about platelet plug formation Fibrinolytic and anti platelet agents pathology, classes of drugs with mechanism of action , adverse effects uses and novel drugs..

1. FIBRINOLYTICS AND
ANTI PLATELET AGENTS…
FROM: Mr. PRITHVI. L TO: Dr. S.N. MANJULA
1ST M PHARM PROFESSOR ,HOD
DEPT OF PHARMACOLOGY DEPT OF PHARMACOLOGY
JSSCP, MYSORE JSSCP, MYSORE

3. TISSUE INJURY
CONTRACTION OF BLOOD VESSEL
ADHESION AND ACTIVATION OF
PLATELETS TO FORM PLUG
ANTI-PLATELET DRUGS
FORMATION OF FIBRIN
FORMATION OF BLOOD CLOTS
FIBRINOLYTIC DRUGS
DISSOLUTION OF BLOOD CLOT

4. PLATELET PLUG FORMATION:
Initially, platelets contact
and stick to parts of a
damaged blood vessel, such
as collagen fibers of the
connective tissue
underlying the damaged
endothelial cells. This
process is called platelet
adhesion.

5. PLATELET PLUG FORMATION:
• Due to adhesion, the platelets become
activated, and their characteristics change
dramatically. They extend many projections that
enable them to contact and interact with one
another, and they begin to liberate the contents of
their vesicles. This phase is called the platelet
release reaction.
• Liberated ADP and thromboxane A2 play a
major role by activating nearby platelets.
Serotonin and thromboxane A2 function as
vasoconstrictors, causing and sustaining
contraction of vascular smooth muscle, which
decreases blood flow through the injured vessel.

6. PLATELET PLUG FORMATION:
The release of ADP makes other
platelets in the area sticky, and
the stickiness of the newly
recruited and activated platelets
causes them to adhere to the
originally activated platelets.
This gathering of platelets is called
platelet aggregation. Eventually,
the accumulation and attachment of
large numbers of platelets form a
mass called a platelet plug.

7. ANTI-PLATELET DRUGS:
• also called as Platelet aggregation inhibitors ,
decrease the formation of a platelet-rich clot or
decrease the action of chemical signals that promote
platelet aggregation.
• The platelet aggregation inhibitors inhibit
cyclooxygenase1
(COX-1) or block Glycoprotein IIb/IIIa or ADP receptors,
thereby interfering with the signals that promote
platelet aggregation.

8. Classification of anti platelet drugs:

9. GENERAL MECHANISM:
von Willebrand
factor (VWF) is
a blood glycoprotein involved
in hemostasis
The enzymes that produce
prostaglandins are called
cyclooxygenase (COX). There are
two types of COX enzymes, COX-1
and COX-2. Both enzymes produce
prostaglandins that promote
inflammation, pain, and fever;
however, only COX-1 produces
prostaglandins that activate platelets
and protect the stomach and
intestinal lining.
glycoprotein
IIb/IIIa (GPIIb/IIIa,
also known
as integrin αIIbβ3) is
an integrin complex
found on platelets.

10. ASPIRIN:
• Aspirin, also known as acetylsalicylic acid, Aspirin is a
nonsteroidal anti-inflammatory drug (NSAID).
• Used as analgesic (pain killer), antipyretic (relieve
fever), anti inflammatory (decrease inflammation) and
as prophylaxis against ischemic event like heart attack
and ischemic stroke.
• There is book about 300 pages only about Aspirin
story, the book name is Aspirin by Diarmuid Jeffreys,
he described Aspirin as “the most remarkable drug the
world has ever seen,”, “one of the most endurably
successful commercial products of all time.”

11. HISTORY:
• Actually people used it from natural
resource for thousand years
• 400BC Greek great doctor
Hippocrates give women willow leaf
tea to relieve the labor (childbirth)
pain. he also advice his patients to
eat the leaves of Willow tree for
fever and pain , the active
component extracted from Willow
tree in Italy and named Salicin.
Aspirin. The title was named “a” from acetyl, and
“spir”
from the spirea plant, meadow sweet ( also known
as Spiraea ulmaria), the source of salicin.

