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M2 Cardio > 11/7 Antiplatelet/Anticoagulant Drugs - Lobel > Flashcards

11/7 Antiplatelet/Anticoagulant Drugs - Lobel Flashcards

1
Q

drug list

  1. indirect thrombin inhibitors
  2. direct thrombin inhibitors (parenteral)
  3. oral anticoagulants
  • vitK antagonist
  • novel oral anticoags
    • direct thrombin inhibitor
    • direct factor Xa inhibitor
  1. fibrinolytic drugs
  2. antiplatelet agents
  • cyclooxygenase inhibitor
  • ADP receptor inhibitors
  • GP IIb/IIIa receptor blockers (IV)
A
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2
Q

coagulation pathway

A
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3
Q

platelet adhesion and aggregation

A
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4
Q

major blood coag rxns

A
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5
Q

antithrombotic mechanisms

A
  1. intact endothelium: keeps plasma factor VII and subendothelial tissue factor separate
  2. blood flow: clears activated coag factors
  3. prostacyclin: PGI2 (inhibit platelets; NO does the same)
  4. t-PA: tissue plasminogen activator: activates plasminogen → plasmin (which degrades fibrin)
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6
Q

antithrombin / heparin sulfate

mechanism, activation

A

antithrombin inhibits:

  • thrombin (IIa)
  • Factor Xa
  • Factor IXa

antithrombin is activated by:

  • endothelial cell heparin sulfate
  • soluble heparin (extracted from tissues rich in mast cells)
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7
Q

Protein C / Protein S / thrombomodulin

A

Protein C → APC (in presence of IIa/TM complex)

APC/S complex leads to rapid degradation of active Va/VIIIa complex

Protein C or Protein S deficiency → incr risk of venous thrombosi

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8
Q

heparin

basics: what is it, where can you find it, clinical preps

how does it do its job?

what happens after?

A

antithrombin III activator

  • heparin is a highly sulfated mucopolysacchide that is essential for binding and inducing conformational change in antithrombin
  • normal constituent of human body - stored in mast cells
  • clinical preparations:
    • unfractionated (high MW heparin: 5-30kDa)
    • low MW heparin (2-6 kDa)
    • synthetic pentasaccharide (1.7 kDa)

how does heparin do its job?

  • serves as a suicide substrate
  • binds allosterically to antithrombin → conformational change that exposes Arg on reactive site to Factor Xa

what happens after?

  • active protease (either thrombin or Xa) attacks the active site → protease is trapped as a covalently bound intermediate
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9
Q

heparin: mech of action

A

catalyzes antithrombin-protease “suicide substrate” rxn

  • NOT CONSUMED BY RXN: released afterwards

unfractionated heparin is the version that is most specific for thrombin (bc its long enough to bind antithrombin III-thrombin complex)

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10
Q

heparin admin

A

admin: IV

  • NOT effective orally (not absorbed from GI tract)
  • does not cross placenta/enter breastmilk
  • prophylaxis? subQ

what if you need to reverse effect?

  • excessive anticoagulant action →→→ discontinue usage (halflife -.5-2hr)
  • antidote: protamine sulfate
    • basic peptide that binds heparin, forms a stable complex without anticoag activity
      *
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11
Q

heparin : complications

A

1. major bleeding (5-10d course)

  • 2% unfractionated
  • 1% LMWH
  • incr risk with aPTT > 2.5x normal

2. osteoporosis

  • decr bone density in 30% after 1mo of fulldose UFH tx
  • vertebral fracture in 2%

3. heparin resistance

  • elevated Factor VIII and others
  • antithrombin deficiency
  • increased clearance
  • monitor with anti-Xa assay

4. heparin-induced thrombocytopenia (HIT)

  • 2 types
    • immune: onset after 5-10d; HIT ab present; thrombosis likely
    • nonimmune: immediate onset; HIT ab NOT present; thrombosis UNlikely
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12
Q

LMWHs

comparison to heparin

typical use

A

enoxaparin

compared to heparin:

  • less inhibition of thrombin
  • effecient inhibition of factor Xa
  • less inhibition of platelet aggregation
  • less effect on vascular permeability
  • less bound to plasma proteins
  • longer halflife (4.5hr) = less freq dosing
  • incr bioavailability when administered subQ
  • less freq incidence of HIT (but contraindicated in pt with HIT)

typical uses:

  1. prevention of DVT postop
  2. tx of acute venous thromboembolic disease and ACS
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13
Q

fondaparinux

what is it

PK

side effects

A

synthetic analog of pentasaccharide binding seq of heparin

PK:

  • long halflife (17-21h)
  • 100% bioavailability with single/daily/subQ dose
  • renal clearance (i.e. dont give to renal failure pt)

doesn’t cause HIT

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14
Q

props of heparin perps

  • route of admin
  • absorption
  • pl protein binding
  • dosage
  • monitoring
A
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15
Q

direct thrombin inhibitors

parenteral

A

hirudin and bivalirudin bind both active site and exosite I of thrombin

argatroban binds at active site of thrombin

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16
Q

desirudin

A

recombo form of hirudin

leech compound!

