This will discuss Pharmacology of antiplatelets, thrombolytics and hemostats along with their indications and adverse effects.

1. MRK 1
Autacoids
• Angiotensin
• Kinins
PATKI
CARDIO PHARMACOLOGY

2. MRK 2
Antiplatelet drugs

3. MRK 3
What happens when the vessel is damaged?
Vasospasm (immediate response)
Platelet adhesion
Platelet aggregation
Viscous metamorphosis (gelatinous mass)
PLATELET PLUG
Fibrin reinforcement (activation of coagulation)

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5. MRK 5

6. MRK 6
Antiplatelet
A clot that adheres to a vessel wall – Thrombus
An intravascular clot that floats in the blood-
Embolus
Both thrombus and emboli – occlude blood
vessels and deprive tissues of oxygen and
nutrients
Consequences of thrombosis ??
Artery  Ischemia of supplied organ.
Vein  edema of the organ drained and embolism.

7. MRK 7
 Platelets – initial haemostatic plug- vascular
injury
 Participate – pathological thromboses  MI,
Stroke & PVD
Antiplatelet drugs

8. MRK 8
Antiplatelet
Arterial thrombosis usually consists of a platelet-
rich clot (activation and aggregation of platelets)
Venous thrombosis typically involves a clot that
is rich in fibrin with fewer platelets
The outer membrane of the platelet contain
variety of receptors that respond to signals –
promote or inhibit P. aggregation

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12. MRK
Injured endothelium / Ruptured atherosclerotic plaque
Adhesion of platelets to thrombogenic surface & exposure of collagen and
von Willebrand factor activates platelets by binding to GP Ia and Ib
ACTIVATION OF PLATELETS triggers degranulation and release of
TXA2
Modify GP IIb/IIIa so it is able to bind fibrinogen and cross link platelets
Linkage of adjacent platelets by fibrinogen – GPIIb/IIIa
AGGREGATION OF PLATELETS
ADP
COX
TICLOPIDINE
CLOPIDOGREL
ABCIXIMAB
EPTIFIBATIDE
TIROFIBAN
Inhibit binding of
GPIIb/IIIa to
fibrinogen
EPOPROSTENOL
ASPIRIN-
-
- -
-
5HT

13. MRK
Antiplatelet
Damaged endothelial cells can’t synthesize enough PGI2 →
Intracellular cAMP ↓ → P.aggregation
Drug which inhibits phophodiasterase →  cAMP can inhibit
P.aggregation – Dipyridamole, cilostazole
Drug which inhibits ADP binding to its receptors → P.aggregation
Eg. Clopidogrel and Ticlopidine (A/E-N,V,D, neutropenia,thrombocytopenia,jaundice)
Prasugrel (Θ P2Y12 receptor)

14. MRK
Antiplatelet
Drug which irreversibly inhibits platelet COX-1, to preventTXA2
production → P.aggregation - Aspirin, Terutroban(anti-atherosclerotic also)
Drug which blocks GP IIb/IIIa R and prevents fibrinogen from cross
linking activated Plts → inhibit thrombus growth
Abciximab, Eptifibatide, Tirofiban

15. MRK
Dypiridamole
Dypiridamole 25, 75, 100mg tab
 Coronary vasodilator -prophylactically to treat angina pectoris
 It is usually given in combination with aspirin
 It is ineffective when used alone
 It ↑ intracellular levels of cAMP by inhibiting phosphodiesterase
resulting in ↓TXA2 synthesis
Potentiate the effect of PGI2 – inhibit P. aggregation
 In combination with warfarin – effective for inhibiting
embolization from prosthetic heart valves

16. MRK
Aspirin
Platelets – major COX product is TXA2
– platelet aggregation & vasoconstriction.
Aspirin – Ecosprin75, 150mg tab
 Irreversibly inhibits COX
 160 mg/day complete inactivation of platelet COX
 Antithrombotic effect dose  160-320 mg/day
 At low doses TXA2 formation selectively suppressed
 Higher doses > 900mg/d may ↓ both TXA2 & PGI2 production
 Other NSAID’s –short lasting inhibition of P function

17. MRK
Aspirin irreversibly inhibit COX

18. MRK

19. MRK
Ticlopidine- 250mg tab
 Blocks platelet ADP receptor-Inhibit ADP mediated P.
aggregation
 Inhibit the activation of GPIIb/IIIa R required for platelets to bind
to fibrinogen and to each other
 Prodrug – liver CYP450
 Maximal platelet inhibition  8-11 days
 ADR: Most common – nausea, vomiting & diarrhea
Most serious – severe neutropenia (1%), bleeding
Thrombocytopenia, jaundice
It has synergistic effect on platelets with aspirin