12. GENERAL MOA OF ASPIRIN:
• Aspirin cut the chain of reaction form
early beginning, it inhibit cox1 and cox2
• Cox1 give thromboxane, it cause
vasoconstriction and enhance platelet
aggregation which boost clot formation
in your body, that’s why Aspirin is used
as prophylaxis to protect the heart
attack in many patient. it inhibit
platelet from binding to each other
irreversibly.
• Cox2 gave prostaglandin and interleukin
which is inflammatory mediator that
cause pain , fever and inflamation at
the site of release.
Aceclofenac is an oral non-steroidal anti-
inflammatory drug (NSAID) with marked anti-
inflammatory and analgesic properties Aceclofenac
potently inhibits the cyclo-oxygenase enzyme
(COX) that is involved in the synthesis of
prostaglandins, which are inflammatory mediators
that cause pain, swelling, inflammation, and fever.
Through COX-2 inhibition, aceclofenac
downregulates the production of various
inflammatory mediators including prostaglandin E2
(PGE2), IL-1β, and TNF from the arachidonic acid
(AA) pathway.

13. ASPIRIN :
Mechanism of action:
1) Stimulation of platelets by thrombin, collagen, and ADP
results in activation of platelet membrane phospholipases that
liberate arachidonic acid from membrane phospholipids.
2) Arachidonic acid is first converted to prostaglandin H2 by
COX-1 . Prostaglandin H2 is further metabolized to thromboxane
A2, which is released into plasma.
3)Thromboxane A2 promotes the aggregation process that is
essential for the rapid formation of a hemostatic plug.
4) Aspirin inhibits thromboxane A2 synthesis on the active site
of COX-1,
5) thereby irreversibly inactivating the enzyme . This shifts the
balance of chemical mediators to favor the antiaggregatory
effects of prostacyclin, thereby preventing platelet aggregation.

14. ASPIRIN:
• The inhibitory effect of aspirin is rapid, and it is induced
suppression of thromboxane A2 and the resulting suppression of
platelet aggregation last for the life of the platelet, which is
approximately 7 to 10 days.
• Repeated administration of aspirin has a cumulative effect on the
function of platelets.
• Aspirin is the only antiplatelet agent that irreversibly inhibits
platelet function.
• Aspirin is non-selective and irreversibly inhibits both forms (but is
weakly more selective for COX-1 .

15. Therapeutic uses:
• Aspirin is used in the prophylactic treatment of cerebral ischemia, to reduce
the incidence of recurrent MI, cerebral angina.
*used to reduce fever and relieve pain from conditions such as muscle aches,
toothaches,headache.
• Used to reduce swelling conditions such as arthritis.
• For prevention of stroke.
• to decrease mortality in the setting of primary and secondary prevention of MI.
• Complete inactivation of platelets occurs with 75 mg of aspirin given daily.
• The recommended dose of aspirin ranges from 50 to 325 mg daily.
• Pharmacokinetics: When given orally, aspirin is absorbed by passive
diffusion and quickly hydrolyzed to salicylic acid in the liver. Salicylic
acid is further metabolized in the liver, and some is excreted unchanged in the
urine.
The half-life of aspirin ranges from 15 to 20 minutes and for salicylic
acid is 3 to 12 hours

16. SIDE EFFECTS:
• Higher doses of aspirin increase drug-related toxicities as well as the
probability that aspirin may also inhibit prostacyclin production.
• Bleeding time is prolonged by aspirin treatment, causing
complications that include an increased incidence of stroke and
gastrointestinal (GI) bleeding, especially at higher doses of the drug.
• It also can cause GASTRITIS and worsening peptic ulcer because it
inhibits prostaglandin.
• Aspirin like any drug can cause allergy further more it can cause
harmful bronchospasm (constriction of alveli) to Asthmatic patient
• It is well known that ASA decrease the kidney ability to excrete uric
acid so it is contraindicated to use in kidney injury .

