

Aspirin COX inhibition: platelet & endothelial cell

A
  • platelet: inhibits COX1 decreasing TXA2 (platelet aggregator)
  • endothelial cell: inhibits COX1/2 decreasing PGI2 (inhibits aggregation)
36
Q

P2Y12 receptor antagonist: mechanism

A
  • block activation of platelets by reducing ADP activation of P2Y12 receptor
37
Q

Administration of P2Y12 inhibitors

A

ORAL

38
Q

P2Y12 receptor antagonist drugs

A
  • thienopyridines: clopidogrel, ticlopidine, prasugrel–IRREVERSIBLE binding
  • cyclopentyltriazolopyrimidine: ticagrelor–noncompetitive inhibitor (REVERSIBLE)
39
Q

P2Y12 receptor antagonists: adverse effects

A
  • bleeding
  • GI irritation
  • thrombocytopenia, neutropenia
40
Q

Glycoprotein IIb/IIIa antagonists: mechanism

A
  • inhibit binding of fibrinogen to glycoprotein IIa/IIIb (integrin a2bB3)
41
Q

Glycoprotein IIb/IIIa antagonist: drugs

A
  • abciximab: Fab fragment of a monoclonal antibody
  • tirofiban: small molecule
  • eptifibitide: cyclic heptapeptide
42
Q

Administration of glycoprotein IIb/IIIa antagonists

A

IV

43
Q

Adverse effects of glycoprotein IIb/IIIa

A
  • bleeding

- thrombocytopenia (esp. with abciximab)

44
Q

Dipyridamole: mechanisms

A
  • stimulates prostacyclin synthesis, inhibits adenosine deaminase and phosphodiesterase
45
Q

Dipyridamole

A
  • anti platelet drug
  • also has vasodilatory effects
  • oral or IV
  • adverse effects: headache
  • *often used in combination with aspirin**
46
Q

Fibrinolytic agents

A
  • mechanism: promote activation of plasminogen to generate plasmin, which then degrades fibrin
  • streptokinase
  • urokinase (u-PA)
  • tissue plasminogen activator (t-PA)
47
Q

Streptokinase

A
  • derived from beta hemolytic stretococcus
  • bind plasminogen, forming complex that gets allosterically active
  • administration: IV or catheter directed
  • NOT fibrin specific (also cleaves fibrinogen)
48
Q

Streptokinase: adverse effects

A
  • bleeding
  • allergic reactions (anti step antibodies)
  • hypotension
49
Q

Urokinase (u-PA)

A
  • isolated from human urine or kidney cells
  • protease that directly cleaves plasminogen to form plasmin
  • NON-antigenic
  • administration: IV
  • NOT fibrin specific (also cleaves fibrinogen)
50
Q

Tissue plasminogen activator (t-PA)

A
  • recombinant t-PA (alteplase), variants (reteplase, tenecteplase)
  • proteases that directly cleave plasminogen to form plasmin
  • fibrin SPECIFIC (more localized fibrinolytic activity)
  • short half life (minutes): must be used w/ heparin
  • administration: IV
51
Q

Catheter directed thrombolytic therapy

A
  • localized therapy w/ less bleeding risk
52
Q

Apixaban vs. warfarin

A

Apixaban shown to be just as effective with no need for monitoring

53
Q

Mechanism of action of antithrombotic drugs

A
  • anticoagulants: inhibit proteases in the coagulation cascade
  • anti-platelet drugs: inhibit platelet activation or aggregation
  • fibrinolytic agents: promote generation of plasmin, degrading clots
54
Q

Major problem with warfarin

A

many more drug, dietary, pharmacogenetic interactions than other antithrombotic drugs

55
Q

Important adverse effects of antithrombotic drugs

A
  • bleeding: all antithrombotic drugs
  • immunological reactions: HIT, anaphylaxis
  • teratogenicity: warfarin
56
Q

Antithrombotic Drugs

A
  • anticoagulants
  • ani platelet drugs
  • fibrnolytic drugs

MOHDIII - Unit 2 (23 decks)

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