11/7 Antiplatelet/Anticoagulant Drugs - Lobel Flashcards
drug list
- indirect thrombin inhibitors
- direct thrombin inhibitors (parenteral)
- oral anticoagulants
- vitK antagonist
- novel oral anticoags
- direct thrombin inhibitor
- direct factor Xa inhibitor
- fibrinolytic drugs
- antiplatelet agents
- cyclooxygenase inhibitor
- ADP receptor inhibitors
- GP IIb/IIIa receptor blockers (IV)
coagulation pathway
platelet adhesion and aggregation
major blood coag rxns
antithrombotic mechanisms
- intact endothelium: keeps plasma factor VII and subendothelial tissue factor separate
- blood flow: clears activated coag factors
- prostacyclin: PGI2 (inhibit platelets; NO does the same)
- t-PA: tissue plasminogen activator: activates plasminogen → plasmin (which degrades fibrin)
antithrombin / heparin sulfate
mechanism, activation
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)
Protein C / Protein S / thrombomodulin
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
heparin
basics: what is it, where can you find it, clinical preps
how does it do its job?
what happens after?
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
heparin: mech of action
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)
heparin admin
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
*
- basic peptide that binds heparin, forms a stable complex without anticoag activity
heparin : complications
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
LMWHs
comparison to heparin
typical use
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:
- prevention of DVT postop
- tx of acute venous thromboembolic disease and ACS
fondaparinux
what is it
PK
side effects
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
props of heparin perps
- route of admin
- absorption
- pl protein binding
- dosage
- monitoring
direct thrombin inhibitors
parenteral
hirudin and bivalirudin bind both active site and exosite I of thrombin
argatroban binds at active site of thrombin
desirudin
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
bivalirudin
synthetic peptide congener of hirudin
approved for: coronary angioplasty; HIT
halflife: 25min
renal and metabolic clearance
argatroban
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
oral anticoagulants
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
warfarin issues
- 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
conditions that alter response to warfarin
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!!!
warfarin: pros & cons
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)
new/novel direct oral anticoagulants (NOACs)
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)
fibrinolysis
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
fibrinolytic drugs
example
main issue
half life
approved use
contraindications
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
antiplatelet agents
mechanisms
- inhibition of prostaglandin metabolism
- inhibition of ADP-induced platelet aggregation
- blockade of GP IIb/IIIa receptors on platelets
aspirin
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
ADP receptor antagonists
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
platelet GP IIb/IIIa receptor blockers
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