17. Ticlopidine, clopidogrel, prasugrel, and
ticagrelor :
Mechanism of action:
• These drugs 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.
• Ticagrelor binds to the P2Y12 ADP receptor in a reversible
manner . The other agents bind irreversibly.
• The maximum inhibition of platelet aggregation is achieved in
1 to 3 hours with ticagrelor,
2 to 4 hours with prasugrel,
3 to 4 days with ticlopidine,
and 3 to 5 days with clopidogrel.
When treatment is suspended, the platelet system requires time to recover.

18. Therapeutic uses:
• Clopidogrel is approved for prevention of atherosclerotic events in
patients with a recent MI or stroke and in those with established
peripheral arterial disease.
• It is also approved for prophylaxis of thrombotic events in acute
coronary syndromes (unstable angina ).
• clopidogrel is used to prevent thrombotic events associated with
percutaneous coronary intervention (PCI) with or without coronary
stenting.
• Ticlopidine is similar in structure to clopidogrel.
• It is indicated for the prevention of transient ischemic attacks (TIA)
and strokes in patients with a prior cerebral thrombotic event.

19. Contraindications:
• due to life-threatening hematologic adverse reactions, ticlopidine
is generally reserved for patients who are intolerant to other
therapies.
• Prasugrel is approved to decrease thrombotic cardiovascular
events in patients with acute coronary syndromes (unstable
angina, MI)
• Ticagrelor is approved for the patients with unstable angina and
acute MI.

20. Pharmacokinetics:
• These agents require doses for quicker antiplatelet effect. After
oral ingestion, the drugs are extensively bound to plasma proteins.
• Elimination of the drugs and metabolites occurs by both the renal and
fecal routes.
• Clopidogrel is a prodrug, and its therapeutic efficacy relies
entirely on its active metabolite, it is
recommended that other antiplatelet agents (prasugrel or ticagrelor) be
prescribed for these patients. omeprazole and esomeprazole, should not
be administered
concurrently with clopidogrel.

21. Adverse effects:
• These agents can cause prolonged bleeding for which there is no
antidote. Ticlopidine is associated with severe hematologic
reactions that limit its use, such as agranulocytosis,( lowered wbc)
and aplastic anemia.(its very rare condition in which body stops
producing new cells)
• Prasugrel and ticagrelor causes bleeding , Rapid weight gain ,
black stools,dizziness.
• Additionally, ticagrelor causes diminished effectiveness with
aspirin doses above 100 mg.

22. Abciximab, eptifibatide, and tirofiban:
• Mechanism of action:
• The GP IIb/IIIa receptor plays a key role in stimulating platelet
aggregation.
• abciximab inhibits the GP IIb/IIIa receptor complex. By binding to
GP IIb/IIIa
abciximab blocks the binding of fibrinogen consequently, aggregation
does not occur .
Eptifibatide and tirofiban act similarly to abciximab, by blocking the
GP IIb/IIIa receptor.
Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa at the site that
interacts with the arginine–glycine– aspartic acid sequence of fibrinogen.
Tirofiban is not a peptide, but it blocks the same site as eptifibatide.

23. Therapeutic uses and pharmacokinetics:
• Therapeutic use:
• These agents are given intravenously, along with heparin and aspirin, for the prevention of
cardiac ischemic complications.
• Abciximab is also approved for patients with unstable angina.
• Pharmacokinetics:
• Abciximab is given by IV bolus, followed by IV infusion
• Plasma t1/2 30 minutes
• Dose : 0.25-mg/kg bolus followed by 0.125 g/kg/min for 12 hours or longer.
• The metabolism of abciximab is unknown.
• Eptifibatide and its metabolites are excreted by the kidney.
• Tirofiban is excreted largely unchanged by the kidney and in the feces.
• Adverse effects:
• The major adverse effect of these agents is bleeding, especially if used with anticoagulants.

