Post on 25-Dec-2015
Prof. Aboubakr ElnasharEmail: elnashar53@hotmail.com
• Vascular Phase• Platelet Phase• Coagulation Phase• Fibrinolytic Phase
1. Vascular Phase
• V.C• Exposure to tissues activate tissue factor
and initiate coagulation
Tissue Factor
2. Platelet phase
• Blood vessel wall (endothelial cells) prevent platelet adhesion & aggregation
• Platelets contain receptors for fibrinogen and von Willebrand factor.
• After vessel injury: Platelets adhere & aggregate• Release permeability increasing factors (e.g. vascular
permeability factor, VPF)• Loose their membrane & form a viscous plug
3. Coagulation Phase
• 2 major pathways• Intrinsic pathway• Extrinsic pathway
• Both converge at a common point• Clotting factors:13 soluble Biosynthesis is dependent on Vitamin K1& K2 Most are proteases Normally inactive & sequentially activated
Intrinsic Pathway• All clotting factors are
within the blood vessels• Clotting: slower• aPTT
Extrinsic Pathway• Initiating factor is outside the blood
vessels: tissue factor• Clotting: faster in Seconds• 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
ThrombiAcc to location & composition
Arterial• Occur in areas of rapid flow
(arteries)• In response to an injured or
abnormal vessel wall• White • Composed: primarily of platelets, also fibrin &
occasional leukocytes• Associated withMI Strokeischemia
Venous•Occur primarily in the venous circulation•In response to venous stasis or vascular injury •Red•Composed almost entirely of fibrin & erythrocytes•Associated withCongestive Heart Failure, CancerSurgery.
4. Fibrinolysis
Enhance degradation of clotsActivation of endogenous proteasePlasminogen (inactive form) is converted to Plasmin (active form)Plasmin breaks down fibrin clots
Drug Class Prototype Action Effect1. Anticoagulant Parenteral
Heparin Inactivation of clottingfactors
Prevent DVT
Oral Warfarin Decrease synthesis ofclotting factors
Prevent DVT
2. Antiplatelet
Aspirin Decrease plateletaggregation
Prevent arterialthrombosis
3. Thrombolytic Streptokinase Fibinolysis Breakdown ofthrombi
I. Anticoagulants1. Heparin
StructureMucopolysaccharide MetabolismPartially in the liver by heparinase to uroheparin, which has
only slight antithrombin activity. 20-50 % is excreted unchanged. {The heparin polysaccharide chain is degraded in the gastric
acid} administered IV or SC. Heparin should not be given IM } danger of hematoma
formation{ .
Unfractionated heparin (UFH)Mol weight:3000-30000Mechanism of action:•Primarily: interaction with antithrombin III: alters the molecular configuration of antithrombin III, making it 1,000 to 4,000 times more potent as an inhibitor of thrombin formation: limits conversion of fibrinogen to fibrin: prolongs aPTT•Also inhibits the effects of factor Xa on the coagulation cascade & limits platelet aggregation. Half-life:IV: 1 hr SC: 3 hrs.
UFH inactivate factor IIa through formation of a tertiary complex (unlike LMWH).
UFH binds more to plasma proteins, endothelium and macrophages: reduced bioavailability & greater patient variability to a given dose.
UFH inactivates factors IIa and Xa & affects the aPTT (measure of anti-factor IIa activity).
Heparin-induced thrombocytopenia 20% . Diagnosis: platelet count falls below the lower limits of normal or by 50% but remains in the normal range. a.Type 1Mild, rarely dropping below 100,000 platelets/ML. Platelet count monitoring is important, but therapy usually can continue {platelet count returns to normal even with continued use}. {platelet activation & is not immune-mediated}.b. Type 27 to 14 days after starting therapy. Platelet counts frequently drop to 20,000/ML. {an immune response caused by antibodies to the heparin-platelet factor 4 complex}.
It is related to: Mol wt, dose & duration of therapy. immediate withdrawal of all forms of heparin is mandatory. Platelet concentration should be monitored at least every 2 days.
Dosing options. Preoperative: 5,000U 2 hours before surgery. {The single preoperative dose seems to be as effective as multiple preoperative doses}.
