objectives to learn how blood clots are formed. how the blood clots are broken down ? what drugs...
TRANSCRIPT
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
within the blood
vessels
Clotting slower
Activated partial
thromboplastin test
(aPTT)
Extrinsic Pathway
Initiating factor is
outside the blood
vessels - tissue factor
Clotting - faster - in
Seconds
Prothrombin test (PT)
Blood Vessel Injury
IX IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen Fribrin monomer
Fibrin polymerXIII
Intrinsic Pathway Extrinsic Pathway
Factors affectedBy Heparin
Vit. K dependent FactorsAffected by Oral Anticoagulants
Anticoagulant drugs to treat thromboembolism
Drug Class Prototype Action Effect
AnticoagulantParenteral
Heparin Inactivation of clottingFactors
Prevent venousThrombosis
AnticoagulantOral
Warfarin Decrease synthesis ofClotting factors
Prevent venousThrombosis
Antiplateletdrugs
Aspirin Decrease plateletaggregation
Prevent arterialThrombosis
Thrombolytic Drugs
Streptokinase Fibinolysis Breakdown ofthrombi
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
NADHNAD
WarfarinNormally, 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. ( المطيري (عبدالله
Warfarin Side EffectSevere 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
Drugs that Increase Warfarin Activity
Decrease binding toAlbumin
Inhibit Degradation
Decrease synthesis ofClotting Factors
Aspirin, Sulfonamides
Cimetidine, Disulfiram
Antibiotics (oral)
Category Mechanism Representative Drugs
Drug interaction with Warfarin
Drugs that promotebleeding
Inhibition of platelets Aspirin
Inhibition of clotting heparinFactors antimetabolites
Drugs that decreaseWarfarin activity
Induction of metabolizing BarbituratesEnzymes Phenytoin
Promote clotting factor Vitamin KSynthesisReduced absorption 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), MephytonOral : 5 mg tablets
Plasma fractions - for hemophiliaAntihemophilic 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 drugsGelatin sponge (Gelfoam)Gelatin filmOxidized cellulose ( Oxycel)Microfibrillar collagen (Avitene)Thrombin