Drugs for coagulation, Anti platelets, Fibrinolytics & Antifibrinolytics

1. DRUGS
FOR
COAGULATION

2. Hemostasis: Prevention of blood loss
from damaged blood vessels
Dynamic process of maintaining
⇒ Fluidity of the blood,
⇒ Repairing vascular injury
⇒ Limiting blood loss
Mechanism:
i) Vascular constriction
ii) Formation of platelet plug
iii) Formation of blood clot
iv) Growth of fibrous tissue into
blood clot

3. Coagulants

4. Coagulants contd……
Intrinsic pathway Extrinsic pathway
XII XIIa VIIa VII
XI XIa
Ca++
IX IXa Ca++ III
Ca++ Pl. Ph Phospholipid
X Xa X
V Pl. Ph
Ca++
Prothrombin (II) Thrombin (IIa)
Fibrinogen Fibrin

5. Coagulants contd……
Coagulants:
⇒ Agents that promote coagulation
⇒ Indicated in haemorrhagic states
⇒ Fresh blood/ plasma act
immediately
Hemostasis: Hemostasis is the cessation of blood loss
from a damaged vessel. Platelets first adhere to
macromolecules in the subendothelial regions of the
injured blood vessel; they then aggregate to form the
primary hemostatic plug.

6. Coagulants contd……
Vitamin K:
Types:
 K1 (Plant source -cabbage, spinach): Phytonadione
 K2 (Produced by bacteria): Menaquinones
 K3 (Synthetic)
Fat soluble – Menadione
Water soluble –Menadione sodium bisulfite,
Menadione sodium diphosphate
Vit. K2 produced by bacteria in GIT supplies almost
50% of requirements

7. Coagulants contd……
Vitamin K Contd…….
Mechanism of Action:
 Acts as a cofactor in last stage in synthesis
of coagulation protein – Prothrombin,
factors VII, IX, X
Daily requirement:
50 – 100 mcg/day (Adult) but only
3-10 mcg/day is required externally

8. Coagulants contd……
Vitamin K Contd…….
Uses: In prophylaxis & t/t of bleeding due to
deficiency of clotting factors:
a) Dietary deficiency of vit K
b) Prolonged antimicrobial therapy
c) Newborns
 Low level of prothrombin & other factors
 Defect is exaggerated in the premature infant
Vit K1 given soon after birth or to mother 4-12
hrs before delivery
d) Obstructive jaundice or malabsorption
syndromes (ulcerative colitis, dysentery,
extensive bowel reaction)
oral (along with bile salt)/injection

9. Coagulants contd……
Vitamin K Contd…….
e) Liver disease (Cirrhosis, viral hepatitis)
Associated bleeding responds poorly to vit K
f) Overdose of oral anticoagulants
Adverse reactions:
 Rapid i.v injection cause Flushing,
breathlessness, fall in BP, constriction in
chest
 Menadione (K3) & its water soluble
derivatives cause haemolysis (dose
dependent) especially in G-6-PD deficit
patient & Neonates

10. Coagulants contd……
ETHAMSYLATE:
MOA: Reduce capillary bleeding when
platelets are adequate
⇒ Haemostatic action
⇒ Corrects abnormal platelet function
⇒ Improve capillary wall stability
Uses:
prevention & treatment of capillary bleeding
after abortion, in menorrhagia, Epistaxis,
tooth extraction etc
Dose: 250-500mg TDS oral/iv
Adverse Effects:
Nausea, Rash, headache, Fall in BP (esp. i.v.)

