Anti thrombotic drugs

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 How blood clots

Damage to endothelium (vessels) – releases thromboxane A2 (TXA2),

Adenosine diphosphate (ADP), Serotonin, which cause platelet
aggregation

 Leading to platelet plug formation

 Activation of Glycoprotein GP IIb/IIIa receptor promote

the binding of fibrinogen to it

 Activation of coagulation cascade that

 leads to conversion of fibrinogen to fibrin

 Activated Fibrin: fibers woven into a patch

 Coagulation Cascade
Intrinsic pathway
Extrinsic pathway
XIIa XII
TF VIIa
XIa XI

IXa IX
VIIIa

X Xa
Va
Common pathway
II (prothrombin) IIa (thrombin) XIII XIIIa

Each step requires: Fibrinogen Fibrin Stabilized

Fibrin
• Zymogen (precursor protein)
• Activated Protease from step before
• Cofactors like Ca++
 Effects of clot formation

• Clotting is beneficial at sites of injury because it minimizes blood

loss and prevents infectious agents from getting into our systems.

• Clotting can be serious when occurs inappropriately in normal

vessels [called thrombus] …clot can break free [called embolus]
and lodge in the

– Lungs causing pulmonary embolism,

– Heart causing myocardial infarction,
– Brain causing stroke
Drugs: To treat thromboembolic disorders
Group 1 Group 2 Group 3

Anticoagulants Thrombolytics Antiplatelets

Oral Streptokinase Aspirin
Parenteral t-PA derivatives Glycoprotein IIb/IIIa
Inhibitors

ADP Inhibitors
PDE/Adenosine uptake
inhibitors
 Oral Anticoagulants
Drugs: Warfarin and Dicumarol

MOA:
Inhibit Vitamin K reductase thereby ↓the synthesis of clotting
factors II,VII, IX & X, essential for coagulation.
• Onset of drugs anticoagulant action is delayed because of
presence of working or already activated clotting factors.

• Therapeutic effect is monitored by

– Prothrombin time (PT)
– International Normalised Ratio (INR)
Vitamin K antagonists

Effect on Coagulation

• Vitamin K dependent clotting factors: Factors II, VII, IX, and X

Intrinsic pathway
Extrinsic pathway
XIIa XII
TF VIIa
XIa XI

IXa IX
VIIIa

X Xa
Va
Common pathway
II (prothrombin) IIa (thrombin) XIII XIIIa

Fibrinogen Fibrin Stabilized

Fibrin
 Oral Anticoagulants
PK:
• 99% bound to plasma protein
• Narrow therapeutic index
• Transplacental passage - goes into placenta in pregnant mommies!

ADR:
• Bleeding (ecchymosis-bruising, epistaxis-nose bleed, hematuria-blood
in urine)
• Teratogenicity :
– Craniofacial deformities, Intracranial hemorrhage
• Fat necrosis - skin, breast, fatty tissues.

Overdosage: Severe bleeding

Antidote : Inj. Vitamin K1 (Phytonadione).
Fresh frozen plasma or plasma concentrates of II, VII, IX and X factors.
 Interactions & Factors affecting Warfarin action

Prothrombin Time (  risk of bleeding)

• Hepatic microsomal inhibitors (↓ Metabolism ↑toxicity)
– Cimetidine
• Potentiate the action of Warfarin:
– Aspirin, Heparin, Liver disease
• Displacement from plasma protein ( Sulfonamides ↑toxicity)

Prothrombin Time ( therapeutic effects)

• Hepatic microsomal inducers ( ↑ Metabolism & ↓ efficacy)
– Barbiturates
• Cholestyramine (↓ Absorption of Warfarin)
• Alcohol, green leafy vegetables (Vit K)
 Warfarin: Uses

Prophylaxis OR prevention of
• Thromboembolism in Atrial fibrillation
• Deep Vein Thrombosis
• Pulmonary embolism
• Thrombosis on Prosthetic heart valves

Contraindications: Pregnancy & Lactation

 Heparins Parenteral Anticoagulants

• Naturally present in endothelium (as heparan sulfate)

• Complex mucopolysaccharide (MW 10000 – 40000)

Unfractionated heparin
MOA:
• Binds Antithrombin III & potentiates (increases) its action 1000
times (Antithrombin III inhibits thrombin (IIa), VIIa, IXa, & Xa)
• Produces rapid onset of action because it acts on preformed
clotting factors.

