Anticoagulant
Dr Rasha
Blood Coagulation
• The coagulation process that generates thrombin consists
of two interrelated pathways:
• the extrinsic pathways.
• The intrinsic pathways.
cascad
Anticoagulants
• Low molecular weight heparins (LMWHs)
• Unfractionated heparin (UFH)
• Factor Xa inhibitors: oral
(eg, rivaroxaban, apixaban, edoxaban) and parenteral
(fondaparinux)
• Direct thrombin inhibitors: oral (dabigatran, etexilate) and
parenteral (argatroban, bivalirudin, desirudin)
• Warfarin
❖ direct oral anticoagulant: Oral factor Xa inhibitors and direct
thrombin inhibitors .
Heparin and low molecular weight heparin
Mechanism of action:
• Heparin acts at a number of molecular
• binding to antithrombin III.
• Antithrombin III is an α-globulin. It inhibits serine proteases(
thrombin (Factor IIa) and Factor Xa ).
• catalytic template for the interaction of antithrombin III and
the activated coagulation factors.
• In contrast, LMWHs complex with antithrombin III and
inactivate Factor X (platelet surfaces)but do not bind as avidly
to thrombin.
• A unique pentasaccharide sequence contained in heparin and
LMWHs permits their binding to antithrombin III
Pharmacokinetics:
Process Heparin Low molecular weight
heparin (Enoxaparin)
absorption onset of action are achieved immediately 100% bioavailability after
after intravenous administration SC administration
Volume of 0.07 l/kg 4-5 l
distribution
Protein Heparin is highly bound to antithrombin, liver via desulfation
binding fibrinogens, globulins, serum proteases,
and lipoproteins
Elimination Zero-1st order kidney
Half life 0.5-2 hr 4 hr
Adverse effects
• Bleeding complications (protamine
sulfate). Infused slowly, (1 mg for every
100).
• Hypersensitivity reactions.
• Thrombosis.
• Thrombocytopenia:(lepirudin or
argatroban).
• Heparin may produce abnormal liver
function tests, and osteoporosis.
• Contraindications: hypersensitive,
bleeding disorders,alcoholics, recent
surgery(brain, eye, or spinal cord).
Other parenteral anticoagulants
• Lepirudin:
• A highly specific, direct thrombin antagonist.
• a polypeptide that is closely related to hirudinâ (a thrombin
inhibitor derived from medicinal leech saliva)
• blocke thrombogenic activity of thrombin.
• It has little effect on platelet aggregation.
• Administered intravenously .
• treatment of HIT and other thromboembolic disorders.
• half-life of about 1 hour, and it undergoes hydrolysis. The
parent drug and its fragments are eliminated in the urine.
• Bleeding is the major adverse effect of treatment with
Argatroban:
• a parenteral anticoagulant that is a small molecule that direct
inhibits thrombin.
• prophylactically for the treatment of thrombosis in patients
with HIT, and it is also approved for use during percutaneous
coronary interventions in patients .
• metabolized in the liver and.
• half life of about 50 minutes.
• It is monitored by aPTT.
• The patient's hemoglobin and hematocrit must also be
monitored.
• the major side effect is bleeding.
Fondaparinux
• less monitoring than heparin.
• eliminated in urine mainly as unchanged drug with an
elimination
• half-life of 17 to 21 hours.
• It is contraindicated in patients with severe renal impairment
(<30 mL/min).
• Bleeding episodes are the major side effect of fondaparinux
therapy.
• thrombocytopenia, is not a problem, and this agent may be
used in patients with HIT.
Vitamin K antagonists
• The coumarin anticoagulants, which include warfarin,
and dicumarol .
• antagonize the cofactor functions of vitamin K.
• Universal color:
• White .5mg.
• Brown 1mg
• Blue 3mg
• Pink 5mg
Mechanism of action
• Several of the protein coagulation
factors (including Factors II, VII,
IX, and X require vitamin K as a
cofactor for their synthesis by the
liver.
• anticoagulant effects of 8 to 12 hours
after drug administration, but peak
effects may be delayed for 72 to 96
hours.
• The anticoagulant effects of
warfarin can be overcome by the
administration of vitamin K.
Pharmacokinetics:
• Absorption: rapidly absorbed after oral administration.
• (100% bioavailability .
• 99 percent bound to plasma albumin.
• Warfarin readily crosses the placental barrier.
• The mean half life of warfarin is approximately 40 hours.
• Prothrombin time, the international normalized ratio (INR)
was adopted to monitor warfarin concentration.
• Fate: The products of warfarin metabolism, catalyzed
by the cytochrome P450 system, are inactive. After
conjugation to glucuronic acid, they are excreted in the
urine and stool.