11. ANTIPLATELET DRUGS
 Inhibitors ofTXA2 Formation
Low Dose Aspirin (75-150mg)
 ADP receptor antagonist
Ticlopidine, Clopidogrel,Prasugrel
 Glycoprotein IIb/IIIa receptor antagonist
Abciximab, Eptifibatide, Tirofiban
 Phosphodiesterase inhibitors
Dipyridamole

12. Low Dose Aspirin
 Inhibits platelet aggregation
 MOA:Aspirin irreversibly acetylate COX
enzyme in platelets & inhibits the synthesis of
TXA2 from arachidonic acid
 Platelet has no nuclei so can’t synthsize fresh
enzyme (COX)
TXA2 formation
Platelet aggregation

14.  In low dose (75-150mg/day) it only inhibits
TXA2 not PGI2
 PGI2:Vasodilator, syn thesized by endothelial
cell, strong inhibitor of platelet aggregation
 WHY LOW DOSEASPIRIN ?
 In high dose it also inhibits PGI2
 High dose: more adverse effects & toxicity

15.  Ticlopidine, clopidogrel, and prasugrel (Oral)
 Closely related thienopyridines that also block
platelet aggregation, but by a mechanism different
from that of aspirin.
 MOA: These drugs irreversibly inhibit the binding
of ADP to its receptors on platelets and, thereby,
inhibit the activation of the GP IIb/IIIa receptors
required for platelets to bind to fibrinogen and to
each other.
 Abciximab, Eptifibatide, Tirofiban (Injectables)
 MOA: It inhibits the activation of the GP IIb/IIIa
receptors required for platelets aggregation.
 Aspirin and heparin are generally given
concurrently to improve antiplatelet action.

16. DIPYRIDAMOLE
 MOA: It inhibits phosphodiesterase as well as
blocks uptake of adenosine to increase cAMP
which in turn potentiates PGI2 and interferes
with platelet aggregation.
 Dipyridamole alone has little clinically
significant effect, but improves the response to
warfarin.
 Dipyridamole has also been used to enhance
the antiplatelet action of aspirin.
 Dose: 150–300 mg/day.

17. Indications:
 Coronary artery disease
 Acute coronary syndromes
 Unstable angina
 STEMI & NSTEMI
 Cerebrovascular disease
 Prosthetic heart valves and arteriovenous shunts
 Venous thromboembolism
 Peripheral vascular disease
A/E: Bleeding, neutropenia, thrombocytopenia,
haemolysis and jaundice.

18. FIBRINOLYTICS (THROMBOLYTICS)
 These are drugs used to lyse thrombi/clot to recanalize
occluded blood vessels (mainly coronary artery).
 They are therapeutic rather than prophylactic and work
by activating the natural fibrinolytic system.
 In general, venous thrombi are lysed more easily by
fibrinolytics than arterial, and recent thrombi respond
better.
 They have little effect on thrombi > 3 days old. The
clinically important fibrinolytics are:
Streptokinase Alteplase (rt-PA)
Urokinase Reteplase
Tenecteplase

20. Plasmin is generated from plasminogen by tissue plasminogen
activator (t-PA), which is produced primarily by vascular
endothelium.
Plasmin is the enzyme responsible for digesting fibrin & lysing
thrombi/clot. It is a serine protease.

22.  STREPTOKINASE is the first fibrinolytic drug to be
used clinically.
 It is obtained from Streptococcus haemolyticus.
 MOA: It binds with plasminogen that undergoes
proteolysis to form plasminogen activator complex
& forms active enzyme plasmin.
 Plasmin is responsible for lysis of thrombi/clot.
 INDICATIONS & DOSE:
 For MI: 7.5–15 lac IU infused i.v. over 1 hr.
 For deep vein thrombosis and pulmonary embolism:
2.5 lac IU loading dose over ½–1 hr, followed by 1
lac IU/hr for 24 hr. CHEAPER!
 A/E: Nausea,Vomiting,Tachycardia, Fever, etc

24.  UROKINASE
 It is an enzyme isolated from human urine; but
commercially prepared from cultured human kidney cells.
 MOA: It activates plasminogen directly and has a plasma
t½ of 10–15 min.
 A/E: Fever occurs during treatment, but hypotension and
allergic phenomena are rare.
 Urokinase is Indicated in patients in whom streptokinase
has been given for an earlier episode.
 INDICATION & DOSE:
 For MI: 2.5 lac IU i.v. over 10 min followed by 5 lac IU over
next 60 min (stop in between if full recanalization occurs)
or 6000 IU/min for upto 2 hr.
 For venous thrombosis and pulmonary embolism: 4400 IU/kg
over 10 min i.v. followed by 4400 IU/kg/hr for 12 hr.

