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Drugs Affecting Blood Coagulation (Thrombolytic Drugs (Adverse Effects…
Drugs Affecting Blood Coagulation
Overview
Thromboembolic Diseases
thrombosis
- formation of unwanted clot within blood;
thrombus
- clot that adhere to vessel wall
detached thrombus becomes
embolus
- intravascular clot that floats in blood
eg: acute MI, deep vein thrombosis (DVT), pulmonary embolism (PE) & acute ischemic stroke
Coagulation Process
consist of extrinsic & intrinsic pathways
Extrinsic system initiated by activation of clotting factor VII to VIIa in response to vascular injury
In intrinsic pathway, XII to XIIa, XI to XIa, IX to IXa, and ultimately, X to Xa which converts prothrombin (factor II) to thrombin (factor IIa)
formation of unwanted thrombus & embolus are similar to clot formation
physical trauma initiates interactions between platelets, endothelial cells & coagulation cascade
Platelet Aggregation Inhibitors
Aspirin
Overview
stimulation of platelets by thrombin results in activation of platelet membrane phospholipases that
liberate arachidonic acid
from membrane phospholipids
arachidonic acid converted to
prostaglandin H2 (PGH2) by cyclooxygenase-1 (COX-1)
which further metabolized to
thromboxane A2 (TXA2)
TXA2
promotes aggregation- essential for rapid formation of hemostatic plug (platelet plug)
Mechanism of Action
Aspirin inhibits TXA2 synthesis by
irreversibly
inactivating COX-1 preventing platelet aggregation
inhibitory effect-rapid. Last for 7-10 days
Therapeutic Use
Transient cerebral ischemia
- as a prophylatic treatment
MI
- to reduce recurrent MI. Complete inactivation of platelet occurs with 75 mg of aspirin given daily. Recommended dose= 50-325 gm daily
Precautions
Prolonged bleeding time
increased incidence of
hemorrhagic stroke & GI bleeding
, esp at higher dose
Ibuprofen
(COX-1 inhibitor), if taken within 2 hours prior to aspirin, will
antagonize platelet inhibition by aspirin
. Aspirin should be taken 60 mins before or 8 hrs after ibuprofen
Overview
decrease formation of platelet-rich clot & action of chemical signals that promote platelet aggregation
inhibit cyclooxygenase-1
(eg: aspirin);
block ADP receptors
(eg: clopidogrel);
block GP IIb/IIIa receptors
(eg: abciximab)
known as anti-platelets
beneficial in prevention & treatment of occlusive cardiovascular diseases & as
adjuncts
to thrombin inhibitor (eg: heparin) or thrombolytic therapy (eg: urokinase) for MI
Clopidogrel
Overview
rely entirely on its
active metabolite
produced via metabolism by CYP2C19
poor metabolizer
of clopidogrel need to use other anti-platelet agents (eg: prasugrel) with different metabolizing enzyme (CYP2B6 & CYP3A4)
drugs that inhibit CYP2C19 (eg: omeprazole & esomeprazole) should not be administered concurrently with clopidogrel
Therapeutic Use
Prevention of atherosclerotic
events in patients with recent MI/stroke & those with peripheral arterial disease
Prophylaxis
of thrombotic events in **acute coronary syndromes (unstable angina)
Precautions
prolonged bleeding
- no antidote
Abciximab
Mechanism of Action
Inhibits glycoprotein (GP) IIb/IIIa receptor
by binding to GP IIb/IIIa, thus blocking binding of fibrinogen & von Willebrand factor (vWF), therefore aggregation will not occur
Therapeutic Use
Prevention of cardiac ischemic complications
- given IV with heparin & aspirin as
adjunct
to percutaneous coronary intervention (PCI)
Unstable angina
- for patients not responding to conventional medical therapy when PCI is planned within 24 hrs
Anti-Coagulant
Heparin & Low MW Heparin
Overview
Heparin
=
injectable, rapid acting
anti-coagulant, often used
acutely to interfere formation of thrombi
;
macromolecule
(complex with histamine in mast cell); extracted from
porcine intestinal mucosa
; unfractionated heparin (straight-chain, anionic GAG with wide range of MW); strongly
acidic
Low MW Heparin
