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Coagulants & Anti-coagulants

Clotting Process
 Formation of a blood clot (thrombus) in blood vessels or the
heart.
 May be life saving (when it plugs a severed vessel) or life-
threatening if it occludes a vessel supplying a vital structure.
 May break loose to create an embolus that flows downstream
to lodge at a distant site.
 The potential consequence is ischemic necrosis of cells and
tissues known as infarction.
 Cerebral vascular accidents (stroke), myocardial infarction and
pulmonary embolisms are examples of disorders resulting from
thrombosis or embolism.
Classification of Coagulant
(i) Calcium salts
(ii) Vitamin-K / Vitamin-K1 / Phytomenadione (Natural)
(iii) Vitamin-k3 / Menadione (Synthetic)

Classification of Anti-Coagulant (Prevention of deep vein


thrombosis, pulmonary embolism, Venous thromboembolism, MI
and stroke/cerebrovascular accident)
(i) In-Vitro anti-coagulant
(e.g) Heparin- Glucosaminoglycan in mast cells, disaccharide unit
composed of a 2-O-sulfated iduronic acid / gluconic acid and 6-O-
sulfated, N-sulfated glucosamine.
Sodium oxalate, Sodium citrate

(ii) In-Vivo anti-coagulant (Vitamin-K antagonist, blocks the


formation of prothrombin from it’s precursor and thereby blood
coagulation is impaired)
(a) Coumarin derivatives
(e.g) Dicoumarol, Phenprocoumon, Warfarin, Acenocoumarol, Coumachlor
(b) Indandione derivatives
(e.g) Phenindione, Anisindione, Bromindione, Diphenadione
(iii) Thrombolytics / Fibrinolytics
(e.g) Streptokinase, Urokinase, Alteplase, Reteplase, Tenecteplase
MOA - Plasminogen activators, Plasmin degrades fibrin and breaks up thrombi
(iv) Anti-platelet Drugs (class of pharmaceuticals that decrease platelet aggregation
and inhibit thrombus formation. They are effective in the arterial circulation,
where anticoagulants have little effect. They are widely used in primary and
secondary prevention of thrombotic cerebrovascular or cardiovascular disease)
a) Prostaglandin synthesis inhibitors – Aspirin, Triflusal
b) Gp IIb / IIIa receptor complex inhibitors - Abciximab, Eptifibatide, Tirofiban
c) ADP receptor inhibitor - Ticlopidine, Clopidogrel, Prasugrel, Ticagrelor
d) By inhibiting platelet phospho-diesterase activity, stimulating prostacyclin
synthesis and blocking adensoine uptake – Dipyridamole, Cilostazol
e) Miscellaneous - Picotamide, Sulphinpyrazone
Synthesis of Dicoumarol

Synthesis of Warfarin

Michael addition is the addition of an enolate of a ketone or aldehyde to an α,β-


unsaturated carbonyl compound at the β carbon to form new c-c bond.

Synthesis of Phenindione
Synthesis of Ticlopidine

Synthesis of Dipyridamole
Adverse Effects of Heparin

 Increased bleeding - antidote (protamine sulfate)


 Heparin induced thrombocytopaenia
 Osteoporosis with long term high-dose administration 3-6mths
 Inhibit aldosterone synthesis – rarely causes ↑K+
Mechanism of action of Heparin
- Enhances the action of Antithrombin III (AT-III) (plasma
protease inhibitor) 1000 fold ↑ activity
- antithrombin III inhibits clotting factor proteases like,
thrombin (IIa), IXa, Xa, XIa and XIIa, by forming stable complexes
- heparin binds to AT-III and causes a conformational change
thereby activating AT-III
Mechanism of action of Coumarins

 Block the Vitamin K-dependent glutamate carboxylation of precursor


clotting factors II, VII, IX and X
 Also inhibits Proteins C & S
 8-12 hour delay in action because of T1/2 of clotting factors in plasma
 Recovery needs synthesis of new clotting factors
 Action is reversed with vitamin K

Adverse Effects of Coumarins


 Bleeding
 Contraindicated in pregnancy
- teratogenic effects, crosses placenta
 Warfarin induced skin necrosis
 Purple toes syndrome
 Hepatic dysfunction
Antiplatelet Drug Targets

 Prostaglandin synthesis

 ADP binding

 GPIIb/IIIa receptor complex -


inhibit cross-bridging of
platelets by fibrinogen
 Cyclic AMP

Adverse Effects
GI upset
Bleeding
Drug-induced thrombocytopaenia
Blood dyscrasias
Adverse Effects of Fibrinolytics
 Bleeding
 Allergic reactions
 Hypotension
 Arrhythmias
 Re-perfusion injury

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