Anti-Coagulants Flashcards
Factors that predispose to thrombosis:?
1) Atheromatous plug rupture;
2) Altered blood flow- Blood stasis (atrial fibrillation and long flights);
3) abnormal coagulability
(Pregnancy, oral contraceptives and thrombophilia);
4) Thrombi can break away forming an embolus. It can interrupt blood flow causing ischemia or infarction
Drugs used in the tx of Venous Thrombi?
Anticoagulants
Drugs used in the Tx of Arterial thrombi?
Antiplatelets
Anticoagulant Drugs
1) Heparins (LMWH,HMWH) - 1st line
2) Hirudins (direct thombin inhibitors) - 2nd line
3) Novel oarl Anticoagulants (NOAC) -
direct thrombin inhibitros and Selective Xa inhibitors
4) Vitamine K Antagonists
Clinical uses of Heparin (HMWH/LMWH)
1st line
- DVT
- PE
- MI
* safe in pregnancy
* LMWH are prefered over HMWH
LMWH examples
* Low molecular weight heparin (LMWH)
enoxaparin,
dalteparin,
fondaparinux
- parin
Contraindications of LMWH
1) renal failure (As they are eliminated by renal excretion)
2) ATIII deficiency (rare) –> can cause Thrombophilia
Heparin inhibits thrombin (IIa) and factor Xa activation. How?
Actiavtion of ATIII (Anti-thrombin III), thus ATIII conformation changes and increases its affinity for serine proteases–> inhibits Thrombin (IIa) and factor Xa.
What is the pathogenesis of Heparin-induced Thrombocytopneia (HIT)
IgG Abs form a complex w/ Heparin bound to platelet factor IV –> platelet activation -> thrombosis –> ↓↓ Platelets
- LMWH are less likely to cause HIT than HMWH
MoA of LMWH
LMWH increases the action of ATIII on Xa only –> it cannot increase the action on ATIII on thrombin and it cannot bind both simultaneouslY
**Act mainly on factor Xa ONLY**
what is used to reverse Heparin AE?
Protamine sulfate
AE of Heparin
1) Haemorrage (bleeding)
2) Heparin -induced Thrombocytopenia (HIT) - caused mainly by Unfractioned Heparins (HMWH)
3) Osteoperosis
4) Drug-Drug rxn- hypersensitivity
5) Hyperaldosteronism (w/ Hyperkalaemia) - Uncommon but monitore K+ levels if tx is to be continued for > 7days
Administration of HMWH
IV- they cannot be absorbed from the gut
Monitoring method for HMWH (Unfractioned Heparin)
Activated Partial Thromboplastin Time (aPTT)
- The dose must be adjusted to reach a value within a target range (eg 1.5-2.5 times control)
Monitoring method for LMWH
anti-Factor Xa assays
NOTE:
Monitoring not required routinely,eliminated
mainly by renal excretion
Direct thrombin inhibitors Examples
Hirudins
Lepidurin,
Bivalirudin,
Argatroban(IV)
LAB
MoA Bivalirudin, Argatroban, Dabigatran?
Direct thrombin inhibitors (Factor IIa)
Clinical uses of Direct thrombin inhibitors?
- Used as an alternative to heparins in patients with type II HIT (and for HIT treatment)
- DVT
- Afib
*HIT : herapin induced thrombocytopnia
main AE of Direct thrombin inhibitors and selvetive Xa inhibitors?
bleeding
bleeding caused by Selective Xa inhibitors can reversed by?
Andexanet alfa
An oral direct thrombin inhibitor
*inhibits the converstion of fibrinogen to fibrin
Dabigatran
*NOAC
MoA of Dabigatran
Pro-drug direct thrombin inhibitor which inhibits the conversion of fibrinogen into fibrin
Clinical uses of Direct thrombin inhibitors and Selective Xa inhibitors
1) Tx and prophylaxis for DVT and PE (followed by knee or hip replacement)
2) Prophylaxis for stroke in patients w/ Afib
Antidote for Dabigatran
idarucizumab
( info:antibody fragment that can reverse the anticoagulant effects of dabigatran)
Factor Xa inhibitors?
Rivaroxaban
Apixaban
Edoxaban
*NOAC
MoA of Rivaroxaban
Apixiban, Edoxaban
Factor Xa selectivity rather than for thrombin.
AE of factor Xa inhibitors?
bleeding, anaemia
Rivaroxaban–> commonly causes nausea
Characteristics of Vitamin K
1) fat soluble vitamin
2) Essential for the formation of clotting factors II, VII, IX and X (Glycoproteins with several γ-carboxyglutamic acid (Gla) residues)
3) Other vitamin K-dependent Gla proteins, include
proteins C and S (anticoagulants) and osteocalcin in bone
Natural vitamin K1?
phytomenadione
(orally or Subcutaneously)
synthetic Vitamin K?
menadiol sodium phosphate
(takes longer to act than phytomenadione)
Clinical uses of phytomenadione (Natural Vitamin K) and menadiol sodium phosphate (synthetic)
Treatment and/or prevention of bleeding
* From excessive oral anticoagulation (e.g. by warfarin)
* In babies to prevent haemorrhagic disease of the newborn
* Coeliac disease
* Lack of bile (e.g. with obstructive jaundice)
* Liver disease
Vitamine K Antagnosits Examples
Warfarin (oral)
Phenidione (Alternatice to warfarin in patients with idiosyncratic-distict AE)
Clinical uses of Warfarin
standard anticoagulant for treatment and prevention of thromboembolic disease
MoA of Warfarin
Inhibition of of vitamin K epoxide reductase —> Inhibits γ-carboxylation of factors II, VII, IX ,X, protein C,S)
AE of warfarin
1) Haemorrhage - bleeding
2) skin/soft tissue necrosis –> due to microthrombi as a resutl of initial Hypercoagulable state ( by the inhibition of protein C biosynthesis)
3) Teratogenic
A patient receiving long-term warfarin needs which weekly labs to determine if they are within therapeutic range ( to reverse/prevent AE)?
Prothrombine time/ International normalized ratio (INR)
(due to effect of warfarin on the extrinsic pathway of coagulation)
ADJUSTED INR 2-4
What treatment can reverse Warfarin AE?
Fresh-frozen plasma (FPP) or Prothrombin complex concentrate (PCC) for rapid reversal; Vitamine K for slower reversal
Factors that potentiate (increase) warfarin?
° Liver disease (coagulation factors are synthesised in the liver by hepatocytes)
° Drugs that inhibit platelet function
° Drugs that displace warfarin from albumin (NSAIDS, sulfonamides, phenytoin)
° Drugs that decrease the availability of vitamin K.(broad spectrum Abx that depress intestinal flora that synthetises vit K.)
Factors that lessen the effect of Warfarin
1) Physiological state/disease
- Increased coagulation factor synthesis (eg. pregnancy)
- reduced degradation of coagulation factors in hypothyroidism.
2) Drugs:
- vit K; (synthesis of coagulation factors)
- CYP450 inducers (Rifampicin, carbamazepine, barbiturates);
- drugs that reduce absorption–> drugs that bind warfarin in the gut (Cholestyramine)
Coagulation factors: II, VII,IX,X also proteins C and S
Contraindications of Warfarin
PREGNANCY - teratogenic (cosses the placenta)
Which is teratogenic, Heparin or warfarin?
Warfarin
- heparin is safe in pregnancy
Polymorphism in what gene affects the metabolism of warfarin?
Vitmain K epoxide reductase gene (VKORC1)
Which hepatic enzyme is responsible for the metabolism of warfarin and is implicated in warfarin drug-drug interactions?
CYP2C9
