M3 L5: Anticoagulants Flashcards
antithrombotic agents (3)
- antiplatelets (inhibit platelet function)
- anticoagulants (inhibit coagulation factors)
- thrombolytic (profibrinolytic) agents (breakdown fibrin)
antiplatelet agents (6)
- cyclooxygenase inhibitors
- ADP receptor blockers
- phosphodiesterase (PDE) inhibitors
- prostacyclin (PGI2) analogues
- adenosine reuptake inhibitors
- glycoprotein 2b/3a receptor blockers
cyclooxygenase inhibitors
mechanism: decreased cyclooxygenase (cox) enzyme -> decreased TxA2
include: acetylsalicylic acid (aspirin), other NSAIDS ex: ibuprofen
Aspirin is strongest
This group inhibits cyclooxygenase enzyme
Some inhibit platelets, some stimulate
When you inhibit cyclooxygenase, you decrease thromboxane you inhibit platelet aggregation
aspirin
very powerful platelet inhibitor!
- effect is more prolonged than other NSAIDS
dose: 350mg/day for treatment of myocardial infarction. 81mg/day for prophylaxis (baby aspirin).
side effects: bleeding, peptic ulcer, bronchial asthma
Till very recently was #1 with very little competition, can be used as an anti-inflammatory
Very powerful very strong
If you go to Europe, it is a smaller dose for baby aspirin
The inhibition of cyclooxygenase can result in inhibition of not just platelets, that causes the other side effects other than bleeding
ADP receptor blockers
1. mechanism
2. side effects
- block ADP receptor (P2Y12) -> decreased ADP-induced platelet aggregation
- safe when aspirin is contraindicated - neutropenia, TTP, bleeding
examples: thienopyridines (ticlopidine - clopidogrel)
Prefer this over aspirin because of the adverse affects
Block ADP and inhibit platelet receptors
Side effects are safer than aspirin
Neutropenia: low levels of neutrophils
TTP: thrombotic thrombocytic purapura
phosphodiesterase inhibitors
PDE decreased that is used as an antiplatelet is… cilostazol
- selective decrease of PDE3 -> increase cAMP in platelets -> increase active PKA -> decrease platelet aggregation
indication: intermittent claudication in peripheral vascular disease (vasodilator effect)
- avoid in heart failure
Group of enzymes
1-11 enzymes with subtypes
PDE3 has A and B
PDE4 has A B C and D
Inhibits PDE3, increases cAMP level, high levels of this in platelets leads to decreased platelet aggregation
Intermittent claudication causes severe pain in legs and muscle cramping with swelling
Cilostazol - don’t use w pts w CHF bc it could affect the condition of the heart
prostacyclin analogues
- synthetic analogues of prostacyclin (PGI2)
mechanism: directly increases cAMP levels in platelets
thru inhalation or IV
ex: iloprost, carbacyclin
Also called PGI2
Part of a family with members, it is slightly smaller group than previous side but each member has a function to do with different parts of the body
Prostacyclin - platelet inhibitor
Cyclic AMP is a large factor for inhibiting platelets
mechanism of clopidogrel, cilostazol, and prostacyclin analogues action: inhibition of platelet aggregation thru increased cAMP
Drugs that rely on increasing cAMP to keep platelets inhibited
Clopidogrel competes with ADP
Cilostazol inhibits PDE3, breaks down cAMP, then it becomes linear gets hydrolyzed to become 5-AMP
The drugs overall increase the level of cAMP
adenosine reuptake inhibitors
mechanism:
- inhibit adenosine uptake by RBC’s, platelets, and endothelial cells
- increase extracellular adenosine concentration -> acts on receptors
- increase platelet cAMP synthesis
- cAMP inhibits platelet aggregation
ex: dipyridamole (+PDE5 decrease -> VD)
Dipyridamole: when it was found it was a new era of a treatment of platelet inhibition, was found after aspirin. Shortly after they found it was not as affective, and have adverse effects so now it is 2nd or 3rd choice.
