Anticoagulant Drugs Flashcards
The clot does not extend beyond wound site into general circulation. Why?
Fibrin absorbs thrombin into the clot and inactivates it.
Natural Mechanisms to control blood clotting (4)
- PGI2: inhibit platelet aggregation
- ATIII: blocks factors 12,11,9,10,2
- Protein C: inactivates factor 5 and 8
- Heparan sulfate:
synthesized by endothelial cells
Enhance the activity of ATIII
Drugs given to
1. Prevent thrombus
2. Rx thrombus
3. Delay resolution of thrombus
- Anticoagulants, anti platelets
- Fibrinolytics
- Anti fibrinolytics.
How does the body maintain hemostasis?
After few mins bleeding stops
1. Vasoconstriction
2. Formation of primary plug-platelet adhesion, activation,aggregation
3. Formation of secondary plug
Platelets + fibrin = clot
4. Dissolve plasmin
Natural coagulant and anticoagulants
Coagulant: vit K , factor 1-12
Anticoagulants :
AT3
ATP
Protein C
Protein S
Plasminogen
At which step does bleeding stop?
Test for any abnormality
Primary plug
Bleeding time: tests for platelet count and quality
Normal: 2-9 mins
Normal BT,APTT,PT,TT values
BT: 2-9mins
APTT: 28- 35 secs
PT: 11-13 secs
TT: 15 -20 secs
How is testing for BT,PT,APTT , TT done ?
BT: take a filter paper, needle prick , and see the time blood clots.
PT: take blood in test tube , centrifuge it, separates the plasma-> add tissue thromboplastin + ca2+——> clot.
APTT: take blood in test tube, centrifuge it, separates the plasma—> add kaolin + ca2+ ———> clot
TT: fibrinogen——> fibrin
Activated by factor 2.
Used for fibrinogen deficiency
Steps to primary homestasis
Injury, exposes VWF and collagen, platelet adhesion, activation of secretary granules (ADP, TXA2) ,platelet aggregation and clot.
Steps to secondary homestasis
Tissue factor is exposed to injury , activates intrinsic (factor 12) and extrinsic clotting factors (factor7) and cause clot.
Causes of high INR (3)
- Anticoagulants-warfarin
- Decreased synthesis of clotting factor : CLD,
vit K def: malnutrition,malabsorption,antibiotic - Increased consumption of clotting factor : sepsis,DIC
Heparin consists of …….units
Polymer consisting of 2 sulfated dissarcharide units.
D-glucosamine-L-iduronic acid
D-glucosamine-D-glucoronic acid
Heparin is naturally occuring in …..
Synthetic ones are produced from ….
Mast cells
Ox lung and pig intestine mucosa
MOA of unfractionated heparin
- Provides scaffolding of AT 3 to factor 2,10.
- Provides confirmational change to AT 3.
For Xa inhibition: only the above is needed
For factor 2a inhibition: both are required.
AT3 + heparin —> inhibit intrinsic factor by binding and inactivating them.
Difference between unfractionated heparin , LMWH, Fondaparinox in terms of:
1. Nature
2. MOA
3. t1/2
- Heteropolysaccharides: UFH,LMWH
Pentazaccharide : Fondaparinox - UFH: inhibit both 10a, 2a
LMWH, Fondaparinox: only 10a, - UFH : 2hrs
LMWH: 4 hrs
Fondaparinox: 17hrs
Difference between UFH,LMWH,Fp in terms of:
1. Bioavailability
2. Response
3 . monitoring
4. S/e HIT,TCP
- UFH: 30%, LMWH: 90%, FP: 100%
- UFH: variable
LMWH, FP: predictable - UFH: APTT
LMWH, FP: no monitoring - More for UFH
less for LMWH,Fp
Egs of direct thrombin inhibitors
Parenteral, oral
Parenteral:
lepirudin,Bivalirudin , argatroban
Oral:
Dabigatran
Monitoring for parenteral anticoagulants required for ….