Therapeutic uses:
• Warfarin is used to prevent the progression or recurrence
of acute deep-vein thrombosis or
• pulmonary embolism after initial heparin treatment. It is
also used for the prevention of venous
• thromboembolism during orthopaedic or gynecologic
surgery. Prophylactically, it is used in patients with
acute
• myocardial infarction, prosthetic heart valves, or chronic
atrial fibrillation.
Adverse effects:
• Bleeding disorders.
• Drug interactions:
• Disease states: Vitamin K
deficiency, hepatic disease
that impairs synthesis of the
clotting factors or affects
warfarin metabolism, and
hypermetabolic.
• Contraindications: Warfarin
should never be used during
pregnancy, because it is
teratogenic and can cause
abortion as well as birth
defects.
monitoring
• Warfarin overdose
rapid: fresh frozen plasma
Slow: vitamine K
• Direct oral anticoagulant (Dabigatran)
➢Activation of the prodrug Dabigatran etexilate
➢Prothrombin inhibitor
• Direct oral factor Xa inhibitors
➢Apixaban,betrixaban ,edoxaban, and
rivaroxaban .
➢oral inhibitors of factor Xa
Thrombolytic Therapy
Thrombolytic agent
• convert plasminogen to plasmin lead to degradation of fibrin
(fibrinolysis) that results in clot lysis.
➢ Streptokinase
➢ Tissue Plasminogen Activator (rt-PA)
➢ Urokinase
➢ Retavase
➢ Tenecteplase, TNK-tPA ( TNKase )
Anticoagulant Therapy
Thrombolysis
PLASMINOGEN ACTIVATOR
PLASMINOGEN ACTIVATOR
INHIBITOR-1
(PAI-1)
PLASMINOGEN PLASMIN
alpha - ANTIPLASMIN
2
FIBRIN DEGRADATION
FIBRIN PRODUCTS
Streptokinase Tissue Plasminogen Activator
• Streptokinase is a nonenzyme • is converted by plasmin to a two
protein (streptococci) chain form by made by
• activates plasminogen to plasmin recombinant DNA technology.
indirectly • t-PA has affinity for fibrin
• Plasma half-life of 20 min
• Neutralized by anti-streptokinase • plasmin bound to fibrin is
antibodies due to previous protected from the rapid
infections with ß-hemolytic inactivation of its enzymatic
streptococci activity.
• Anti-streptokinase titer increases • free plasmin in the plasma has a t
50 - 100 times within a few days 1/2 of 0.1 seconds as compared to
after administration, remains high plasmin that is bound to fibrin (10
for 4 - 6 months to 100 secs).
• Repeated therapy within this time • rt-PA (Alteplase; Activase )
is impractical approved for use in: myocardial
infarction and stroke.
Absolute contraindication Relative contraindication
Aortic dissection Blood pressure > 180/110 mm Hg
after initial antihypertensive therapy
Previous hemorrhagic stroke (at any Trauma or major surgery within 4
time) weeks
Previous ischemic stroke within 1 Active peptic ulcer
year
Active internal bleeding (not Pregnancy
menses)
Intracranial tumor Bleeding diathesis
Pericarditis (INR > 2)
Guidelines for use of rt-PA in stroke
-1
• Intravenous rt-PA should be given within 3 hours
of onset of ischemic stroke in a dose of 0.9 mg/kg
(max 90 mg), with 10% of the dose given as a
bolus followed by a 60 min infusion.
• rt-PA can not be recommended for use beyond 3
hours after stroke onset.
• Data are inadequate to permit recommendation
of i.v. streptokinase for ischemic stroke.
Guidelines for use of rt-PA in stroke
-2
• Thrombolysis is not recommended unless the
proper diagnosis (with CT of the brain) made by
physicians expert in diagnosing stroke and
reading CT.
• Avoid thrombolysis where there is evidence of
recent major infarction, mass effect, edema or
possible hemorrhage, on heparin in the last 48
hrs or warfarin or with a platelet count <100,000.
• Patients treated with rt-PA for stroke, should not
be given aspirin, ticlopidine, clopidogrel,
heparin, or warfarin.
Comparative Pharmacologic
Features
Feature SK APSAC UK SCUPA
rtPA
Half-Life (min) 23 90 16 7
5
Fibrin-Selective + + ++ ++++
+++
Duration of
Infusion 60 min 2-5 m 5-15 m Hours
Hours
Antigenicity Yes Yes No No?
No?
Incidence of
Reperfusion (%) 60-70 60-70 60-70 60-70
60-70
Frequency of