24. Dipyridamole:
• Dipyridamole is a coronary vasodilator, increases intracellular levels of
cAMP by inhibiting cyclic nucleotide phosphodiesterase, thereby
resulting in
decreased thromboxane A2 synthesis.
• The drug may potentiate the effect of prostacyclin to antagonize
platelet
stickiness and, therefore, decrease platelet adhesion to thrombogenic
surfaces .
• Dipyridamole is used for stroke prevention and is usually given in
combination with aspirin.
• Dipyridamole has variable bioavailability following oral administration.
• It is highly protein bound. The drug is excreted mainly in the feces.
• Patients with unstable angina should not use dipyridamole because of
its vasodilating
properties, which may ischemia .
Dipyridamole commonly causes headache and can lead to orthostatic
hypotension (especially if administered IV).

25. Cilostazol:
• Cilostazol is an oral antiplatelet agent
• it has vasodilating activity.
• Cilostazol and its active metabolites inhibit phosphodiesterase type III, which
prevents the degradation of cAMP, thereby increasing levels of cAMP in platelets
and vascular tissues. The increase in cAMP levels in platelets and the vasculature
prevents platelet aggregation and promotes vasodilation of blood vessels.
• Cilostazol alters the lipid profile, causing an increase in high-density lipoprotein cholesterol.
Cilostazol is extensively metabolized in the liver by the 2C19, and 1A2
isoenzymes.
The primary route of elimination is via the kidney.
Headache and GI side effects (diarrhea, abnormal stools, dyspepsia, and abdominal pain) are
the most common adverse effects observed with cilostazol.
• It is contraindicated in patients with heart failure.

28. FIBRINOLYSIS:
• BLOOD COAGULATION : Coagulation, also
known as clotting, is the process by which
blood changes from a liquid to a gel, forming a
blood clot. It potentially results in hemostasis,
the cessation of blood loss from a damaged
vessel, followed by repair.
• Platelets immediately form a plug at the
site of injury; this is called primary hemostasis.
Secondary hemostasis occurs simultaneously
additional coagulation (clotting) factors beyond
factor VII respond in a cascade to
form fibrin strands, which strengthen
the platelet plug.

29. • Formation of fibrin : factor Xa converts
prothrombin (factor II ) to thrombin
(factor II a).
• Thrombin plays a key role in coagulation,
because it is responsible
• for generation of fibrin, which forms the
mesh-like matrix of the
blood clot.
• If thrombin is not formed coagulation is
inhibited.

30. FIBRINOLYTICS:
• Used to lyse the thrombi / clot to
recanalize the occluded blood vessel (mainly
coronary artery)
• Work by activating the Fibrinolytic system

31. Classification:
• STREPTOKINASE
• UROKINASE
• RETEPLASE (analogue of
alteplase)
• ALTEPLASE (t- PA )
• TENECTEPLASE

32. Streptokinase:
Streptokinase (Stk) Obtained from β haemolytic Streptococci group C,
it is the first fibrinolytic drug to be used clinically, but is not employed now except
for considerations of cost.
Streptokinase is inactive as such; combines with circulating plasminogen molecules
to form an activator complex which then causes limited proteolysis of other
plasminogen molecules to generate the active enzyme plasmin.
* Stk is non-fibrin specific, i.e. activates both circulating as well as fibrin bound
plasminogen. Therefore, it depletes circulating fibrinogen and predisposes to
bleeding. Compared to newer more fibrin-specific tissue plasminogen activators.

33. Mechanism of action:
It is the proteolytic enzyme from haemolytic
streptococcus.
* It acts indirectly, inhibits the conversion of
plasminogen to plasmin " degradation both of fibrin
and fibrinogen " systemic activation of fibrinolysis and
dissolving of thrombus.
*Plasma half-life is 30-80 min; is administered by IV
infusion (intracoronary infusion in myocardial
infarction).
* It is more active than fibrinolysin, does not cause
arrhythmia
*Destroyed by circulating antistreptococcal Antibodies

34. Uses:
• Streptokinase is used to dissolve blood clots that have formed in the
blood vessels.
• It is used immediately after symptoms of a heart attack occur to
improve patient survival.
• This may also be used to treat blood clots in the lungs (pulmonary
embolism) and in the legs (deep venous thrombosis) .
• Contraindications :
• Recent trauma, surgery, abortion, stroke, severe hypertension, peptic
ulcer,
• bleeding disorders
• Adverse effects:
• Bleeding, hypotension,allergic reactions,Fever due to activation of
plasminogen.