UFH, direct thrombin inhibitors (parenteral)
LMWH,oral direct thrombin and factor 10a inhibitors don’t need monitoring
Dabigatran is a prodrug.T or F
Antidote for dabigatran associated bleeding
True:
Dabigatran etoxilote—-> dabigatran
Idarucizumab
S/e of direct thrombin inhibitor (2)
Hemorrhage
Hypotension
Direct factor Xa inhibitors
MOA
Rivaroxaban and all xabans
Reversible
Oral
Xa
Inhibitor
Inhibit both free and plasma Factor Xa attached to prothrombin complex
Antidote of direct factor Xa inhibitors
Andexanet alfa
MOA of Fondaparinox
C/I
Oral indirect factor Xa inhibitor without activity against thrombin.
Renal failure
Advantages of rivaroxaban (3)
- No lag time, rapid action
- No lab monitoring of PT,APTT
- Efficacy similar to LMWH+ warfarin
Why is LMWH given s/c?
Benefit of LMWH
Due to better bioavailability by this route.
2-4 longer t1/2, hence once daily dosing is required.
Types of VitK
K1: from plants- phytonadione
K2: from bacteria: menaquinone
K3: synthetic: menadione
T1/2 of Vit K
T1/2 of warfarin
MOA of VitK
72 hours
36 hours
Factor 2,7,9,10 is glutamate chains —> gamma carboxylation —> active factor 2,7,9,10.
Vit K is cofactor.
It gets inactivated in the process by enzyme Vit K Epoxide reductase.
Warfarin-inactivates VitKER
A/e of Vit K
Menadione- hemolysis ; so C/I in G6PD and neonates.
Menadione competitively inhibits glucoronidation of bilirubin —> displaces bilirubin—> kernicterus
Sequence fall of various factors with warfarin action.
Factor 7: 6 hrs
Factor9: 24 hrs
Factor 10: 40 hrs
Factor 2: 60 hrs
Longest and shortest acting warfarin
Longest: dicumarol -bishydoxycaumarin
Shortest: ethylbiscoumaacetate
Dosage of heparin in iv and sc
Iv:
5000-10000 U bolus —-> continues infusion @750 -1000U/hr
S/c:
5000 Unit S/C every 8-12 hrs
Uses of VitK (3)
- Defiency states :
CLD
Obstructive jaundice
Prolonged Ab
Malabsorption syndrome
Dietary deficiency - Hemorrhagic disease of new born
1mg VitK is given IM at time of delivery - overdose of oral anticoagulants
Structure of heparin vs warfarin.
Heparin: large, anionic, acidic polymer
Warfarin: small lipid soluble molecule
IM route is not given for heparin. Why?
Site of action of heparin vs warfarin
Hematoma
Heparin: blood
Warfarin: liver
Inhibit coagulation of heparin vs warfarin
Heparin : both in vivo and vitro
Warfarin: only in vivo
Rx for acute overdose of heparin vs warfarin
Heparin : protamine sulfate
Warfarin : bleeding:
prothrombin complex /FFP
Stable: Vit K
Monitoring of heparin vs warfarin
Heparin : APTT
Warfarin: PT/INR
Chemistry of heparin vs warfarin
Heparin : mucopokysaccharide
Warfarin: coumarin
Source of heparin vs warfarin
Heparin : hog liver, pig intestine
Warfarin : synthetic
Heparin causes ……renal problem
Long term use of heparin causes ….
Calciphylaxis seen with …..
Type 4 RTA
Osteoporosis
Warfarin
Warfarin was initially marketed as …
C/I of warfarin (7)
Rat poison
C/I
1. Bleeding
2. HIT
3. Severe HTN- increased risk of cerebral hge, threatened abortion, piles,GI ulcer
- SABE
- Chronic alcoholics, cirrhosis,renal failure
- Aspirin and other plt products
- Pregnancy
Interactions of warfarin (5)
- Enzyme inhibitors - increase action
- Broad spectrum Ab
- Aspirin
- Long acting sulfonamide, indomethacin,
phenytoin,, probenecid - Liquid paraffin
Define Glansmann thrombasthenia
Defect is in ……
AR
Defect in Gp 2b/3a
Defect in platelet aggregation
Define Bernard soulier syndrome
Defect is in…..