  • most potent known inhibitor of thrombin
    • action indep of antithrombin III
  • can reach and inactivate fibrin-bound thrombin in thrombi
  • does not cause thrombocytopenia

subQ admin

halflife 2hr

renal clearance

17
Q

bivalirudin

A

synthetic peptide congener of hirudin

approved for: coronary angioplasty; HIT

halflife: 25min

renal and metabolic clearance

18
Q

argatroban

A

small synthetic derivative of Arg: blocks active site of soluble and clot-bound thrombin

approved for: HIT

admin: IV
halflife: 40-50min

hepatic metabolism

adverse effects: hemorrhage, allergic rxns

19
Q

oral anticoagulants

A

WARFARIN: inhibitor of VKORC1 (vitK reductase) → inhibits synth of vitK-dep zymogens

pl concentration peaks 2-8hr after oral dose

99% bound to pl protein

halflife: 25-60hr

inhibits biosynthesis of vitK-dep zymogens

  • procoag
    • prothombin
    • factor VII
    • factor IX
    • factor X
  • anticoag
    • protein C
    • protein S
20
Q

warfarin issues

A
  • can shift patients into a pro-coag state (getting rid of Protein C too!!!)
  • v low therapeutic index (diff between thromboembolism and major bleeding is not much)

adverse effects:

  • bleeding
    • risk incrases with INR > 4
    • treated with vitK (delayed resp) or fresh-frozen plasma (immediate resp)
  • birth defects and abortion
    • skeletal/Cns abnormalities
    • contraindicated during preg
  • skin necrosis
    • microvasc thrombosis
    • can occur if heterozygous for protein C or S deficiency (if high intiial dose used or heparin overlap inadequate)
    • frank infarction of breast/fatty tissue/intestine/extremities rare → venous thrombosis
21
Q

conditions that alter response to warfarin

A

compliance

drugs (affect: hepatic metab, pl protein binding, drugs affecting int bacteria → vit K)

diet (vitK)

other:

  • nephrotic syndrome (low pl albumin)
  • preg (high levels of coag factors)
  • liver disease (low levels of coag factors)
  • pharmacogenomic
    • resistance
    • sensitivity

overall: it is a messy drug!!!

22
Q

warfarin: pros & cons

A

PROs: works, long history, inexpensive

  • decr afib
  • decr complications/recurrence in DVT, PE
  • decr risk of valve thrombosis and embolism with mech heart valves

CONs: lots of interactions, involves freq testing (inconvenient)

23
Q

new/novel direct oral anticoagulants (NOACs)

A

dabigatran : thrombin inhibitor

rivaroxaban, apixaban, edoxaban : Xa inhibitors

  • non-inferior or superior to Warfarin
  • similar/less intracranial bleeding
  • similar overall bleeding

uses: similar to warfarin but not approved for thrombus prophylaxis with synthetic heart valves

antidotes:

  • dabigatran → idarucizumab (humanized mAb)
  • others: andexanet alfa (recombo modified human factor Xa decoy)
24
Q

fibrinolysis

A

process of breaking down fibrin

  • URGENT when clot has inappropriately formed or has broken free into gen circ
  • key process: conversion of inactive plasminogen → active plasmin
    • ​catalyst: t-PA (tissue plasminogen activator)
    • physiologically, activated plasmin is restricted to clot
      • activators are effective on plasminogen thats absorbed to fibrin, and plasmin that escapes into circ is inactivated
25
Q

fibrinolytic drugs

example

main issue

half life

approved use

contraindications

A

rapidly lyse thrmbi via catalysis of plasminogen → plasmin rxn

  • recombinant tissue plasminogen activity (tPA or rtPA): alteplase
    issue: physiological tPA activates plasminogen bound to fibrin of thrombus (tPA binding to clot is several 100x higher than elsewhere)
  • HOWEVER, clinical tPA concentrations are much higher → more binding → nonspecific plasmin activation
    halflife: 5 min in plasma

approved uses:

  • acute MI
  • acute ischemic stroke
  • pulmonary embolism
  • central venous catheter occlusion

contraindications: bleeding, incr risk for bleeding

26
Q

antiplatelet agents

mechanisms

A
  • inhibition of prostaglandin metabolism
  • inhibition of ADP-induced platelet aggregation
  • blockade of GP IIb/IIIa receptors on platelets
27
Q

aspirin

A

ASA (acetyl salicylic acid)

mechanism: COX inhibitor

remember…platelets have no nucleus!

  • platelets can’t regenerate COX
  • effect lasts for life of platelet (7-10d)
  • endothelial cells can regenerate COX to produce PGI2 → restoration of antithrombotic effect
    • endothelial COX requires higher doses of aspirin for inhibition
    • low dose can selectively inhibit platelet COX! → spares endothelial COX → sustains antithrombotic effect

uses:

  • primary prophylaxis of MI
  • secondary prevention of vasc events following HD

adverse effects:

  • bleeding (hemm stroke, GI bleeding)
  • incr risk of peptic ulcer disease
28
Q

ADP receptor antagonists

A

clopidogrel, prasugrel : irreversibly inhibits binding of ADP to its receptor on platelets & inhibits platelet aggregation

ticarelor : reversibly inhibits binding of ADP to its receptor on platelets & inhibits platelet aggregation

indications:

  • dual antiplatelet tx (ex coronary artery stenting) → ADP inhibitor + aspirin
  • triple therapy (ex. coronary artery stenting plus atrial fibrillation) → oral anticoagulant + ADP inhibitor + aspirin

adverse effects: BLEEDING

29
Q

platelet GP IIb/IIIa receptor blockers

A

platelet membrane receptor

  • binds to fibrinogen and vitronectin, fibronectin and vWF → facilitates formation of platelet plug
  • all administered parenterally, PCI

abciximab

  • monoclonal ab against GP IIb/IIIa complex
  • use: coronary angioplasty, ACS

tirofiban

  • non-peptide analog of a.a. seq Arg-Gly-Asp (key recog seq of GPIIb/IIIa receptors) → occupies receptor and inhibits binding

eptifibatide

  • cyclic peptide deriv (based on peptides in pit viper venom!): analog of sequence which mediates binding of fibrinogen to receptor
  • occupies receptor, inhibits binding

adverse effects: BLEEDING

M2 Cardio (22 decks)

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