Postoperative: 8 to 12 hrs after surgery & every 8 to 12 hrs until the patient is fully ambulatory.Antidote: Protamine sulphateMonitor: aPTTUse in pregnancy :{does not cross the placenta} safe
Low-Molecular-Weight Heparin •Molecular weight 1000-10000 Da. •Produced by concentrating the low molecular component of UFH. Enzymatic or chemical controlled hydrolysis of UFH. •The mechanism of actionPrimarily by inhibiting factor Xa, which is higher in the coagulation cascade than antithrombin: LMWH is more efficient than UFH. {the molecular configuration of antithrombin III is not altered by LMWH} thrombin conversion is minimally inhibited and aPTT is not appreciably affected.
LMWH inhibits factor Xa and minimally affects factor IIa; thus aPTT is not used to measure its anticoagulant activity.
Generic TradeManufacturerMol Wt
EnoxaparinLovenex, ClexaneRhone-Poulence-Rorer4500
TinzaparinLogiparineNovo4850
DalteparinFragminKabi6370
Half-life: 4 hrs, by any route: longer dosing interval. BioavailabilityMore consistent than that of UFH: dosing is based on lean body mass & Less thrombocytopenia.Use in pregnancy: Does not cross the placenta: safe.Dosing options. Prophylaxis: Once a dayTherapy: Twice-daily. Enoxaparin is an LMWH Moderate risk: 20 mg/dHigh risk: 40 mg/d. •Advantage Decreased need for monitoring
UFHLMWH
Mol Wt range3000-300001000-10000
Mo Wt average12000-150004000-5000
AntiXa: antiIIa activity1:12:1-4:1
aPTT monitoring requiredYesNo
Inactivation by platelet factor 4YesNo
Capable of inactivation of platelet bound factor Xa
NoYes
Inhibition of platelet function++++++
Increase vascular permeabilityYesNo
Protein binding+++++
Endothelial cell binding+++-
Dose dependent clearanceYesNo
Elimination half life50-20 min2-5 times longer
2. Oral anticoagulants • Coumarins - warfarin, dicumarol
Structure: small, lipid-soluble molecules, Structurally related to vitamin K,
isolated from clover leavesMechanism:• Inhibits production of active clotting factors• blocks the Vitamin K-dependent glutamate carboxylation of
precursor clotting factors e.g. FII, VII, IX , X Metabolism:• Absorption: rapid• Binds to albumin• Clearance is slow: 36 hrs • Delayed onset: 8-12 hr {T1/2 of clotting factors in plasma}
blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting factors
Use:To prevent the formation, recurrence or extension of DVT & PENot used in pregnant women {cross placenta}Not used for arterial thrombi {No effect on platelets} Toxicity:bleeding birth defectsOverdose:Reversed by vitamin K infusionRecovery needs synthesis of new clotting factors
Warfarin tablets, 5, 3 and 1mg
Drugs that Increase Warfarin Activity
Decrease binding toAlbumin
Inhibit Degradation
Decrease synthesis ofClotting Factors
AspirinSulfonamides
Cimetidine, Disulfiram
Antibiotics (oral)
Category Mechanism Representative Drugs
Inhibition of platelets Aspirin
Inhibition of clotting HeparinFactors Antimetabolites
Drugs that promotebleeding
Induction of metabolizing BarbituratesEnzymes Phenytoin
Promote clotting factor Vitamin KSynthesis OCReduced absorption Cholestyramine
Colestipol
Drugs that decreaseWarfarin activity
HeparinWarfarinAbsorptionParentral onlyOral
Vol of distributionPlasma vol (0.07 L/kg)7.6-13.9 L
Metabolism/ClearanceHepatic metabolism & uptake by reticulo endothelial system
Also by thrombin & other clotting factors
Hepatic
Elimination t1/250-90 min36-42 hr
Protein bindingBound to antithrombin III & other serine proteases
99.4% bound to albumin
Plasma concentration (therapeutic)
0.2-0.4 U/ml1.5 mg/L
Side effectsBleeding
Thrmbocytopenia
Osteoporosis
Bleeding
Skin necrosis
Drug interactions
Treatment of bleeding
•Mild: Slow or stop infusion•Severe: Protamine 1 mg/100 u of estimated heparin remaining in body