25.  ALTEPLASE (recombinant tissue plasminogen activator)
(rt-PA) Produced by recombinant DNA technology
from human tissue culture, it is moderately specific for
fibrin-bound plasminogen, so that circulating
fibrinogen is lowered only by ~ 50%.
 The plasma t½ is 4–8 min. It needs to be given by slow
i.v. infusion and often requires heparin
coadministration.
 A/E: Nausea, mild hypotension and fever, EXPENSIVE!
 Indication & Dose
 For MI: (accelerated regimen) 15 mg i.v. bolus injection
followed by 50 mg over 30 min, then 35 mg over the
next 1 hr.
 (total 90 min).
 For pulmonary embolism: 100 mg i.v. infused over 2 hr.
 For ischaemic stroke: 0.9 mg/kg by i.v. infusion over 60
min, with 10% of the dose injected in the first minute.

26.  TENECTEPLASE is genetically engineered t-PA
that has higher fibrin selectivity, slower plasma
clearance (longer duration of action) and
resistance to inhibition by PAI-1.
 It is the only fibrinolytic agent that can be
injected i.v. as a single bolus dose over 10 sec,
while alteplase requires 90 min infusion.
 Useful for ST segment elevation myocardial
infarction (STEMI)
 INDICATION & DOSE:
(Similar to Alteplase) 0.5 mg/kg single i.v. bolus
injection.
 ELAXIM 30 mg, 50 mg per vial inj.
 EXPENSIVE!

27. Coagulation and Fibrinolysis
Fibrinolysis
Fibrin
Coagulation Factors
Fibrinogen
Plasmin
Plasminogen
Tissue Plasminogen
Activator

28. ANTIFIBRINOLYTICS
 These are drugs which inhibit plasminogen
activation and dissolution of clot, and are used
to check fibrinolysis associated bleeding.
 Antifibrinolytics are useful in a number of
bleeding disorders.
 Epsilon amino-caproic acid (EACA)
 Tranexamic acid
 Aprotinin

31. EPSILON AMINO-CAPROIC ACID (EACA)
 MOA: It combines with the lysine binding sites of
plasminogen and plasmin so that the plasmin is not
able to bind to fibrin and lyse it.
 It is a specific antidote for fibrinolytic agents and has
been used in many hyperplasminaemic states
associated with excessive intravascular fibrinolysis
resulting in bleeding
 Indication & Dose:
 Hemophilia, Hemorrhage; Initial priming dose is 5 g
oral/i.v., followed by 1 g hourly till bleeding stops
(max. 30 g in 24 hrs).
 A/E: Rapid i.v. injection results in hypotension,
bradycardia and may be arrhythmias.
 Contraindication: It should be used cautiously when
renal function is impaired.

32. TRANEXAMIC ACID
MOA: It also binds to the lysine binding site on plasminogen
and prevents its combination with fibrin leading to fibrinolysis.
 It is 7 times more potent than EACA, and is preferred for
prevention/control of excessive bleeding due to:
 Fibrinolytic drugs
 Cardio-pulmonary bypass surgery
 Tonsillectomy, prostatic surgery, tooth extraction in
haemophiliacs.
 Menorrhagia, especially due to IUCD.
 Recurrent epistaxis, hyphema due to ocular trauma, peptic
ulcer.
 Dose: 10–15 mg/kg 2–3 times a day or 1–1.5 gTDS oral, 0.5–1
gTDS by slow i.v. infusion.
 A/E: Main side effects are nausea and diarrhoea.
 Thromboembolic events, disturbed colour vision and allergic
reactions are infrequent.Thrombophlebitis of injected vein
can occur.