Drugs used for coagulation

Assoc. Prof. Dr. Dharmani Devi Murugan

Department of Pharmacology
Faculty of Medicine
dharmani79@um.edu.my

https://www.emedicinehealth.com/blood_clots/article_em.htm
Hemostasis – Thrombus –
Arrest of blood loss from damaged vessels Hemostatis in the wrong place (unwanted clot)

- Neil Armstrong

Thrombus – dislodge from arteries & veins →

embolus
 Atherosclerotic plaque

Anticoagulants
Plaque rupture

Activation of clotting factors

Antiplatelets Platelet adhesion & tissue factors
Platelet aggregation

Formation of fibrin

Trapped blood cells

Antifibrinolytics Fibrin degradation products

Plasminogen Plasmin

Proactivators in
Plasminogen activator
plasma and tissues
Fibrinolytics
 Antithrombotic Drugs

Antiplatelets Anticoagulants Fibrinolytics

Aspirin Heparin & LMWH Streptokinase

Ticlopidine, Clopidogrel Warfarin Alteplase

Abciximab Dabigatran
 COX-inhibitor
• Aspirin
Antiplatelet Drugs
Adenosine (PY12) receptor inhibitors
• Drugs that interferes with
• Ticlopidine
platelet function and used • Clopidogrel
in prophylaxis of
thromboembolic disorders Glycoprotein IIB/IIA receptor antagonist
• Abciximab
Antiplatelet drugs
Thrombin, collagen & ADP stimulate platelet –
Aspirin activates platelet phospholipases
Membrane phospholipid
Phospholipase A • Low-dose aspirin (75 mg) → relatively
selective in inhibiting TXA in platelet
ARACHIDONIC ACID
COX • Effects last 7-10 days until new platelet is
Irreversibly inhibit
formed
COX
PGE2, TXA2 PGI2
• Used for long-term thromboprophylaxis in
PGD2,
people with high CV risk (ie. MI)
PGF2α
Antiplatelet drugs
stma
A
S alicylism
P eptic ulceration
I ntestinal bleeding
R eye’s syndrome
I diosyncracy
N oise (tinnitus)
Antiplatelet drugs
Ticlopidine, Clopidogrel
• Inhibit ADP binding to its receptors (P2Y12 receptor) on the platelet
irreversibly → prevent activation of GB IIb/IIIa receptors
• Given by orally
• Clopidogrel – a prodrug that must be metabolized by CYP 2C19
• Peak effect : 5-7 days
• Addictive action with aspirin
Antiplatelet drugs
Ticlopidine, Clopidogrel
Clinical Uses:
• Prevention of MI /stroke and peripheral arterial disease
• Prophylaxis of thrombotic events in acute coronary syndromes
• Prevent thrombotic events assoc. with percutaneous coronary intervention with/ without coronary stenting

Adverse effects:
• Bleeding most common
• Severe hematologic reactions (neutropenia & thrombocytopenia) - ticlopidine
Antiplatelet drugs
Abciximab
• A chimeric monoclonal antibody
• Inhibits the GP IIb/IIIa receptor → blocks the binding of fibrinogen and
von Willebrand factor → no platelet aggregation

• Given IV for short term treatment

Clinical Uses:
• Used along with heparin and aspirin, as an adjunct to PCI for the prevention
of cardiac ischemic complications

• Adverse effects: Bleeding (if used with anticoagulant)

 Heparin and Low Molecular Weight Heparin(LMWH)

Anticoagulants Oral anticoagulant

• Warfarin
Drugs that prevent the
Thrombin inhibitor
development and enlargement
• Dabigatran
of clots
Others
• Fondaparinux
• Rivaroxaban
Review of
coagulation
cascade

14

(II)
 Injectable
anticoagulants
Heparin and LMWH
Regular / unfractionated Low Molecular Weight Heparin
Heparin
Endogenous – a family of sulfated Heparin fragments
glycosaminoglycans

Example Enoxaparin, tinzaparin, dalteparin

Mechanism of action Activate antithrombin III – inactivate clotting factors

Heparin and LMWH – mechanism of action
Pharmacokinetics of Heparin & LMWH
Regular / unfractionated Heparin Low Molecular Weight Heparin

Route of administration Intravenous & subcutaneous Subcutaneous

Pharmacokinetic • Half –life (40-90 min) • Longer half-life (4-6 hr)