Therapeutic effect is monitored by Activated Partial Thromboplastin

Time (aPTT)
 Heparins
PK:
• Highly ionized and NOT absorbed orally
• Given by SC/IV
• No transplacental passage - safe during pregnancy

Uses :
Acute treatment:
• Coronary syndromes, deep vein thrombosis, pulmonary
embolism
• Prevent arterial thrombosis during coronary angioplasty
• IV device insertion (cannula/catheter) prevent clot formation
 Heparins

ADR:

• Bleeding
• Heparin induced Thrombocytopenia (> 8 days of therapy)
– (Less with LMW heparin)
• Hypersensitivity
• Alopecia
• Osteoporosis (> 6 months of therapy)
 Heparins

Overdosage: Severe bleeding (epistaxis-nose bleed,

hematemesis-vomiting blood, hematuria-blood in urine)

Treatment: Reversal of Heparin Action

Stop therapy
Antidote: Inj. Protamine sulfate
• Basic protein, forms inactive complex with Heparin
• Each mg of protamine sulfate neutralizes approximately
100 Heparin units
ADR of protamine sulfate: hypotension and anaphylaxis reaction
 Low Molecular Weight Heparins (LMWH)

Dalteparin & Enoxaparin

• MW 4000 – 7000

MOA:
• Increase the action of AT III on factor Xa but cannot increase
the action of AT III on thrombin (IIa) because they cannot bind
both simultaneously.

Advantages over unfractionated heparins

• Greater bioavailability than heparin
• Longer half life than heparin (less frequent dosing)
• Given subcutaneously
• Less thrombocytopenia
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MOA: Heparins
 Anticoagulant drugs: Uses
 Injectable- heparin (acute use)
 Orally active- warfarin (chronic therapy)

-For patients with venous thromboembolism - DVT

-Atrial fibrillation (potential thrombosis/ pulmonary embolism)
-Prosthetic heart valves (thrombosis)
-Acute coronary events (eg angina)

•Heparin given immediately then warfarin because of slower-onset

effect

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 Anticoagulants: Contraindications

• Active bleeding or bleeding disorders

• Major trauma or injury
• Severe hypertension
• Thrombocytopenia
• Advanced hepatic or renal disease
• Hypersensitivity
 Anti-coagulants: Direct Thrombin Inhibitors

Parenteral : Hirudin obtained from medicinal leeches (Hirudo

medicinalis)

PK: Administered by IV
– Therapeutic effects monitored by aPTT
Uses:
– In patients with thrombosis related to Heparin induced
thrombocytopenia
– Percutaneous coronary angioplasty
ADR:
– Bleeding & Hypersensitivity
 Anti-coagulants: Direct Thrombin Inhibitors

Oral : Dabigatran

• Greater reduction in stroke than Warfarin (similar/less

bleeds)
• No need for INR / dose monitoring (preliminary evidence)
• No/minimal drug/diet interactions

• Indicated and used for DVT, stroke prevention in AF

Presentation title
 28th
February
2011

Presentation title
 Antiplatelet agents

(TXA2, GP2b3a, ADP)

Drugs which impair or prevent the aggregation of platelets

Treating consequences of arterial thrombosis

1. Cyclo-oxygenase inhibitors
- e.g. Aspirin

2. Inhibition of platelet binding/adhesion

– e.g. Clopidogrel, Abciximab

3. Phosphodiesterase inhibitors
- e.g. Dipyridamole, Cilostazol
Cyclo-oxygenase (COX) inhibitors

e.g. Aspirin (low dose)

++ aggregation --
Inhibition: TXA2 >> PGI2

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 Anti-platelet drugs: Aspirin
Aspirin: (Acetyl Salicylic Acid)

MOA: At low doses (75-100 mg) inhibits cyclooxygenase by

irreversible acetylation  ↓TXA2 synthesis

– TXA2 stimulates platelet aggregation

Low dose spares endothelial synthesis of PGI-2 (platelet
aggregation inhibitor and vasodilator) and thus better anti-
platelet activity.

