Pharmacology Team Anti-Coagulants PPT/PDF

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Pharmacology Team


  Done by:
  *Jumana AlShammari.
  * Ibrahim Al-Gamdi.




       Introduction:   The introduction is just for
your information. Thanks to

Hemostasis   refers   to   the   finely   regulated   dynamic   process   of  maintaining   fluidity   of   Pharmacology Team 430
blood,  repairing  vascular  injury,  and  limiting  blood  loss  while  avoiding  vessel  occlusion  
(thrombosis)   and   inadequate   perfusion   of   vital   organs.   Either   extreme—excessive   bleeding   or   thrombosis—represents   a  
breakdown  of  the  hemostatic  mechanism.

Blood  vessel  injury  triggers  the  following  sequence:

• The  vessel  constricts  to  reduce  blood  flow  
• Circulating  platelets  adhere  to  the  vessel  wall  at  the  site  of  trauma  

• Platelet   activation   and   aggregation,   coupled   with   an   intricate   series   of   enzymatic   reactions   involving  
coagulation  proteins,  produces  fibrin  to  form  a  stable  haemostatic  plug.  

Antithrombotic  drugs  are  used  for  prevention  and  treatment  of  thrombosis.  Targeting  the  components  of  thrombi,  these  
agents  include  (1)  antiplatelet  drugs,  (2)  anticoagulants,  and  (3)  fibrinolytic  agents.  With  the  predominance  of  platelets  
 in  arterial  thrombi,  strategies  to  inhibit  or  treat  arterial  thrombosis  focus  mainly  on  antiplatelet  agents,  although,  in  

the  acute  setting,  they  often  include  anticoagulants  and  fibrinolytic  agents.
Anticoagulants  are  the  mainstay  of  prevention  and  treatment  of  venous  thromboembolism  because  fibrin  is  the  
predominant  component  of  venous  thrombi.  Antiplatelet  drugs  are  less  effective  than  anticoagulants  in  this  setting  
because  of  the  limited  platelet  content  of  venous  thrombi.

The  factor  needs  calcium


Anticoagulants: Collagen  Activated  Platelets

The  factor  depends  on  vit  K

Coagulation  cascade:­‐guZMqM Intrinsic  Path
essel  Injury way


12  a Blood  v
Clotting:  slower  /  accessed­‐ by  aPTT


P5nyD8AQ&feature=related 11  a



Extrinsic  pathway

 Clotting:  is  rapid  in Heparin


 sec.  /  accessed  by  PT 9  a LMWH

8  a





         Tissue  injury
     Activates  the  tissue 7  a 10a

5  a Direct  factor  10a  inhibitor




     Factor  which  then


Thrombin  (2a) Direct  thrombin  inhibitor


Fibrin 13  a


Stabilized  fibrin


Works best on venous thrombosis than arterial thrombosis (can be used as 2nd line after anti-platelet)

Parenteral Anticoagulant Oral Anticoagulant
(Used in acute ‘emergency’ Cases)

Unfractiona LMW Direct Thrombin Factor Xa Vitamin K
ted heparin Heparin inhibitors Inhibitor antagonist

Molecule 3000-30000 < 8000 Pentasaccharide

XIIa, XIa, IXa, Xa, IIa Thrombin 2a Factor Xa Factors II, VII, IX

And thrombin & X
(1000 more potent than Anti

Acts on thrombin3)

more on

Heparin Enoxaparin Reversible: Indirect: Coumarins:
Lovenox • Bivaluridin Fondaparinux

Dalteparin • Argatroban Ø Warfarin
• Dabigatran Direct: > 40 times

Rivaroxaban potency than
Irreversible: Which is taken Ø Dicumarol

• Lepirudin Orally

Ø Irreversible is more

It’s not
It’s not important to important to
know which is know which is
reversible/irreversible Direct/Indirect

Inactivation of Coagulation Factors by Anti-thrombin III Decrease

MOA Synthesis

Pharmacokineti • Rapid • Slow
cs • Variable (unpredictable) • Latency

• Variable
• aPTT (1.5 – 2.5 times normal [30sec]) • PT (2 times)

Monitor • CT (2-3 times normal [5-7 min]) • INR (2.5)

• Protamine Sulphate IV – 1mg for each 100 units UFH • Vitamin K1
• Fresh blood infusion

Antidote • Fresh blood
• Needs de novo


APTT: Activated partial thromboplastin time test is a laboratory test used to monitor the anticoagulant effect of unfractionated
heparin and direct thrombin inhibitors; prolonged when drug effect is adequate.