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21. MRK
Uses
1. Secondary prevention of stroke, TIAs
2. Unstable angina
3. Combined with Aspirin - Angioplasty - ↓incidence
of restenosis after PCI & stent thrombosis.
Clopidogrel – 75mg tab
 Similar (MOA )to Ticlopidine also a prodrug
 Safer and better tolerated
 Favorable ADR profile(< neutropenia, diarrhoea, rashes)
 Preferred over Ticlo in stented patients in combination c aspirin

22. MRK
GP IIb/IIIa inhibitors (R antagonists)
GP IIb/IIIa adhesive receptor – fibrinogen & von Willebrand
factor→ P. aggregation-blocked by antagonists
Abciximab
 Fab fragment of humanized monoclonal antibody against GP
 Use: angioplasty – prevent restenosis, recurrent MI. given along
with aspirin+heparin during PCI
 After bolus dose P.aggn. remains inhibited for 12-24 hrs
 0.25mg/kg IV 10-60 min before PCI- 10μg/min for 12 hrs
 ADR: Major– bleeding(1-10%), thrombocytopenia (2%), arrhythms
 Very expensive. Used in unstable angina, PCI with stent

23. MRK
Inhibits fibrinogen cross
linking of platelets

24. MRK
Eptifibatide
Tirofiban
Abciximab Monoclonal antibody
Cyclic peptide
Non peptide
Act similarly to Abciximab – blocking GPIIb/IIIa R
Oral preparations of GPIIb/IIIa blockers – too toxic
When IV infusion stopped effect can persist for4 hrs
Major adverse effect - bleeding

25. MRK
Uses of Antiplatelet drugs
For maintenance of vascular recanalization, stent placement,
vessel grafting
Combination of Antiplatelet drugs having different MOA
used
Coronary artery disease – low dose aspirin
After MI, primary & secondary prevention of MI
Unstable angina (Aspirin + Clopidogrel with
heparin/warfarin)

26. MRK
Uses of Antiplatelet drugs
Cerebrovascular disease
↓ Incidence of TIAs, stroke in patients with TIAs, persistent
AF, past h/o stroke
Combination of aspirin with Dypiridamole – secondary
prevention of stroke

27. MRK
Uses of Antiplatelet drugs
Coronary angioplasty, stents, bypass implants
Patency of recanalized CA, implanted bypass vessel–improved
Abciximab + Aspirin & heparin - ↓ restenosis- subsequent MI
after coronary angioplasty
Prosthetic heart valves and arteriovenous shunts
Antiplatelet drug + warfarin ↓ microthrombi – embolism
Prolong the patency of A-V shunts implanted for hemodialysis

28. MRK
Uses of Antiplatelet drugs
Venous thromboembolism
Anticoagulants are routinely used
Peripheral vascular disease
Aspirin / ticlopidine – intermittent claudication ↓ incidence
of thromboembolism

29. MRK
FIBRINOLYTICS
(Thrombolytics)
&
ANTIFIBRINOLYTICS

30. MRK
FIBRINOLYTICS
• Drugs used to lyse clot / thrombi → recanalise
occluded BV’s (mainly coronaries)
• Curative rather than prophylactic
• Activates natural fibrinolytic system
• Venous thrombi lysed ↑ easily than arterial
thrombi
• Recent thrombi lysed faster than old thrombi

31. MRK
Once the repair is over fibrinolytic system is activated to
remove fibrin
The enzyme serine protease “plasmin”- responsible for
digestion of fibrin
Generated from plasminogen by tissue t-PA produced by
vascular endothelium
Plasminogen circulates in plasma as well as remains bound to
fibrin
Fibrinolytics

32. MRK
t-PA selectively activates fibrin bound plasminogen
within the thrombus
Any plasmin that leaks is inactivated by circulating
antiplasmin
Fibrin bound plasmin is not inactivated by antiplasmins ?
Common binding site for both fibrin and antiplasmin
Fibrinolytics

33. MRK
When excessive amounts of plasminogen are activated
(by administered fibrinolytics)
The α₂ antiplasmin is exhausted and active plasmin
persists in plasma
This degrades even fibrinogen
It induces total lytic state – major complication is
hemorrhage
Even physiological thrombi - bleeding
Fibrinolytic