35. Urokinase:
• • Enzyme isolated from human urine, now prepared from cultured human kidney cells.
• Direct plasminogen activator
• Therapeutic urokinase is isolated from cultures of human kidney cells and has low
antigenicity.
•
t ½ of 10 to 15 min
• Non antigenic, Non allergenic
• Fever can occur but hypotension rare
• Indicated in patients in whom streptokinase has been for an earlier episode
Mechanism of action
Urokinase acts on the endogenous fibrinolytic system. It cleaves the Arg-Val bond in plasminogen to
produce active plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins.

36. Alteplase:
• Alteplase(formerly known as tissue plasminogen activator or t PA) is a
serine protease originally derived from cultured human melanoma cells
It is now obtained as a product of recombinant DNA technology.
recombinant tissue Plasminogen Activator(rt-PA)
• Selectively activates plasminogen bound to fibrin
• Non antigenic ,not destroyed by antibodies
• Rapid acting, more potent
• Superior in dissolving old clots
• Short half life 4-8 min therefore, 10% of the total dose is injected
intravenously as a bolus and the remaining drug is administered over 60
minutes
• Nausea, mild hypotension, fever may occur
• it is Expensive

37. Reteplase and Tenecteplase :
• Reteplase is a genetically engineered, smaller derivative of
recombinant tPA . Longer half life 15 -20 min, but less specific for
fibrin bound plasminogen
• Tenecteplase is another recombinant t PA with a longer half-life
and greater binding affinity for fibrin than alteplase.
Genetically engineered mutant form of alteplase
Reteplase and tenecteplase are approved only for use in acute MI
Both reteplase and tenecteplase have longer half-lives and, therefore,
may be administered as an intravenous bolus.

38. ANTIFIBRINOLYTIC DRUGS:
• These are drugs which blocks the conversion of
plasminogen to plasmin & thus inhibit fibrinolytic
activity.
Examples:-
• Epsilon amino-caproic acid (EACA)
• Tranexamic acid.

39. Epsilon amino-caproic acid (EACA) :
• Inhibits plasminogen to plasmin conversion, hence prevents clot
lysis
• It is a specific antidote for fibrinolytic agents
• It has adjunctive value for controlling bleeding due to tooth
extraction, prostatectomy(a surgical operation to remove part of
prostate gland), trauma, etc.

40. Tranexamic acid :
• It is 7 times more potent than EACA, more commonly used.
• Oral, I.v, topical administration
• tranexamic acid mouthwash is used to reduce bleeding
postoperatively in hemophiliacs on anticoagulants.

41. Novel drugs:

42. Novel drugs:

43. APTT: (activated partial thromboplastin
time)
• aPTT (activated partial thromboplastin time) refers to a test of
blood coagulation used to evaluate the clotting factors of the
intrinsic pathway.
• The main purpose of aPTT is to screen bleeding tendencies and to
monitor heparin therapy.
• Blood clotting is a multi-protein cascade governed by proteins
called clotting factors.
• The deficiencies of the coagulation factors such as Factors V, VIII,
IX, X, XI, and XII increases the aPTT.
• Decalcified blood is used for the aPTT test
• The normal aPTT value is 35 seconds.

44. PTT (partial thromboplastin time):
• The time taken for the formation of the clot, which is measured in
seconds, is known as partial thromboplastin time.
• This is used for the diagnosis of bleeding problems.
• During PTT, the integrity of the intrinsic system is measured by
means of factors VIII, IX, XI, and XII. PTT also evaluates the
common pathway.
• PTT is less sensitive to heparin.
• PTT does not use an activator.

46. REFERENCES:
PHARMACOLOGY 6TH EDITION : LIPPINCOTT ILLUSTRATED
REVIEWS
WEBSITE : PHARMACOLOGY CORNER
TORATORA:PRINCIPLES OF ANATOMY AND PHYSIOLOGY

47. THANK YOU…