Prothrombin time (PT) test: Laboratory test used to monitor the anticoagulant effect of warfarin; prolonged when drug effect
is adequate

INR: It is a laboratory test that measure the time it takes for blood to clot and compares it to an average.





• Unfractionated heparin inhibits both antithrombin 2a and Factor Xa equally.
• Low Molecular Weight heparin inhibits Factor Xa more (double) than Antithrombin 2a

v Both can cause recurrence of thrombosis (does not inhibit the fibrin bound thrombin)
• Direct thrombin inhibitors works only on the fibrin bound thrombin (no re-thrombosis)

Unfractionated Heparin Limitations:
• No predictable anticoagulant effects: inter-patient & intra-patient variability in response to a given

dosage – in hospital setting, repeated monitoring

• Low bioavailability – binds to plasma proteins, endothelium & macrophages

• Re-thrombosis – activates platelets & it does not neutralize fibrin-bound II a (usually occurs
after 1 day or less)

• Heparin Induced Thrombocytopenia (HIT): In 4% pts. On heparin Venous > Arterial thrombosis
• Latency:

• 5-10 days after 1st exposure

• Or 2-3 days after re-exposures

• Signs:

• Thrombocytopenia AND Thrombosis

• Treatment
• Heparin Disconnection
• No Packed Platelets à will cause more

• No Warfarin à will cause venous

• GIVE Direct Thrombin Inhibitors



Comparison between Unfractionated Heparin and Low Molecular Weight Heparin





Low Molecular Weight Heparin Benefits:

• — Predictability of anticoagulant response i.e. little inter-patient and intra-patient variability in

response to a given dosage. So – effective anticoagulant activity can be achieved by calculating
dosages based on body weight without the need for laboratory monitoring

• — Bioavailability: as it hardly binds to plasma proteins, endothelium &

• ¤Incidence of thrombocytopenia: as it seldom sensitive to PF4
• ¤Incidence of bleeding tendency: ¤ effect AT III & ¤ platelet interactions
• Much better tolerability:

§ Given subcutaneous
§ ¤ Frequency of administration due to longer duration of action
§ ¤ Need for regular monitoring
§ Outside hospital settings

Vitamin K Antagonists:


Precursors of factors II, VII, IX & X require carboxylation of their glutamic a. residues to allow them to
bind to phospholipid surfaces. Vitamin provides this. K as it changes from its oxidized to its reduced form.
Instantaneously, the reduced Vitamin K has to recycle back to oxidized form by Vitamin K epoxide
reductase. This enzyme is blocked by VKAs – losing the coagulation factors the ability to function.


Vitamin K Antagonists Limitations:

• Wide variation in drug response – a necessity for continuous monitoring (PT) and INR & dose

• Has narrow therapeutic window; high Plasma Protein Bound & action depends on very small
fraction of free drug. So any change in that level can be hazardous.

• Slow onset of action, so NOT in given in emergency conditions
• Has latency in its action– presents the time needed to launch new biologically inactive

coagulation factors
• Common genetic polymorphism in CYT P450 isoforms that metabolizes warfarin – adds to its

non-predictable response – liability to toxicities or under use.
• Numerous food- & drug-drug interactions – liability to toxicities or under use.
• Contraindicated in some conditions liable to develop thrombosis i.e. as in PREGNANCY – give

heparin or LMWH instead

Factors Altering Response To VKAs: Not Important
Increasing Factors:
1. Vitamin K deficiency;

a- Inadequate diet: malnutrition, dieting,….
b- Inadequate absorption: diseases of small intestine, diseases ¤ biliary secretion

