anticoagulants naser
TRANSCRIPT
Anticoagulants
Dr Naser
Case study
• A 25-year-old woman presents to the emergency department complaining of acute onset of shortness of breath & pleuritic pain. she noted that her left leg was swollen and red 2 days prior . Her only medication was oral contraceptives. Family history was significant for a history of "blood clots" in multiple members of the maternal side of her family. The left lower extremity demonstrates erythema and edema and is tender to touch.
Common Thrombo Embolic Disorders For Drug Intervention
• Post myocardial infarction• Prosthetic heart valves• Chronic atrial fibrillation • Acute deep vein thrombosis• Pulmonary embolism• Patients undergone orthopedic or
gynecological surgery & in bed ridden patients
Hemostasis
• Hemostasis:– Minimization or arrest of blood loss
• Haemostatic mechanisms– Vasoconstriction – Platelet plug formation – Blood coagulation (Formation of clot)
Factors involved in coagulation
Factor I: Fibrinogen Factor II : Prothrombin Factor III:Tissue factor/ tissue
thromboplastin Factor IV : calcium
Factor V: proaccelerin Factor VII: stable factor/
proconvertin Factor VIII: antihaemophilic
factor A
Factor IX: Christmas factor / Anti HB/ PTC
Factor X: Stuart –Prower factor
Factor XI: PTA
Factor XII: Hageman Factor
Factor XIII: Fibrin Stabilizing Factor
Extrinsic Pathway Intrinsic Pathway
Tissue Trauma
VII
VIIa
X
IXa
Prothrombinase
Prothrombin Thrombin
FibrinogenFibrin insoluble
Stabilized fibrin threads
Damaged endothelial cells/ contact with glass
XII
XIa XI
IX
XIIa
Xa XVIIIVIIIa
XIII
XIIIa
Ca2+
TF
Ca2+
PL
Ca2+VIIa
Ca2+
PL
Activation of platelets
PL (Used in cascade)
Ca2+ PLVa
Fibrinolytic system
• The process of dissolution of clot is called fibrinolysis
Plasminogen
t-PA Endothelial cells
Plasmin
Digests fibrin
Natural anticoagulant mechanisms
• Prostacyclin (PGI2)– Inhibits action of TXA2
• Antithrombin III:– blocks the action of factors II,IX,X,XI,XII
• Protein C:– Blocks the action of factors V &VIII– ↑ t-PA action
• Heparan sulphate :– Cofactor , enhances activity of antithrombin III
• Used in vivo – Parenteral
• Heparin, Low molecular weight heparins, heparinoids
– Oral• Coumarin derivatives• Indandione derivatives
• Used in vitro – Heparin – Calcium complexing agents
• Sodium citrate, sodium oxalate, sodium edetate
Classification of anticoagulants
Classification of anticoagulants(used in Vivo)
Parenteral :• Heparin • LMW heparins
– Enoxaparin, dalteparin, ardeparin, nadoparin, reviparin
• Heparinoids– Heparan sulfate,
danaparoid, lepirudin, ancrod
Oral anticoagulants:• Coumarin derivatives
– Warfarin, dicumarol, acenocoumarol, ethyl-biscoumacetate
• Indandione derivates– Phenindione
Heparin
• Discovered by Mc Lean in 1916 • Mixture of sulfated mucopolysaccharides
10,000 to 20000 MW • Strong electronegative compound• Strongest organic acid in body • Present in all tissues containing mast cells • Commercially prepared from beef lung and pig
intestinal mucosa
Mechanism of action
Antithrombin IIISlowly
Inactive Coagulation factors
+
Heparin accelerates Antithrombin III activity by 1000 foldEspecially against IIa & Xa
Fast Heparin AT-III complex
AT-IIIHeparin
•Heparin provides scaffolding for clotting factors & AT-III•Induces confirmational changes in AT-III to expose its interactive site
Other actions of heparin
• Antiplatelet – High doses inhibits platelet aggregation and
prolongs bleeding time • Lipaemia clearing
– Clears turbid postprandial lipaemic plasma by releasing lipoprotein lipase from vessel wall & tissues
Pharmacokinetics
• Orally not absorbed -Large molecules • Route – IV/SC• Does not cross BBB/ Placenta• Metabolised by Heparinase in Liver• Heparin sodium - 5ml vials 1000 & 5000 units/ml• t1/2 – 1 hr
Dosage
• 5000-10000 units I.V , 4-6 hrly or• IV bolus 5000 units followed by continuous 750-