ADR: GI upset; dyspepsia, vomiting & bleeding

 Anti-platelet drugs: Aspirin

Uses:
• Prevention of stroke
• Prevention of myocardial infarction
• High risk patients (unstable angina)
• Following surgery (bypass, angioplasty)

Contraindications:
• Aspirin intolerance
• Bleeding disorders

• History of GI bleeding or peptic ulcer

Anti-platelet drugs: CLOPIDOGREL, TICLOPIDINE

MOA: Block ADP receptor (P2Y12) on platelets => inhibit

activation of the GP IIb/IIIa receptors => inhibit platelet
aggregation
• Combined with Aspirin = synergistic action.

Uses: Prevention of Ischemia and ischemic attack, prevents

ischemic strokes in patients who can not tolerate Aspirin

ADR (Ticlopidine):
• Bleeding agranulocytosis (lowered white
blood cell count), aplastic anemia
• Thrombotic thrombocytopenic purpura.
– Ticlopidine: reserved for patients who can not tolerate other therapies
 Anti-platelet drugs: DIPYRIMADOLE

MOA: Inhibits PDE-III  cAMP  Inhibits TXA2 synthesis,

• It also  plasma concentration of Adenosine which acts thru
platelets A2 receptors to platelet cAMP & thus inhibits
platelet aggregation.

ADR: Headache, palpitations, Less hematotoxicity

Uses : Intermittent claudication

 Anti-platelet drugs: ABCIXIMAB

MOA:
• Monoclonal antibody against IIb/IIIa receptors in the platelets
• Inhibits the binding of fibrinogen to this receptor thereby
prevents platelet aggregation

Uses:
• Percutaneous coronary surgery
• Acute coronary syndromes
• Given IV along with either heparin or aspirin as an adjunct
 Thrombolytics/Fibrinolytics
Streptokinase, Alteplase, Urokinase,

MOA:
– These are plasminogen activators which convert
plasminogen into plasmin that catalyzes the degradation of
fibrin.
– These are used for the lysis of the already formed clots –
recanalize the occluded vessel.

PK:
• Effect is monitored by Thromboplastin time
• Given IV <6-8 hrs following MI
 Thrombolytic/Fibrinolytic drugs
Streptokinase Urokinase t-pa
ANISTREPLASE ALTEPLASE

Hemolytic Human renal cells DNA recombinant

streptococci

Antigenic- trigger Non-antigenic Non-antigenic

immune response

Non-fibrin specific Non-fibrin specific Fibrin specific

Half life~30min Half life~15min Half life~10min

 Thrombolytics

Uses of Thrombolytics:
• Acute myocardial infarct (within 12 hrs)
• Pulmonary embolism
• Acute thrombotic stroke (within 3 hrs)

ADR: Bleeding, hypersensitivity, hypotension

Antidote: Aminocaproic acid or Tranexamic acid
Endogenous Inhibitors of Coagulation always working in balance with clot formation

o Anti-thrombin III inhibits clotting factors IIa, VIIa, IXa, & Xa.

o Prostacyclin (PGI2): Inhibits platelet aggregation

o Nitric oxide (NO): Inhibits platelet aggregation

o Tissue plasminogen activator:  it catalyzes the conversion of 

plasminogen to plasmin, the major enzyme responsible for clot
breakdown.

o Tissue Factor Pathway Inhibitor (TFPI)

– inhibits tissue factor bound factor Va or VIIa
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