2. Impaired synthesis of clotting factors;
a. In hepatocellular disorders: (hepatitis; viral, autoimmune, drug-induced, chronic
alcoholism … etc.)
b. In hepatic congestion: in congestive HF…etc)

3. Increased catabolism of clotting factors;
In hypermetabolic states: as in fever, thyrotoxicosis

Decreasing Factors:
1. Decreased plasma protein binding;
£ elimination of free drug & shortening of its t1/2. as pts with nephrotic syndrome (proteinuria)
2. Decreased catabolism of clotting factors; Hypothyroidism
3. Hereditary resistance to oral anticoagulants

VERY IMPORTANT You should know the
Drugs Modulating Response To VKAs: drugs and how they modulate VKAs

Drugs that increase INR:
1. Inhibition of Vitamin K synthesis by intestinal flora: oral antibiotics
2. Inhibition of Vitamin K absorption: liquid paraffin
3. Decrease in drug metabolism by microsomal enzyme inhibitors: chloramphenicol, &

4. Displacement of the drug from protein binding sites: phenylbutazone & salicylates
5. Co-administration of drugs that increase bleeding tendency by:

§ Inhibiting platelet function: NSAIDs
§ Inhibiting coagulation factors: heparin

Drugs that decrease INR:
1. Inhibition of drug absorption from GIT: cholystyramine, colestipol
2. Increase in synthesis of clotting factors: Vitamin K, oral contraceptives
3. Increase in drug metabolism by microsomal enzyme inducers: carbamazepine,



Case 1: An old, peptic ulcer patient, sustained on cimetidine, has been bed ridden since a month following a

major orthopedic surgery for pelvic fracture. The last week he began to complain of pain, tenderness,
warmth & swelling of his left leg. He was diagnosed as deep vein thrombosis. His treating physician
put him first on heparin that was replaced after three days by VKAs. Today he began to show
bleeding of gums.

What is the expected explanation of his finding?

VKAs toxicity due to interaction with cimetidine which is an enzyme inhibitor

Will the treating physician 1st of all, consider giving an antidote to stop bleeding (if so then state) or
will he probably ask for lab investigation (if so then state)?

No need for an antidote or blood transfusion because it is minor bleeding

Once lab findings are there, is the physician expected first to withdraw or to adjust the existing

Gum bleeding is considered as a mild bleeding, so Dose adjustment is enough.

Case 2: A young rheumatic artheritic patient has undergone valve replacement and is sustained on warfarin
therapy for the last three years. When she married, last summer, she did not want to get pregnant, so
she has taken since then, oral contraceptive pills. Her regular lab monitoring today showed a
decrease in INR this time.

What is the expected explanation of her lab result?

Since the patient is taking oral contraceptive there will be an increase in synthesis of clotting factors
reducing the efficacy of the warfarin

What will the treating physician consider doing?

a) Giving heparin on top
b) Adjusting warfarin dose
c) Stopping the OC
d) Stopping warfarin

Answer is b

Case 3: A 53 years old patient had an aortic valve replacement since 5 years and he is sustained on
warfarin. A week ago, he developed low grade fever, diarrhea and was diagnosed as having
typhoid. He was given rehydration fluid and a course of chloramphenicol. Today he is complaining
from haematuria.

Which one of the following best explains the haematuria?

a) Inhibition of Vitamin K synthesis by chloramphenicol
b) Displacement of warfarin from protein binding site by rehydration
c) Decrease in warfarin metabolism induced by chloramphenicol
d) Inhibition of Vitamin K absorption caused by the diarrhea

Answer is c




Which is the right decision to do in such a case?

a) Give a urinary antiseptic for fear of infection
b) Stop administering the regular intake of warfarin
c) Adjust the dose of warfarin after monitoring the situation.
d) Stop the course of chloramphenicol intended for typhoid therapy

Answer is c


Anticoagulants  are  mainly  used  in  treatment  of  venous  thromboembolism  while  antiplatelets  used  mainly  

in  treatment  of  arterial  thrombosis.  

• Heparin  :  inactivate  factors  12a  ,11a  ,9a,  10a  ,  thrombin,  and  has  a  variable  response  monitored  by  PTT  or  
A PPT.  