glycoprotein 2b/3a receptor blockers
mechanism: block glycoprotein 2b/3a receptors on platelets -> decrease platelet aggregation
side effects: thrombocytopenia
route of administration: IV
ex: abciximab
Have a big problem, only used through IV not orally
These receptors are on platelets, the bow looking thing has two ends one would connect to the receptor, the other would connect to another receptor on another platelet. This helps with platelet aggregation. These meds block these receptors. Very effective, pt has to be hospitalized
Thrombocytopenia is a side effect
thromboxane inhibitors
- thromboxane synthase inhibitors
- thromboxane receptor antagonists
Inhibits thromboxane synthetase through inhibiting the enzyme, the other competes with the receptor
example of thrombin receptor (protease-activated receptor-1 [PAR1]) antagonists
vorapaxar
heparin
- unfractionated heparin
- low molecular weight heparin (LMWH)
- taken by injection
oral anticoagulants
- warfarin and dicoumarol
- direct thrombin inhibitors
- direct FXa inhibitors
unfractionated heparin
mechanism:
- augments the effect of AT
- inhibition of thrombin (factor 2a) and factor Xa
side effects:
- bleeding, thrombocytopenia, allergic reactions, osteoporosis
administration:
- IV or SC injection
Natural substance in the body
Antithrombin: acts thru heparin, inhibits Factor 2 and Factor 10
Thrombocytopenia: reduction in platelet count
Taken by IV or subcutaneous injection
low molecular weight heparin
compared to unfractionated heparin:
- lower molecular weight
- more selective inhibition of factor Xa w relative sparing of thrombin
- improved pharmacokinetics
- less side effects
- no need for coagulation monitoring
- administered mainly thru SC injection
ex: tinzaparin, enoxaparin
Piece of heparin, not the whole piece
Unfractionated: is 15kg (or something w a k)
Has lower molecular weight, smaller than heparin. This will make them have better pharmakinetics, mainly used by subcutaneous injections, safer than heparin, and lower risk of bleeding. This can be taken when patient is ambulatory, whereas heparin you have to be in the hospital and you have to follow up to monitor levels.
Low molecular weight: focus on factor 10, not both.**** Figure out the difference between low molecular weight and unfractionated guaranteed question on midterm
warfarin
mechanism:
- Vitamin K is required for activation of factors 2, 7, 9, 10 in the liver by carboxylation.
- vitamin k has to b in reduced form under effect of vitamin k epoxide reductase enzyme
- enzyme in inhibited by warfarin
Vitamin K must be in reduced form to activate these factors, and to be in this it must be reduced by the reductase enzyme. Then reduced vitamin K will activate factors through carboxylase reactions.
Vitamin K stimulates the coagulation process
Warfarin will inhibit Vit K epoxide reductase enzyme
heparin vs warfarin
1. chemistry
2. source
3. mechanism
4. administration
5. onset
6. duration of action
7. monitoring
8. antidote
- chemistry
heparin: mucopolysaccharide (-‘ve charge_
warfarin: vitamin k antagonist - source
heparin: natural product
warfarin: vitamin k antagonist - mechanism
heparin: activates AT -> decreased thrombin and FXa
warfarin: decreases vit k epoxide reductase enzyme - administration
heparin: SC, IV
warfarin: oral - onset
heparin: immediate
warfarin: >2 days - duration of action
heparin: short (hrs)
warfarin: long (days) - monitoring
heparin: PTT
warfarin: PT (INR) - antidote
heparin: protamine (+’ve charge)
warfarin: vit k
Heparin is natural, short acting (starts fast, ends after a few hours)
Warfarin is a synthetic, late onset (take once a day)
Start them together, bc warfarin will take a while to start
Both need monitoring because they are both strong (talking about unfractioned heparin)
Warfarin can accumulate bc it is long lasting which can lead to toxic effects
Protamine is a +’ve charged substance by itself
direct thrombin inhibitors
- recent oral anticoagulants
- directly inhibit thrombin (factor 2a)
- no specific monitoring test
- don’t require frequent monitoring
- antidote: approved by WHO in 2015
ex: dabigatran
*know this has an antidote
direct FXa inhibitors
- recent oral anticoagulants
- directly inhibit factor 10a
- rapid onset of action
- don’t require frequent monitoring
- antidote: approved by WHO in may 2018
ex: rivaroxaban
“oxaban” is Fxa inhibitor
thrombolytic agents
- activate plasminogen -> plasmin
include:
- tissue plasminogen activator (t-PA)
- urokinase
- streptokinase
Have a huge advantage - Try to break down the thrombus, thrombus has to be quite fresh so it can be dissolved - can dissolve the clot
Tissue plasminogen activator - most useful drug of this group
tissue plasminogen activator (t-PA)
- initially isolated from a tumor cell line (melanoma)
- directly promotes the conversion of plasminogen -> plasmin
- selective for fibrin-bound plasminogen
- low antigenicity: repeated uses
Natural in our body
When it was found it was isolated from melanoma cells, now they make it available to use it as a drug
Also specific for plasmid, that is connected to the fibrin
T-PA can work on the area with the thrombus
Less allergenic, and causes bleeding
streptokinase vs. t-PA
1. plasminogen binding
2. potential allergic reaction
3. antigenicity
4. risk of bleeding
5. plasma clearance (mins)
6. relative cost
- plasminogen binding
streptokinase: indirect
t-PA: direct - potential allergic reaction
streptokinase: yes
t-PA: no - antigenicity
streptokinase: high
t-PA: low - risk of bleeding
streptokinase: more
t-PA: less - plasma clearance (mins)
streptokinase: 15-25
t-PA: 4-8 - relative cost
streptokinase: +
t-PA: +++
T-PA is much better, the only advantage for streptokinase is that it is cheaper.