= 1/3 of size of unfractionated heparin
Mechanism of Action
Heparin
= bind to anti-thrombin III which leads to
rapid
inactivation of coagulation factors; catalyze the inhibition of thrombin to 1000-fold
Low MWHs
= form complex with
anti-thrombin III & inactivate factor Xa
but do not bind to thrombin (factor IIa)
Therapeutic Use
Limit expansion of thrombi by preventing fibrin formation
treatment of
DVT or pulmonary embolism
prophylaxis of post-operative venous thrombosis in patients undergoing surgery
and those with
acute MI
As a choice for pregnant women
- do not cross placenta due to large size & negative charge
Adverse Effects
bleeding
- excessive bleeding treated with protamine sulfate (1 mg for every 100 units of heparin)
heparin-induced thrombocytopenia (HIT)
- abnormally low number of platelets; replaced with argatroban (direct thrombin inhibitor)
osteoporosis
- long-term effect
Warfarin
Overview
oral anti-coagulant
; has
narrow therapeutic index
, monitor using INR (international normalized ratio)
Mechanism of Action
antagonize cofactor function of vit K
; inhibit
vitamin K epoxide reductase
which is essential enzyme for activating vit K
coagulation factor (factor II, VII, IX & X) require vit K. Depletion of vit K by warfarin reduce the synthesis of active clotting factors
Therapeutic Use
prevention & treatment of DVT, PE & stroke
prevention of venous thromboembolism
during orthopedic/gynecologic surgery
Pharmacokinetics
rapidly absorbed
after oral administration (100% bioavailability)
anticoagulant effect
observed
72-96 hrs
after administration
highly-bound to albumin
which prevents its diffusion into CSF, urine & breast milk. Add sulfonamide to displace warfarin, lead to elevated activity of warfarin
readily crosses placental barrier
Adverse Effects
hemorrhage
- need to monitor INR & adjust dose
skin lesions & necrosis
- rare complication of warfarin
purple toe syndrome
- rare, painful, blue-tinged discoloration of toe caused by cholesterol emboli from plaques
teratogenic
- never use during pregnancy; use heparin or LMWHs
Overview
There are several inhibitor of coagulation factors (protein C, protein S,
anti-thrombin III
& tissue factor pathway inhibitor)
inhibit action of coagulation factor
(eg: heparin);
interfere with synthesis of coagulation factor
(eg: warfarin)
Thrombolytic Drugs
Mechanism of Action
directly/indirectly convert plasminogen to plasmin
which
cleaves fibrin, thus lysing thrombi
increased local thrombi may occur as clot dissolves, lead to
enhanced platelet aggregation & thrombosis
. Prevent by
administering aspirin/heparin
together with thrombolytic drugs
Therapeutic Use
helpful in
restoring catheter function
, by lysing clots causing occlusions
dissolve clots that result in strokes
Examples
Streptokinase, Alteplase, Urokinase
Adverse Effects
hemorrhage
thrombolytic agents do not distinguish between fibrin of unwanted thrombus & fibrin of beneficial hemostatic plug
contraindicated
in pregnancy & patients with healing wound
Overview
agents that activate
conversion of plasminogen to plasmin
Streptokinase
protein purified from culture broths of group C B-hemolytic streptococci; rarely used
MOA
forms
active one-to-one complex with plasminogen
which then
convert uncomplexed plasminogen to active enzyme plasmin
which
hydrolyse fibrin plugs
also catalyze
degradation of fibrinogen & clotting factors V & VII
Alteplase
serine protease derived from cultured human melanoma cells; now obtained as product of recombinant DNA tech
MOA
rapidly activates plasminogen
that is bound to fibrin in thrombus/hemostatic plug
treatment of
MI, PE & acute ischemic stroke
; may cause
angioedema
Urokinase
isolated from cultures of human kidney cells, has low antigenicity; usually replaced with other drugs that have higher benefit-to-risk ratio
MOA
directly
cleaves arginine-valine bond of plasminogen
to yield active plasmin
approved for
lysis of PE