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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
Argatroban
- approved for treatment of heparin induced thrombocytopenia - administration: continuous IV - short half life (1 hour) - monitoring: APTT - metabolism: HEPATIC
26
Lepirudin & Bivalirudin
- approved for treatment of HIT - administration: continuous IV - short half life (1-2 hours) - metabolism: RENAL * *derived from the medicinal leach**
27
New oral target specific anticoagulant drugs
- direct thrombin inhibitors: dabigatran | - direct factor Xa inhibitors: rivaroxaban, apixaban
28
Look at table on page 45
DO IT NOW
29
Important features of new oral anticoagulants
- faster onset than warfarin: ~2 hours - shorter half life: 7-17 hours - monitoring: NOT NEEDED
30
Efficacy of new oral anticoagulants
- stroke prevention in non valvular Afib - prevention of VTE in orthopedic surgery - treatment of VTE
31
New oral anticoagulants: antidote
- NO ANTIDOTE - under development: anti dabigatran monoclondal antibody, inactive Xa analogues (decoys) to neutralize factor Xa inhibitors
32
Anti platelet drugs
- aspirin - P2Y12 receptor antagonist (receptor on platelets for ADP) - glycoprotein IIb/IIIa antagonists - dipyridamole
33
Aspirin: mechanism
- 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
Aspirin: adverse effects
- 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
Aspirin COX inhibition: platelet & endothelial cell
- platelet: inhibits COX1 decreasing TXA2 (platelet aggregator) - endothelial cell: inhibits COX1/2 decreasing PGI2 (inhibits aggregation)
36
P2Y12 receptor antagonist: mechanism
- block activation of platelets by reducing ADP activation of P2Y12 receptor
37
Administration of P2Y12 inhibitors
ORAL
38
P2Y12 receptor antagonist drugs
- thienopyridines: clopidogrel, ticlopidine, prasugrel--IRREVERSIBLE binding - cyclopentyltriazolopyrimidine: ticagrelor--noncompetitive inhibitor (REVERSIBLE)
39
P2Y12 receptor antagonists: adverse effects
- bleeding - GI irritation - thrombocytopenia, neutropenia
40
Glycoprotein IIb/IIIa antagonists: mechanism
- inhibit binding of fibrinogen to glycoprotein IIa/IIIb (integrin a2bB3)
41
Glycoprotein IIb/IIIa antagonist: drugs
- abciximab: Fab fragment of a monoclonal antibody - tirofiban: small molecule - eptifibitide: cyclic heptapeptide
42
Administration of glycoprotein IIb/IIIa antagonists
IV
43
Adverse effects of glycoprotein IIb/IIIa
- bleeding | - thrombocytopenia (esp. with abciximab)
44
Dipyridamole: mechanisms
- stimulates prostacyclin synthesis, inhibits adenosine deaminase and phosphodiesterase
45
Dipyridamole
- anti platelet drug - also has vasodilatory effects - oral or IV - adverse effects: headache * *often used in combination with aspirin**
46
Fibrinolytic agents
- mechanism: promote activation of plasminogen to generate plasmin, which then degrades fibrin - streptokinase - urokinase (u-PA) - tissue plasminogen activator (t-PA)
47
Streptokinase
- 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
Streptokinase: adverse effects
- bleeding - allergic reactions (anti step antibodies) - hypotension
49
Urokinase (u-PA)
- 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
Tissue plasminogen activator (t-PA)
- 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
Catheter directed thrombolytic therapy
- localized therapy w/ less bleeding risk
52
Apixaban vs. warfarin
Apixaban shown to be just as effective with no need for monitoring
53
Mechanism of action of antithrombotic drugs
- anticoagulants: inhibit proteases in the coagulation cascade - anti-platelet drugs: inhibit platelet activation or aggregation - fibrinolytic agents: promote generation of plasmin, degrading clots
54
Major problem with warfarin
many more drug, dietary, pharmacogenetic interactions than other antithrombotic drugs
55
Important adverse effects of antithrombotic drugs
- bleeding: all antithrombotic drugs - immunological reactions: HIT, anaphylaxis - teratogenicity: warfarin
56
Antithrombotic Drugs
- anticoagulants - ani platelet drugs - fibrnolytic drugs

MOHDIII - Unit 2 (23 decks)

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