Transcript PowerPoint Presentation - Anticoagulants and Thrombolytics

Objectives
To learn how Blood Clots are formed.
 How the blood clots are broken down ?
 What drugs can be used to regulate
clotting ?
 How to rectify clotting deficiencies

Classes of Drugs

Prevent coagulation

Dissolve clots

Prevent bleeding and hemorrhage Hemostatic

Overcome clotting deficiencies
(replacement therapies)
Blood Clotting

Vascular Phase

Platelet Phase

Coagulation Phase

Fibrinolytic Phase
Vascular Phase
Vasoconstriction
 Exposure to tissues activate Tissue
factor and initiate coagulation

Tissue Factor
Platelet phase

blood vessel wall (endothelial cells) prevent platelet
adhesion and aggregation

platelets contain receptors for fibrinogen and von
Willebrand factor

after vessel injury Platelets adhere and aggregate.

Release permeability increasing factors (e.g.
vascular permeability factor, VPF)

Loose their membrane and form a viscous plug
Coagulation Phase

Two major pathways
 Intrinsic pathway
 Extrinsic pathway

Both converge at a common point

13 soluble factors are involved in clotting

Biosynthesis of these factors are dependent on Vitamin K1
and K2

Normally inactive and sequentially activated

Hereditary lack of clotting factors lead to
hemophilia -A
Intrinsic Pathway

All clotting factors are
Extrinsic Pathway

Initiating factor is
within the blood
outside the blood
vessels
vessels - tissue factor

Clotting slower

Activated partial
thromboplastin test
(aPTT)

Clotting - faster - in
Seconds

Prothrombin test (PT)
Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Tissue Factor
XIIa
XII
Thromboplastin
XIa
XI
IXa
IX
Xa
X
Factors affected
By Heparin
VIIa
Prothrombin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Fibrinogen
XIII
VII
X
Thrombin
Fribrin monomer
Fibrin polymer
Anticoagulant drugs to treat
thromboembolism
Drug Class
Anticoagulant
Parenteral
Prototype
Heparin
Action
Inactivation of clotting
Factors
Effect
Prevent venous
Thrombosis
Anticoagulant Warfarin Decrease synthesis of
Oral
Clotting factors
Prevent venous
Thrombosis
Antiplatelet
drugs
Aspirin
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase Fibinolysis
Decrease platelet
aggregation
Breakdown of
thrombi
Heparin






Sulphated carbohydrate
Different sizebovine lungs
Administration - parenteral- Do not inject IM only IV or deep s.c.
Half-life 1 - 5 hrs - monitor aPTT
Adverse effect: hemorrhage
Antidote : protamine sulphate
Heparin mechanism of action
Heparin
Antithrombin III
Thrombin
Oral anticoagulants







Examples: Coumarins - warfarin, dicumarol
Structurally related to vitamin K
Inhibits production of active clotting factors
Clearance is slow - 36 hrs
Delayed onset 8 - 12 hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - do not use during late
pregnancies
Mechanism of action
Descarboxy Prothrombin
Prothrombin
Reduced Vitamin K Oxidized Vitamin K
NAD
NADH
Warfarin
Normally, vitamin K is converted to vitamin K epoxide in the liver.
→This epoxide is then reduced by the enzyme epoxide reductase.
→The reduced form of vitamin K epoxide is necessary for the synthesis of many
coagulation factors (II, VII, IX and X, as well as protein C and protein S).
→Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting
coagulation. )‫(عبدهللا المطيري‬
Warfarin Side Effect
Severe Side effects:
•Severe bleeding
•Bleeding from the rectum or black stool
•Skin conditions such as hives, a rash or itching
•Swelling of the face, throat, mouth, legs, feet or hands
•Bruising that comes about without an injury you remember
•Chest pain or pressure
•Nausea or vomiting
•Fever or flu-like symptoms
•Joint or muscle aches
•Diarrhea
•Difficulty moving
•Numbness of tingling in any part of your body
•Painful erection lasting four hours or longer
Warfarin Side Effect
Other less serious warfarin side effects:
•Gas
•Feeling cold
•Fatigue
•Pale skin
•Changes in the way foods taste
•Hair loss
Drug interaction- with Warfarin
Category
Drugs that Increase
Warfarin Activity
Mechanism
Representative Drugs
Decrease binding to
Albumin
Aspirin, Sulfonamides
Inhibit Degradation
Cimetidine, Disulfiram
Decrease synthesis of
Clotting Factors
Antibiotics (oral)
Drug interaction with Warfarin
Drugs that promote
bleeding
Drugs that decrease
Warfarin activity
Inhibition of platelets
Aspirin
Inhibition of clotting
Factors
heparin
antimetabolites
Induction of metabolizing
Enzymes
Barbiturates
Phenytoin
Promote clotting factor
Synthesis
Reduced absorption
Vitamin K
cholestyramine
colestipol
Antiplatelet drugs
Example: Aspirin
 Prevents platelet aggregation /adhesion
 Clinical use - prevents arterial thrombus

 Myocardial infarction (MI), stroke, heart valve
replacement and shunts

Other antiplatelet drugs are Dipyridamole, sulfinpyrazone and
Ticlopidine
Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
 COX is a key enzyme involved in the
synthesis of thromboxane 2
(prostaglandins)
 Inhibits platelet aggregation

Prophylactic use of Aspirin

Low dose daily.

Prevents ischemic attack (ministroke) and MI

335 mg/day reduced the risk of heart attack in
patients over 50

More than 1000 mg/day NO EFFECT
 Contraindication - DO NOT give to patients with
glucose 6-PO4 dehydrogenase deficiency
Fibrinolysis

Enhance degradation of clots

Activation of endogenous protease

Plasminogen (inactive form) is
converted to Plasmin (active form)

Plasmin breaks down fibrin clots
Fibrinolysis

Exogenously administered drugs
 Streptokinase - bacterial product
○ - continuous use - immune reaction
 Urokinase - human tissue derived –
○ no immune response
 Tissue plasminogen activator (tPA) - genetically
cloned
○ no immune reaction
○ EXPENSIVE
Drug preparations : To reduce clotting

Heparin (generic, Liquaemin sodium)
 Parenteral - 1000 - 40,000 U/ml

Warfarin (generic , Coumadin)
 Oral : 2 - 20 mg tablets

Dipyridamole (Persantine)
 Oral : 25,50,75 mg tablets
Drug preparations : to lyse clots

Alteplase recombinant (tPA, Activase)
 20, 50 mg Lyophilized powder - reconstitute for iv

streptokinase (Kabikinase, streptase)
 Parenteral : 250000 - 1.5 million units per vial .
Lyophilized powder. Reconstitute for iv

Urokinase ( Abbokinase)
 Parenteral : 250000 units per vial. Powder to
reconstitute to 5000 u/ml for injection
Drug preparations: clotting deficiencies

Vitamin K ( Phytonadione (K1), Mephyton
 Oral : 5 mg tablets

Plasma fractions - for hemophilia
 Antihemophilic factor ( VIII, AHF)
 Parenteral

Factor IX complex (konyne HT, proplex T)
 Parenteral : in vials
Drug preparations : to stop bleeding


Systemic use : aminocaproic acid (Amicar);
Tranexamic acid (cyclokapron),Vitamin K
Local adsorbable drugs
 Gelatin sponge (Gelfoam)
 Gelatin film
 Oxidized cellulose ( Oxycel)
 Microfibrillar collagen (Avitene)
 Thrombin