34. MRK
FIBRINOLYTIC AGENTS
• STREPTOKINASE
• ANISTREPLASE
(it is anisolyated plasminogen streptokinase activator complex)
• UROKINASE
• ALTEPLASE
• RETEPLASE
• TENECTEPLASE
• DUTEPLASE

35. MRK
Fibrinogen Fibrin
Fibrin split
products
Degradatio
n products
Thrombin
Plasmin
+ +
PlasminogenActivation Inhibition
Blood
proactivat
Blood
activator
AntiactivatorsStreptokinase,
Anistreplase,Urokinase,
Alteplase, Duteplase,
Reteplase, Tenecteplase
Epsilon
aminocaproic
acid (EACA),
Tranexemic
acid, Aprotinin
+ -

36. MRK

37. MRK
THERAPEUTIC USES OF FIBRINOLYTICS
Fibrinolytic
agent
Indication Dose
Streptokinase
MI
DVT & PE
7.5 – 15 lac IU infused IV over 1 hr
2.5 lac IU loading dose , 1 lac IU/hr * 24hr
Urokinase
MI
DVT & PE
2.5 lac IU infused IV over 10 min, 5 lac * 1hr
4400 IU/kg over 10 min IV, 4400 IU/kg/hr * 12 hr
Alteplase
MI
PE
15mg IV bolus inj, 50mg over 30 min, 35mg over
over the next 1 hr
100mg IV infused over 2 hr
Reteplase
Longer acting
rt-PA
MI 10mg over 10 min rpted after 30 min
Tenecteplase
rt-PA , higher
fibrin
selectivity
MI Single IV bolus dose 50mg over 5 sec
It is expensive

38. MRK
THERAPEUTIC USES OF FIBRINOLYTICS
• ACUTE MI, UNSTABLE ANGINA
• ACUTE THROMBOTIC STROKE
• DEEP VEIN THROMBOSIS
• PULMONARY EMBOLISM
• PERIPHERAL ARTERIAL OCCLUSION
• CLEARING THROMBOSED SHUNTS & CANNULAE

39. MRK
CONTRAINDICATIONS TO USE OF FIBRINOLYTICS
• RECENT TRAUMA . AORTIC DISSECTION
• SURGERY . ACUTE PERICARDITIS
• BIOPSIES . ANEURYSMS
• HEMORRHAGIC STROKE
• PEPTIC ULCER
• SEVERE HYPERTENSION
• BLEEDING DISORDERS
• CARDIOPULMONARY RESUSCITATION
• ACUTE PANCREATITIS
• PUNCTURE OF NON-COMPRESSIBLE VESSELS

40. MRK
ANTIFIBRINOLYTICS
Drugs which block the conversion of
plasminogen to plasmin and thus inhibit the
fibrinolytic activity
• EPSILON AMINO CAPROIC ACID
• TRANEXEMIC ACID
• APROTININ

41. MRK
EPSILON AMINO CAPROIC ACID
• Administered orally/IV
• Can be used in menorrhagia, bleeding due to surgery
• Specific antidote – fibrinolytic over dosage - controls
bleeding
• A/E’s :
• Rapid inj- hypotension, bradycardia
• Intravascular thrombosis, uretric obstruction by unlysed
clot
• Caution – impaired renal function, rarely myopathy
5g oral/iv, followed by 1g hrly till bleeding stops
(max 30 gm in 24 hrs)

42. MRK
USES
• Fibrinolytic over dosage / hyperplasminaemic
states
• Subarachanoid & GI bleeding
• Tonsillectomy, prostectomy & tooth extraction –
haemophilics
• Abruptio placentae, PPH & menorrhagia

43. MRK
TRANEXEMIC ACID
• Analogue of aminocaproic acid
• Actions similar to EACA
• 7 times ↑ potent
• A/E’s: Nausea, diarrhoea, headache, giddiness,
thrombophlebitis

44. MRK
USES:
• Fibrinolytic overdosage
• After cardiac bypass surgery
• After tonsillectomy, prostectomy & tooth extraction –
haemophilics
• Epistaxis, ocular trauma, bleeding peptic ulcer
• Menorrhagia, metrorrhagia,

45. MRK
A 65 yr old man is brought to the emergency department 30 min after the onset of
right sided weakness and aphasia. Imaging studies ruled out cerebral hemorrhage
as the cause of his acute symptoms of strike
Prompt administration of which of the following drugs is most likely to improve
this patient’s clinical outcome?
(A) Abciximab
(B) Alteplase
(C) Factor VIII
(D) Streptokinase
(E) Vitamin K