• Does not cross BBB & placenta • Does not cross BBB & placenta
• Elimination follows first order kinetic (low • Elimination follows first order kinetics
doses) & saturation at higher doses • Eliminated by renal excretion
• Eliminated by different processes – binding
to endothelial cells, macrophages and renal
excretion
 Heparin and LMWH
Regular / unfractionated Heparin Low Molecular Weight Heparin

Monitoring Activated partial thromboplastin time Not routinely required

(aPTT) If required, use anti-factor Xa assay

Clinical uses 1. Treatment of acute venous thromboembolism (DVT or PE)

2. Prophylaxis against venous & arterial thrombosis

Antidote Protamine sulphate

Adverse effect of Heparin / LMWH
1. Stop therapy
2. Give protamine sulphate (heparin)

Other AE
1. Osteoporosis – long term (more than 6 months)
2. Hypoaldosteronism (with consequent hyperkalemia)

Adverse effect of LMWH is similar but incidence level is lower

 Longer biological Predictable
half –life anticoagulation
dose response

Less need for

routine
Advantages of Dose-
laboratory LWMH over dependence
clearance
monitoring
UFH
Lower incidence
Improved SC
of
bioavailability
thrombocytopenia
 Mechanism of action
Fondaparinux

• Synthetically derived
pentasaccharide anticoagulant

Selectively binds to antithrombin III, and potentiates (300- to 1000-fold)

the innate neutralization of factor Xa by antithrombin III → Selectively
https://sci-hub.ee/10.2217/1745509x.2.5.731 inhibit only Factor Xa
 Fondaparinux
PK: Uses:
• Well absorbed from the subcutaneous route with • Treatment of DVT and PE and for the
a predictable pharmacokinetic profile → prophylaxis of venous thromboembolism
Requires less monitoring. in the setting of orthopedic and
• Eliminated unchanged in the urine abdominal surgery
• Crosses placental barrier
• Caution in patients with severe renal impairment A/E: Bleeding ( no agent for its reversal)
ORAL ANTICOAGULANTS
Oral anticoagulant: Warfarin
MOA:
• Main vitamin K antagonist
• Competitively inhibit vitamin K epoxide reductase component 1
(VKORC1) → prevent reduction of vitamin K epoxide to its
reduced form
• Also inhibit inhibitory factors C and S – procoagulant effect
initially
• Anticoagulant actions starts in 1-3 days only
Oral anticoagulant: Warfarin
Dosing : Variable
• Dose is individualized based on repeated
measurement of Prothrombin Time (PT) or
International Normalised Unit (INR)

• Optimum ratio of INR: 2-3

Oral anticoagulant: Warfarin
Pharmacokinetics
absorption Distribution Metabolism Elimination

• Small lipid-soluble • Highly protein bound • Half-life: 36hr • Eliminated via kidney
molecule and bile
• Readily crosses placenta • Metabolized by CYP450
• Rapidly absorbed orally system
 Adverse effects:
Oral anticoagulant :Warfarin
• Bleeding – esp. in bowel or brain
• Minor bleeding – Vit K
• Life-threating - Fresh frozen plasma /and plasma
concentrates of blood factors
• Teratogenic – should never be used
during pregnancy. If anticoagulant therapy is needed
during pregnancy, heparin or LMWH may be administered

• Skin necrosis – rare but serious. Can be reduced by

starting heparin & warfarin concomitantly
 Factors that affect the effect of warfarin
Cimetidine, Amiodarone, Metronidazole, Fluconazole etc - Inhibit hepatic
metabolism

Inhibit platelet functions – Aspirin

Decrease bioavailability of Vit K – cephalosporins

Displace warfarin from binding sites– Choral Hydrate

potentiation of anticoagulation
 Factors that affect the effect of warfarin
Vitamin K rich food (green leafy vegetables)- antagonism of warfarin

Induce hepatic metabolism – Rifampin, Barbiturates, Carbamazepine

Reduce absorption– Cholestyramine

attenuation of anticoagulation
 Non vitamin K oral
anticoagulants (NOACs)
Dabigatran :
Direct thrombin inhibitor

Rivaroxaban/ Apixaban:
Direct Factor Xa inhibitor
 Non vitamin K oral
anticoagulants (NOACs)
Dabigatran :
Direct thrombin inhibitor

Rivaroxaban/ Apixaban:
Direct Factor Xa inhibitor
NOAC: Dabigatran etexilate
Pharmacokinetics
absorption Distribution Metabolism Elimination