• – If  there  is  toxicity  à  Antidote;  Protamine  Sulphate  IV–  1mg  /  100  units  UFH  +  Fresh  blood  
• – It  does  not  inhibit  the  fibrin  bound  thrombin  that’s  why  it  has  an  incidence  of  causing  re  thrombosis.  

– It  also  causes    Heparin Induced  Thrombocytopenia  (HIT); latency  5-­‐10    dys.  after  1 exposure  or  2-­‐

3  dys  After  re-­‐exposures  if  this  occurs:  Heparin  withdrawn  and  give  DTIs  .No  packed  
platelets  or


• Lower  molecular  weight  heparin  works  more  on  inhibiting  activated  factor  10.It  has  —  Predictability  of  
anticoagulant  response  ,  —  Bioavailability  ,  ¤Incidence  of  thrombocytopenia  ,¤Incidence  of  bleeding  
tendency  and  better  tolerability  than  UFH  

• Direct  factor  10a  inhibitors  affects  factor10a  ,  monitored  by  APTT  or  PPT  (they  are  the  same)  

• ·Direct  thrombin  inhibitors  affect  fibrin  bound  thrombin  ,  monitored  by  PTT.  It  is  the  only  drug  that  doesn’t  
cause  re  thrombosis.  

• Vitamin  K  Antagonists   (warfarin)  affects  on   the   factors   that  depend  on  vit   k  which  are   7a   ,   9  a   ,   10  a   ,  
t hrombin  by  inhibiting  Vit  K  epoxide  reductase.  Monitored  by  PT  due  to  its  variable  response.  

• Contraindicated  in  pregnancy  –  give  heparin  or  LMWH  instead  

• Slow  onset  of  action,  so  not  in  given  in  emergency  conditions  

– Metabolize  in  the  liver  by  CYT  P450  à  Numerous  food-­‐  &  drug-­‐drug  interactions.








Thanks to Pharmacology Team 430 For the introduction & summar



1- which one of the following is considered an advantage of low molecular weight heparin (LMWH)over unfractionated heparin?

a) has  no  sepecific  antidote  if  bleeding  occurs    

b) is  only  given  in  a  hospital  setting.    

c) has  a  predictable  anticoagulant.    

d) increase  similar  activation  to  antithrombine-­‐111and  Xa.    

Answer  :  C    

2- five years ago, a 53 year old patient had an aortic valve replacement and was sustained on warfarin. Two weeks ago, his lipid
profile showed hypertriglyceridemia for which he received clofibrate. Today he began to develop bleeding from the gums. Which
one of the following decisions should his treating physician consider?

a) stop  the  regular  warfarin  intake  that  he  has  been  receiving  for  years.    

b) Administer  protamine  sulphate  intravenously  as  antidote.    

c) stopthelipidloweringagentthatwasgivenrecently.    

d) Ask  for  an  INR  and  adjust  the  dose  of  warfarin  accordingly.  

     Answer  :  D  

3- A patient on oral anticoagulant therapy for treatment of deep vein thrombosis, developed severe gastroenteritis and was put on
rehydration therapy and a course of oral cephalosporin. Today, on lab checkup, the INR is high. Which one of the following
reasons is the likely cause of this lab finding?

a) inhibition  of  vitamin  K  synthesis  by  the  suppressed  intestinal  flora.    

b) displacemint  of  the  anticoagulant  from  its  protein  binding  site  by  the  current  treatment.    

c) inhibition  of  absorption  of  vitamin  K  by  cephalosporin.    

d) increased  bleeding  tendency  by  activating  the  platelets  by  cephalosporin.      

Answer  :  A    

4- A patient previously on heparin developed thrombocytopenia and thrombosis on second exposure to the drug. He was
diagnosed as heparin induced thrombocytopenia. Which one of the following drugs can best treat such condition?

a) vitamin  K  antagonists.    

b) directthrombininhibitors.    

c) low  molecular  weight  heparin.    

d) anti-­‐factor  X  inhibitors.  


Answer  :  B