46. MRK
A 65 yr old man is brought to the emergency department 30 min after the onset of
right sided weakness and aphasia. Imaging studies ruled out cerebral hemorrhage
as the cause of his acute symptoms of strike
Over the next 2 days, the patient’s symptoms resolved completely. To prevent the
recurrence of this disease, the patient is most likely to be treated indefinitely with
(A) Aminocaproic acid
(B) Aspirin
(C) Enoxaparin
(D) Lepirudin
(E) Warfarin

47. MRK
A 65 yr old man is brought to the emergency department 30 min after the onset of
right sided weakness and aphasia. Imaging studies ruled out cerebral hemorrhage
as the cause of his acute symptoms of strike
If the patient is unable to tolerate the drug, he may be treated with Clopidogrel.
Relative to Ticlopidine, Clopidogrel
(A) Has shorter duration of action
(B) Is less likely to cause neutropenia
(C) Is more likely to induce antiplatelet antibodies
(D) Is more likely to precipitate serious bleeding
(E) Will have a greater antiplatelet effect

48. MRK
A 58-yr-old business executive is brought to the emergency department 2 hrs after
the onset of severe chest pain during a vigorous tennis game. She has a history of
poorly controlled mild hypertension and elevated blood cholesterol but does not
smoke. ECG changes confirm the diagnosis of myocardial infarction. The decision is
made to attempt to open her occluded artery.
Occluded artery was opened by an agent which accelerates the conversion of
plasminogen to plasmin
(A) Epsilon Aminocaproic acid (EACA)
(B) Heparin
(C) Lepirudin
(D) Reteplase
(E) Warfarin

49. MRK
A 58-yr-old business executive is brought to the emergency department 2 hrs after
the onset of severe chest pain during a vigorous tennis game. She has a history of
poorly controlled mild hypertension and elevated blood cholesterol but does not
smoke. ECG changes confirm the diagnosis of myocardial infarction. The decision is
made to attempt to open her occluded artery.
If a fibrinolytic drug is used, the adverse drug effect that is most likely to occur is
(A) Acute renal failure
(B) Development of antiplatelet antibodies
(C) Encephalitis secondary to liver dysfunction
(D) Hemorrhagic stroke
(E) Neutropenia

50. MRK
A 58-yr-old business executive is brought to the emergency department 2 hrs after
the onset of severe chest pain during a vigorous tennis game. She has a history of
poorly controlled mild hypertension and elevated blood cholesterol but does not
smoke. ECG changes confirm the diagnosis of myocardial infarction. The decision is
made to attempt to open her occluded artery.
If this patient undergoes a percutaneous coronary angiography procedure and
placement of a stent in a coronary blood vessel, she may be given eptifibatide. The
mechanism of eptifibatide anticlotting action is
(A) Activation of antithrombin III
(B) Direct thrombin inhibition
(C) Inhibition of thromboxane production
(D) Irreversible inhibition of platelet ADP receptors
(E) Reversible inhibition of GP IIb/IIIa receptors

51. MRK
A 67-yr-old woman presents with pain in her left thigh muscle. Duplex
ultrasonography indicates the presence of DVT in the affected limb.
The decision was made to treat this woman with enoxaparin. Relative to
unfractionated heparin, enoxaparin
(A) Can be used without monitoring the patient’s aPTT
(B) Has a shorter duration of action
(C) Is less likely to have a teratogenic effect
(D) Is more likely to be given intravenously
(E) Is more likely to cause thrombosis and thrombocytopenia

52. MRK
A 67-yr-old woman presents with pain in her left thigh muscle. Duplex
ultrasonography indicates the presence of DVT in the affected limb.
During the next week, the patient was started on warfarin and her heparin was
discontinued. Two months later, she returned after a severe nosebleed Lab
analysis revealed an INR of 7.0 (INR value in such a warfarin treated patient should
be 2.5 – 3.5). To prevent severe hemorrhage, the warfarin should be discontinued
and this patient should be treated immediately with
(A) Epsilon Aminocaproic acid (EACA)
(B) Desmopressin
(C) Factor VIII
(D) Protamine
(E) Vitamin K1

53. MRK
A patient develops severe thrombocytopenia in response to treatment with
unfractionated heparin and still requires parenteral anticoagulation. The patient is
most likely to be treated with.
(A) Abciximab
(B) Aprotinin
(C) Lepirudin
(D) Plasminogen
(E) Vitamin K2

54. MRK
TERIMA KASIH