AR
Defect in Gp 1b/2a
Defect in platelet adhesion
Function of Gp 2b3a
Eg of gp 2b3a antagonist
Use.
Which one is given iv?
Causes fibrogen to bind to the receptor —> platelet aggregation
Mab- abciximab
For percutaneous angioplasty
Tirofiban.
S/e of gp 2b 3a antagonist
- Bleeding —> rx: platelet infusion
- Thrombotic TCP
Side effects of gp 2b3a antagonists (3)
Nausea
Back pain
Hypotension
Classification of ADP receptor antagonist
Irreversible inhibitors of P2Y12:
Ticlopidine
Clopidogrel
Prasugrel
Reversible inhibitor of P2Y12:
Ticagrelor
Cangrelor
S/e of ticlopidine
BMS- TCP/neutropenia
S/e of clopidogrel
Requires CYP2C19 to activate it.
This enzyme is acted upon by PPI,especially omeprazole, lansoprazole —> failure of clopidogrel.
Those that have least action on CYP2C19: pantoprazole
Rabiprazole
Prazugrel is also a …..
S/e
Prodrug
Increases bleeding —> c/i in stroke
Which of the reversible P2Y12 inhibitor is given iv?
Action.
Cangrelor
Fastest -5-10mins
Action of ticagrelor
MOA of vorapaxar
S/e
2hrs
Platelet PAR-1 antagonist
Inhibits thrombin mediates aggregation
Similar to prasugrel-c/I in stroke
What are the ADP receptor antagonist?
ADP + P2Y12–> inhibit adenylate Cyclase—> decrease CAMP—-> change in gp2b 3a to go to the surface and cause aggregation.
MOA of PDE inhibitors
Eg
Increase CAMP
Dipyridamole, cilostazole
adenosine reuptake inhibitor
S/e of dipyridamole
S/e of cilostazole
Use.
Coronary steal syndrome
Do not give in heart failure - Milrinone like action-increase mortality.
Antiplatelet+ vasodilators action - used for intermittent claudication.
Use of pentoxiphylline
Improve flexibility of RBC, use for intermittent Claudication- beurger’s ds
Thromboxane A2 synthase inhibitor ….
Aspirin inhibits ….
Dazoxiban
COX , which inhibits PGI2, TXA2.
Drug of choice for arterial vs venous thrombus
Arterial: MI/ stroke :
Antiplatelet drugs work better as thrombus in artery is rich in platelets.
Venous : DVT/P.E
Anticoagulant-warfarin
What is Reye’s syndrome?
When a child recovering from viral ds is ( influenza / chicken pox) is given aspirin , can cause liver failure and encephalopathy .
Egs of fibrinolytics
MOA
Streptokinase, urokinase,TPA, reteplase.
Directly/indirectly convert plasminogen/plasmin- which cleaves thrombin and fibrin clots.
Labs for thrombolytics
Which thrombi works better with fibrinolytics ?
Increase PT,APTT no change in platelet count.
Venous thrombi lysed better, recent thrombi <3 days.
Clinical indications of fibrinolytics (2)
Early MI
Early ischemic stroke
Adverse effects of thrombolytics?
Bleeding - c/I in active bleeding , recent surgery, IC bleeds, severe HTN.
MOA of antifibrinolytics
Inhibit plasminogen activation and dissolution of clot .
Inhibit fibrinolysis associated bleeding
Most potent antifibrinolytic use . (4)
Tranexaminic acid
Prevent /control excess bleeding due to:
1. Fibrinolytic drugs
2. Tonsillectomy/tooth extraction in hemophilics
3. Menorrhagia
4. Recurrent epistaxis, hyphema-due to ocular trauma,peptic ulcer etc.