1000 units/IV/hr• Deep SC 10000-20000 units every 8-12hrly • Low dose SC regimen 5000 units every 8-12hrly
to prevent post operative DVT• Dose controlled by APTT (1.5-2.5 times normal) Total Clotting time (2 times the normal)
HEPARIN – ADVERSE EFFECTS
1. Bleeding due to overdose2. Osteoporosis 3. Thrombocytopenia4. Hypersensitivity (Anaphylaxis)5. Transient alopecia
• Antidote – Protamine sulphate 50 mg in 5ml for IV
1mg IV for 100 units heparin
Contraindications
• Bleeding disorders • Heparin induced thrombocytopenia• Severe hypertension • Threatened abortion, piles • SABE • Occular , neurosurgery , lumbar puncture • Chronic alcoholics, cirrhosis• Aspirin other antiplatelet drugs use cautiously
Protamine sulfate
• Strongly basic LMW protein • Obtained from sperm of certain fish• 1 mg IV neutralizes 100 U of heparin• Needed infrequently to antagonize heparin
action rapidly • Can act as week anticoagulant in absence of
heparin • Rapid IV injection causes flushing and
breathing difficulty
Low Molecular Weight Heparins• M.Wt : 3000-7000• Selectively inhibit factor Xa ,No effect on IIa• Used for prophylaxis of Deep Vein Thrombosis
Pulmonary Embolism, Unstable angina• ENOXAPARIN: 20-40 mg S.C , O.D • REVIPARIN:13.8mg(0.25ml) S.C/OD for 5-10
days• NADROPORIN :0.3ml(3075 units)• TINZAPARIN :3500 units S.C every 24hr)
LOW MOLECULAR WEIGHT HEPARINS
• Higher S.C bioavailability• Longer duration of action • Do not routinely require aPTT monitoring • Lesser antiplatelet action• Less antigenic• Less hemorrhagic complications• Better patient compliance
HEPARINOIDS• Used In patients developing thrombocytopenia
with Heparin1. HEPARAN SULPHATE : less potent, better profile. 2. LEPIRUDIN : Recombinant preparation of Hirudin .
Inhibits Thrombin directly, it is indicated in patients with heparin induced thrombocytopenia.
3. ANCROD : enzyme from Malayan Pit Viper venom
Fibrinogen
Unstable fibrin(Taken up by RE cells)
Slow IV infusion 2units/kg over 6hrs for DVT
Oral Anticoagulants 1924 – Hemorrhagic disease in cattle due to feeding of spoiled sweet clover (contained bishydroxy coumarin)
Mechanism of action
Vitamin K reduced form Hydroquinone KH
Vitamin K oxidized form Epoxide KO
Descarboxy factors II,VII,IX,X
carboxylated factors II,VII,IX,X
NAD NADH
VitK reductase
Warfarin
Pharmacokinetics & dosage of oral Anticoagulants :
DRUG t½ (hr) DURATION OF ACTION(days)
DOSAGELOADING (mg)
DOSAGE MAINTENANCE(mg)
Bishydroxycoumarin
25-100 4-7 200 for 2 days
50-100
Warfarin sodium
36-48 3-6 10-15 2-10
Ethylbiscoumacetate
24 1-3 900 300-600
Acenocoumarol
18-24 2-3 8-12 2-4
Phenindione 5 1-3 200 50-100
• Most popular oral anticoagulant• Racemate • Absorbed orally, crosses placenta • 99% pl.protein bound• Partially conjugated with glucuronic acid• Available as 1,2.5 mg tablet • Can be given parenterally as it is water
soluble
Warfarin Sodium
• Dose Regulation Of Oral Anticoagulants : By Prothrombin time
• INR
• ADVERSE EFFECTS :1. Bleeding- antidote: Vit.K2. Teratogenic 3. Agranulocytosis 4. nephropathy 5. Hepatitis by phenindione6. orange urine
DRUG INTERACTIONS Oral anticoagulant effect
ed by• Broad spectrum
antibiotics • Phenylbutazone• Aspirin• Sulfonamides• Phenytoin
ed by
• Barbiturates• Rifampin• Oral contraceptives
Uses of anticoagulants
• Deep Vein Thrombosis & Pulmonary Embolism in bed ridden , old , post operative, leg fracture pts
• MI – for short period till pts become ambulatory• Unstable angina• Rheumatic Heart Disease , Atrial Fibrillation• CerebroVascular Diseases• Prosthetic heart valves• Hemodialysis • Disseminated Intravascular Coagulation
Comparison
HEPARIN • Mucopolysaccharide • Parenteral • Immediate onset • Duration of action 4-6 hrs• Activity invitro & in vivo • Blocks action of factor X & II
• Antagonist - protamine • Monitor aPTT
WARFARIN • Coumarin derivative • Oral • Delayed onset of action • 3-6 days • Only invivo • X synthesis of clotting
factors • Antagonist is Vit K • Monitor PT/INR