• Well-absorbed orally • Well distributed • Pro-drug hydrolyzed • 80% eliminated via

to the active drug by kidney and 20% via
various plasma bile
esterases
 NOAC: Clinical uses
Dabigatran Rivaroxaban/ Apixaban
• Clinical uses:
• Clinical uses:
❑ prevention of stroke & systemic embolism in
❑ treatment and prevention of DVT and PE
atrial fibrillation
❑ prevention of stroke in nonvalvular atrial
❑ prevention of venous thromboembolism following
fibrillation
knee/ hip surgery (alternative to enoxaparin)

• Contraindication : Patients with mechanical prosthetic • Contraindication : Neither

heart valves and is not recommended in patients with drug should be used in severe renal dysfunction
bioprosthetic heart valves.
Dabigatran NOAC: Adverse effects Rivaroxaban/ Apixaban

Bleeding Bleeding

Dyspepsia, abdominal pain,

esophagitis, and Bowel / bladder dysfunction
GI bleeding

Hypersensitivity Burning, crawling, numbness,

prickling, “pin & needle”,
tingling feeling
 NOAC: Monitoring and Reversal
Dabigatran Rivaroxaban/ Apixaban
• No specific monitoring required • No specific monitoring required
• Idarucizumab: first specific reversal agent for • Andexxa : first reversal of Rivaroxaban/ Apixaban.
dabigratran. Idarucizumab is a humanized monoclonal Andexxa is a modified form of factor Xa and act as
antibody fragment and binds free and thrombin-bound reversal of direct factor Xa inhibition
dabigatran to neutralize its activity
 Immediate Predictable
effect anticoagulation
dose response

No drug
monitoring Advantages of NOACs over Warfarin

Selective
inhibition of Less drug
thrombin/ Factor interaction
Xa
 Summary of MOA

Warfarin
(Vit K antagonist)

Warfarin
(Vit K antagonist)

https://doi.org/10.3390/medicines6040103
 ❖ Fibrinolysis – process of breaking down the fibrin that holds
the clot together
❖ Initiated by activation of plasminogen to plasmin

Fibrinolytics
Drugs that are used to lyse Streptokinase
Urokinase
already formed clots Alteplase (t-PA)

t-PA = tissue plasminogen activator

Fibrinolytics

• Streptokinase (1st gen) → causes a systemic fibrinolytic High titer antibody

state → bleeding problems. develop 1-2weeks
after use

• Alteplase (2nd gen) → acts more locally on the thrombotic

fibrin (clot selective) to produce fibrinolysis.
• Administered intravenously
• Beneficial effect is addictive with aspirin
• Adv. Effects: Bleeding (GI haemorrhage/ haemorrhage
stroke), hypersensitivity rxn (streptokinase), hypotension
(streptokinase)
Fibrinolytics

Uses of fibrinolytics
• Acute myocardial infraction (within 3-4 h by iv infusion) – aspirin+ heparin co-administrated to
prevent re-occlusion

• Deep vein thrombosis – leg, pelvis, shoulder

• Pulmonary embolism

• Stroke : selected patients

Drugs used to treat bleeding
J Can Dent Assoc 2020;86:k17
Dézsi, C. A., Dézsi, B. B., & Dézsi, A. D. (2017). Management of dental patients receiving antiplatelet therapy or chronic oral anticoagulation: A review of the latest
evidence. The European journal of general practice, 23(1), 196–201. https://doi.org/10.1080/13814788.2017.1350645
Dézsi, C. A., Dézsi, B. B., & Dézsi, A. D. (2017). Management of dental patients receiving antiplatelet therapy or chronic oral anticoagulation: A review of the latest
evidence. The European journal of general practice, 23(1), 196–201. https://doi.org/10.1080/13814788.2017.1350645
 Management algorithm for
patients with warfarin therapy
scheduled for invasive dental
treatment.
OAC: oral anticoagulant; LMWH: low
molecular weight heparin.

Mingarro-de-León, A., Chaveli-López, B., & Gavaldá-Esteve, C. (2014). Dental management of patients
receiving anticoagulant and/or antiplatelet treatment. Journal of clinical and experimental dentistry, 6(2),
e155–e161. https://doi.org/10.4317/jced.51215
 References
1. Basic and Clinical Pharmacology (Katzung, 13th
Edition).
2. Pharmacology (Rang and Dale, 9th Edition)
3. Lippincott’s Illustrated Review (Harvey and Champe,
7th Edition)

If you have any questions, drop an email to me at

dharmani79@um.edu.my