•Mild: hold 1-2 doses, observe, restart at lower dose•Severe: Vit K or fresh frozen plasma
II. Antiplatelet DrugsActivation and aggregation of platelets is a major component of thrombosis especially in arteries
Targets for platelet inhibitory drugs:(a) inhibition of prostaglandin metabolism through inhibition of cyclooxygenase (aspirin)
(b) inhibition of ADP-induced platelet aggregation (ticlopidine)
Platelet Activation:•Endothelial damage of vessel: exposes collagen •Activated platelets release ADP, serotonin (5-HT)& thromboxane A2 (TXA2-) from arachidonic acid: platelet aggregation by causing the appearance of binding sites for fibrinogen on platelet membrane •Fibrinogen is involved: platelet to platelet adhesion (aggregation) •Thrombin causes further platelet activation by releasing platelet ADP & stimulating PG synthesis prostacyclin (PGI2) - synthesized within vessel walls inhibits thrombogenesis by increasing platelet cAMP. Nitric oxide (NO) - released by endothelium - increases cAMP
(a) NSAIDSAspirin - prototypeMechanism:inhibits cyclooxygenase (COX)COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins). Inhibits platelet aggregationlong acting because new proteins must be synthesized other NSAIDS:shorter duration because of reversible competitive inhibitory action potency varies, e.g. Naproxen, meclofenamic acid, Ibuprofen, Indomethacin, phenylbutazare
Contraindication: Patients with glucose 6-PO4 dehydrogenase deficiency
Dose:• Low dose daily (180 mg/day): Prevents ischemic attack
(ministroke) and MI• 335 mg/day: reduced the risk of heart attack in patients
over 50Use:• Prevention of recurrent infarcts in patients with myocardial
infarction, also reduces the incidence of first infarcts• low-dose aspirin, compared with placebo, reduces by
36% the risk of VTE after orthopaedic surgery• Meta-analysis of trials in surgical and medical patients: significant
reduction in DVT and PE with antiplatelet prophylaxis. (Pulmonary embolism prevention (PEP) Trial . Prevention of PE and DVTwith low dose aspirin: Lancet 2000; 355:1295–302.)
(b) Ticlopidinedecrease platelet aggregation by inhibiting ADP pathway of platelets no effect on PG metabolism used as alternative for patients intolerant to aspirin expensive (C) Other antiplatelet drugs: Dipyridamole, sulfinpyrazone
III. Thrombolytic AgentsAgents which reduce the formation of arterial platelet thrombi Mechanism:• Rapid lysis of thrombi by catalyzing the formation of plasmin from
plasminogen • Endogenous plasmin breaks down fibrin promoting clot dissolutionUse:• Emergency treatment of coronary artery thrombonís in M.I. • IV or intracoronary injection • DVT: rapid recanalization of occluded vessels Toxicity:• Bleeding (intracranial, G.I.) • Allergic reactions (i.e. streptokinase)
Streptokinase: Purified from bacteria Continuous use: immune reaction Forms a complex with plasminogen & catalyzes it: rapid conversion to plasmin Urokinase:From cultured human kidney cellsNo immune response Directly converts plasminogen to plasmintPA:Produced by recombinant techniquesNo immune reaction - EXPENSIVE Promotes conversion of plasminogen (that is found to fibrin) to plasmin In theory, selective for formed clots
Enzymatic efficiency for clot lysis
Fibrin specificity
Potential antigenicity
Average dose
Dosing administration
Cost
StreptokinaseHighMinimalYes1.5 MU1 hr IV infusionLow
AntistreplasehighMinimalYes30 u2-5 min IV infusion
Moderate
Tissue plasminogen activator
HighModerateNo100 mg15 mg IV bolus, 50 mg over 30 min, then 35 mg over 60 min
Moderate
UrokinaselowmoderateNo2 mu1 mu IV bolus,
1 mu over 60 min
high
Thank youAboubakr Elnashar